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What was the outcome of reaction 'Rebound effect'?	Hyperammonemic Encephalopathy Mimicking Ornithine Transcarbamylase Deficiency in Fibrolamellar Hepatocellular Carcinoma: Successful Treatment with Continuous Venovenous Hemofiltration and Ammonia Scavengers. Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver cancer affecting adolescents and young adults without any pre existing liver disease. Hyperammonemic encephalopathy (HAE) is a serious paraneoplastic syndrome, and several cases of HAE have been reported in patients with FLHCC. This condition is rare; hence, there are currently no management guidelines for cancer-related HAE. Herein, we report a case of an 18-year-old man with advanced FLHCC who developed HAE during the first course of chemotherapy consisting of cisplatin, doxorubicin, 5-fluorouracil, and interferon-α. He was successfully treated with continuous venovenous hemofiltration, sodium benzoate, sodium phenylbutyrate, and amino acid supplementation for HAE. After the second course of chemotherapy, he underwent surgery, and thereafter, his ammonia levels were normal without any ammonia scavenger therapy. Treatments for HAE described here will be helpful for this rare, but serious metabolic complication of FLHCC and could partially applied to HAE related to any malignancies. Introduction Fibrolamellar hepatocellular carcinoma (FLHCC) is different from conventional hepatocellular carcinoma (HCC) [1]. The incidence of FLHCC is very low, and it affects adolescents and young adults without any pre existing liver disease [1]. Recent studies suggest that FLHCC is an independent entity, showing distinctive molecular profile [2]. Several case reports described paraneoplastic syndrome of FLHCC with symptoms such as hyperammonemia [3–6], gynecomastia [7], and venous thrombosis [8]. Hyperammonemic encephalopathy (HAE) is the most serious paraneoplastic syndrome. However, owing to its rarity, no management guidelines exist for cancer-related HAE. Herein, we report a case of an 18-year-old male patient with FLHCC who developed HAE during the first course of chemotherapy. He was successfully treated with hemofiltration, sodium benzoate, and sodium phenylbutyrate. He underwent surgery and successive chemotherapy, and his ammonia levels were maintained in the normal range without ammonia scavenger therapy. Case Report An 18-year-old boy presented with a history of fatigue, vomiting, abdominal pain, and distension. Computed tomography (CT) revealed a huge mass (13.7×10.7 cm) occupying the left liver and two masses (8.7×7.3 cm, 3.9×2.9 cm) in the pelvic cavity. Multiple lymph nodes were enlarged in right anterior and posterior cardiophrenic angles (Fig. 1). An initial laboratory investigation showed normal bilirubin, slightly elevated aminotransferase levels (aspartate aminotransferase [AST], 85 U/L; alanine aminotransferase [ALT], 154 U/L) and α-fetoprotein (27.2 ng/mL). He was previously healthy with no signs of chronic liver disease and had negative results on serologic testing for hepatitis B (hepatitis B virus surface antigen, hepatitis B virus surface antibody) and hepatitis C (anti–hepatitis C virus). He underwent fine needle biopsy and was diagnosed with FLHCC (Fig. 2). Considering the extent of the tumor, the patient was not considered a candidate for surgical resection. Systemic chemotherapy was initiated with cisplatin (80 mg/m2 on day 1), doxorubicin (30 mg/m2 on days 1 and 2), 5-fluorouracil (5-FU; 400 mg/m2 on days 1–4), and interferon-α (5×108 U/m2 on days 1–4). At midnight on day 3 of chemotherapy, the patient became agitated and was walking and running around the ward, not responding to verbal stimuli. Laboratory testing revealed a serum ammonia level of 393 μg/dL, AST/ALT level of 201/126 U/L, and total bilirubin level of 0.3 mg/dL. Head CT did not reveal any significant findings. He was diagnosed as HAE, and chemotherapy (4th dose of 5-FU and interferon-α) was stopped. Treatment with rifaximin and lactulose was initiated. However, his serum ammonia level rapidly increased to 500 μg/dL, and his mental status deteriorated to the semicoma state. The patient was transferred to the intensive care unit (ICU) and was on mechanical ventilator support under sedation using midazolam, remifentanil, and vecuronium. The metabolic and genetics department was consulted, and treatment for hyperammonemia was started as follows: (1) continuous venovenous hemofiltration, (2) intravenous infusion of sodium benzoate at a loading dose of 8.8 g (170 mg/kg), followed by continuous infusion (8.8 g/day) and sodium phenylbutyrate (5 g four times a day, via Levin tube), (3) 20% dextrose for caloric intake (6 mg/kg/min), and (4) administration of lactulose and rifaximin via Levin tube. His ammonia level decreased to 164 μg/dL but rebounded to 442 μg/dL on the third day of ICU care. Sodium benzoate (8.8 g) was loaded again, and his ammonia level decreased to 135 μg/dL. On the sixth day of the above-mentioned treatment, continuous venovenous hemofiltration was discontinued. On the eighth day, the patient was extubated, and sodium benzoate/sodium phenylbutyrate administration was changed to an intermittent schedule, with sodium benzoate 1.8 g administered as intravenously every 8 hours, sodium phenylbutyrate 3 g four times a day, and arginine 2.5 g twice a day. He was started on a low-protein diet (1 g/kg/day) through a Levin tube. Two days later (10th day of ICU care), he became disoriented and could not properly respond to verbal stimuli, with an ammonia level of 173 μg/dL. The low-protein diet was discontinued, and a continuous infusion of sodium benzoate (5.5 g/day, after a loading dose of 5.5 g) was started again, as well as citrulline (5 g three times a day). There were no focal neurologic signs, and brain magnetic resonance imaging (MRI) did not reveal any abnormality. As the serum ammonia level started decreasing (59 μg/dL), his conscious level improved. On the 12th day, he started Levin tube feeding and oral medications (sodium phenylbutyrate 6 g/day, L-carnitine 2,550 mg/day); citrulline was discontinued. On the 14th day of ICU care, sodium benzoate infusion was changed to an intermittent schedule (1.8 g every 8 hours). He resumed the low-protein diet (0.5 g/kg/day), and his ammonia level was maintained in the range of 90–100 μg/dL. He was transferred to a general ward on the 16th day of ICU care, and sodium benzoate was changed to an oral form (3 g three times a day). With sodium benzoate, sodium phenylbutyrate (3 g three times a day), arginine (2.5 g twice a day), and L-carnitine (660 mg once daily), his ammonia level further decreased to 50–60 μg/dL (Fig. 3). On the ninth day at the general ward, laboratory analyses were performed to identify the underlying mechanism of his HAE. The patient’s serum amino acid analysis revealed the following findings: decreased citrulline and ornithine, normal alanine and glutamine. His urine orotic acid level was elevated, and serum acylcarnitine was slightly elevated. These results suggested impaired activity of ornithine transcarbamylase (OTC). However, polymerase chain reaction (PCR) and direct sequencing of the OTC gene did not reveal any pathogenic variant, deletion, or duplication. On the 20th day at the general ward, the patient underwent a second course of chemotherapy involving cisplatin+doxorubicin+5-fluorouracil+interferon-α. One month later, he underwent extended left hemihepatectomy en bloc with the caudate lobe, excision of pelvic mass, and peritoneal seeding. Extensive lymph node dissection was also performed at the hepatoduodenal, cardiophrenic, para-aortic, and pelvic lymph nodes. Immunohistochemical staining confirmed a profile consistent with that of FLHCC, that is, positive for cytokeratin 7, glypican 3, and CD68. We did not test for the DNAJB1-PRKACA fusion. Next-generation sequencing (NGS) was performed to identify actionable therapeutic targets but only revealed APC mutation (c.4666delA, p.T1556fs), with an allele frequency of 15.53%. His postoperative period was uneventful and the ammonia level further decreased (30–40 μg/dL). One month after the surgery, treatment for hyperammonemia was discontinued. He received two additional courses of chemotherapy involving cisplatin+doxorubicin+5-FU+interferon-α. However, CT and MRI obtained 3 months after the surgery revealed enlarged left external iliac lymph nodes and multiple enhancing nodules at the perihepatic, perigastric, mesentery, omentum, and pelvic cavity. The chemotherapy regimen was changed to vincristine (1.5 mg/m2 on days 1, 8)+irinotecan (50 mg/m2 on days 1–5) and then to gemcitabine (1,000 mg/m2 on day 1)+cisplatin (20 mg/m2 on days 1–5). CT performed after three courses of gemcitabine+cisplatin showed a decrease in the size of the peritoneal nodules and iliac lymph node. Furthermore, the patient experienced severe, recurrent abdominal pain with vomiting, and CT images suggested obstructive ileus. Exploratory laparotomy was performed, and multiple adhesive bands were dissected off the small intestine and excised. Additionally, two metastatic nodules were resected. At the time of this report writing, the patient had just completed the sixth course of gemcitabine-cisplatin, and his disease was stable. He is on normal regular diet and his ammonia level remains normal (30–40 μg/dL). Discussion We report an 18-year-old male patient with advanced FLHCC who developed HAE during the first course of chemotherapy comprising o cisplatin, doxorubicin, 5-FU, and interferon-α. His HAE was successfully treated with continuous venovenous hemofiltration, ammonium scavengers, and amino acid supplementation. Serum amino acid and urine organic acid analyses suggested urea cycle dysfunction. However, PCR and direct sequencing of the OTC gene did not reveal any pathogenic variants. Intriguingly, APC gene mutation was detected from NGS of the tumor tissue, suggesting a possible relation to the development of HAE. After tumor excision, serum ammonia levels were maintained in the normal range without treatment with ammonium scavengers. HAE in FLHCC was first reported in 2009 [3]. This condition is very rare, and approximately 10 cases are reported thus far; many of the patients present HAE at the time of diagnosis of FLHCC [3–6]. One of them recovered from HAE after liver transplantation [4]. Similar to our case, a 31-year-old man developed HAE on the third day of gemcitabine+oxaliplatin chemotherapy [5]. Several mechanisms were proposed on the development of HAE in patients with FLHCC. Some studies suggest that urea cycle dysfunction is caused by an imbalance in the activities and ratios of OTC and ornithine decarboxylase (ODC) [6]. Reduced activity of OTC or augmented activation of ODC results in ornithine consumption and urea cycle disturbance, thereby causing hyperammonemia [6,9]. A recent study suggested that the molecular pathogenesis of FLHCC may contribute to urea cycle dysfunction [6]. Heterozygous deletion of chromosome 19 results in chimeric DNAJB1-PRKACA kinase, which is frequently identified in FLHCC [10]. This chimeric DNAJB1-PRKACA kinase increases the expression of Aurora kinase A, leading to the overexpression of c-Myc that upregulates ODC function [6,10]. The precise mechanism of the development of HAE in our case is unclear. Initially, there were no specific findings in his metal or neurologic status, and his serum ammonia level was not tested. He developed HAE on the third day of chemotherapy, which suggests a causal relationship between chemotherapeutic agents and HAE. There are case reports about chemotherapy-associated hyperammonemia. For example, patients with acute lymphoblastic leukemia receiving corticosteroids [11] and L-asparaginase [12] show a transient increase in the serum ammonia level. Several case reports described HAE in patients receiving 5-FU, cytarabine, cyclophosphamide, oxaliplatin, vincristine, etoposide, anthracycline, busulfan, methotrexate, topotecan, gemcitabine, and tyrosine kinase inhibitors [5]. Our patient received steroids (as antiemetics) and 5-FU. Another culprit that might have contributed to HAE is APC tumor suppressor gene mutation identified by the NGS assay of the tumor. Unfortunately, our case was not tested for heterozygous deletion of chromosome 19 or chimeric DNAJB1-PRKACA kinase. APC mutation was identified by NGS assay of the tumor with an allele frequency of 15.53%. Several in vitro studies suggest that APC mediates ODC expression through a c-Myc– dependent mechanism, thereby affecting ODC transcription [13]. Tumor cells with truncated APC exhibit high levels of β-catenin, leading to increased expression of c-Myc [13]. We presume that both APC mutation and chemotherapy might have caused HAE resembling OTC deficiency. There are no management guidelines for cancer- or chemotherapy-associated hyperammonemia or HAE. Therefore, treatment of hyperammonemia or HAE is extrapolated from that for hepatic encephalopathy or OTC deficiency [14]. Clinical features of hyperammonemia can deteriorate from irritability, confusion to seizure, coma, and even death [14]. Ammonia scavenger therapy should be initiated when ammonia levels are greater than 100 μg/dL [5]. When the serum ammonia level is extremely high (500 μg/dL), dialysis/rapid hemofiltration should be started immediately [5]. In our case, the patient developed HAE during the first course of chemotherapy. Ammonia scavenger therapy normalized his ammonia level and was maintained until the second course of chemotherapy and surgery. After surgery, his ammonia level remained normal without ammonia scavenger therapy, suggesting that his HAE was a paraneoplastic phenomenon of FLHCC. While HCC is prevalent in Asia, the incidence of FLHCC is similar across different ethnic groups [1]. FLHCC comprises less than 1% of all primary liver cancer cases in the United States [1]. Recent studies suggest that FLHCC has a distinctive molecular profile, with focal deletion leading to DNAJB1-PRKACA gene fusion [2]. There are limited studies on the treatment outcome of patients with FLHCC. Despite the large tumor size and advanced stage at presentation, FLHCC patients exhibit significantly better 5-year relative survival than those with conventional HCC [1]. It is unclear whether biologic difference or absence of pre existing liver disease in FLHCC attributes to better survival. Except for surgery, no consensus exists for the treatment of FLHCC. Chemotherapy regimens for unresectable cases include cytotoxic agents, bevacizumab, and tyrosine kinase inhibitors [5]. A phase II trial involving nine cases of FLHCC suggested a potential benefit of 5-FU and interferon [15]. Our patient received perioperative chemotherapy including 5-FU and interferon. Generally, surgical resection is not considered for case like ours, even after systemic chemotherapy. However, there are several reports favoring aggressive cytoreductive surgery prolongs the survival of HCC patients with peritoneal metastases [16,17]. Our case received surgery for the following reasons: (1) the patient was young without any underlying disease, (2) tumors, including liver mass, peritoneal and pelvic metastases appeared to be feasible for resection without compromising patient’s safety, (3) to alleviate clinical symptom (HAE, early satiety, nausea, abdominal discomfort and pain) caused by the multiple large tumors. In the absence of any evidence-based treatment options for aggressive FLHCC, disappearance of HAE after surgery showed that our decision was appropriate. However, the size of the peritoneal nodule increased 3 months after the surgery and combination chemotherapy. The chemotherapy regimen was changed, and the patient was on third-line chemotherapy consisting of cisplatin and gemcitabine, and the patient has been alive for 12 months since the diagnosis of FLHCC. In conclusion, a young boy with FLHCC presenting HAE, which mimicks OTC deficiency, was successfully treated with hemofiltration and ammonia scavenger therapy. Lack of significant findings in OTC gene analysis and the normal ammonia level after surgery imply that FLHCC directly caused urea cycle dysfunction. We assume that APC mutation might be partially related to the development of HAE in our case. Oncologists should be aware about the HAE, a rare but serious metabolic complication of FLHCC. Treatments extrapolated from OTC deficiency, such as continuous venovenous hemofiltration and ammonia scavengers, will be helpful and could partially applied to HAE related to any malignancies. Ethical Statement The present study was approved by the Institutional Review Board of National Cancer Center in Korea (NCC2020-0175), who waived the requirement for informed consent because of the retrospective nature of the study. Author Contributions Conceived and designed the analysis: Lee JA. Collected the data: Lee JS, Han N, Lee JA. Contributed data or analysis tools: Jin HY, Ko JM, Kim SH, Park BK, Park M, Park HJ. Performed the analysis: Lee JS, Lee JA. Wrote the paper: Lee JA, Kim SH, Lee JS. Conflicts of Interest Conflicts of interest relevant to this article was not reported. Fig. 1 Dynamic liver computed tomography at the time of diagnosis of fibrolamellar hepatocellular carcinoma (coronal view, portal phase). Fig. 2 Photographs of the fine needle biopsy and surgical resection specimen. (A) Histologic features of fibrolamellar hepatocellular carcinoma (FLHCC). Large, polygonal tumor cells with abundant oncocytic cytoplasm in background of dense collagen bundles (H&E, ×100). Cytokeratin 7 (B) and CD68 (C) protein expression were noted in FLHCC evaluated by immunohistochemistry (×100). (D) Representative image of surgical specimen. Bulging, large mass with well-circumscribed border was observed. Fibrous bands and central stellate scar are noted. Fig. 3 Change of the serum ammonia levels with ammonia scavengers and hemofiltration. HF, hemofiltration; IV, intravenously; PO, orally.	Recovered	ReactionOutcome	CC BY-NC	32898940	18,380,427	2021-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'.	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	ATENOLOL, DEXAMETHASONE, ENOXAPARIN, HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, PREDNISONE, TOCILIZUMAB	DrugsGivenReaction	CC BY	32910321	18,339,887	2021-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperglycaemia'.	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	ATENOLOL, DEXAMETHASONE, ENOXAPARIN, HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, PREDNISONE, TOCILIZUMAB	DrugsGivenReaction	CC BY	32910321	18,339,887	2021-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'.	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	AMIODARONE, ATENOLOL, DEXAMETHASONE, ENOXAPARIN, HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, PREDNISONE, TOCILIZUMAB	DrugsGivenReaction	CC BY	32910321	18,354,382	2021-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	AMIODARONE, ATENOLOL, DEXAMETHASONE, ENOXAPARIN, HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, PREDNISONE, TOCILIZUMAB	DrugsGivenReaction	CC BY	32910321	18,354,382	2021-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	AMIODARONE, ATENOLOL, DEXAMETHASONE, ENOXAPARIN, HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, OXYGEN, PREDNISONE, TOCILIZUMAB	DrugsGivenReaction	CC BY	32910321	18,340,500	2021-06
What was the administration route of drug 'DEXAMETHASONE'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY	32910321	18,339,887	2021-06
What was the administration route of drug 'TOCILIZUMAB'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY	32910321	18,339,887	2021-06
What was the dosage of drug 'ATENOLOL'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	UNKNOWN	DrugDosageText	CC BY	32910321	18,339,887	2021-06
What was the dosage of drug 'ENOXAPARIN'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	UNKNOWN	DrugDosageText	CC BY	32910321	18,339,887	2021-06
What was the dosage of drug 'HYDROXYCHLOROQUINE'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	UNKNOWN	DrugDosageText	CC BY	32910321	18,339,887	2021-06
What was the dosage of drug 'LOPINAVIR\RITONAVIR'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	UNKNOWN	DrugDosageText	CC BY	32910321	18,339,887	2021-06
What was the dosage of drug 'OXYGEN'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	HIGH-FLOW SUPPLEMENTAL OXYGEN SUPPORT AND OXYGEN WEANING ON DAY 27TH OF HOSPITALIZATION.	DrugDosageText	CC BY	32910321	18,340,500	2021-06
What was the outcome of reaction 'Condition aggravated'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	Recovering	ReactionOutcome	CC BY	32910321	18,339,887	2021-06
What was the outcome of reaction 'Infection'?	Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. BACKGROUND SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. METHODS We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. CONCLUSIONS We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19. Background The recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10]. Previous experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11]. Strongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13]. Rhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15]. So far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17]. Case report A 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension. Treatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization. On day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination. The patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement. Discussion To date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened). Strongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy. In case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22]. Hyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23]. Given these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted. Our patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection. A dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available. In confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection. In conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered. Author contributions VM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text. Funding Open access funding provided by UniversitÃ degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards Conflict of interest All authors had no financial or other conflicts of interest to disclose. Ethics declarations Informed consent was obtained from the subject.	Recovering	ReactionOutcome	CC BY	32910321	18,354,382	2021-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus infection reactivation'.	Letermovir for the compassionate therapeutic use of cytomegalovirus infection. OBJECTIVE Data on the efficacy, dosing and safety of letermovir for the compassionate therapeutic use of CMV infections are limited. METHODS Clinical and virological efficacy of letermovir was assessed in a retrospective single-centre study of patients who received letermovir for the compassionate therapeutic use of CMV infections. RESULTS Letermovir initiation yielded prompt treatment response in 7 out of 9 patients (77.7%). CONCLUSIONS Letermovir may be an effective and well tolerated option in the compassionate treatment of CMV infections, although recurrence of CMV and emergence of resistance may be issues. Background Cytomegalovirus (CMV) infections remain a prevalent cause for morbidity and mortality in immunosuppressed solid-organ and bone-marrow transplant patients [1]. The first line therapeutic agents, ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV), inhibit CMV replication by targeting the viral DNA polymerase pUL54. However, haematological side effects limit its therapeutic potential in 10–20% of the cases. Furthermore, genetic mutations of UL97 and UL54, conferring antiviral resistance, were reported, especially in cases of prolonged antiviral therapy, lack of prior CMV immunity in transplant patients and strong immunosuppression [2]. In cases of clinical or virological treatment failure, guidelines recommend the escalation of valganciclovir dose or escalating to cidofovir or foscarnet [1]. Both options are often limited by the toxic profile. Furthermore, cross-resistances were reported [2]. Hence, novel drugs that target alternative viral mechanisms are urgently required. Recently, letermovir, a new antiviral compound, was approved for the prophylaxis of CMV disease in bone-marrow transplant recipients [3]. Letermovir inhibits the terminase complex, which is essential for viral replication, for cleavage and packaging of large concatemers of CMV-DNA [4]. According to its licence, letermovir was mainly used as a prophylaxis agent for CMV infections. However, its different mechanism of action as well as its excellent side effect profile made it an appealing off-label option for the therapy of GCV resistant CMV infections, as well was for patients who reported severe leukopenia or reduced kidney function. However, data are limited to case series [5–7]. In the present report we document a case series of patients who have received letermovir for the compassionate use for CMV infections, highlighting its antiviral potential, but also pointing out possible difficulties, thus judging its efficacy in the clinical setting. Materials and methods Subjects and data collection The present retrospective single-centre study exclusively comprises patients suffering from CMV infections who received letermovir for the compassionate use for treatment of CMV infections. The study protocol was approved by the Ethics Committee of the Medical University of Vienna, Austria (ECS 2013/2019), and all study-related procedures were conducted according to the declaration of Helsinki. We included adult patients who got diagnosed with CMV infection, defined as CMV DNA copy levels > 200 IU/ml measured in plasma and were treated with letermovir due to ganciclovir refractory or resistant CMV viremia or patients who were intolerant to receive ganciclovir or foscarnet. Intolerance to receive ganciclovir or foscarnet was decided by the responsible team of clinicians. The same dosage of LMV was used for treatment as for prophylaxis of CMV infection—480 mg qd or 240 mg if on concomitant cyclosporin [3]. As suggested in the international consensus guidelines, CMV infection was separated into three groups: asymptomatic infections, viral syndrome, or tissue invasive (“end organ”) disease [1]. CMV syndrome and tissue invasive disease were diagnosed according to Ljungman et al. [8]. Treatment was monitored closely, and patients were regularly controlled for adverse events or development of viral syndrome or tissue invasion. Baseline demographics, CMV associated symptoms, previously received CMV prophylaxis or therapy, viral kinetics, ongoing immunosuppression and clinical outcome were retrospectively collected. Clinical response was defined as a decline of viral load to < 200 IU/ml. Furthermore, viral half-life was calculated, according to the formula t1/2 = −ln2/slope [9]. Patients who achieved the endpoint were further controlled for reactivation of CMV. Results A total of 11 patients were identified who received letermovir for the compassionate use for CMV infection. One patient had to be excluded as the exact time of termination of treatment was not documented. Another patient was excluded as she was already discussed in an earlier case report, which has not yet been published. The other nine patients are discussed below. Table 1 gives an overview of the demographic characteristics. The median age was 66 years (45–70), and 77.8% of the patients was male. Five patients were solid organ transplant recipients (55.6%), two developed CMV infection after HSCT (22.2%), one patient suffered from TARFO syndrome (11.1%) and one patient suffered from systemic lupus erythematosus (SLE) (11.1%). Six patients experienced asymptomatic CMV viremia (66.7%), one CMV syndrome (11%), one a probable CMV pneumonia (11%) and one patient with probable CMV enteritis (11%) [8]. Clinical reasoning for compassionate use of letermovir was as follows: confirmed antiviral resistance against GCV (n = 2, 22.2%), virological treatment failure of GCV (n = 1, 11.1%) and HSCT associated with significant CMV viremia (n = 2, 22.2%). In the other four patients, the clinicians opted for letermovir instead of ganciclovir or foscarnet, to prevent aggravation of coexisting diseases. In three of the patients severe leukopenia and concomitant infection (two of them septic) were the reasons for letermovir selection. Finally, one patient (11.1%) suffering from a multicentric form of Castleman disease called TAFRO syndrome (an acronym for thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly), experienced CMV reactivation under therapy with high-dose cortisone and tocilizumab. To prevent further aggravation thrombocytopenia, which would have ultimately led to discontinuation of tocilizumab, clinicians decided for compassionate use of letermovir instead of valganciclovir.Table 1 Characteristics of the patients treated with letermovir Patients Demographics Immuno-suppression Presentation of CMV Previous antivirals Indication for LMV Daily dose of LMV (mg) Adaption of immuno-suppression Initial CMV DNA IU/ml Time to suppression of virus replication (days) Recurrence of CMV infection Patient 1 f, 69a, kidney transplantation MMF, TAC and cortisone Asymptomatic VGCV Leukopenia and GCV refractory viremia 480 MMF stopped 833 8 No Patient 2 m, 60a, HSCT MMF, CsA and cortisone Asymptomatic None Prevent aggravation of leuko- and thrombocytopenia after HSCT 240 MMF paused 261 14 Yes Patient 3 m, 70a, heart transplantation MMF, TAC and cortisone Probable pneumonia GCV1 Leukopenia under GCV and sepsis 480 MMF paused 898 Not achieved Patient 4 m, 58a, heart transplantation MMF, TAC and cortisone Asymptomatic VGCV Confirmed resistance 480 None 39,600 1852 No Patient 5 m, 74a, kidney transplantation MMF and TAC CMV syndrome VGCV Confirmed resistance 480 MMF paused 2770 34 Bo Patient 6 m, 45a, TARFO-syndrome tocilizumab and cortisone Asymptomatic None Prevent aggravation of thrombocytopenia under tocilizumab 480 None 1610 23 No Patient 7 m, 68a, kidney transplantation MMF, TAC and cortisone Asymptomatic None Leukopenia and sepsis 480 MMF dose reduction 1550 29 No Patient 8 f, 65a, SLE MMF and cortisone Probable enteritis None Prevent aggravation of leukopenia 480 None 16,000 83 No Patient 9 m, 61a, HSCT MMF and CsA Asymptomatic None Prevent aggravation of leuko- and thrombocytopenia after HSCT 240 None 224 23 No f female, m male, a age, HSCT haematopoietic stem cell transplantation, SLE systemic lupus erythematosus, MMF mycophenolate mofetil, TAC tacrolimus, CsA cyclosporine A, LMV letermovir, VGCV valganciclovir, GCV ganciclovir 1CMV IgG co-administration 2In patient 4 letermovir treatment was prematurely discontinued at CMV DNA load 739 IU/ml, and later on re-administered. Although treatment course was prolonged (185 days) no signs of CMV end-organ disease were reported Initiation of letermovir treatment yielded a viral response, after an initial viral load increase, in 7 out of 9 patients (77.8%). The median duration of letermovir treatment was 31 (8–127) days. The median duration to achieve a decrease of viral load < 200 IU/ml was 23 (8–83) days. Viral kinetic curves are shown in Fig. 1. In the other two patients (patients 3 and 4), treatment was discontinued prematurely at CMV DNA copy levels > 200 IU/ml, at 211 IU/ml and 739 IU/ml respectively. Both patients experienced an increase of viral load within the next month, and letermovir was re-administered. After re-administration, patient 4 experienced a slow but steady decrease of viral load, resulting in CMV DNA copies < 200 IU/ml within a total of 185 days of treatment. Re-administration of letermovir in patient 3 yielded a decrease of CMV copy load, but general estate of the patient further aggravated and the patient developed sepsis. In a discussion with the family treatment discontinuation was decided and the patient died within the following days. End-organ disease occurred in none of the asymptomatic CMV patients under letermovir treatment, but one patient (patient 2) experienced a CMV end-organ disease only 2 weeks after treatment discontinuation. The episode was subsequently treated with VGCV, as leukopenia had improved.Fig. 1 Relative change of CMV DNA copies in percent after initiation of letermovir treatment. The average increase was 2.7-fold (SD = 1.3). Final descent, defined by the definite negative movement, was seen as late as day 30 (mean = 8.7, SD = 8.8) The initiation of letermovir therapy was associated with an initial increase of viral load in 7 out of 9 (77.8%) patients. The average increase was 2.7-fold (SD = 1.3) of the viral load at start of treatment. Final descent, defined by the definite negative movement, was seen as late as day 30 (median = 6, range [3–30]). The viral half-life was 7.1 (1.49–9.1) days. Discussion The present report demonstrates the potential of letermovir for the effective treatment of CMV infections. All present patients received letermovir as a monotherapy. The therapy was generally well tolerated, and no adverse events were reported. Treatment initiation yielded a decrease of viral load to < 200 copies/ml in 88.9% of the patients. However, one patient with complete clinical response experienced CMV end-organ disease within 2 weeks after treatment discontinuation. Immunosuppression was adapted in all SOT patients, by either dose reduction or pausing of cell-cycle inhibitor. Therapeutic strategies for clinical or virological failure of CMV infections include the escalation of valganciclovir dose or switching to cidofovir or foscarnet [1]. However, both drugs are associated with the potential for severe adverse events, such as nephrotoxicity and myelosuppression, which limit their therapeutic usefulness. Letermovir, a novel inhibitor of the terminase complex, was recently approved for the prophylaxis of CMV infection in allogenic HSCT, but is not yet approved for pre-emptive therapy [3]. Its favourable side effect profile has led to an increased off-label use for GCV-resistant CMV infections or if the patients were intolerant to receive other treatment options. However, first observations of letermovir resistance have been reported [10–13]. A recently published letermovir resistance analysis among HSCT recipients receiving letermovir prophylaxis identified all letermovir resistance associated variants within the UL 56 gene [13]. Although some treatment durations were prolonged, no viremia breakthrough was reported in our cohort. Dosing of letermovir for preemptive therapy remains uncertain, as there is no approval for letermovir in this indication. Stoelben et al. successfully used lower letermovir doses of 40 bid or 80 qd for preemptive therapy in kidney transplant recipients, whereas Turner et al. used higher doses of up to 960 mg qd for the salvage therapy of drug-resistant CMV retinitis without an emergence of adverse events [6, 14]. Letermovir dose in our cohort coincided with the dose recommendations for the prophylaxis of CMV infection, 480 mg qd or 240 mg if on concomitant cyclosporin [3]. The same treatment protocol was recently chosen by Phoompoung et al. for the salvage therapy of CMV infections in transplant recipients [7]. The average duration until decrease of viral load to under < 200 mg/ml was 32.9 days. The viral half-life time under letermovir was 6.3 days, which is longer than previously published viral half-lives of solid-organ transplant patients treated with GCV [9]. As demonstrated in earlier reports, the viral load initially increases after therapy start. The average increase in our cohort was 2.7-fold of the viral load at treatment start. However, the increase in viral load was not associated with an increase in symptoms. This may be explicable by the mode of action of letermovir, as viral replication is blocked at a late stage, possibly yielding high intracellular titre of viral DNA in absence of a viable virus. This emphasizes the need for alternative methods to estimate the risk of CMV disease under letermovir treatment. The present study has some limitations. As a result of the retrospective study design, the included cohort is heterogenous, leading to a broad spectrum of indication for letermovir. However, precisely this highlights the clinicians’ desire for alternative treatment options, as existing first-line therapies are often limited by their severe side effect profile, especially in patients with concomitant bacterial infections. Further, we could not exclude that the patient’s immune status contributed significantly to the treatment outcome, especially in patients with long lasting viremia. Hence, prospective trials evaluating efficacy, safety, drug dosing, treatment duration and emergence of drug resistance are urgently required. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The authors thank the members of the Division of Infectious Diseases and Tropical Medicine, Medical University Vienna, for their help. Author contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Lisa Fisecker and Lorenz Schubert. The first draft of the manuscript was written by Lorenz Schubert and Christoph Steininger, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open access funding provided by Medical University of Vienna. Data availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethics approval Ethical approval was waived by the local Ethics Committee of the Medical University Austria in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care. Informed consent Not applicable.	CORTISONE, LETERMOVIR, TOCILIZUMAB	DrugsGivenReaction	CC BY	32914220	18,980,760	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukopenia'.	Letermovir for the compassionate therapeutic use of cytomegalovirus infection. OBJECTIVE Data on the efficacy, dosing and safety of letermovir for the compassionate therapeutic use of CMV infections are limited. METHODS Clinical and virological efficacy of letermovir was assessed in a retrospective single-centre study of patients who received letermovir for the compassionate therapeutic use of CMV infections. RESULTS Letermovir initiation yielded prompt treatment response in 7 out of 9 patients (77.7%). CONCLUSIONS Letermovir may be an effective and well tolerated option in the compassionate treatment of CMV infections, although recurrence of CMV and emergence of resistance may be issues. Background Cytomegalovirus (CMV) infections remain a prevalent cause for morbidity and mortality in immunosuppressed solid-organ and bone-marrow transplant patients [1]. The first line therapeutic agents, ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV), inhibit CMV replication by targeting the viral DNA polymerase pUL54. However, haematological side effects limit its therapeutic potential in 10–20% of the cases. Furthermore, genetic mutations of UL97 and UL54, conferring antiviral resistance, were reported, especially in cases of prolonged antiviral therapy, lack of prior CMV immunity in transplant patients and strong immunosuppression [2]. In cases of clinical or virological treatment failure, guidelines recommend the escalation of valganciclovir dose or escalating to cidofovir or foscarnet [1]. Both options are often limited by the toxic profile. Furthermore, cross-resistances were reported [2]. Hence, novel drugs that target alternative viral mechanisms are urgently required. Recently, letermovir, a new antiviral compound, was approved for the prophylaxis of CMV disease in bone-marrow transplant recipients [3]. Letermovir inhibits the terminase complex, which is essential for viral replication, for cleavage and packaging of large concatemers of CMV-DNA [4]. According to its licence, letermovir was mainly used as a prophylaxis agent for CMV infections. However, its different mechanism of action as well as its excellent side effect profile made it an appealing off-label option for the therapy of GCV resistant CMV infections, as well was for patients who reported severe leukopenia or reduced kidney function. However, data are limited to case series [5–7]. In the present report we document a case series of patients who have received letermovir for the compassionate use for CMV infections, highlighting its antiviral potential, but also pointing out possible difficulties, thus judging its efficacy in the clinical setting. Materials and methods Subjects and data collection The present retrospective single-centre study exclusively comprises patients suffering from CMV infections who received letermovir for the compassionate use for treatment of CMV infections. The study protocol was approved by the Ethics Committee of the Medical University of Vienna, Austria (ECS 2013/2019), and all study-related procedures were conducted according to the declaration of Helsinki. We included adult patients who got diagnosed with CMV infection, defined as CMV DNA copy levels > 200 IU/ml measured in plasma and were treated with letermovir due to ganciclovir refractory or resistant CMV viremia or patients who were intolerant to receive ganciclovir or foscarnet. Intolerance to receive ganciclovir or foscarnet was decided by the responsible team of clinicians. The same dosage of LMV was used for treatment as for prophylaxis of CMV infection—480 mg qd or 240 mg if on concomitant cyclosporin [3]. As suggested in the international consensus guidelines, CMV infection was separated into three groups: asymptomatic infections, viral syndrome, or tissue invasive (“end organ”) disease [1]. CMV syndrome and tissue invasive disease were diagnosed according to Ljungman et al. [8]. Treatment was monitored closely, and patients were regularly controlled for adverse events or development of viral syndrome or tissue invasion. Baseline demographics, CMV associated symptoms, previously received CMV prophylaxis or therapy, viral kinetics, ongoing immunosuppression and clinical outcome were retrospectively collected. Clinical response was defined as a decline of viral load to < 200 IU/ml. Furthermore, viral half-life was calculated, according to the formula t1/2 = −ln2/slope [9]. Patients who achieved the endpoint were further controlled for reactivation of CMV. Results A total of 11 patients were identified who received letermovir for the compassionate use for CMV infection. One patient had to be excluded as the exact time of termination of treatment was not documented. Another patient was excluded as she was already discussed in an earlier case report, which has not yet been published. The other nine patients are discussed below. Table 1 gives an overview of the demographic characteristics. The median age was 66 years (45–70), and 77.8% of the patients was male. Five patients were solid organ transplant recipients (55.6%), two developed CMV infection after HSCT (22.2%), one patient suffered from TARFO syndrome (11.1%) and one patient suffered from systemic lupus erythematosus (SLE) (11.1%). Six patients experienced asymptomatic CMV viremia (66.7%), one CMV syndrome (11%), one a probable CMV pneumonia (11%) and one patient with probable CMV enteritis (11%) [8]. Clinical reasoning for compassionate use of letermovir was as follows: confirmed antiviral resistance against GCV (n = 2, 22.2%), virological treatment failure of GCV (n = 1, 11.1%) and HSCT associated with significant CMV viremia (n = 2, 22.2%). In the other four patients, the clinicians opted for letermovir instead of ganciclovir or foscarnet, to prevent aggravation of coexisting diseases. In three of the patients severe leukopenia and concomitant infection (two of them septic) were the reasons for letermovir selection. Finally, one patient (11.1%) suffering from a multicentric form of Castleman disease called TAFRO syndrome (an acronym for thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly), experienced CMV reactivation under therapy with high-dose cortisone and tocilizumab. To prevent further aggravation thrombocytopenia, which would have ultimately led to discontinuation of tocilizumab, clinicians decided for compassionate use of letermovir instead of valganciclovir.Table 1 Characteristics of the patients treated with letermovir Patients Demographics Immuno-suppression Presentation of CMV Previous antivirals Indication for LMV Daily dose of LMV (mg) Adaption of immuno-suppression Initial CMV DNA IU/ml Time to suppression of virus replication (days) Recurrence of CMV infection Patient 1 f, 69a, kidney transplantation MMF, TAC and cortisone Asymptomatic VGCV Leukopenia and GCV refractory viremia 480 MMF stopped 833 8 No Patient 2 m, 60a, HSCT MMF, CsA and cortisone Asymptomatic None Prevent aggravation of leuko- and thrombocytopenia after HSCT 240 MMF paused 261 14 Yes Patient 3 m, 70a, heart transplantation MMF, TAC and cortisone Probable pneumonia GCV1 Leukopenia under GCV and sepsis 480 MMF paused 898 Not achieved Patient 4 m, 58a, heart transplantation MMF, TAC and cortisone Asymptomatic VGCV Confirmed resistance 480 None 39,600 1852 No Patient 5 m, 74a, kidney transplantation MMF and TAC CMV syndrome VGCV Confirmed resistance 480 MMF paused 2770 34 Bo Patient 6 m, 45a, TARFO-syndrome tocilizumab and cortisone Asymptomatic None Prevent aggravation of thrombocytopenia under tocilizumab 480 None 1610 23 No Patient 7 m, 68a, kidney transplantation MMF, TAC and cortisone Asymptomatic None Leukopenia and sepsis 480 MMF dose reduction 1550 29 No Patient 8 f, 65a, SLE MMF and cortisone Probable enteritis None Prevent aggravation of leukopenia 480 None 16,000 83 No Patient 9 m, 61a, HSCT MMF and CsA Asymptomatic None Prevent aggravation of leuko- and thrombocytopenia after HSCT 240 None 224 23 No f female, m male, a age, HSCT haematopoietic stem cell transplantation, SLE systemic lupus erythematosus, MMF mycophenolate mofetil, TAC tacrolimus, CsA cyclosporine A, LMV letermovir, VGCV valganciclovir, GCV ganciclovir 1CMV IgG co-administration 2In patient 4 letermovir treatment was prematurely discontinued at CMV DNA load 739 IU/ml, and later on re-administered. Although treatment course was prolonged (185 days) no signs of CMV end-organ disease were reported Initiation of letermovir treatment yielded a viral response, after an initial viral load increase, in 7 out of 9 patients (77.8%). The median duration of letermovir treatment was 31 (8–127) days. The median duration to achieve a decrease of viral load < 200 IU/ml was 23 (8–83) days. Viral kinetic curves are shown in Fig. 1. In the other two patients (patients 3 and 4), treatment was discontinued prematurely at CMV DNA copy levels > 200 IU/ml, at 211 IU/ml and 739 IU/ml respectively. Both patients experienced an increase of viral load within the next month, and letermovir was re-administered. After re-administration, patient 4 experienced a slow but steady decrease of viral load, resulting in CMV DNA copies < 200 IU/ml within a total of 185 days of treatment. Re-administration of letermovir in patient 3 yielded a decrease of CMV copy load, but general estate of the patient further aggravated and the patient developed sepsis. In a discussion with the family treatment discontinuation was decided and the patient died within the following days. End-organ disease occurred in none of the asymptomatic CMV patients under letermovir treatment, but one patient (patient 2) experienced a CMV end-organ disease only 2 weeks after treatment discontinuation. The episode was subsequently treated with VGCV, as leukopenia had improved.Fig. 1 Relative change of CMV DNA copies in percent after initiation of letermovir treatment. The average increase was 2.7-fold (SD = 1.3). Final descent, defined by the definite negative movement, was seen as late as day 30 (mean = 8.7, SD = 8.8) The initiation of letermovir therapy was associated with an initial increase of viral load in 7 out of 9 (77.8%) patients. The average increase was 2.7-fold (SD = 1.3) of the viral load at start of treatment. Final descent, defined by the definite negative movement, was seen as late as day 30 (median = 6, range [3–30]). The viral half-life was 7.1 (1.49–9.1) days. Discussion The present report demonstrates the potential of letermovir for the effective treatment of CMV infections. All present patients received letermovir as a monotherapy. The therapy was generally well tolerated, and no adverse events were reported. Treatment initiation yielded a decrease of viral load to < 200 copies/ml in 88.9% of the patients. However, one patient with complete clinical response experienced CMV end-organ disease within 2 weeks after treatment discontinuation. Immunosuppression was adapted in all SOT patients, by either dose reduction or pausing of cell-cycle inhibitor. Therapeutic strategies for clinical or virological failure of CMV infections include the escalation of valganciclovir dose or switching to cidofovir or foscarnet [1]. However, both drugs are associated with the potential for severe adverse events, such as nephrotoxicity and myelosuppression, which limit their therapeutic usefulness. Letermovir, a novel inhibitor of the terminase complex, was recently approved for the prophylaxis of CMV infection in allogenic HSCT, but is not yet approved for pre-emptive therapy [3]. Its favourable side effect profile has led to an increased off-label use for GCV-resistant CMV infections or if the patients were intolerant to receive other treatment options. However, first observations of letermovir resistance have been reported [10–13]. A recently published letermovir resistance analysis among HSCT recipients receiving letermovir prophylaxis identified all letermovir resistance associated variants within the UL 56 gene [13]. Although some treatment durations were prolonged, no viremia breakthrough was reported in our cohort. Dosing of letermovir for preemptive therapy remains uncertain, as there is no approval for letermovir in this indication. Stoelben et al. successfully used lower letermovir doses of 40 bid or 80 qd for preemptive therapy in kidney transplant recipients, whereas Turner et al. used higher doses of up to 960 mg qd for the salvage therapy of drug-resistant CMV retinitis without an emergence of adverse events [6, 14]. Letermovir dose in our cohort coincided with the dose recommendations for the prophylaxis of CMV infection, 480 mg qd or 240 mg if on concomitant cyclosporin [3]. The same treatment protocol was recently chosen by Phoompoung et al. for the salvage therapy of CMV infections in transplant recipients [7]. The average duration until decrease of viral load to under < 200 mg/ml was 32.9 days. The viral half-life time under letermovir was 6.3 days, which is longer than previously published viral half-lives of solid-organ transplant patients treated with GCV [9]. As demonstrated in earlier reports, the viral load initially increases after therapy start. The average increase in our cohort was 2.7-fold of the viral load at treatment start. However, the increase in viral load was not associated with an increase in symptoms. This may be explicable by the mode of action of letermovir, as viral replication is blocked at a late stage, possibly yielding high intracellular titre of viral DNA in absence of a viable virus. This emphasizes the need for alternative methods to estimate the risk of CMV disease under letermovir treatment. The present study has some limitations. As a result of the retrospective study design, the included cohort is heterogenous, leading to a broad spectrum of indication for letermovir. However, precisely this highlights the clinicians’ desire for alternative treatment options, as existing first-line therapies are often limited by their severe side effect profile, especially in patients with concomitant bacterial infections. Further, we could not exclude that the patient’s immune status contributed significantly to the treatment outcome, especially in patients with long lasting viremia. Hence, prospective trials evaluating efficacy, safety, drug dosing, treatment duration and emergence of drug resistance are urgently required. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The authors thank the members of the Division of Infectious Diseases and Tropical Medicine, Medical University Vienna, for their help. Author contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Lisa Fisecker and Lorenz Schubert. The first draft of the manuscript was written by Lorenz Schubert and Christoph Steininger, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open access funding provided by Medical University of Vienna. Data availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethics approval Ethical approval was waived by the local Ethics Committee of the Medical University Austria in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care. Informed consent Not applicable.	CORTISONE, GANCICLOVIR, MYCOPHENOLATE MOFETIL, TACROLIMUS	DrugsGivenReaction	CC BY	32914220	18,354,465	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'.	Transcatheter Arterial Embolization Using Microspheres for Palliating Pain from Bone Metastasis in a Patient with Cholangiocellular Carcinoma. A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis. Introduction In recent years, the number of patients with bone metastases has increased due to the increase in the number of cancer patients and their prolonged prognoses due to advances in cancer treatment (1, 2). Bone metastases are often asymptomatic in the early stages (3), but as they progress, they cause pain, spinal cord compression, and pathological fractures resulting in dyskinesias, paralysis, and a significantly decreased quality of life (QOL) (4-8). Pain is the most frequent symptom of bone metastasis. Half of the cancer pain cases have been attributed to bone metastases (4). Therefore, it is important to properly control pain in patients with bone metastasis. There are several standard treatments for metastatic bone pain, including medication (9-11), radiation therapy (12, 13), and surgery (14). Each treatment has been reported to have high efficacy, and patients can receive multiple treatment types in combination. However, 20-40% of patients with bone metastasis receiving multiple standard treatments reportedly experience difficulty with pain control (4). In recent years, several reports have indicated that transcatheter arterial embolization (TAE) is an effective treatment method for metastatic bone pain (15-19). We herein report a case of cholangiocellular carcinoma with bone metastasis-induced pain that was refractory to standard treatment methods but rapidly relieved by TAE. Case Report This study was conducted according to the Declaration of Helsinki. It was approved by our institution's review board, and the patient provided his consent for the specific treatment and publication of the results. A 72-year-old Japanese man was referred to our hospital due to severe pain in his left shoulder. He had been diagnosed with cholangiocellular carcinoma eight months earlier (Fig. 1A). A large tumor occupying the left lobe of the liver was observed, and dynamic contrast-enhanced computed tomography (CT) showed that the whole tumor was gradually well enhanced. Therefore, tumor needle biopsies were performed to distinguish it from hepatocellular carcinoma, and a pathological diagnosis of cholangiocellular carcinoma was established. He was performed systemic chemotherapy involving the combination administration of gemcitabine and cisplatin as the first treatment and tegaful/gimeracil/oteracil as the second treatment and then discontinued chemotherapy one month before referral our hospital due to the progression of the disease. He was receiving supportive care at the time of his presentation to our hospital. Laboratory tests during admission revealed increased levels of alkaline phosphatase (ALP, 1,551 IU/L). Regarding the tumor markers, carbohydrate antigen 19-9 (CA19-9, 1,849 U/mL) was remarkably increased, whereas normal levels of α-fetoprotein (AFP, 3.5 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 12 mAU/mL) were observed (Table). Figure 1. Abdominal and chest computed tomography images. a: A well-enhanced cholangiocellular carcinoma is located in the left hepatic lobe (arrowheads). b: Osteoblastic bone metastasis is present in the left scapula bone (arrowheads). Table. Results of Laboratory Investigation. Hematologic test Chemistry BUN 16.9 mg/dL White blood cells 4,900 /μL Total protein 6.8 g/dL Creatinine 0.7 mg/dL Neutrophils 73.6 % Albumin 3.4 g/dL Sodium 135 mmol/L Lymphocytes 20.3 % AST 37 IU/L Potassium 4.5 mmol/L Monocytes 5.1 % ALT 28 IU/L Chloride 98 mmol/L Eosinophils 0.8 % ALP 1,551 IU/L CRP 3.15 mg/dL Basophils 0.2 % γ-GTP 125 IU/L CEA 9.1 ng/mL Red blood cells 375×104 /μL T.Bil 0.7 mg/dL CA19-9 1,849 U/mL Hemoglobin 11.4 g/dL D.Bil 0.2 mg/dL AFP 3.5 ng/mL Platelet count 31.5×104 /μL LDH 141 IU/L PIVKA-II 12 mAU/mL AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T.Bil: total bilirubin, D.Bil: direct bilirubin, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reactive protein, CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, AFP:α-fetoprotein, PIVKA-II: protein induced by vitamin K absence or antagonist-II CT of the left shoulder revealed an osteoblastic metastatic lesion of the left scapula (Fig. 1B). He was administered bisphosphonates, oral morphine, and external irradiation (20 Gy), but the pain persisted with a score of 7/10 on the numerical rating scale (NRS). The dose of morphine was increased to 120 mg/day as needed for severe pain, but the patient experienced drowsiness that prohibited further increases in the morphine dose. The patient's Eastern Cooperative Oncology Group Performance Status worsened from 1 to 3 due to uncontrollable pain and drowsiness from the morphine. Therefore, TAE was performed to control the left shoulder pain because the tumor was well-enhanced by contrast CT. With the informed consent of the patient, TAE was performed via a left radial artery approach. Left brachial artery angiography showed a tumor stain from the thoracoacrominal artery and the circumflex scapular artery (Fig. 2A-C). A microcatheter (Sniper 2-μ7; Terumo Clinical Supply, Tokyo, Japan) with a 2.0-F tip was inserted into these arteries, and TAE was performed with microspheres (Embosphere; Nippon Kayaku, Tokyo, Japan) ranging from 300 to 500 μm in diameter. Subsequent angiography performed immediately after the TAE procedure revealed the almost complete disappearance of the tumor stain (Fig. 2D). No adverse events were observed during the procedure. Although the patient experienced transient pain [Numerical Rating Scale (NRS) score 8/10] with mild pyrexia requiring additional administration of analgesics for a couple of days due to post-embolism syndrome, the pain gradually improved in the following week (NRS score 3/10) resulting in the reduction of the morphine dose to 90 mg/day and alleviation of the drowsiness. Figure 2. Angiography images. a: Angiography via the left brachial artery shows tumor enhancement (arrows). The tumor is mainly fed by the circumflex scapular artery (white arrowhead) and the thoracoacromial artery (black arrowhead). b: Selective angiography via the circumflex scapular artery demonstrates prominent tumor enhancement (arrows). c: Selective angiography via the thoracoacromial artery demonstrates prominent tumor enhancement (arrows). d: Angiography via the left brachial artery immediately after TAE shows the nearly complete disappearance of tumor enhancement. Arterial depiction, showing that the circumflex scapular artery and the thoracoacromial artery are well preserved. Three months later, the patient died due to the progression of the primary disease. Shortly before his death, his shoulder pain was managed with rescue oral morphine taken several times a day. The clinical course and changes in serum C-reactive protein and CA19-9 before and after TAE are shown in Fig. 3. Figure 3. Clinical course of the patient before and after TAE. The time-dependent levels of the pain score with NRS are shown in the upper panel. In the lower panel, the solid line and dotted line show the serum CRP and CA19-9 levels, respectively. NRS: Numerical Rating Scale, CRP: C-reactive protein, CA19-9: carbohydrate antigen 19-9, TAE: transcatheter arterial embolization Discussion In this case, TAE alleviated bone metastasis-induced pain that was refractory to a combination of standard treatments, including bone-modifying agents (BMAs), opioids, and external irradiation. TAE is an interventional radiologic technique in which a catheter is advanced to a target artery, and embolic materials are injected into the blood vessel to block the arterial blood flow. Preoperative TAE is a widely accepted technique for reducing blood loss during metastatic bone surgery (20, 21). In addition, the pain-relieving effect of TAE on bone metastases has been reported in several pilot studies and retrospective studies (15-19). The effective rate of pain relief ranges between 60-80%, and the median time to pain alleviation is 2 days (19). The analgesic effect of TAE lasts an average of 2-8 months, and TAE can be repeated when the effect diminishes (15, 18). Furthermore, TAE has been reported to be effective against bone metastases of not only hypervascular tumors, such as hepatocellular carcinoma, thyroid cancer, and renal cell carcinoma, but also colorectal cancer, ovarian cancer, uterine cervical cancer, and esophageal cancer (19). This case showed a similar profile, with the pain alleviated shortly after the TAE intervention and lasting for at least three months. Injection and/or impregnation of anticancer agents can be simultaneously performed with embolization (19). Therefore, TAE is a promising option for palliating pain from bone metastasis. However, thus far, there have been no well-evidenced studies on this issue. Therefore, a further prospective evaluation of the safety and efficacy should be conducted. The mechanism underlying the pain relief provided by TAE is unclear and likely multi-faceted. Several hypotheses have been reported (19). TAE blocks the arterial supply of the metastatic tumors, which is expected to slow tumor growth and reduce the tumor burden, resulting in the delay or cessation of the destruction of the periosteum. In addition, reduced blood flow and edema within the tumor may decrease the direct pressure on adjacent tissues and nerves. The complications of TAE are typically minor and infrequent and mainly occur at the puncture site or with the use of contrast medium; the frequency is approximately 3% or 5-7%, respectively (22). Approximately 10% of patients undergoing TAE experience post-embolism syndrome that induces a fever and temporary deterioration of pain (22). When embolization occurs in arteries supplying soft bone tissues, neuropathy, osteonecrosis, muscle necrosis, or dermal necrosis can occur. If the artery of Adamkiewicz, which joins the anterior spinal artery from outside of the spine, is embolized during TAE for spinal tumor, it can result in paraplegia, a loss of sensation for pain and temperature, and bladder-rectal dysfunction-so-called spinal artery syndrome (23). However, given adequate training, the procedure is sophisticated enough to avoid these complications due to the embolization of non-target arteries. There are several types of embolic materials used in TAE. Gelatin particles are classically used for blocking the blood supply in tumors, such as in transcatheter arterial chemoembolization for hepatocellular carcinoma (24); however, microspheres have been popularized in recent years (25). Gelatin particles are temporary embolic materials, and the embolized blood vessels are recanalized within a few weeks (26). However, microspheres are spheres with a uniform particle shape comprising non-aggregating permanent embolic materials that do not cause inflammation. Possibly, a blood vessel meeting the target diameter can be embolized, resulting in less inflammation and pain after embolization. Therefore, microspheres were used in this case because we considered the technique safe and the embolic effect prolonged (27). The particle size of the microspheres used for TAE of bone metastases is recommended to be 300-500 μm (20, 21). Vessels in the bone and soft tissue areas are predominantly arterio-venous shunts, and the use of small-diameter embolic materials increases the risk of pulmonary embolism (28). In addition, drug-eluting beads can be loaded with anticancer drugs; however, adverse events associated with the anticancer drugs may occur (29). In this case, the purpose of TAE was palliation, and TAE was performed without using an anticancer drug, considering the risk of adverse events. The standard treatment of metastatic bone pain is performed with a combination of BMAs (9), opioids (10, 11), external irradiation (12, 13), and surgery (14); however, 20-40% of cancer patients are refractory to these treatments (4). The main purpose of BMAs, such as bisphosphonate and denosumab, is to reduce skeletal-related events and shorten the duration of the pain. BMA has been reported to be useful for bone metastases arising from breast cancer, prostate cancer, and digestive cancers. Although the long-term administration of BMA can prevent metastatic bone pain, it has little analgesic effect on existing pain. Opioids are highly effective and are the first choice in the treatment of cancer pain. The various dosages and forms allow for adjustments depending on the patient's pain type and level. However, adverse effects occasionally limit the tolerated dose needed for sufficient pain relief. External irradiation can relieve pain and significantly improve the patients' QOL in 59-73% of the cases (12, 13). Although combinatorial prescription of analgesics is required until the irradiation starts showing efficacy in the several-weeks-long early treatment phase, the therapeutic effect of external irradiation lasts for approximately 30 weeks on average. Surgery is considered the salvage treatment for pathological fractures and spinal cord compression due to bone metastases. Surgery is performed for the purpose of pain relief and improvement in the QOL, considering the general condition of the patient, invasiveness of the surgery, and the patient's prognosis. Patients at the terminal stage of their disease are not often good candidates for surgery. In conclusion, TAE is expected to achieve a relatively quick response with high efficacy and low invasiveness in the majority of patients experiencing metastatic bone pain. This case suggests that TAE performed at an early stage complements the standard treatments and improves the QOL in patients with painful bone metastasis. This case report was approved by the institutional Human Investigation Committee of Uonuma Institute of Community Medicine Niigata University Hospital. Written informed consent was obtained from the patient in accordance with the Declaration of Helsinki for the publication of this case report. The authors state that they have no Conflict of Interest (COI).	CISPLATIN, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, MORPHINE	DrugsGivenReaction	CC BY-NC-ND	32921687	19,703,168	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.	Transcatheter Arterial Embolization Using Microspheres for Palliating Pain from Bone Metastasis in a Patient with Cholangiocellular Carcinoma. A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis. Introduction In recent years, the number of patients with bone metastases has increased due to the increase in the number of cancer patients and their prolonged prognoses due to advances in cancer treatment (1, 2). Bone metastases are often asymptomatic in the early stages (3), but as they progress, they cause pain, spinal cord compression, and pathological fractures resulting in dyskinesias, paralysis, and a significantly decreased quality of life (QOL) (4-8). Pain is the most frequent symptom of bone metastasis. Half of the cancer pain cases have been attributed to bone metastases (4). Therefore, it is important to properly control pain in patients with bone metastasis. There are several standard treatments for metastatic bone pain, including medication (9-11), radiation therapy (12, 13), and surgery (14). Each treatment has been reported to have high efficacy, and patients can receive multiple treatment types in combination. However, 20-40% of patients with bone metastasis receiving multiple standard treatments reportedly experience difficulty with pain control (4). In recent years, several reports have indicated that transcatheter arterial embolization (TAE) is an effective treatment method for metastatic bone pain (15-19). We herein report a case of cholangiocellular carcinoma with bone metastasis-induced pain that was refractory to standard treatment methods but rapidly relieved by TAE. Case Report This study was conducted according to the Declaration of Helsinki. It was approved by our institution's review board, and the patient provided his consent for the specific treatment and publication of the results. A 72-year-old Japanese man was referred to our hospital due to severe pain in his left shoulder. He had been diagnosed with cholangiocellular carcinoma eight months earlier (Fig. 1A). A large tumor occupying the left lobe of the liver was observed, and dynamic contrast-enhanced computed tomography (CT) showed that the whole tumor was gradually well enhanced. Therefore, tumor needle biopsies were performed to distinguish it from hepatocellular carcinoma, and a pathological diagnosis of cholangiocellular carcinoma was established. He was performed systemic chemotherapy involving the combination administration of gemcitabine and cisplatin as the first treatment and tegaful/gimeracil/oteracil as the second treatment and then discontinued chemotherapy one month before referral our hospital due to the progression of the disease. He was receiving supportive care at the time of his presentation to our hospital. Laboratory tests during admission revealed increased levels of alkaline phosphatase (ALP, 1,551 IU/L). Regarding the tumor markers, carbohydrate antigen 19-9 (CA19-9, 1,849 U/mL) was remarkably increased, whereas normal levels of α-fetoprotein (AFP, 3.5 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 12 mAU/mL) were observed (Table). Figure 1. Abdominal and chest computed tomography images. a: A well-enhanced cholangiocellular carcinoma is located in the left hepatic lobe (arrowheads). b: Osteoblastic bone metastasis is present in the left scapula bone (arrowheads). Table. Results of Laboratory Investigation. Hematologic test Chemistry BUN 16.9 mg/dL White blood cells 4,900 /μL Total protein 6.8 g/dL Creatinine 0.7 mg/dL Neutrophils 73.6 % Albumin 3.4 g/dL Sodium 135 mmol/L Lymphocytes 20.3 % AST 37 IU/L Potassium 4.5 mmol/L Monocytes 5.1 % ALT 28 IU/L Chloride 98 mmol/L Eosinophils 0.8 % ALP 1,551 IU/L CRP 3.15 mg/dL Basophils 0.2 % γ-GTP 125 IU/L CEA 9.1 ng/mL Red blood cells 375×104 /μL T.Bil 0.7 mg/dL CA19-9 1,849 U/mL Hemoglobin 11.4 g/dL D.Bil 0.2 mg/dL AFP 3.5 ng/mL Platelet count 31.5×104 /μL LDH 141 IU/L PIVKA-II 12 mAU/mL AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T.Bil: total bilirubin, D.Bil: direct bilirubin, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reactive protein, CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, AFP:α-fetoprotein, PIVKA-II: protein induced by vitamin K absence or antagonist-II CT of the left shoulder revealed an osteoblastic metastatic lesion of the left scapula (Fig. 1B). He was administered bisphosphonates, oral morphine, and external irradiation (20 Gy), but the pain persisted with a score of 7/10 on the numerical rating scale (NRS). The dose of morphine was increased to 120 mg/day as needed for severe pain, but the patient experienced drowsiness that prohibited further increases in the morphine dose. The patient's Eastern Cooperative Oncology Group Performance Status worsened from 1 to 3 due to uncontrollable pain and drowsiness from the morphine. Therefore, TAE was performed to control the left shoulder pain because the tumor was well-enhanced by contrast CT. With the informed consent of the patient, TAE was performed via a left radial artery approach. Left brachial artery angiography showed a tumor stain from the thoracoacrominal artery and the circumflex scapular artery (Fig. 2A-C). A microcatheter (Sniper 2-μ7; Terumo Clinical Supply, Tokyo, Japan) with a 2.0-F tip was inserted into these arteries, and TAE was performed with microspheres (Embosphere; Nippon Kayaku, Tokyo, Japan) ranging from 300 to 500 μm in diameter. Subsequent angiography performed immediately after the TAE procedure revealed the almost complete disappearance of the tumor stain (Fig. 2D). No adverse events were observed during the procedure. Although the patient experienced transient pain [Numerical Rating Scale (NRS) score 8/10] with mild pyrexia requiring additional administration of analgesics for a couple of days due to post-embolism syndrome, the pain gradually improved in the following week (NRS score 3/10) resulting in the reduction of the morphine dose to 90 mg/day and alleviation of the drowsiness. Figure 2. Angiography images. a: Angiography via the left brachial artery shows tumor enhancement (arrows). The tumor is mainly fed by the circumflex scapular artery (white arrowhead) and the thoracoacromial artery (black arrowhead). b: Selective angiography via the circumflex scapular artery demonstrates prominent tumor enhancement (arrows). c: Selective angiography via the thoracoacromial artery demonstrates prominent tumor enhancement (arrows). d: Angiography via the left brachial artery immediately after TAE shows the nearly complete disappearance of tumor enhancement. Arterial depiction, showing that the circumflex scapular artery and the thoracoacromial artery are well preserved. Three months later, the patient died due to the progression of the primary disease. Shortly before his death, his shoulder pain was managed with rescue oral morphine taken several times a day. The clinical course and changes in serum C-reactive protein and CA19-9 before and after TAE are shown in Fig. 3. Figure 3. Clinical course of the patient before and after TAE. The time-dependent levels of the pain score with NRS are shown in the upper panel. In the lower panel, the solid line and dotted line show the serum CRP and CA19-9 levels, respectively. NRS: Numerical Rating Scale, CRP: C-reactive protein, CA19-9: carbohydrate antigen 19-9, TAE: transcatheter arterial embolization Discussion In this case, TAE alleviated bone metastasis-induced pain that was refractory to a combination of standard treatments, including bone-modifying agents (BMAs), opioids, and external irradiation. TAE is an interventional radiologic technique in which a catheter is advanced to a target artery, and embolic materials are injected into the blood vessel to block the arterial blood flow. Preoperative TAE is a widely accepted technique for reducing blood loss during metastatic bone surgery (20, 21). In addition, the pain-relieving effect of TAE on bone metastases has been reported in several pilot studies and retrospective studies (15-19). The effective rate of pain relief ranges between 60-80%, and the median time to pain alleviation is 2 days (19). The analgesic effect of TAE lasts an average of 2-8 months, and TAE can be repeated when the effect diminishes (15, 18). Furthermore, TAE has been reported to be effective against bone metastases of not only hypervascular tumors, such as hepatocellular carcinoma, thyroid cancer, and renal cell carcinoma, but also colorectal cancer, ovarian cancer, uterine cervical cancer, and esophageal cancer (19). This case showed a similar profile, with the pain alleviated shortly after the TAE intervention and lasting for at least three months. Injection and/or impregnation of anticancer agents can be simultaneously performed with embolization (19). Therefore, TAE is a promising option for palliating pain from bone metastasis. However, thus far, there have been no well-evidenced studies on this issue. Therefore, a further prospective evaluation of the safety and efficacy should be conducted. The mechanism underlying the pain relief provided by TAE is unclear and likely multi-faceted. Several hypotheses have been reported (19). TAE blocks the arterial supply of the metastatic tumors, which is expected to slow tumor growth and reduce the tumor burden, resulting in the delay or cessation of the destruction of the periosteum. In addition, reduced blood flow and edema within the tumor may decrease the direct pressure on adjacent tissues and nerves. The complications of TAE are typically minor and infrequent and mainly occur at the puncture site or with the use of contrast medium; the frequency is approximately 3% or 5-7%, respectively (22). Approximately 10% of patients undergoing TAE experience post-embolism syndrome that induces a fever and temporary deterioration of pain (22). When embolization occurs in arteries supplying soft bone tissues, neuropathy, osteonecrosis, muscle necrosis, or dermal necrosis can occur. If the artery of Adamkiewicz, which joins the anterior spinal artery from outside of the spine, is embolized during TAE for spinal tumor, it can result in paraplegia, a loss of sensation for pain and temperature, and bladder-rectal dysfunction-so-called spinal artery syndrome (23). However, given adequate training, the procedure is sophisticated enough to avoid these complications due to the embolization of non-target arteries. There are several types of embolic materials used in TAE. Gelatin particles are classically used for blocking the blood supply in tumors, such as in transcatheter arterial chemoembolization for hepatocellular carcinoma (24); however, microspheres have been popularized in recent years (25). Gelatin particles are temporary embolic materials, and the embolized blood vessels are recanalized within a few weeks (26). However, microspheres are spheres with a uniform particle shape comprising non-aggregating permanent embolic materials that do not cause inflammation. Possibly, a blood vessel meeting the target diameter can be embolized, resulting in less inflammation and pain after embolization. Therefore, microspheres were used in this case because we considered the technique safe and the embolic effect prolonged (27). The particle size of the microspheres used for TAE of bone metastases is recommended to be 300-500 μm (20, 21). Vessels in the bone and soft tissue areas are predominantly arterio-venous shunts, and the use of small-diameter embolic materials increases the risk of pulmonary embolism (28). In addition, drug-eluting beads can be loaded with anticancer drugs; however, adverse events associated with the anticancer drugs may occur (29). In this case, the purpose of TAE was palliation, and TAE was performed without using an anticancer drug, considering the risk of adverse events. The standard treatment of metastatic bone pain is performed with a combination of BMAs (9), opioids (10, 11), external irradiation (12, 13), and surgery (14); however, 20-40% of cancer patients are refractory to these treatments (4). The main purpose of BMAs, such as bisphosphonate and denosumab, is to reduce skeletal-related events and shorten the duration of the pain. BMA has been reported to be useful for bone metastases arising from breast cancer, prostate cancer, and digestive cancers. Although the long-term administration of BMA can prevent metastatic bone pain, it has little analgesic effect on existing pain. Opioids are highly effective and are the first choice in the treatment of cancer pain. The various dosages and forms allow for adjustments depending on the patient's pain type and level. However, adverse effects occasionally limit the tolerated dose needed for sufficient pain relief. External irradiation can relieve pain and significantly improve the patients' QOL in 59-73% of the cases (12, 13). Although combinatorial prescription of analgesics is required until the irradiation starts showing efficacy in the several-weeks-long early treatment phase, the therapeutic effect of external irradiation lasts for approximately 30 weeks on average. Surgery is considered the salvage treatment for pathological fractures and spinal cord compression due to bone metastases. Surgery is performed for the purpose of pain relief and improvement in the QOL, considering the general condition of the patient, invasiveness of the surgery, and the patient's prognosis. Patients at the terminal stage of their disease are not often good candidates for surgery. In conclusion, TAE is expected to achieve a relatively quick response with high efficacy and low invasiveness in the majority of patients experiencing metastatic bone pain. This case suggests that TAE performed at an early stage complements the standard treatments and improves the QOL in patients with painful bone metastasis. This case report was approved by the institutional Human Investigation Committee of Uonuma Institute of Community Medicine Niigata University Hospital. Written informed consent was obtained from the patient in accordance with the Declaration of Helsinki for the publication of this case report. The authors state that they have no Conflict of Interest (COI).	CISPLATIN, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, MORPHINE	DrugsGivenReaction	CC BY-NC-ND	32921687	19,703,168	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'.	Transcatheter Arterial Embolization Using Microspheres for Palliating Pain from Bone Metastasis in a Patient with Cholangiocellular Carcinoma. A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis. Introduction In recent years, the number of patients with bone metastases has increased due to the increase in the number of cancer patients and their prolonged prognoses due to advances in cancer treatment (1, 2). Bone metastases are often asymptomatic in the early stages (3), but as they progress, they cause pain, spinal cord compression, and pathological fractures resulting in dyskinesias, paralysis, and a significantly decreased quality of life (QOL) (4-8). Pain is the most frequent symptom of bone metastasis. Half of the cancer pain cases have been attributed to bone metastases (4). Therefore, it is important to properly control pain in patients with bone metastasis. There are several standard treatments for metastatic bone pain, including medication (9-11), radiation therapy (12, 13), and surgery (14). Each treatment has been reported to have high efficacy, and patients can receive multiple treatment types in combination. However, 20-40% of patients with bone metastasis receiving multiple standard treatments reportedly experience difficulty with pain control (4). In recent years, several reports have indicated that transcatheter arterial embolization (TAE) is an effective treatment method for metastatic bone pain (15-19). We herein report a case of cholangiocellular carcinoma with bone metastasis-induced pain that was refractory to standard treatment methods but rapidly relieved by TAE. Case Report This study was conducted according to the Declaration of Helsinki. It was approved by our institution's review board, and the patient provided his consent for the specific treatment and publication of the results. A 72-year-old Japanese man was referred to our hospital due to severe pain in his left shoulder. He had been diagnosed with cholangiocellular carcinoma eight months earlier (Fig. 1A). A large tumor occupying the left lobe of the liver was observed, and dynamic contrast-enhanced computed tomography (CT) showed that the whole tumor was gradually well enhanced. Therefore, tumor needle biopsies were performed to distinguish it from hepatocellular carcinoma, and a pathological diagnosis of cholangiocellular carcinoma was established. He was performed systemic chemotherapy involving the combination administration of gemcitabine and cisplatin as the first treatment and tegaful/gimeracil/oteracil as the second treatment and then discontinued chemotherapy one month before referral our hospital due to the progression of the disease. He was receiving supportive care at the time of his presentation to our hospital. Laboratory tests during admission revealed increased levels of alkaline phosphatase (ALP, 1,551 IU/L). Regarding the tumor markers, carbohydrate antigen 19-9 (CA19-9, 1,849 U/mL) was remarkably increased, whereas normal levels of α-fetoprotein (AFP, 3.5 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 12 mAU/mL) were observed (Table). Figure 1. Abdominal and chest computed tomography images. a: A well-enhanced cholangiocellular carcinoma is located in the left hepatic lobe (arrowheads). b: Osteoblastic bone metastasis is present in the left scapula bone (arrowheads). Table. Results of Laboratory Investigation. Hematologic test Chemistry BUN 16.9 mg/dL White blood cells 4,900 /μL Total protein 6.8 g/dL Creatinine 0.7 mg/dL Neutrophils 73.6 % Albumin 3.4 g/dL Sodium 135 mmol/L Lymphocytes 20.3 % AST 37 IU/L Potassium 4.5 mmol/L Monocytes 5.1 % ALT 28 IU/L Chloride 98 mmol/L Eosinophils 0.8 % ALP 1,551 IU/L CRP 3.15 mg/dL Basophils 0.2 % γ-GTP 125 IU/L CEA 9.1 ng/mL Red blood cells 375×104 /μL T.Bil 0.7 mg/dL CA19-9 1,849 U/mL Hemoglobin 11.4 g/dL D.Bil 0.2 mg/dL AFP 3.5 ng/mL Platelet count 31.5×104 /μL LDH 141 IU/L PIVKA-II 12 mAU/mL AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T.Bil: total bilirubin, D.Bil: direct bilirubin, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reactive protein, CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, AFP:α-fetoprotein, PIVKA-II: protein induced by vitamin K absence or antagonist-II CT of the left shoulder revealed an osteoblastic metastatic lesion of the left scapula (Fig. 1B). He was administered bisphosphonates, oral morphine, and external irradiation (20 Gy), but the pain persisted with a score of 7/10 on the numerical rating scale (NRS). The dose of morphine was increased to 120 mg/day as needed for severe pain, but the patient experienced drowsiness that prohibited further increases in the morphine dose. The patient's Eastern Cooperative Oncology Group Performance Status worsened from 1 to 3 due to uncontrollable pain and drowsiness from the morphine. Therefore, TAE was performed to control the left shoulder pain because the tumor was well-enhanced by contrast CT. With the informed consent of the patient, TAE was performed via a left radial artery approach. Left brachial artery angiography showed a tumor stain from the thoracoacrominal artery and the circumflex scapular artery (Fig. 2A-C). A microcatheter (Sniper 2-μ7; Terumo Clinical Supply, Tokyo, Japan) with a 2.0-F tip was inserted into these arteries, and TAE was performed with microspheres (Embosphere; Nippon Kayaku, Tokyo, Japan) ranging from 300 to 500 μm in diameter. Subsequent angiography performed immediately after the TAE procedure revealed the almost complete disappearance of the tumor stain (Fig. 2D). No adverse events were observed during the procedure. Although the patient experienced transient pain [Numerical Rating Scale (NRS) score 8/10] with mild pyrexia requiring additional administration of analgesics for a couple of days due to post-embolism syndrome, the pain gradually improved in the following week (NRS score 3/10) resulting in the reduction of the morphine dose to 90 mg/day and alleviation of the drowsiness. Figure 2. Angiography images. a: Angiography via the left brachial artery shows tumor enhancement (arrows). The tumor is mainly fed by the circumflex scapular artery (white arrowhead) and the thoracoacromial artery (black arrowhead). b: Selective angiography via the circumflex scapular artery demonstrates prominent tumor enhancement (arrows). c: Selective angiography via the thoracoacromial artery demonstrates prominent tumor enhancement (arrows). d: Angiography via the left brachial artery immediately after TAE shows the nearly complete disappearance of tumor enhancement. Arterial depiction, showing that the circumflex scapular artery and the thoracoacromial artery are well preserved. Three months later, the patient died due to the progression of the primary disease. Shortly before his death, his shoulder pain was managed with rescue oral morphine taken several times a day. The clinical course and changes in serum C-reactive protein and CA19-9 before and after TAE are shown in Fig. 3. Figure 3. Clinical course of the patient before and after TAE. The time-dependent levels of the pain score with NRS are shown in the upper panel. In the lower panel, the solid line and dotted line show the serum CRP and CA19-9 levels, respectively. NRS: Numerical Rating Scale, CRP: C-reactive protein, CA19-9: carbohydrate antigen 19-9, TAE: transcatheter arterial embolization Discussion In this case, TAE alleviated bone metastasis-induced pain that was refractory to a combination of standard treatments, including bone-modifying agents (BMAs), opioids, and external irradiation. TAE is an interventional radiologic technique in which a catheter is advanced to a target artery, and embolic materials are injected into the blood vessel to block the arterial blood flow. Preoperative TAE is a widely accepted technique for reducing blood loss during metastatic bone surgery (20, 21). In addition, the pain-relieving effect of TAE on bone metastases has been reported in several pilot studies and retrospective studies (15-19). The effective rate of pain relief ranges between 60-80%, and the median time to pain alleviation is 2 days (19). The analgesic effect of TAE lasts an average of 2-8 months, and TAE can be repeated when the effect diminishes (15, 18). Furthermore, TAE has been reported to be effective against bone metastases of not only hypervascular tumors, such as hepatocellular carcinoma, thyroid cancer, and renal cell carcinoma, but also colorectal cancer, ovarian cancer, uterine cervical cancer, and esophageal cancer (19). This case showed a similar profile, with the pain alleviated shortly after the TAE intervention and lasting for at least three months. Injection and/or impregnation of anticancer agents can be simultaneously performed with embolization (19). Therefore, TAE is a promising option for palliating pain from bone metastasis. However, thus far, there have been no well-evidenced studies on this issue. Therefore, a further prospective evaluation of the safety and efficacy should be conducted. The mechanism underlying the pain relief provided by TAE is unclear and likely multi-faceted. Several hypotheses have been reported (19). TAE blocks the arterial supply of the metastatic tumors, which is expected to slow tumor growth and reduce the tumor burden, resulting in the delay or cessation of the destruction of the periosteum. In addition, reduced blood flow and edema within the tumor may decrease the direct pressure on adjacent tissues and nerves. The complications of TAE are typically minor and infrequent and mainly occur at the puncture site or with the use of contrast medium; the frequency is approximately 3% or 5-7%, respectively (22). Approximately 10% of patients undergoing TAE experience post-embolism syndrome that induces a fever and temporary deterioration of pain (22). When embolization occurs in arteries supplying soft bone tissues, neuropathy, osteonecrosis, muscle necrosis, or dermal necrosis can occur. If the artery of Adamkiewicz, which joins the anterior spinal artery from outside of the spine, is embolized during TAE for spinal tumor, it can result in paraplegia, a loss of sensation for pain and temperature, and bladder-rectal dysfunction-so-called spinal artery syndrome (23). However, given adequate training, the procedure is sophisticated enough to avoid these complications due to the embolization of non-target arteries. There are several types of embolic materials used in TAE. Gelatin particles are classically used for blocking the blood supply in tumors, such as in transcatheter arterial chemoembolization for hepatocellular carcinoma (24); however, microspheres have been popularized in recent years (25). Gelatin particles are temporary embolic materials, and the embolized blood vessels are recanalized within a few weeks (26). However, microspheres are spheres with a uniform particle shape comprising non-aggregating permanent embolic materials that do not cause inflammation. Possibly, a blood vessel meeting the target diameter can be embolized, resulting in less inflammation and pain after embolization. Therefore, microspheres were used in this case because we considered the technique safe and the embolic effect prolonged (27). The particle size of the microspheres used for TAE of bone metastases is recommended to be 300-500 μm (20, 21). Vessels in the bone and soft tissue areas are predominantly arterio-venous shunts, and the use of small-diameter embolic materials increases the risk of pulmonary embolism (28). In addition, drug-eluting beads can be loaded with anticancer drugs; however, adverse events associated with the anticancer drugs may occur (29). In this case, the purpose of TAE was palliation, and TAE was performed without using an anticancer drug, considering the risk of adverse events. The standard treatment of metastatic bone pain is performed with a combination of BMAs (9), opioids (10, 11), external irradiation (12, 13), and surgery (14); however, 20-40% of cancer patients are refractory to these treatments (4). The main purpose of BMAs, such as bisphosphonate and denosumab, is to reduce skeletal-related events and shorten the duration of the pain. BMA has been reported to be useful for bone metastases arising from breast cancer, prostate cancer, and digestive cancers. Although the long-term administration of BMA can prevent metastatic bone pain, it has little analgesic effect on existing pain. Opioids are highly effective and are the first choice in the treatment of cancer pain. The various dosages and forms allow for adjustments depending on the patient's pain type and level. However, adverse effects occasionally limit the tolerated dose needed for sufficient pain relief. External irradiation can relieve pain and significantly improve the patients' QOL in 59-73% of the cases (12, 13). Although combinatorial prescription of analgesics is required until the irradiation starts showing efficacy in the several-weeks-long early treatment phase, the therapeutic effect of external irradiation lasts for approximately 30 weeks on average. Surgery is considered the salvage treatment for pathological fractures and spinal cord compression due to bone metastases. Surgery is performed for the purpose of pain relief and improvement in the QOL, considering the general condition of the patient, invasiveness of the surgery, and the patient's prognosis. Patients at the terminal stage of their disease are not often good candidates for surgery. In conclusion, TAE is expected to achieve a relatively quick response with high efficacy and low invasiveness in the majority of patients experiencing metastatic bone pain. This case suggests that TAE performed at an early stage complements the standard treatments and improves the QOL in patients with painful bone metastasis. This case report was approved by the institutional Human Investigation Committee of Uonuma Institute of Community Medicine Niigata University Hospital. Written informed consent was obtained from the patient in accordance with the Declaration of Helsinki for the publication of this case report. The authors state that they have no Conflict of Interest (COI).	CISPLATIN, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, MORPHINE	DrugsGivenReaction	CC BY-NC-ND	32921687	19,703,168	2021-01-15
What was the administration route of drug 'MORPHINE'?	Transcatheter Arterial Embolization Using Microspheres for Palliating Pain from Bone Metastasis in a Patient with Cholangiocellular Carcinoma. A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis. Introduction In recent years, the number of patients with bone metastases has increased due to the increase in the number of cancer patients and their prolonged prognoses due to advances in cancer treatment (1, 2). Bone metastases are often asymptomatic in the early stages (3), but as they progress, they cause pain, spinal cord compression, and pathological fractures resulting in dyskinesias, paralysis, and a significantly decreased quality of life (QOL) (4-8). Pain is the most frequent symptom of bone metastasis. Half of the cancer pain cases have been attributed to bone metastases (4). Therefore, it is important to properly control pain in patients with bone metastasis. There are several standard treatments for metastatic bone pain, including medication (9-11), radiation therapy (12, 13), and surgery (14). Each treatment has been reported to have high efficacy, and patients can receive multiple treatment types in combination. However, 20-40% of patients with bone metastasis receiving multiple standard treatments reportedly experience difficulty with pain control (4). In recent years, several reports have indicated that transcatheter arterial embolization (TAE) is an effective treatment method for metastatic bone pain (15-19). We herein report a case of cholangiocellular carcinoma with bone metastasis-induced pain that was refractory to standard treatment methods but rapidly relieved by TAE. Case Report This study was conducted according to the Declaration of Helsinki. It was approved by our institution's review board, and the patient provided his consent for the specific treatment and publication of the results. A 72-year-old Japanese man was referred to our hospital due to severe pain in his left shoulder. He had been diagnosed with cholangiocellular carcinoma eight months earlier (Fig. 1A). A large tumor occupying the left lobe of the liver was observed, and dynamic contrast-enhanced computed tomography (CT) showed that the whole tumor was gradually well enhanced. Therefore, tumor needle biopsies were performed to distinguish it from hepatocellular carcinoma, and a pathological diagnosis of cholangiocellular carcinoma was established. He was performed systemic chemotherapy involving the combination administration of gemcitabine and cisplatin as the first treatment and tegaful/gimeracil/oteracil as the second treatment and then discontinued chemotherapy one month before referral our hospital due to the progression of the disease. He was receiving supportive care at the time of his presentation to our hospital. Laboratory tests during admission revealed increased levels of alkaline phosphatase (ALP, 1,551 IU/L). Regarding the tumor markers, carbohydrate antigen 19-9 (CA19-9, 1,849 U/mL) was remarkably increased, whereas normal levels of α-fetoprotein (AFP, 3.5 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 12 mAU/mL) were observed (Table). Figure 1. Abdominal and chest computed tomography images. a: A well-enhanced cholangiocellular carcinoma is located in the left hepatic lobe (arrowheads). b: Osteoblastic bone metastasis is present in the left scapula bone (arrowheads). Table. Results of Laboratory Investigation. Hematologic test Chemistry BUN 16.9 mg/dL White blood cells 4,900 /μL Total protein 6.8 g/dL Creatinine 0.7 mg/dL Neutrophils 73.6 % Albumin 3.4 g/dL Sodium 135 mmol/L Lymphocytes 20.3 % AST 37 IU/L Potassium 4.5 mmol/L Monocytes 5.1 % ALT 28 IU/L Chloride 98 mmol/L Eosinophils 0.8 % ALP 1,551 IU/L CRP 3.15 mg/dL Basophils 0.2 % γ-GTP 125 IU/L CEA 9.1 ng/mL Red blood cells 375×104 /μL T.Bil 0.7 mg/dL CA19-9 1,849 U/mL Hemoglobin 11.4 g/dL D.Bil 0.2 mg/dL AFP 3.5 ng/mL Platelet count 31.5×104 /μL LDH 141 IU/L PIVKA-II 12 mAU/mL AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T.Bil: total bilirubin, D.Bil: direct bilirubin, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reactive protein, CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, AFP:α-fetoprotein, PIVKA-II: protein induced by vitamin K absence or antagonist-II CT of the left shoulder revealed an osteoblastic metastatic lesion of the left scapula (Fig. 1B). He was administered bisphosphonates, oral morphine, and external irradiation (20 Gy), but the pain persisted with a score of 7/10 on the numerical rating scale (NRS). The dose of morphine was increased to 120 mg/day as needed for severe pain, but the patient experienced drowsiness that prohibited further increases in the morphine dose. The patient's Eastern Cooperative Oncology Group Performance Status worsened from 1 to 3 due to uncontrollable pain and drowsiness from the morphine. Therefore, TAE was performed to control the left shoulder pain because the tumor was well-enhanced by contrast CT. With the informed consent of the patient, TAE was performed via a left radial artery approach. Left brachial artery angiography showed a tumor stain from the thoracoacrominal artery and the circumflex scapular artery (Fig. 2A-C). A microcatheter (Sniper 2-μ7; Terumo Clinical Supply, Tokyo, Japan) with a 2.0-F tip was inserted into these arteries, and TAE was performed with microspheres (Embosphere; Nippon Kayaku, Tokyo, Japan) ranging from 300 to 500 μm in diameter. Subsequent angiography performed immediately after the TAE procedure revealed the almost complete disappearance of the tumor stain (Fig. 2D). No adverse events were observed during the procedure. Although the patient experienced transient pain [Numerical Rating Scale (NRS) score 8/10] with mild pyrexia requiring additional administration of analgesics for a couple of days due to post-embolism syndrome, the pain gradually improved in the following week (NRS score 3/10) resulting in the reduction of the morphine dose to 90 mg/day and alleviation of the drowsiness. Figure 2. Angiography images. a: Angiography via the left brachial artery shows tumor enhancement (arrows). The tumor is mainly fed by the circumflex scapular artery (white arrowhead) and the thoracoacromial artery (black arrowhead). b: Selective angiography via the circumflex scapular artery demonstrates prominent tumor enhancement (arrows). c: Selective angiography via the thoracoacromial artery demonstrates prominent tumor enhancement (arrows). d: Angiography via the left brachial artery immediately after TAE shows the nearly complete disappearance of tumor enhancement. Arterial depiction, showing that the circumflex scapular artery and the thoracoacromial artery are well preserved. Three months later, the patient died due to the progression of the primary disease. Shortly before his death, his shoulder pain was managed with rescue oral morphine taken several times a day. The clinical course and changes in serum C-reactive protein and CA19-9 before and after TAE are shown in Fig. 3. Figure 3. Clinical course of the patient before and after TAE. The time-dependent levels of the pain score with NRS are shown in the upper panel. In the lower panel, the solid line and dotted line show the serum CRP and CA19-9 levels, respectively. NRS: Numerical Rating Scale, CRP: C-reactive protein, CA19-9: carbohydrate antigen 19-9, TAE: transcatheter arterial embolization Discussion In this case, TAE alleviated bone metastasis-induced pain that was refractory to a combination of standard treatments, including bone-modifying agents (BMAs), opioids, and external irradiation. TAE is an interventional radiologic technique in which a catheter is advanced to a target artery, and embolic materials are injected into the blood vessel to block the arterial blood flow. Preoperative TAE is a widely accepted technique for reducing blood loss during metastatic bone surgery (20, 21). In addition, the pain-relieving effect of TAE on bone metastases has been reported in several pilot studies and retrospective studies (15-19). The effective rate of pain relief ranges between 60-80%, and the median time to pain alleviation is 2 days (19). The analgesic effect of TAE lasts an average of 2-8 months, and TAE can be repeated when the effect diminishes (15, 18). Furthermore, TAE has been reported to be effective against bone metastases of not only hypervascular tumors, such as hepatocellular carcinoma, thyroid cancer, and renal cell carcinoma, but also colorectal cancer, ovarian cancer, uterine cervical cancer, and esophageal cancer (19). This case showed a similar profile, with the pain alleviated shortly after the TAE intervention and lasting for at least three months. Injection and/or impregnation of anticancer agents can be simultaneously performed with embolization (19). Therefore, TAE is a promising option for palliating pain from bone metastasis. However, thus far, there have been no well-evidenced studies on this issue. Therefore, a further prospective evaluation of the safety and efficacy should be conducted. The mechanism underlying the pain relief provided by TAE is unclear and likely multi-faceted. Several hypotheses have been reported (19). TAE blocks the arterial supply of the metastatic tumors, which is expected to slow tumor growth and reduce the tumor burden, resulting in the delay or cessation of the destruction of the periosteum. In addition, reduced blood flow and edema within the tumor may decrease the direct pressure on adjacent tissues and nerves. The complications of TAE are typically minor and infrequent and mainly occur at the puncture site or with the use of contrast medium; the frequency is approximately 3% or 5-7%, respectively (22). Approximately 10% of patients undergoing TAE experience post-embolism syndrome that induces a fever and temporary deterioration of pain (22). When embolization occurs in arteries supplying soft bone tissues, neuropathy, osteonecrosis, muscle necrosis, or dermal necrosis can occur. If the artery of Adamkiewicz, which joins the anterior spinal artery from outside of the spine, is embolized during TAE for spinal tumor, it can result in paraplegia, a loss of sensation for pain and temperature, and bladder-rectal dysfunction-so-called spinal artery syndrome (23). However, given adequate training, the procedure is sophisticated enough to avoid these complications due to the embolization of non-target arteries. There are several types of embolic materials used in TAE. Gelatin particles are classically used for blocking the blood supply in tumors, such as in transcatheter arterial chemoembolization for hepatocellular carcinoma (24); however, microspheres have been popularized in recent years (25). Gelatin particles are temporary embolic materials, and the embolized blood vessels are recanalized within a few weeks (26). However, microspheres are spheres with a uniform particle shape comprising non-aggregating permanent embolic materials that do not cause inflammation. Possibly, a blood vessel meeting the target diameter can be embolized, resulting in less inflammation and pain after embolization. Therefore, microspheres were used in this case because we considered the technique safe and the embolic effect prolonged (27). The particle size of the microspheres used for TAE of bone metastases is recommended to be 300-500 μm (20, 21). Vessels in the bone and soft tissue areas are predominantly arterio-venous shunts, and the use of small-diameter embolic materials increases the risk of pulmonary embolism (28). In addition, drug-eluting beads can be loaded with anticancer drugs; however, adverse events associated with the anticancer drugs may occur (29). In this case, the purpose of TAE was palliation, and TAE was performed without using an anticancer drug, considering the risk of adverse events. The standard treatment of metastatic bone pain is performed with a combination of BMAs (9), opioids (10, 11), external irradiation (12, 13), and surgery (14); however, 20-40% of cancer patients are refractory to these treatments (4). The main purpose of BMAs, such as bisphosphonate and denosumab, is to reduce skeletal-related events and shorten the duration of the pain. BMA has been reported to be useful for bone metastases arising from breast cancer, prostate cancer, and digestive cancers. Although the long-term administration of BMA can prevent metastatic bone pain, it has little analgesic effect on existing pain. Opioids are highly effective and are the first choice in the treatment of cancer pain. The various dosages and forms allow for adjustments depending on the patient's pain type and level. However, adverse effects occasionally limit the tolerated dose needed for sufficient pain relief. External irradiation can relieve pain and significantly improve the patients' QOL in 59-73% of the cases (12, 13). Although combinatorial prescription of analgesics is required until the irradiation starts showing efficacy in the several-weeks-long early treatment phase, the therapeutic effect of external irradiation lasts for approximately 30 weeks on average. Surgery is considered the salvage treatment for pathological fractures and spinal cord compression due to bone metastases. Surgery is performed for the purpose of pain relief and improvement in the QOL, considering the general condition of the patient, invasiveness of the surgery, and the patient's prognosis. Patients at the terminal stage of their disease are not often good candidates for surgery. In conclusion, TAE is expected to achieve a relatively quick response with high efficacy and low invasiveness in the majority of patients experiencing metastatic bone pain. This case suggests that TAE performed at an early stage complements the standard treatments and improves the QOL in patients with painful bone metastasis. This case report was approved by the institutional Human Investigation Committee of Uonuma Institute of Community Medicine Niigata University Hospital. Written informed consent was obtained from the patient in accordance with the Declaration of Helsinki for the publication of this case report. The authors state that they have no Conflict of Interest (COI).	Oral	DrugAdministrationRoute	CC BY-NC-ND	32921687	19,703,168	2021-01-15
What was the outcome of reaction 'Somnolence'?	Transcatheter Arterial Embolization Using Microspheres for Palliating Pain from Bone Metastasis in a Patient with Cholangiocellular Carcinoma. A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis. Introduction In recent years, the number of patients with bone metastases has increased due to the increase in the number of cancer patients and their prolonged prognoses due to advances in cancer treatment (1, 2). Bone metastases are often asymptomatic in the early stages (3), but as they progress, they cause pain, spinal cord compression, and pathological fractures resulting in dyskinesias, paralysis, and a significantly decreased quality of life (QOL) (4-8). Pain is the most frequent symptom of bone metastasis. Half of the cancer pain cases have been attributed to bone metastases (4). Therefore, it is important to properly control pain in patients with bone metastasis. There are several standard treatments for metastatic bone pain, including medication (9-11), radiation therapy (12, 13), and surgery (14). Each treatment has been reported to have high efficacy, and patients can receive multiple treatment types in combination. However, 20-40% of patients with bone metastasis receiving multiple standard treatments reportedly experience difficulty with pain control (4). In recent years, several reports have indicated that transcatheter arterial embolization (TAE) is an effective treatment method for metastatic bone pain (15-19). We herein report a case of cholangiocellular carcinoma with bone metastasis-induced pain that was refractory to standard treatment methods but rapidly relieved by TAE. Case Report This study was conducted according to the Declaration of Helsinki. It was approved by our institution's review board, and the patient provided his consent for the specific treatment and publication of the results. A 72-year-old Japanese man was referred to our hospital due to severe pain in his left shoulder. He had been diagnosed with cholangiocellular carcinoma eight months earlier (Fig. 1A). A large tumor occupying the left lobe of the liver was observed, and dynamic contrast-enhanced computed tomography (CT) showed that the whole tumor was gradually well enhanced. Therefore, tumor needle biopsies were performed to distinguish it from hepatocellular carcinoma, and a pathological diagnosis of cholangiocellular carcinoma was established. He was performed systemic chemotherapy involving the combination administration of gemcitabine and cisplatin as the first treatment and tegaful/gimeracil/oteracil as the second treatment and then discontinued chemotherapy one month before referral our hospital due to the progression of the disease. He was receiving supportive care at the time of his presentation to our hospital. Laboratory tests during admission revealed increased levels of alkaline phosphatase (ALP, 1,551 IU/L). Regarding the tumor markers, carbohydrate antigen 19-9 (CA19-9, 1,849 U/mL) was remarkably increased, whereas normal levels of α-fetoprotein (AFP, 3.5 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 12 mAU/mL) were observed (Table). Figure 1. Abdominal and chest computed tomography images. a: A well-enhanced cholangiocellular carcinoma is located in the left hepatic lobe (arrowheads). b: Osteoblastic bone metastasis is present in the left scapula bone (arrowheads). Table. Results of Laboratory Investigation. Hematologic test Chemistry BUN 16.9 mg/dL White blood cells 4,900 /μL Total protein 6.8 g/dL Creatinine 0.7 mg/dL Neutrophils 73.6 % Albumin 3.4 g/dL Sodium 135 mmol/L Lymphocytes 20.3 % AST 37 IU/L Potassium 4.5 mmol/L Monocytes 5.1 % ALT 28 IU/L Chloride 98 mmol/L Eosinophils 0.8 % ALP 1,551 IU/L CRP 3.15 mg/dL Basophils 0.2 % γ-GTP 125 IU/L CEA 9.1 ng/mL Red blood cells 375×104 /μL T.Bil 0.7 mg/dL CA19-9 1,849 U/mL Hemoglobin 11.4 g/dL D.Bil 0.2 mg/dL AFP 3.5 ng/mL Platelet count 31.5×104 /μL LDH 141 IU/L PIVKA-II 12 mAU/mL AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T.Bil: total bilirubin, D.Bil: direct bilirubin, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reactive protein, CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, AFP:α-fetoprotein, PIVKA-II: protein induced by vitamin K absence or antagonist-II CT of the left shoulder revealed an osteoblastic metastatic lesion of the left scapula (Fig. 1B). He was administered bisphosphonates, oral morphine, and external irradiation (20 Gy), but the pain persisted with a score of 7/10 on the numerical rating scale (NRS). The dose of morphine was increased to 120 mg/day as needed for severe pain, but the patient experienced drowsiness that prohibited further increases in the morphine dose. The patient's Eastern Cooperative Oncology Group Performance Status worsened from 1 to 3 due to uncontrollable pain and drowsiness from the morphine. Therefore, TAE was performed to control the left shoulder pain because the tumor was well-enhanced by contrast CT. With the informed consent of the patient, TAE was performed via a left radial artery approach. Left brachial artery angiography showed a tumor stain from the thoracoacrominal artery and the circumflex scapular artery (Fig. 2A-C). A microcatheter (Sniper 2-μ7; Terumo Clinical Supply, Tokyo, Japan) with a 2.0-F tip was inserted into these arteries, and TAE was performed with microspheres (Embosphere; Nippon Kayaku, Tokyo, Japan) ranging from 300 to 500 μm in diameter. Subsequent angiography performed immediately after the TAE procedure revealed the almost complete disappearance of the tumor stain (Fig. 2D). No adverse events were observed during the procedure. Although the patient experienced transient pain [Numerical Rating Scale (NRS) score 8/10] with mild pyrexia requiring additional administration of analgesics for a couple of days due to post-embolism syndrome, the pain gradually improved in the following week (NRS score 3/10) resulting in the reduction of the morphine dose to 90 mg/day and alleviation of the drowsiness. Figure 2. Angiography images. a: Angiography via the left brachial artery shows tumor enhancement (arrows). The tumor is mainly fed by the circumflex scapular artery (white arrowhead) and the thoracoacromial artery (black arrowhead). b: Selective angiography via the circumflex scapular artery demonstrates prominent tumor enhancement (arrows). c: Selective angiography via the thoracoacromial artery demonstrates prominent tumor enhancement (arrows). d: Angiography via the left brachial artery immediately after TAE shows the nearly complete disappearance of tumor enhancement. Arterial depiction, showing that the circumflex scapular artery and the thoracoacromial artery are well preserved. Three months later, the patient died due to the progression of the primary disease. Shortly before his death, his shoulder pain was managed with rescue oral morphine taken several times a day. The clinical course and changes in serum C-reactive protein and CA19-9 before and after TAE are shown in Fig. 3. Figure 3. Clinical course of the patient before and after TAE. The time-dependent levels of the pain score with NRS are shown in the upper panel. In the lower panel, the solid line and dotted line show the serum CRP and CA19-9 levels, respectively. NRS: Numerical Rating Scale, CRP: C-reactive protein, CA19-9: carbohydrate antigen 19-9, TAE: transcatheter arterial embolization Discussion In this case, TAE alleviated bone metastasis-induced pain that was refractory to a combination of standard treatments, including bone-modifying agents (BMAs), opioids, and external irradiation. TAE is an interventional radiologic technique in which a catheter is advanced to a target artery, and embolic materials are injected into the blood vessel to block the arterial blood flow. Preoperative TAE is a widely accepted technique for reducing blood loss during metastatic bone surgery (20, 21). In addition, the pain-relieving effect of TAE on bone metastases has been reported in several pilot studies and retrospective studies (15-19). The effective rate of pain relief ranges between 60-80%, and the median time to pain alleviation is 2 days (19). The analgesic effect of TAE lasts an average of 2-8 months, and TAE can be repeated when the effect diminishes (15, 18). Furthermore, TAE has been reported to be effective against bone metastases of not only hypervascular tumors, such as hepatocellular carcinoma, thyroid cancer, and renal cell carcinoma, but also colorectal cancer, ovarian cancer, uterine cervical cancer, and esophageal cancer (19). This case showed a similar profile, with the pain alleviated shortly after the TAE intervention and lasting for at least three months. Injection and/or impregnation of anticancer agents can be simultaneously performed with embolization (19). Therefore, TAE is a promising option for palliating pain from bone metastasis. However, thus far, there have been no well-evidenced studies on this issue. Therefore, a further prospective evaluation of the safety and efficacy should be conducted. The mechanism underlying the pain relief provided by TAE is unclear and likely multi-faceted. Several hypotheses have been reported (19). TAE blocks the arterial supply of the metastatic tumors, which is expected to slow tumor growth and reduce the tumor burden, resulting in the delay or cessation of the destruction of the periosteum. In addition, reduced blood flow and edema within the tumor may decrease the direct pressure on adjacent tissues and nerves. The complications of TAE are typically minor and infrequent and mainly occur at the puncture site or with the use of contrast medium; the frequency is approximately 3% or 5-7%, respectively (22). Approximately 10% of patients undergoing TAE experience post-embolism syndrome that induces a fever and temporary deterioration of pain (22). When embolization occurs in arteries supplying soft bone tissues, neuropathy, osteonecrosis, muscle necrosis, or dermal necrosis can occur. If the artery of Adamkiewicz, which joins the anterior spinal artery from outside of the spine, is embolized during TAE for spinal tumor, it can result in paraplegia, a loss of sensation for pain and temperature, and bladder-rectal dysfunction-so-called spinal artery syndrome (23). However, given adequate training, the procedure is sophisticated enough to avoid these complications due to the embolization of non-target arteries. There are several types of embolic materials used in TAE. Gelatin particles are classically used for blocking the blood supply in tumors, such as in transcatheter arterial chemoembolization for hepatocellular carcinoma (24); however, microspheres have been popularized in recent years (25). Gelatin particles are temporary embolic materials, and the embolized blood vessels are recanalized within a few weeks (26). However, microspheres are spheres with a uniform particle shape comprising non-aggregating permanent embolic materials that do not cause inflammation. Possibly, a blood vessel meeting the target diameter can be embolized, resulting in less inflammation and pain after embolization. Therefore, microspheres were used in this case because we considered the technique safe and the embolic effect prolonged (27). The particle size of the microspheres used for TAE of bone metastases is recommended to be 300-500 μm (20, 21). Vessels in the bone and soft tissue areas are predominantly arterio-venous shunts, and the use of small-diameter embolic materials increases the risk of pulmonary embolism (28). In addition, drug-eluting beads can be loaded with anticancer drugs; however, adverse events associated with the anticancer drugs may occur (29). In this case, the purpose of TAE was palliation, and TAE was performed without using an anticancer drug, considering the risk of adverse events. The standard treatment of metastatic bone pain is performed with a combination of BMAs (9), opioids (10, 11), external irradiation (12, 13), and surgery (14); however, 20-40% of cancer patients are refractory to these treatments (4). The main purpose of BMAs, such as bisphosphonate and denosumab, is to reduce skeletal-related events and shorten the duration of the pain. BMA has been reported to be useful for bone metastases arising from breast cancer, prostate cancer, and digestive cancers. Although the long-term administration of BMA can prevent metastatic bone pain, it has little analgesic effect on existing pain. Opioids are highly effective and are the first choice in the treatment of cancer pain. The various dosages and forms allow for adjustments depending on the patient's pain type and level. However, adverse effects occasionally limit the tolerated dose needed for sufficient pain relief. External irradiation can relieve pain and significantly improve the patients' QOL in 59-73% of the cases (12, 13). Although combinatorial prescription of analgesics is required until the irradiation starts showing efficacy in the several-weeks-long early treatment phase, the therapeutic effect of external irradiation lasts for approximately 30 weeks on average. Surgery is considered the salvage treatment for pathological fractures and spinal cord compression due to bone metastases. Surgery is performed for the purpose of pain relief and improvement in the QOL, considering the general condition of the patient, invasiveness of the surgery, and the patient's prognosis. Patients at the terminal stage of their disease are not often good candidates for surgery. In conclusion, TAE is expected to achieve a relatively quick response with high efficacy and low invasiveness in the majority of patients experiencing metastatic bone pain. This case suggests that TAE performed at an early stage complements the standard treatments and improves the QOL in patients with painful bone metastasis. This case report was approved by the institutional Human Investigation Committee of Uonuma Institute of Community Medicine Niigata University Hospital. Written informed consent was obtained from the patient in accordance with the Declaration of Helsinki for the publication of this case report. The authors state that they have no Conflict of Interest (COI).	Recovering	ReactionOutcome	CC BY-NC-ND	32921687	19,703,168	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxia'.	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	MINOCYCLINE HYDROCHLORIDE, RUXOLITINIB	DrugsGivenReaction	CC BY-NC-ND	32921692	19,277,792	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paradoxical embolism'.	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	MINOCYCLINE HYDROCHLORIDE	DrugsGivenReaction	CC BY-NC-ND	32921692	19,814,070	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Right ventricular failure'.	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	MINOCYCLINE HYDROCHLORIDE, RUXOLITINIB	DrugsGivenReaction	CC BY-NC-ND	32921692	19,277,792	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombophlebitis'.	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	MINOCYCLINE HYDROCHLORIDE, RUXOLITINIB	DrugsGivenReaction	CC BY-NC-ND	32921692	19,277,792	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vascular pain'.	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	MINOCYCLINE HYDROCHLORIDE, RUXOLITINIB	DrugsGivenReaction	CC BY-NC-ND	32921692	19,277,792	2021-01-15
What was the administration route of drug 'RUXOLITINIB'?	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	Oral	DrugAdministrationRoute	CC BY-NC-ND	32921692	19,277,792	2021-01-15
What was the outcome of reaction 'Hypoxia'?	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	Recovering	ReactionOutcome	CC BY-NC-ND	32921692	19,277,792	2021-01-15
What was the outcome of reaction 'Paradoxical embolism'?	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	Recovered	ReactionOutcome	CC BY-NC-ND	32921692	19,814,070	2021-01-15
What was the outcome of reaction 'Right ventricular failure'?	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	Recovering	ReactionOutcome	CC BY-NC-ND	32921692	19,277,792	2021-01-15
What was the outcome of reaction 'Thrombophlebitis'?	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	Recovering	ReactionOutcome	CC BY-NC-ND	32921692	19,277,792	2021-01-15
What was the outcome of reaction 'Vascular pain'?	Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera. A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. Introduction In patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5). We herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline. Case Report A 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL. However, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea. He subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain. Figure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle. Along with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table). Table. Laboratory Data. Complete Blood Count Coagulation WBC 7.0×103 /µL PT-INR 1.21 RBC 3.91×106 /µL APTT 34.8 sec Hb 11.9 g/dL Fibrinogen 522 mg/dL PLT 209×103 /µL FDP 4.2 µg/mL Biochemistry D-dimer 4.2 µg/mL AST 76 IU/L LAC DRVVT 1.28 ALT 94 IU/L Protein C activity 130 LDH 587 IU/L Protein S antigen level 132 ALP 678 IU/L Lipoprotein(a) 6.0 CRP 6.63 mg/dL Cardiolipin antibody IgG <8 Homocysteine 20.8 nmol/mL Blood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction. On an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness. Figure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm. Ultrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO. Figure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm. Figure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system. As a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy. Figure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall. Discussion PV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident. Regarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts. We also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration. Conclusion We herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis. The authors state that they have no Conflict of Interest (COI).	Recovering	ReactionOutcome	CC BY-NC-ND	32921692	19,277,792	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'.	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	CYCLOPHOSPHAMIDE, DOXORUBICIN, PREDNISOLONE, PREDNISONE, RITUXIMAB, VINCRISTINE	DrugsGivenReaction	CC BY	32944800	19,048,567	2021-05
What was the administration route of drug 'PREDNISOLONE'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Oral	DrugAdministrationRoute	CC BY	32944800	19,048,567	2021-05
What was the administration route of drug 'PREDNISONE'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Oral	DrugAdministrationRoute	CC BY	32944800	19,048,567	2021-05
What was the administration route of drug 'RITUXIMAB'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY	32944800	19,048,567	2021-05
What was the administration route of drug 'VINCRISTINE'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY	32944800	19,048,567	2021-05
What was the dosage of drug 'CYCLOPHOSPHAMIDE'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	750 MG/M2	DrugDosageText	CC BY	32944800	19,048,567	2021-05
What was the dosage of drug 'DOXORUBICIN'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	50 MG/M2	DrugDosageText	CC BY	32944800	19,048,567	2021-05
What was the dosage of drug 'PREDNISOLONE'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	100 MG (ON DAYS 2 TO 6)	DrugDosageText	CC BY	32944800	19,048,567	2021-05
What was the dosage of drug 'PREDNISONE'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	100 MG (ON DAYS 2 TO 6)	DrugDosageText	CC BY	32944800	19,048,567	2021-05
What was the dosage of drug 'RITUXIMAB'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	375 MG/M2 (DAY 1)	DrugDosageText	CC BY	32944800	19,048,567	2021-05
What was the dosage of drug 'VINCRISTINE'?	Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study. BACKGROUND Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. METHODS One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. BACKGROUND ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23. Introduction Elderly patients with non-Hodgkin lymphoma (NHL) receiving chemotherapy, such as R-CHOP, are at high risk of developing clinically significant neutropenia [1–3], which can lead to dose reductions, cycle delays, or even treatment discontinuation. Clinically significant neutropenia is defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) according to the Common Terminology Criteria for Adverse Events, the most widely used scale for grading chemotherapy-related cytopenias [4]. Maintenance of chemotherapy intensity is important in patients with NHL, as there is strong evidence that survival is negatively impacted by reductions in relative dose intensity in this population [5–8]. Use of recombinant granulocyte colony–stimulating factors (G-CSFs) is recommended for patients at high risk of chemotherapy-induced neutropenia [9–11], and has been shown to improve survival, especially in elderly patients and those receiving dose-dense regimens [5]. Short-acting G-CSFs, such as filgrastim (Neupogen®; Amgen Inc., Thousand Oaks, CA, USA), require daily subcutaneous injections during each chemotherapy cycle. Pegylation decreases plasma clearance of filgrastim and extends its half-life in the body, allowing for less frequent dosing. Lipegfilgrastim (Lonquex®; Teva B.V., Haarlem, Netherlands) is a long-acting G-CSF indicated for reduction of the duration of neutropenia and the incidence of febrile neutropenia (FN) in adult patients receiving cytotoxic chemotherapy [12]. Lipegfilgrastim is glycopegylated in a site-specific manner, resulting in greater structural homogeneity and improved pharmacokinetic and pharmacodynamic properties compared with conventionally pegylated G-CSFs [13, 14]. Lipegfilgrastim has been shown to induce a longer-lasting increase in ANC than an equivalent dose of the conventionally glycopegalated long-acting G-CSF, pegfilgrastim (Neulasta®; Amgen Inc., Thousand Oaks, CA, USA) [15]. This may reflect the higher cumulative exposure and slower clearance of lipegfilgrastim compared with pegfilgrastim [15]. Lipegfilgrastim, administered once per chemotherapy cycle, has been shown to be non-inferior to pegfilgrastim with respect to duration of severe neutropenia (DSN, defined as the number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]) in breast cancer patients [16]. Pegfilgrastim has been shown to be effective for the reduction of DSN and complications of neutropenia in patients with lymphoma receiving chemotherapy regimens associated with a high risk of FN [17–20]. A systematic review undertaken to assess the effectiveness of pegfilgrastim in cancer patients in real-world clinical settings found the risks of FN and FN-related complications to be lower in patients receiving pegfilgrastim than in those receiving short-acting G-CSFs (namely, filgrastim, lenograstim, and biosimilars) [21]. In particular, pegfilgrastim has been shown to be effective for the reduction of DSN in elderly patients with NHL receiving myelosuppressive chemotherapy [22]. This study was undertaken to demonstrate non-inferiority of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell NHL receiving R-CHOP21, and to compare the efficacy and safety of these long-acting G-CSFs in this elderly NHL population. Methods Study design and patients This was a phase 3b, open-label, multicenter study conducted at 31 sites in Germany, Italy, and Spain between March 2014 and December 2017. The study comprised a 2-week screening period, an 18-week, open-label treatment period (6 cycles of R-CHOP21, each of 3 weeks in duration), and a follow-up period of up to 9 months from the start of the first chemotherapy cycle. Study inclusion and exclusion criteria are summarized in Supplementary Table S1. Patients aged 65–85 years with histologically confirmed aggressive B cell NHL (World Health Organization lymphoma classification criteria [23]) were randomized 1:1 to receive lipegfilgrastim 6 mg or pegfilgrastim 6 mg administered as a single subcutaneous injection on day 3 of each chemotherapy cycle, approximately 24 (± 3) hours after the end of day 2 chemotherapy. During each chemotherapy cycle, patients received (i) rituximab 375 mg/m2 intravenously on day 1; (ii) cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (capped at 2.0 or 1.0 mg) intravenously on day 2; and (iii) prednisone or prednisolone 100 mg orally on days 2 to 6. The study was approved by independent ethics committees at each study site, and complied with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Patients provided written informed consent to participate. Study assessments Blood samples were collected for determination of ANC on days 1, 8, and 15 of each cycle, and on days 3, 5, 10, and 12 of cycle 1. ANC analyses were performed by local laboratories. Patients recorded their oral body temperature daily throughout the study (≤ 1 h before chemotherapy administration on days 1 and 2 and before study drug administration on day 3). Patients were also instructed to measure their body temperature if they felt feverish at any time during the day. If body temperature was > 38.0 °C, patients were instructed to measure their body temperature again after 1 h. Patients were instructed to contact study site personnel if their body temperature was > 38.0 °C for more than 1 h. The primary efficacy measure was ANC, and the primary efficacy outcome was DSN in cycle 1 (number of days with grade 4 neutropenia [ANC < 0.5 × 109/L]). Secondary efficacy measures included the incidence of FN (body temperature > 38.5 °C for ≥1 h and ANC < 0.5 × 109/L [strict definition], or a single body temperature value ≥ 38.3 °C or body temperature ≥ 38.0 °C for ≥1 h and ANC < 1.0 × 109/L [non-strict definition], including cases of neutropenic sepsis or neutropenic serious or life-threatening infection), the incidence of very severe and severe neutropenia during cycle 1 (ANC < 0.1 × 109/L and < 0.5 × 109/L, respectively), the ANC nadir, and the time to ANC recovery (return to ANC ≥ 1.0, ≥ 1.5, and ≥ 2.0 × 109L) in cycle 1. The incidence and severity of infections, rates of hospitalization and intravenous/oral antibiotic administration, and the percentage of chemotherapy dose delivered were also assessed. Adverse events (AEs) were monitored throughout the study period (classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03). Quality of life was assessed prior to administration of chemotherapy in cycles 1 and 4 and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) [24] and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) [25]. Statistical analysis Analysis of the primary endpoint was performed for both the per-protocol and intent-to-treat populations. Efficacy data are shown for the per-protocol population unless otherwise noted. Differences in DSN in cycle 1 between treatment groups were analyzed using the two-sided 95% confidence interval (CI), calculated by Poisson regression with identity link, including treatment, body weight, and country as fixed factors and baseline ANC as a covariate. Lipegfilgrastim was considered non-inferior to pegfilgrastim if the upper limit of the two-sided 95% CI for the difference in DSN between groups (lipegfilgrastim minus pegfilgrastim) was < 1 day. A sample size of 50 patients per treatment group provided at least 85% power to reject the null hypothesis. Secondary endpoints were analyzed by fitting a logistic regression model including the same explanatory variables, and the 95% CI for the odds ratio (lipegfilgrastim versus pegfilgrastim) was calculated. All secondary endpoint analyses were regarded as exploratory; no adjustment for multiple comparisons was performed. The safety population included all randomized patients who received at least one dose of study medication. All analyses were performed using SAS statistical software version 9.1 or later (SAS Institute, Inc. Cary, NC, USA). Results Study population One hundred and one patients (median age, 75 years [range, 65–82 years]) were enrolled and randomized. Patient disposition is summarized in Fig. 1. The two treatment groups were generally well-matched in terms of patient demographics and baseline disease characteristics (Table 1).Fig. 1 Patient disposition over the study period. These patients were excluded as they did not receive study drug. ANC absolute neutrophil count, ITT intent-to-treat, PP per-protocol Table 1 Patient demographics and baseline disease characteristics (per-protocol population) Characteristic Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) Age (years), mean (SD) 72.4 (4.65) 75.2 (4.45) Sex, n (%) Male 18 (44) 24 (55) Female 23 (56) 20 (45) Race, n (%) White 41 (100) 44 (100) Time from diagnosis to screening (days), mean (SD) 40.1 (126.3) 87.9 (350.7) Type of B cell lymphoma, n (%) DLBCL 29 (71) 32 (73) Common morphologic variants 4 (10) 2 (5) Follicular lymphoma grade IIIb 3 (7) 2 (5) Other 5 (12) 8 (18) Stage (modified Ann Arbor), n (%) I 16 (39) 11 (25) II 4 (10) 9 (20) III 9 (22) 12 (27) IV 11 (27) 12 (27) Missing 1 (2) 0 Number of sites of extranodal involvement, mean (SD) 1.6 (2.00) 0.8 (0.82) B symptoms detected, n (%) 14 (34) 12 (27) IPI score, mean (SD) 2.2 (1.05) 2.2 (0.94) ECOG performance status, n (%) 0 26 (63) 22 (50) 1 12 (29) 19 (43) 2 3 (7) 3 (7) DLBCL diffuse large B cell lymphoma, ECOG Eastern Cooperative Oncology Group, IPI International Prognostic Index, SD standard deviation Efficacy Duration of severe neutropenia in cycle 1 Lipegfilgrastim was non-inferior to pegfilgrastim for the reduction in DSN in cycle 1 (Table 2). Mean (standard deviation [SD]) DSN in cycle 1 was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively. The adjusted mean DSN difference between groups was − 0.3 days (95% CI, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population (adjusted mean DSN difference between groups, − 0.1 days [95% CI, − 0.56 to 0.30]).Table 2 Analysis of the primary efficacy endpoint, duration of severe neutropenia in cycle 1 Duration of severe neutropenia (days) Lipegfilgrastim Pegfilgrastim Per-protocol population n 41 44 Mean (SD) 0.8 (0.92) 0.9 (1.11) Adjusted mean (95% CI) 0.7 (0.34, 1.11) 1.0 (0.60, 1.36) Adjusted mean difference between groups (95% CI) − 0.3 (− 0.70, 0.19) Intent-to-treat population n 46 50 Mean (SD) 0.8 (0.96) 0.9 (1.08) Adjusted mean (95% CI) 0.9 (0.29, 1.48) 1.0 (0.44, 1.59) Adjusted mean difference between groups (95% CI) − 0.1 (− 0.56, 0.30) CI confidence interval, SD standard deviation *Patients from the intent-to-treat population with evaluable values for duration of severe neutropenia Incidence of febrile neutropenia and severe neutropenia Over all cycles, FN according to the strict definition was reported in 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). When assessed using the non-strict definition, FN was reported by 5 (12%) and 2 (5%) patients, respectively. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group (adjusted odds ratio, 0.51 [95% CI, 0.131 to 2.016]). Severe neutropenia (ANC < 0.5 × 109/L) was reported by 21 (51%) and 23 (52%) patients, respectively (adjusted odds ratio, 0.99 [95% CI, 0.396 to 2.470]). Absolute neutrophil counts Mean daily ANC during cycle 1 is shown in Supplementary Table S2; mean ANC across all cycles is shown in Fig. 2. In both groups, the highest ANC was observed on day 5 of cycle 1. During subsequent cycles, mean ANC peaked on day 15, and was consistently higher in the lipegfilgrastim group. In cycle 1, the ANC nadir was reached around day 10 and was similar in both groups (1.00 ± 1.36 × 109L and 1.19 ± 1.92 × 109L, respectively). The mean time to ANC recovery (≥ 2.0 × 109/L) was 8.3 ± 3.30 days in the lipegfilgrastim group and 9.4 ± 4.92 days in the pegfilgrastim group (Table 3).Fig. 2 Mean absolute neutrophil count in cycles 1 to 6 by treatment group (per-protocol population). ANC absolute neutrophil count, EOV end-of-treatment visit Table 3 Time to absolute neutrophil count recovery in cycle 1 from the start of chemotherapy (per-protocol population) ANC recovery criteria Days to ANC recovery in cycle 1 Lipegfilgrastim (N = 41) Pegfilgrastim (N = 44) ≥ 1.0 × 109L Mean (SD) 6.2 (4.34) 6.8 (5.41) Median (range) 8.0 (0–10) 9.5 (0–22) ≥ 1.5 × 109L Mean (SD) 7.7 (3.69) 8.2 (4.98) Median (range) 9.0 (0–12) 10.0 (0–22) ≥ 2.0 × 109L Mean (SD) 8.3 (3.30) 9.4 (4.92) Median (range) 10.0 (0–12) 10.0 (0–22) ANC absolute neutrophil count, SD standard deviation Incidence and severity of infection Over all cycles, infection was reported in 16 (39%) patients in the lipegfilgrastim group and 6 (14%) patients in the pegfilgrastim group (adjusted odds ratio, 4.61 [95% CI, 1.43 to 14.89]). Most infections occurred during cycle 1 (6/16 and 4/6 patients in the two groups, respectively). There was only one infection of grade 4 severity during the study (sepsis in the pegfilgrastim group). Infections of any severity reported by more than a single patient in either group were viral upper respiratory tract infection, herpes zoster, bronchitis, conjunctivitis, oral candidiasis, urinary tract infection, infection, cystitis, influenza, and fungal infection. Infection was microbiologically documented in 4/16 and 2/6 patients in the two groups, respectively. Incidence of hospitalization and antibiotic administration due to febrile neutropenia Hospitalization due to FN was reported in 5 (12%) patients in the lipegfilgrastim group and 1 (2%) patient in the pegfilgrastim group (all during cycle 1). Intravenous or oral antibiotics were prescribed as treatment or prophylaxis for FN in 16 (39%) and 4 (9%) patients in the two groups, respectively. Chemotherapy dose and delivery Across all cycles, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, except for vincristine in the pegfilgrastim group (71.4%). Chemotherapy was administered as planned to all patients in cycle 1. Over cycles 2 to 6, 32 (80%) patients in the lipegfilgrastim group and 33 (75%) in the pegfilgrastim group had delays in their chemotherapy treatment. Two (5%) patients in the pegfilgrastim group omitted at least one chemotherapy cycle. The overall incidence of chemotherapy dose reduction was low in both groups. Safety Almost all patients (98%) reported at least one AE (Supplementary Table S3). The only AE occurring more frequently (≥ 10% difference between groups) in patients receiving lipegfilgrastim was cough. AEs occurring more frequently in patients receiving pegfilgrastim were anemia, nausea, diarrhea, and weight decrease. Bone pain was reported in 2 (4%) patients in the lipegfilgrastim group and 3 (6%) in the pegfilgrastim group. AEs were considered at least possibly related to treatment in 11 (24%) and 10 (20%) patients in the two groups, respectively. No treatment-related AE was reported by more than two patients in either group. Serious AEs occurred in 46% of patients (21/46 in the lipegfilgrastim group and 23/50 in the pegfilgrastim group). Ten patients withdrew from the study due to AEs (1 [2%] in the lipegfilgrastim group and 9 [18%] in the pegfilgrastim group), none of which were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 patient randomized to lipegfilgrastim who died before starting study treatment). No deaths occurred during the treatment period, all were considered to be related to the underlying disease, and none were due to infection. Quality of life There were no noteworthy differences between groups or changes over time for any of the EORTC QLQ-C30 or FACT-N scores over the study period. Discussion This study demonstrated non-inferiority of lipegfilgrastim compared with pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Results of the analysis in the intent-to-treat population were similar to those in the per-protocol population, confirming the robustness of this finding. Lipegfilgrastim also demonstrated generally comparable efficacy to pegfilgrastim across all secondary endpoints. The incidence of FN was low in both treatment groups, and there were no clinically relevant differences in the incidence of severe or very severe neutropenia, incidence of DSN by duration, depth and time of the ANC nadir, delays in chemotherapy administration, or any quality-of-life measures. Of note, the median cumulative percentage of the scheduled chemotherapy dose actually delivered was 100% for all drugs in both groups, with the exception of vincristine in the pegfilgrastim group. To date, few other studies have assessed the clinical utility of long-acting G-CSFs in this specific patient population [22]. The risk of developing FN in patients receiving R-CHOP21 without G-CSF prophylaxis according to the strict definition used in this study is estimated to be 10–20% [2, 3, 9]. The corresponding incidence of FN in this study was 2% in both groups. This represents a reduction in the incidence of FN of approximately 90%, highlighting the value of treatment with lipegfilgrastim or pegfilgrastim in this patient population. During the study, six patients were hospitalized due to investigator-defined FN (5 in the lipegfilgrastim group and 1 in the pegfilgrastim group). These hospitalizations did not result in an increase in morbidity and mortality, and it could be that other safety issues influenced the need for hospital admission in this high-risk population of elderly cancer patients. The incidence of infection was somewhat higher in the lipegfilgrastim group than in the pegfilgrastim group, but this did not appear to correlate with low neutrophil counts, compromise chemotherapy treatment or lead to increased AEs or serious AEs. Infections were predominantly of grade 3 severity or lower, and the only grade 4 infection occurred in the pegfilgrastim group. The safety profile of lipegfilgrastim was similar to that of pegfilgrastim, and no new safety signals for lipegfilgrastim were identified. The incidence of AEs was as expected in a population of elderly patients with NHL receiving myelosuppressive chemotherapy, and reported AEs were consistent with the underlying disease and the chemotherapy regimen administered. Bone pain was reported by few patients. More patients withdrew from the study due to AEs in the pegfilgrastim group than in the lipegfilgrastim group; however, none of the AEs leading to withdrawal were considered treatment-related. None of the 8 deaths during the study occurred during the active treatment phase, and all were considered to be related to the underlying disease. Results of this study are in line with those of a subanalysis of the prospective, non-interventional NADIR study undertaken to evaluate the effectiveness and safety of lipegfilgrastim in patients with NHL undergoing chemotherapy in routine practice settings [26]. A meta-analysis and indirect treatment comparison of lipegfilgrastim versus pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia and related events demonstrated significant and clinically meaningful differences in favor of lipegfilgrastim for both time to ANC recovery (which is typically longer than DSN) and risk of severe neutropenia [27]. Lipegfilgrastim was also associated with a lower risk of FN over all cycles; however, differences between groups were not statistically significant [27]. As a result of its novel pegylation method [13, 14], lipegfilgrastim has a different pharmacokinetic and pharmacodynamic profile than pegfilgrastim, specifically higher cumulative exposure and slower clearance, and induces a longer-lasting increase in ANC at equivalent doses [15]. Analyses utilizing data from patients with breast cancer suggest that lipegfilgrastim is likely to be a cost-effective alternative to pegfilgrastim for primary prohylaxis of complications of chemotherapy-induced neutropenia and associated complications [28, 29]. In conclusion, this study shows that lipegfilgrastim is an effective option to reduce the duration of severe chemotherapy-induced neutropenia and to prevent febrile neutropenia in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy. Electronic supplementary material ESM 1 (PDF 237 kb) Editorial support was provided by Jennifer Coward and Uta Gomes, and was funded by TEVA Europe B.V. Funding The AVOID study and preparation of this manuscript were supported by TEVA Europe B.V. Data availability The authors confirm to have full control of all primary data. Qualified researchers may request access to patient level data and related study documents including the study protocol and the statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Compliance with ethical standards Confict of interest HL declares to have received personal fees from Teva, Amgen, Chugai, Hexal-Sandoz-Novartis, Mundipharma, Accord Healthcare, and G1 Therapeutics; AK has received a grant from Amgen; AS has received grants from Roche and Gilead and personal fees from Roche, Gilead, Celgene, and Janssen; MZ has received personal fees from Novartis, Hexal, Pfizer, Roche; GI, ME, RD, SM, and UM have no disclosures to declare; PB, AB, and AL are employees of Teva and hold stock options in the company. Key message Lipegfilgrastim is non-inferior to pegfilgrastim for the reduction of duration of severe neutropenia in elderly patients with aggressive B-NHL receiving myelosuppressive chemotherapy (R-CHOP21), with a comparable safety profile. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	1.4 MG/M2 (CAPPED AT 2.0 OR 1.0 MG) ON DAY 2	DrugDosageText	CC BY	32944800	19,048,567	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrial fibrillation'.	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	CISPLATIN, DOCETAXEL, FLUOROURACIL, NIVOLUMAB, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963156	19,040,434	2021-02-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytokine release syndrome'.	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	CISPLATIN, DOCETAXEL, FLUOROURACIL, NIVOLUMAB, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963156	19,040,434	2021-02-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neoplasm progression'.	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	CEFMENOXIME, HYDROCORTISONE, LINEZOLID, MEROPENEM, MINOCYCLINE HYDROCHLORIDE, NOREPINEPHRINE, POLYMYXIN B, PREDNISOLONE	DrugsGivenReaction	CC BY-NC-ND	32963156	20,851,605	2021-02-01
What was the administration route of drug 'NIVOLUMAB'?	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	Intravenous drip	DrugAdministrationRoute	CC BY-NC-ND	32963156	19,040,434	2021-02-01
What was the dosage of drug 'HYDROCORTISONE'?	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	UNK,MG/DAY	DrugDosageText	CC BY-NC-ND	32963156	20,851,605	2021-02-01
What was the dosage of drug 'NIVOLUMAB'?	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	3 MILLIGRAM/KILOGRAM	DrugDosageText	CC BY-NC-ND	32963156	19,040,434	2021-02-01
What was the dosage of drug 'PREDNISOLONE'?	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	UNK,MG/DAY	DrugDosageText	CC BY-NC-ND	32963156	20,851,605	2021-02-01
What was the outcome of reaction 'Neoplasm progression'?	The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy. We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy. Introduction Cytokines are soluble proteins roughly 5 to 20 kDa in size that regulate host immune activity through a highly complex network. With only a limited half-life, they work as pro-inflammatory or anti-inflammatory signals by binding high-affinity receptors (1,2). The cytokine network can contribute to the pathogenesis of a number of disorders, such as bronchial asthma, inflammatory bowel disease, and rheumatoid arthritis (3-5). The discovery of immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has advanced our understanding of immunity. As a result, immune checkpoint inhibitors (ICIs) have brought about a new era in cancer therapy (6). ICIs activate T-cell proliferation and exert anti-tumor immunity but also induce a wide spectrum of immune-related adverse effects (irAEs) via the release of cytokines [e.g., tumor necrosis factor (TNF)-α, interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, and IL-1β] (7,8). irAE-related myocarditis is reported with frequency between 18/20,594 (0.09%) and 11/964 (1.14%) (9,10), with wide variation in severity (from smoldering to fulminant myocarditis) (11,12). Circulatory cytokine concentrations are increased in viral myocarditis and cardiomyopathy (13,14), so we measured the serum cytokine concentrations of three cancer patients with cardiac complications after ICI therapy at different stages in their clinical course. The present study explored the activation of cytokines associated with cardiac complications after ICI therapy. In addition, we postulated that increased levels of cytokines at certain time points may predict immune-related cardiac toxicity. Materials and Methods Residual serum samples were collected as a by-product of daily clinical biochemistry testing and stored at -80℃ until a cytokine analysis could be performed. We measured IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, monocyte chemotactic and activating factor (MCAF), and TNF-α simultaneously with a pro-inflammatory multiplex ELISA Kit (Cat No. CK500900; Antigenix America, Huntington Station, USA). The major functions of these cytokines are as follows (2): IL-1α and IL-1β, pyrogenic, pro-inflammatory, proliferation and differentiation, bone marrow cell proliferation; IL-6, differentiation into plasma cells, IgG production; IL-8, chemotaxis, pro-inflammatory; MCAF (also called monocyte chemotactic factor-1), chemotaxis, angiogenesis; IFN-γ, anti-viral, macrophage activation, an increased neutrophil and monocyte function, major histocompatibility complex-I and complex-II expression on cells; TNF-α, phagocyte cell activation, endotoxic shock; and GM-CSF, granulocyte, monocyte, and eosinophil production. In addition, we measured the concentrations of pembrolizumab and nivolumab with an ELISA Kit (C-PE01Q, C-NI01Q; Metallogenics, Chiba, Japan). Case Reports Case 1 A 75-year-old man developed subclinical myocarditis (grade 1 irAEs) on the 21st day after his first pembrolizumab (200 mg) infusion for recurrent squamous cell carcinoma of the lung. He had had his left-upper lobe and regional lymph nodes resected 27 months earlier and undergone 4 administrations of cisplatin and vinorelbine. He was admitted to our hospital due to an elevated creatine kinase level. However, he did not show any clinical signs of acute coronary syndrome or heart failure. His temperature was 35.8°C, blood pressure 140/92 mmHg, and heart rate 80 beats per minute. Chest X-ray revealed a cardiothoracic ratio of 45% without congestion in the lung fields. A 12-lead electrocardiogram (ECG) exhibited sinus rhythm and a previously unrecognized, completely blocked right branch bundle (Fig. 1A). At the time of admission, blood tests showed elevated levels of creatine kinase at 2,859 U/L (reference range, 30-200 U/L), creatine kinase-MB isoenzyme at 117 U/L (reference range, 0-12 U/L), and cardiac troponin-T at 0.37 ng/mL (Roche Diagnostics, Mannheim, Germany; reference range, <0.014 ng/mL). The pembrolizumab concentration in the blood was 7.77 μg/mL. Magnetic resonance imaging showed a left ventricular ejection fraction of 57% (Fig. 1B-a, -b) and minimal myocardial edema (Fig. 1B-c) but displayed late gadolinium enhancement in the subepicardial regions of the mid- and lateral wall (Fig. 1B-d). Two endomyocardial biopsies performed at a one-month interval both showed active myocardial inflammation in hematoxylin-eosin staining (Fig. 1C-a, -f). In adjacent sections at the first biopsy, CD3 T-lymphocytes expressed PD-1 (Fig. 1C-b, -c), whereas CD68 macrophages expressed PD-L1 (Fig. 1C-d, -e). A transthoracic echocardiogram displayed a left ventricular ejection fraction of 56% without regional wall motion abnormalities (Fig. 1D). Figure 1. A: A 12-lead electrocardiograms during the clinical course in Case 1. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 30. C: An immunohistochemical study using endomyocardial biopsy specimens obtained from the septal wall of the right ventricle at day 36 [a, Hematoxylin and Eosin (H&E) staining; b, CD3 (Clone F7.2.38, DakoCytomation); c, PD-1 [anti-PD1 antibody (EPR4877 (2), ab137132, abcam)]; d, CD68 (Clone PG-M1, DakoCytomation); e, PD-L1 (IHC 22C3 pharmDx, DakoCytomation)], and H&E staining (f) in a specimen obtained at day 71. Scale bar, 200 μm. D: Clinical course and changes in the parameters of the left ventricular structure and function, as assessed by a transthoracic echocardiogram. E: Cytokine expressions. F: Creatine kinase (CK), and C-reactive protein (CRP) levels in the clinical course. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PSL: prednisolone Monotherapy for methylprednisolone was continuously administered intravenously, and oral prednisolone was given followed by the methylprednisolone treatment. At admission, all cytokine values were negative except for MCAF (88 pg/mL). By the 115th hospital day, the concentrations were as follows: IL-6 (2,214 pg/mL), IL-8 (3,211 pg/mL), MCAF (2,333 pg/mL), and GM-CSF (1,460 pg/mL) (Fig. 1E). At that time, the 12-lead ECG revealed widespread T-wave inversion concomitant with QT prolongation, and the transthoracic echocardiogram displayed apical ballooning form in the left ventricle, suggesting Takotsubo cardiomyopathy. We did not perform coronary angiography. Cytokines IL-1α, IL-1β, IFN-γ, and TNF-α were not detected during the clinical course. The immune-suppressive treatment decreased the creatine kinase level, but troponin I (133 pg/mL, Abbott Japan, Tokyo, Japan, reference range <30 pg/mL) and C-reactive protein (CRP) levels increased as Takotsubo cardiomyopathy (Fig. 1F) and pericardial effusion progressed. The patient died on the 120th day at the affiliated hospital, possibly due to ventricular wall rupture. No autopsy was performed. Case 2 A 47-year-old man suffering from ethmoid sinus cancer developed subclinical myocarditis (grade 1 irAEs) on the 16th day after his third nivolumab (3 mg/kg) infusion. He had been treated three times with cisplatin and irinotecan and received radiation. His temperature was 36.9°C, blood pressure 130/82 mmHg, heart rate 90 beats per minute, and respiratory rate 17 breaths per minute. He had no signs of heart failure or acute coronary syndrome, and the 12-lead ECG displayed a sinus rhythm without ST-T segment changes (Fig. 2A). Figure 2. A: A 12-lead electrocardiograms in Case 2. B: Cardiac magnetic resonance imaging at diastole (a) and systole (b), dark-blood sequence for non-enhanced T2-weighted imaging (c) and delayed gadolinium-enhanced imaging (d) performed at day 28. C: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. D: Clinical course. E: Cytokine expressions. F: CK, and CRP levels. LVPWTd: left ventricular posterior wall thickness at end-diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction At the time of admission, blood tests showed white-blood cells at 18,800/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 90.3% (reference range, 37-72%), platelet cell count at 70,000/mm3 (reference range 158,000-348,000/mm3), creatine kinase at 3,385 U/L (reference range, 59-248 U/L), creatine kinase-MB isoenzyme at 1,221 U/L (reference range, <12 U/L), cardiac troponin-T at 3.30 ng/mL (reference range, <0.014 ng/mL), and CRP at 0.50 mg/dL (reference range, 0-0.14 mg/dL). The nivolumab concentration was 3.45 μg/mL in the blood. Magnetic resonance imaging showed a left ventricular ejection fraction of 55% (Fig. 2B-a, -b) with minimal myocardial edema over the entire left ventricular wall (Fig. 2B-c) and delayed gadolinium enhancement at the mid-inferior and septal wall (Fig. 2B-d). A transthoracic echocardiogram showed normal left ventricular dimensions and a normal systolic function throughout the clinical course (Fig. 2C). He was given methylprednisolone, by adding γ-globulin for progressive thrombocytopenia, and cyclosporine for hemophagocytic syndrome (Fig. 2D). The levels of cytokines IL-6 (max, 24 pg/mL), IL-8 (max, 633 pg/mL), MCAF (max, 113 pg/mL), and TNF-α (max, 114 pg/mL) increased over time during the clinical course (Fig. 2E), but IL-1α, IL-1β, and IFN-γ were not detected. Creatine kinase levels continuously increased, and CRP showed trimodal activation despite treatment (Fig. 2F). The findings of a repeated 12-lead ECG did not show changes in the ST-T segment, nor did they reveal intraventricular block or new arrhythmias. The patient died on the 57th day in the hospital because of cancer progression. Neither an endomyocardial biopsy nor autopsy was performed. Case 3 A 63-year-old man suffering from hypopharyngeal cancer was admitted to our hospital with a high fever, leukopenia, and a decreased in appetite on the 32nd day after his fifth nivolumab (3 mg/kg) infusion. He had received one dose of docetaxel/cisplatin/5-fluorouracil, two of paclitaxel/cetuximab, and the second paclitaxel/cetuximab 12 days prior to admission. His body temperature was 38.2℃, blood pressure 84/42 mmHg, heart rate 132 beats per minute, and respiratory rate 22 breaths per minute (grade 4 irAEs). At the time of admission, blood tests showed white-blood cells were 2,100/mm3 (reference range, 3,300-8,600/mm3), neutrophils at 63.9% (reference range, 37-72%), hemoglobin at 13.3 g/dL (reference range, 13.7-16.8 g/dL), a platelet count of 134,000 /μL (reference range, 158,000-348,000 /μL), creatinine at 1.03 mg/dL (reference range, 0.65-1.07 mg/dL), aspartate transaminase at 25 U/L (reference range, 13-30 U/L), and alanine transaminase at 15 U/L (reference range, 10-42 U/L). His nivolumab concentration in the blood was 8.76 μg/mL. His condition deteriorated with the appearance of paroxysmal atrial fibrillation. He received cardioversion. Chest X-ray exhibited a cardiothoracic ratio of 56% and bilateral pulmonary congestion while in the supine position. Blood test findings worsened on the second hospital day with creatinine at 2.47 mg/dL, aspartate transaminase at 12,422 U/L, alanine transaminase at 4,321 U/L, and CRP at 8.08 mg/dL. In addition, creatine kinase 894 U/L (reference range, 30-200 U/L) and cardiac troponin-T 0.16 ng/mL (reference range, <0.014 ng/mL) were markedly elevated at this point. The endotoxin test and serial blood culture were negative. The 12-lead ECG revealed a low-voltage R wave at the limb leads and a completely blocked right branch bundle (Fig. 3A). A transthoracic echocardiogram showed a left ventricular ejection fraction of 60%, a 22-mm-thick left ventricular wall, and subsequent mild pericardial effusion (Fig. 3B). Figure 3. A: A 12-lead electrocardiograms in Case 3. B: Changes in the parameters of the left ventricular structure and function as assessed by a transthoracic echocardiogram. C: Clinical course. D: Cytokine expressions. E: CRP levels. LVPWTd: left ventricular posterior wall thickness at diastole, LVIDd: left ventricular diastolic internal dimension, LVIDs: left ventricular systolic internal dimension, LVEF: left ventricular ejection fraction, PE: pericardial effusion, PMX: polymyxin B hemoperfusion, CHDF: continuous hemodiafiltration, TM: thrombomodulin, NrAd: noradrenalin, CMX: cefmenoxime, MEPM: meropenem, LZD: linezorid, MINO: minocycline He received extracorporeal hemoperfusion with polymyxin B (Toray Medical, Tokyo, Japan) along with continuous hemodiafiltration (cytokine-adsorbing hemofilter, AN69ST; Baxter, Tokyo, Japan), catecholamine support, broad-spectrum antibiotics, recombinant thrombomodulin, γ-globulin, and high-dose corticosteroids (Fig. 3C). Afterward, his general condition, laboratory findings, and R voltage normalized, and his left ventricular wall shrank to 11 mm in thickness. The levels of cytokines IL-6 (max, 2,226 pg/mL), IL-8 (max, 3,752 pg/mL), GM-CSF (max, 253 pg/mL), IFN-γ (max, 247 pg/mL), MCAF (max, 1,465 pg/mL), and CRP (max, 8.08 mg/dL) increased on the third hospital day but decreased following the treatment (Fig. 3D, E). TNF-α was not detected while in the hemodynamically unstable state but increased throughout recovery (326 pg/mL). IL-1β was not detected. Neither an endomyocardial biopsy nor magnetic resonance imaging was performed. The patient died on the 305th day at the affiliated hospital due to the cancer progression. No autopsy was performed. Discussion This report demonstrated for the first time to evaluate that cytokines were differentially expressed with cardiac complication in the individual clinical presentation after ICI therapy. The cytokine levels did not follow the course of ICI-related myocarditis, and might be influenced by a variety of factors, such as Takotsubo cardiomyopathy, and cardiac complication of cytokine-releasing syndrome, as well as the underlying cancer, other cancer therapies, and immunosuppressive treatment. The first case presented with biopsy-proven “definite” ICI-related myocarditis (15). Surprisingly, most cytokines were not active, despite the presence of active myocardial inflammation. It is possible for a smoldering phenotype presented little cytokine activation and/or previously administered anti-inflammatory treatment to have masked the activation. However, IL-8, MCAF, IL-6, and GM-CSF selectively increased with the development of Takotsubo cardiomyopathy in the later course. Takotsubo cardiomyopathy is assumed to be the consequence of psychological stress (16) or could be another form of ICI-related cardiac toxicity (17), and IL-6 is activated in the disorder (14). The second case presented clinically “possible” myocarditis (15), and that IL-8 was the predominant cytokine among the eight cytokines examined. It is likely that IL-8 level reflects cancer progression (18), but not to myocardial structure and function. The third case presented with high fever, was hemodynamically unstable, and required vasopressor support. IL-1α, IL-6, IL-8, GM-CSF, and INF-γ were all substantially elevated and exacerbated hemodynamic abnormalities and exerted transient left ventricular hypertrophy (possibly edema). We defined this case as cardiac complication of cytokine-releasing syndrome, and it can be triggered by various factors, including ICIs (19-21). Hemodiafiltration, to absorb excess cytokines, seemed an effective treatment to decline the cytokine concentrations in advance of an improved clinical presentation. In this case, CRP levels paralleled with IL-6 and IL-8 concentrations (19,22). TNF-α increased during the recovery phase, consistent with a report by Oda et al. (23), who also reported that TNF-α increased during the recovery of cytokine-releasing syndrome after nivolumab infusion. However, the role of TNF-α plays as an anti-inflammatory response in a host defense remains unclear (24). Taken together, mechanism of cytokine activation may differ between ICI-related myocarditis, Takotsubo cardiomyopathy, and cardiac complication of cytokine releasing syndrome. Changes in serum IL-8 levels reflect tumor response to ICI therapy (18). IL-8 was the predominant cytokine in our three patients, and our data suggest that the levels may reflect not only tumor burden but also severity of cardiac complications after ICI therapy. Creatine kinase-MB isoenzyme and troponin-T levels were exceedingly elevated regardless of cardiac function and damage in the second patient. Troponin-T may not be heart-specific in the context of ICI therapy, especially not in cases of highly elevated creatine kinase (15,25-27). One may consider if the elevated troponin-T as the result of concomitant myositis (15), myocyte toxic effects of pro-inflammatory cytokines (28), or ectopic production from cancer cells (29). Chen et al. (30) also reported that spreading cancer cells express cardiac troponin-I. We measured ICI concentration if they may affect the occurrence of irAEs. However, concentrations of pembrolizumab and nivolumab on the day of admission were demonstrated to be lower than expected, according to the pharmacokinetic model (31,32). There are no reports that serum ICI concentration correlates with efficacy or adverse effects, and our data suggests it does not directly predict the occurrence of irAEs. Management of irAEs is recommended based on anecdotal evidence and the life-threatening nature of cardiovascular complications (33). We continued to administer the prednisolone without adding other drugs or anti-thymoglobulin after recognizing the sustained myocardial inflammation at the second biopsy of the first case. Our experience indicates that the repeated histological information might provide chance to reconsider the strategy to treat the ICI-related myocarditis. However, it is unclear whether cytokine levels are useful for predicting, or managing the cardiac complications after ICI therapy. Conclusion We described the time-sequential cytokine expressions of three cases who developed myocarditis, Takotsubo cardiomyopathy, and cardiac complications of cytokine-releasing syndrome after ICI therapy. We did not mention the cytokine levels before ICI therapy, but IL-8 appears to reflect the disease severity of tumor progression and respective cardiac complications. The conclusions that can be drawn from this case series are very limited, and further studies will be needed in order to explore the utility of cytokine activation for monitoring patients after ICI therapy. This study was approved by the Human Investigation Review Committee of the University of Miyazaki and conforms with the principles outlined in the Declaration of Helsinki, as revised in 2013. We state that, because the patients have now passed away, written informed consent was obtained from their relatives (case 1, son; case 2, mother; case 3, sister), for the publication of this case report. The authors state that they have no Conflict of Interest (COI). Financial Support This study was supported by a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.	Fatal	ReactionOutcome	CC BY-NC-ND	32963156	20,851,605	2021-02-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'.	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	FLUOROURACIL, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEVOLEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963157	19,122,828	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'.	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	FLUOROURACIL, GEMCITABINE, IRINOTECAN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963157	17,549,249	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'.	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	FLUOROURACIL, GEMCITABINE, IRINOTECAN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963157	17,549,249	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Jejunal stenosis'.	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	FLUOROURACIL, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEVOLEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963157	19,122,828	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal disorder'.	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	FLUOROURACIL, GEMCITABINE, IRINOTECAN, LEUCOVORIN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963157	18,900,762	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Small intestinal obstruction'.	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	FLUOROURACIL, GEMCITABINE, IRINOTECAN, LEUCOVORIN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963157	18,900,762	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'.	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	FLUOROURACIL, GEMCITABINE, IRINOTECAN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963157	17,549,249	2021-01-15
What was the administration route of drug 'FLUOROURACIL'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Intravenous drip	DrugAdministrationRoute	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the administration route of drug 'GEMCITABINE'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Intravenous drip	DrugAdministrationRoute	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the administration route of drug 'GIMERACIL\OTERACIL\TEGAFUR'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Oral	DrugAdministrationRoute	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the administration route of drug 'PACLITAXEL'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Intravenous drip	DrugAdministrationRoute	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the dosage of drug 'LEUCOVORIN CALCIUM'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	17 COURSES	DrugDosageText	CC BY-NC-ND	32963157	17,549,249	2021-01-15
What was the dosage of drug 'LEVOLEUCOVORIN CALCIUM'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	UNK (17 COURSES)	DrugDosageText	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the outcome of reaction 'Condition aggravated'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Fatal	ReactionOutcome	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the outcome of reaction 'Disease progression'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Fatal	ReactionOutcome	CC BY-NC-ND	32963157	17,549,249	2021-01-15
What was the outcome of reaction 'Jejunal stenosis'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Recovering	ReactionOutcome	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the outcome of reaction 'Neutropenia'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Recovered	ReactionOutcome	CC BY-NC-ND	32963157	19,122,828	2021-01-15
What was the outcome of reaction 'Small intestinal obstruction'?	Hepatic Arterial Infusion Chemotherapy for Liver Metastases Following Standard Chemotherapy for Pancreatic Cancer. A 65-year-old man diagnosed with locally advanced pancreatic cancer underwent distal pancreatectomy and combined portal vein resection. One month after surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases. We administered two courses of gemcitabine plus nab-paclitaxel combination therapy followed by 17 modified FOLFIRINOX courses. However, the response was insufficient, and the patient thereafter developed grade 3 neutropenia, which made it difficult to continue the treatment regimen. As a result, we administered hepatic arterial infusion chemotherapy comprising gemcitabine plus 5-fluorouracil because the residual tumor was limited to liver metastases. The progression-free survival period was 7 months, and no drug-related adverse effects were noted during the treatment. Introduction Pancreatic cancer is either the fourth or fifth most frequent cause of death from cancer in most developed countries. Despite developments in the detection and management of pancreatic cancer, only approximately 4% of patients are able to survive for 5 years after their diagnosis (1). In Japan, the median survival time (MST) of all patients with pancreatic cancer from 2001 to 2004 was 10.2 months, and the 3-year survival rate was 11.7%. The MST for all resected cases was 18.2 months, and the 3-year survival rate was 23.2% (2). Recurrent pancreatic cancer (RPC) generally has a poor prognosis. Groot et al. (3) reported that the median overall survival of 662 patients with postoperative recurrence of pancreatic cancer was 21.1 months. Chemotherapy is the standard therapy for RPC but it has limited efficacy and it is also associated with serious adverse events. Hepatic arterial infusion chemotherapy (HAIC) is a treatment strategy that involves local delivery of anticancer drugs into the nutrient vessel of a tumor directly via an implantable port to increase the concentration of drugs locally and reduce systemic adverse events. We herein report one patient who received HAIC for RPC that was limited to liver metastases following standard chemotherapy. Case Report A 65-year-old Japanese man was initially diagnosed with borderline resectable pancreatic cancer (solid tumor contacted with portal vein more than 180°, but allowing for safe and complete resection and vein reconstruction) (Fig. 1a, b). As no distant metastases and tumor progression were noted after neoadjuvant chemoradiation [30 Gy/10 fractions+oral tegafur/gimeracil/oteracil combination therapy (S-1) for 10 days], he underwent distal pancreatectomy and combined portal vein resection in September 2017. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition (Fig. 1c, d). At 1 month after the surgery, contrast-enhanced magnetic resonance imaging revealed multiple liver metastases (Fig. 2). Figure 1. (a, b) Abdominal contrast-enhanced computed tomography image showing a 45-mm ischemic mass in the pancreatic body. (c, d) Resected pancreatic cancer specimen. Pathological examination reveals invasive ductal carcinoma of the pancreas body with two metastatic regional lymph nodes. The tumor stage was found to be T3N1M0 (stage II b) according to the UICC TNM classification 8th edition. Figure 2. (a-c) One month after the surgery, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed new multiple tumors with perilesional ring enhancement in the arterial phase (arrows). (d) Diffusion-weighted image shows perilesional high signal that is not shown in the center. (e) T2-weighted HASTE image shows hyperintense lesions with a fluid-fluid level, which is considered to be an intratumoral hemorrhage. There were no symptoms or blood biochemical findings suggestive of infection; therefore, we ruled out abscesses from our differential, and considered the presence of multiple lesions to be metastases. HASTE: half-Fourier acquisition single-shot turbo spin echo Initially, we administered two courses of gemcitabine plus nab-paclitaxel (GnP); however, contrast-enhanced computed tomography after 2 months showed tumor growth, and we could not continue the treatment according to the standard regimen because the patient developed grade 3 neutropenia. Thereafter, we administered 17 courses of modified FOLFIRINOX. However, as grade 3 neutropenia in the patient recurred, we had to administer granulocyte colony-stimulating factor (G-CSF) concomitantly to continue the treatment according to the standard regimen. In addition, renal dysfunction, neuralgia, and dysgeusia (all grade 1) were all observed (Fig. 3). The treatment seemed to be effective, but nevertheless both the tumor and tumor markers increased again. Figure 3. The clinical course of the patient after surgery, along with the details of the course of chemotherapy and adverse events. G-CSF had to be administered to the patient for grade 3 neutropenia. G-CSF: granulocyte colony-stimulating factor As the residual tumor was limited to liver metastases, we administered HAIC using gemcitabine (GEM) and 5-fluorouracil (5-FU) after obtaining approval from the relevant ethical review board in October 2018. We placed an anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) into the peripheral branch of the hepatic artery and positioned the handmade side hole at the common hepatic artery (Fig. 4). Then, we connected the catheter to a subcutaneous implantable port system located in the right thigh. GEM [800 mg/standard liver volume (SLV)] was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was administered continuously over 24 hours for days 1-6. Each treatment cycle was continued biweekly (Fig. 5). The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). Figure 4. (a) Abdominal angiogram revealing the replaced left hepatic artery. (b) It was embolized with microcoils to redistribute the entire hepatic arterial flow from multiple arteries into a single artery (white arrow). The gastroduodenal artery was also embolized to prevent chemotherapeutic agent distribution to the gastrointestinal tract (black arrow). (c) An anticoagulant-coated indwelling catheter (5-Fr W spiral catheter, Piolax Medical Devices, Yokohama, Japan) was placed. The catheter tip was inserted into the peripheral branch of the hepatic artery, and the handmade side hole (arrow head) was positioned at the common hepatic artery. Figure 5. The treatment regimen of hepatic arterial infusion chemotherapy (GEM plus 5-FU combination therapy). GEM (800 mg/SLV) was administered over 30 min on the 1st day. Subsequently, 250 mg of 5-FU was continuously administered over 24-h for days 1-6. Each treatment cycle was continued biweekly. The SLV was calculated as follows: (706.2×body surface area+2.4)/1,000 (4). GEM: gemcitabine, 5-FU: 5-fluorouracil, SLV: standard liver volume We administered a total of 14 courses of the regimen. The progression-free-survival period was 7 months (Fig. 6), and no drug-related adverse events were noted during treatment (Fig. 7). The overall status of the patient was generally good. However, after the 14th cycle (7 months since the initial HAIC), peritoneal dissemination was detected. Thereafter, additional systemic chemotherapy comprising GEM plus S-1 was performed, but could not be continued owing to a jejunal passage disorder. The patient was able to eat after gastrojejunostomy, but his general condition did not improve sufficiently to continue additional chemotherapy. He died 2 years after the initial visit. Figure 6. Follow-up contrast-enhanced computed tomographic image revealing a decrease in the size of the liver metastases. There was no local recurrence or distant metastasis except for the liver. (a, b) Computed tomography findings during arterial portography before HAIC; (c, d) after the second treatment cycle; (e, f) after the sixth treatment cycle; (g, h) after the 10th treatment cycle. HAIC: hepatic arterial infusion chemotherapy Figure 7. The clinical course of the patient. Hepatic arterial infusion chemotherapy was continued up to the 14th cycle without any adverse events. The graph shows the reduction of tumor markers and stable neutrophil count. Discussion After the radical resection of pancreatic cancer, approximately 80% of patients would develop recurrence (3). A meta-analysis showed that the weighted median rate of initial recurrence in the liver after resection of pancreatic cancer was 26.5% (5). Pancreatic cancer has a poor prognosis for postoperative recurrence, especially liver recurrence (3, 6). Therefore, the control of liver recurrence is important to improve the prognosis after surgery. Chemotherapy is the standard therapy for RPC but has limited efficacy. In Japan, FOLFIRINOX and GnP are used as first-line therapies. However, the MST in phase-III studies has not been satisfactory (11.1 and 8.5 months for FOLFIRINOX and GnP, respectively) (7, 8). Furthermore, chemotherapy is associated with serious adverse events. In phase-III studies, grade 3 or 4 neutropenia occurred in 45.7% and 37.8% of cases for FOLFIRINOX and GnP, respectively (7, 8). In the present case, the patient could not continue treatment with the standard drug volumes and needed concomitant G-CSF for severe neutropenia due to systemic chemotherapy. At present there is no strongly recommended second-line therapy (9). As such, we often experience a lack of chemotherapeutic methods and selectable drugs despite a patient's good general condition. Arterial infusion is suggested to take advantage of the first pass effect of chemotherapeutic drugs by increasing their concentrations locally at the tumor cell membrane and enhancing cellular drug uptake (10). Previous reports, in which HAIC was used as an adjuvant chemotherapy or treatment for postoperative liver metastases for pancreatic cancer, are summarized in Table (11-18). There are many regimens using 5-FU and GEM. Adjuvant chemotherapy is common, and there are few reports where HAIC was used as a treatment for postoperative liver metastases. Hashimoto et al. (11) performed HAIC using 5-FU combined with systemic GEM for liver metastases after pancreatectomy in nine patients. In their report, the overall response and disease control rates were 44.4% and 88.9%, respectively. There were two cases of a complete response. The appropriate hepatic arterial infusion doses and flow rates for GEM and 5-FU have been reported previously (19-23). Tajima et al. (23) analyzed seven cases, in which the GEM concentration in the peripheral blood was measured after hepatic arterial infusion and concluded that 800 mg/SLV was the optimal dose. Tajima et al. (12) also adopted 250 mg of 5-FU as a dose with low adverse events based on peripheral blood concentrations when injected into the hepatic artery over a 24-h period. Their regimen was referred to in the present case. Table. Previous Reports of Hepatic Arterial Infusion Chemotherapy as an Adjuvant Chemotherapy or Treatment for Postoperative Liver Metastases for Pancreatic Cancer (excluding Case Reports). Reference Study design n Aim Treatment beforeHAIC HAIC Regimen Concurrent therapy or Monotherapy Followed treatment MST 14 prospective 15 ACT NACRT 24Gy+5-FU 5-FU 125mg/d 28days +LPC via portal vein 5-FU 125mg/d 28days CRT 36Gy+SCT 5-FU 500mg/d 6days 62.0m 15 prospective phase2 study 27 ACT 5-FU 125mg/24h 21-28days +LPC via portal vein 5-FU 125mg/24h 21-28days SCT GEM 1,000mg/m2 /2w, at least 12c 27.5m 16 pilot study 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg (d1)+5-FU 250mg (d1-5)/2w 22.4m 17 retrospective 31 ACT 5-FU 1,000mg/m2(d1, 8, 15)/ 4w, 3c ±SCT GEM 1,000mg/m2(d1, 8, 15)/4w, 3c SCT GEM 1,000mg/m2 (d1, 8, 15)/4w, 3c 37.7m 11 retrospective 9* chemotherapy for PLM ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1,8,15)/4w, repeated ±SCT GEM 1,000mg/m2 14.1m† 42* ACT 5-FU 1,000mg/m2(d1,8,15)/4w, 3c ±SCT GEM 1,000mg/m2 36.8m 12 retrospective 5 chemotherapy for PLM ±NAC GEM+S-1, ±ACT GEM GEM 800mg/SLV(d1)+5-FU 250mg/SLV/24h (d1-5)/2w 22.4m 2 GEM 800mg/SLV(d8)/2w +S-1 60mg/m2/d (d1-7)/2w 13 RCT 52 ACT GEM 800mg/m2 (d1,8)+5-FU 1,000mg/m2(d1), 2c SCT GEM 800mg/m2 (d1, 8)+5-FU 1,000mg/m2(d1), 4c 30.0m‡ 54 SCT GEM 800mg/m2(d1,8)+5-FU 1,000mg/m2(d1), 6c 23.0m‡ 18 retrospective 93 ACT ±NACRT 50-54Gy+GEM 5-FU 1,000mg/m2(d1, 8, 15)/4w, 3c +SCT GEM 1,000mg/m2(d1, 8, 15)/4w SCT GEM, 3c 44.0m *: includes 2 periampullary cancer, †: median survival time from beginning of HAIC, ‡: inferred from Kaplan-Meier curve. ACT: adjuvant chemotherapy, PLM: postoperative liver metastases, HAIC: hepatic arterial infusion chemotherapy, NACRT: neoadjuvant chemoradiotherapy, NAC: neoadjuvant chemotherapy, LPC: liver perfusion chemotherapy, SCT: systemic chemotherapy, CRT: chemoradiotherapy, RCT: randomized controlled trial, 5-FU: 5-fluorouracil, GEM: gemcitabine, S-1: oral tegafur/gimeracil/oteracil combination therapy, SLV: standard liver volume, n: number of patients, MST: median survival time, c: cycles, h: hours, d: day, w: weeks, m: months HAIC seemed to be effective in the present case. A unique aspect of this case was the fact that the effect could be obtained by changing the drug administration method used in the preceding systemic chemotherapy to arterial injection. It was also noteworthy that the patient lived a normal life without any adverse events during the treatment course. One of the disadvantages in the use of the regimen adopted in the present case was that it required the hospitalization of patients for 5-6 days every 2 weeks. It is important to devise a dosing regimen that allows outpatient chemotherapy to improve patient acceptance. It may also be possible to improve the therapeutic effect by changing the order of administration of chemotherapeutic drugs (e.g., administering 5-FU before GEM). 5-FU leads to an increase in the major mediator of the cellular uptake of GEM (24). In addition, it is unclear whether controlling liver metastases with HAIC improves the prognoses. In our case, peritoneal dissemination was finally deemed to be associated with the prognosis. Pancreatic cancer is a systemic disease and the application of local therapy alone presents critical limitations. Zheng et al. (13) in their randomized controlled trial reported that HAIC combined with systemic chemotherapy after pancreatectomy for pancreatic cancer significantly prevented liver metastases and improved the prognosis compared with systemic chemotherapy only. Their report does not adapt to chemotherapy for recurrent tumors, which was similar to that in our case, but it is important evidence that the combination of HAIC and systemic chemotherapy improved the prognosis of patients after surgery for pancreatic cancer. To perform effective treatments, it is therefore important to consider a combination of HAIC with systemic chemotherapy to control local recurrences and occult extrahepatic metastases. To date, HAIC appears to be a useful method for local control in cases where effective chemotherapy cannot be administered in sufficient volume due to adverse events caused by systemic administration, and it plays a significant role in performing effective multidisciplinary treatment. Conclusion In the present case, HAIC caused no major adverse events and it may therefore be a useful technique for administering chemotherapy for the local control of RPC that is limited to liver metastases. The authors state that they have no Conflict of Interest (COI).	Recovered	ReactionOutcome	CC BY-NC-ND	32963157	18,900,762	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'.	Secondary Minimal Change Disease Due to Pancreatic Cancer Improved by Chemotherapy. We herein describe an 82-year-old patient who presented with proteinuria and systemic edema. He was diagnosed with minimal change disease (MCD) and was found to have stage III pancreatic cancer. He could not undergo surgical resection due to invasion to the celiac artery and he was thus treated with chemotherapy. After a month of chemotherapy, his proteinuria improved to a normal level. After two months of chemotherapy, computed tomography indicated a partial response to the therapy. MCD can occur as paraneoplastic syndrome in patients with malignant disease, and chemotherapy can be effective for MCD associated with paraneoplastic syndrome. Introduction In adults, minimal change disease (MCD) represents approximately 10-15% of patients with idiopathic nephrotic syndrome (1, 2). Secondary MCD is associated with neoplasia, drug use (e.g., non-steroidal anti-inflammatory drugs), infections, and atopy superimposed on another renal diseases. However, MCD is an uncommon occurrence associated with malignant tumors (3). Lymphoma are among the most frequently reported neoplastic processes associated with MCD (3), and a few solid tumors with MCD have been reported, especially with thymoma, renal cell carcinoma, colorectal carcinoma, and lung carcinoma (4). However, only two cases of pancreatic cancer (PC) associated with MCD have been previously reported (5, 6). The complications of nephrotic syndrome include increased susceptibility to infections due to urinary loss of immunoglobulins, an increased frequency of thromboembolic events due to urinary loss of antithrombotic factors, and increased frequency of acute kidney injury (7-11). The prognosis for secondary MCD is generally favorable because the remission rate for prednisolone in MCD is high and the relapse rate is low (10, 12). However, when MCD is secondary to paraneoplastic syndrome, the relapse rate for prednisolone in MCD is high (13). The relationship between the treatment of the malignant lesion and the prognosis of MCD has been reported; for example, Hodgkin's disease associated with MCD that is refractory to chemotherapy has very adverse prognoses (3), and mesotheliomas with MCD are associated with a poor prognoses (14). Therefore, aggressive therapy for cancer is preferable in patients with cancer-associated MCD. However, there have beenfew reports about the treatment for MCD associated with PC. We herein report a rare case of MCD associated with PC that was effectively treated with chemotherapy for both PC and MCD. Case Report An 82-year-old man presented with a 2-month history of upper abdominal pain and a 2-week history of bilateral lower limb edema. He had a history of hyperuricemia, and he had received allopurinol treatment. He had no history of smoking. Computed tomography (CT) revealed a pancreatic tumor measuring 3 cm in diameter which had invaded the celiac artery (Fig. 1a, b). Among the serum tumor markers, carbohydrate antigen 19-9, Duke pancreatic monoclonal antigen type 2 (DUPAN-2), and s-pancreas antigen-1 (SPan-1) were elevated to 772 U/mL (normal range: <37 U/mL), 1,600 or more U/mL (normal range: <150 U/mL) and 824 U/mL (normal range: <30 U/mL), respectively; carcinoembryonic antigen was within the normal limits. Tests for hepatitis B virus surface antigens and for antibodies to hepatitis C virus were negative. The following laboratory tests were normal level: Immunoglobulins IgG, IgA, and IgM; complement proteins C3 and C4; antinuclear antibody; rheumatoid factor; and antineutrophil cytoplasmic antibodies. Serum protein electrophoresis was normal. Serum creatinine was 1.05 mg/dL. A urine protein-to-creatinine ratio was high: 6.94 g/gCr (per gram of creatinine) and a 24-hour urine specimen contained 7.46 g of protein. The urine protein selectivity index was low (0.08). He was found to have a reduced serum albumin level of 2.9 g/dL and total protein level of 5.7 g/dL. The total cholesterol level was normal. Renal ultrasonography showed no abnormal findings. (Table 1) Figure 1. CT findings on admission. (a, b) Computed tomography on admission revealed a pancreatic tumor (red arrow) which invaded the celiac and common hepatic arteries. Table 1. Blood Test and Urinalysis. WBC 4,700 /μL Hb 13.0 g/dL Ht 37.6 % MCV 91.0 fL PLT 162,000 /μL PT-INR 1.00 APTT 30.2 s T-BIL 0.3 mg/dL AST 28 U/L ALT 15 U/L LDH 211 U/L γGTP 15 U/L ALP 2.9 U/L TP 5.7 g/dL ALB 2.9 g/dL T-chol 196 mg/dL HbA1c 5.8 % BUN 16.2 mg/dL CRE 1.05 mg/dL Na 139 mEq/L K 4.3 mEq/L Cl 105 mEq/L Ca 8.5 mg/dL CRP 0.023 mg/dL CA19-9 772 U/mL DUPAN-2 >1,600 U/mL SPan-1 824 U/mL CEA 4.5 ng/mL HBs antigens (-) HBs antibody (-) HCV antibody (-) IgG 656 mg/dL IgA 242 mg/dL IgM 56 mg/dL C3 95 mg/dL C4 25 mg/dL RF 2.69 U/mL PR3-ANCA 0.1 U/mL MPO-ANCA 0.1 U/mL Serum protein electrophoresis Normal A urine protein-to-creatinine ratio 6.94 g/gCr a 24-hour urine specimen 7.46 g The urine protein selectivity index 0.08 T-chol: total cholesterol, DUPAN-2: Duke pancreatic monoclonal antigen type 2, SPan-1: s-pancreas antigen-1, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, HBs antigens: tests for hepatitis B virus surface antigens, HCV antibodies: antibodies to hepatitis C virus, Ig: immunoglobulins, C3 and C4: complement proteins C3 and C4, RF: rheumatoid factor, ANCA: antineutrophil cytoplasmic antibodies We performed a renal biopsy and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for a pancreatic tumor (Fig. 2). The specimen obtained by EUS-FNA revealed a well-differentiated adenocarcinoma (Fig. 3). Renal biopsy specimens showed minor glomerular abnormalities on light microscopy (Fig. 4a, b) and negative staining on immunofluorescence microscopy against IgG, IgA, IgM, and carbohydrate antigen 19-9. Electron microscopy showed diffuse foot process effacement without electron-dense deposits (Fig. 4c). Therefore, he was diagnosed with pancreatic cancer and nephrotic syndrome due to MCD. The patient was classified as stage III (T4N0M0) in accordance with the Union for International Cancer Control 7th edition. Figure 2. Endoscopic ultrasound. (a, b) A pancreatic tumor (red arrowhead) is observed to have invaded the superior mesenteric vein (yellow arrowhead) and common hepatic artery (orange arrowhead). (c) Endoscopic ultrasound-guided fine needle aspiration with aspiration needle via the gastric wall (green arrowhead). Figure 3. Pathology of pancreatic cancer (×400). Normal pancreatic duct cells (blue arrow), Adenocarcinoma cells (red arrow). Figure 4. Pathology of the renal biopsy. (a) PAS staining (b) PAM staining (×400). A renal biopsy shows a minor glomerular abnormality on light microscopy. (c) Electron microscopy (×5,000) shows diffuse foot process effacement without any electron dense deposits (red arrow). PAM: periodic acid-methenamine silver, PAS: periodic acid-Schiff He was started on angiotensin receptor blocker (ARB); however, ARB treatment was interrupted after one month due to a low blood pressure and totter. In the ARB period, proteinuria remained at a high level with the urine protein-to-creatinine ratio fluctuating from 6.94 to 2.02 to 8.94 to 3.89 g/gCr. After a second opinion, he was started on definitive treatment with chemotherapy (gemcitabine+nab-paclitaxel: GnP) (gemcitabine 1,800 mg; nab-paclitaxel 226 mg). Just before the start of GnP treatment, the serum creatinine was 1.89 mg/dL, serum albumin was 1.7 g/dL, and the urine protein-to-creatinine ratio was 3.89 g/gCr. He was not administered steroids, except for the small amount of dexamethasone (6.6 mg per dose, three times per month) included in the GnP regimen, or any other immunosuppressive agents. His proteinuria improved to the normal level one month after the start of chemotherapy. Because of grade 3 neutropenia based on the common terminology criteria for adverse events version 4.0 (CTCAE ver. 4.0), he required a dose reduction of the GnP therapy (gemcitabine 1,400 mg; nab-paclitaxel 174 mg) during cycles 2 to 5. Because of exertional dyspnea and peripheral neuropathy, he required a two-dose reduction of the GnP therapy (gemcitabine 1,100 mg; nab-paclitaxel 135 mg) during cycles 6 and 7. A follow-up CT performed 2 months after the start of GnP therapy showed a partial response. A follow-up CT performed 6 months after the start of GnP therapy (Fig. 5) showed no further change. The serum level of carbohydrate antigen 19-9 decreased to near-normal levels by 5 months (Fig. 6). However, due to advanced general fatigue, we changed the GnP therapy to chemoradiotherapy [tegafur/gimeracil/oteracil (S-1) + radiation at 50.4 Gy in 28 fractions] (S-1 120 mg). A follow-up CT performed after the completion of chemoradiotherapy showed stable disease (Fig. 7). He was then started on S-1 monotherapy with a two-dose reduction (S-1 80 mg) due to general fatigue and appetite loss. A follow-up CT performed 6 months after the start of S-1 monotherapy showed stable disease (Fig. 8). At 20 months after the start of GnP therapy, the patient was in complete remission for MCD. Figure 5. Computed tomography 6 months after the start of GnP. (a, b) pancreatic cancer (red arrowhead). GnP: gemcitabine+nab-paclitaxel Figure 6. Changes in proteinuria and CA19-9. The yellow line shows the proteinuria level. ARB was not effective. However, it normalized one month after GnP. The red line shows the CA19-9 level. It decreased accompanied by proteinuria. ARB: angiotensin receptor blocker, CA19-9: carbohydrate antigen 19-9, GnP: gemcitabine+nab-paclitaxel, S-1: tegafur/gimeracil/oteracil Figure 7. Computed tomography 2 months after switch of S-1+radiation therapy. (a, b) pancreatic cancer (red arrowhead). S-1: tegafur/gimeracil/oteracil Figure 8. Computed tomography 6 months after switch of S-1. (a, b) pancreatic cancer (red arrowhead). S-1: tegafur/gimeracil/oteracil Discussion Glomerular disease in malignancies has been recognized for decades. Membranous nephropathy is the most common glomerular pathology. MCD has been associated with Hodgkin's lymphoma as well as other hematological malignancies; however, in two large studies on 1,700 Hodgkin's disease patients, only 0.4% of them had MCD (15, 16). MCD has rarely been associated with carcinomas such as thymoma, renal cell carcinoma, colorectal carcinoma, and lung carcinoma (3, 4). We searched for case reports of minimal change nephrotic syndrome patients with malignancy through PubMed using “minimal change nephrotic syndrome,” “pancreatic adenocarcinoma,” or “pancreatic cancer” as queries; only two cases were found (5, 6). The main characteristics of these patients and our case are shown in Table 2. The ages of the patients ranged from 67-82 years. The proteinuria level was in the nephrotic range in all patients (>3.5 g/day or urine test 4+). The creatinine level was high in our patient, but the other cases had no records. Although our patient received chemotherapy, others received no treatment for the malignant tumor. One case was administered a corticosteroid for MCD (5). Although the prognoses of pancreatic cancer with MCD were unclear in the previous reports, a long-term survival was obtained in our case using chemotherapy and chemoradiotherapy. Table 2. The Characteristics of the Patients with Minimal Change Disease (MCD) Associated with Pancreatic Cancer. Reference Age/sex Creatinine level (mg/dL) Proteinuria (g/day) malignat tumor Therapy for MCD Therapy for malignant tumor Evaluate the response to treatment for tumor Proteinuria after treatment (g/day) course of MCD Prognosis (from MCD diagnosis) adverse event our case 82/M 1.89 6.94 Pancreatic carcinoma × chemotherapy effective 0.01 no recurrent survived (24 mo) [5] 67/M NR >3.5 Pancreatic carcinoma Prednizolone × NR <0.15 NR died (8 mo) infection (pneumonia, liver abscess) [6] 68/M NR NR (urine test 4+) Pancreatic carcinoma, Thymoma × × NR NR NR died (3 days) NR: no record, M: man, mo: month Acute renal failure in the setting of MCD has been well described. In one study, it occurred in 25% of adult MCD patients and 4% of cases that required dialysis (10). In our case, the serum creatinine level was elevated at 1.89 mg/dL before the start of the GnP treatment, and it normalized during the therapy for the malignant tumor. Nakayama et al. suggested the possible role of the inflammatory cytokines such as tumor necrosis factor-α in MCD preceding Hodgkin lymphoma (17). Inflammatory responses induced by Th2-related cytokines such as interleukin-13 might be important for development of MCD in patients with Hodgkin lymphoma (18). Although the cause of MCD with solid tumors has not yet been identified, cytokines, chemokines, other related factors produced by tumor cells, and general inflammation caused by tumors may be implicated (14). A diagnosis of paraneoplastic nephrotic syndrome can be considered if the following criteria are present: 1) no evidence of any other etiology, 2) nephrotic syndrome develops 6 months before or after a cancer diagnosis, 3) cancer treatment is associated with a decrease in proteinuria, and 4) cancer relapse is associated with an increase in proteinuria (19). Since the first three criteria were fulfilled in our patient, we considered that the MCD was therefore related to PC. The currently accepted treatment of MCD in adults is prednisolone at 1 mg/kg per day for 16 weeks (10). The remission rate is 80-90%, and immunosuppressive agents such as cyclophosphamide, cyclosporine, or tacrolimus are rarely necessary (12). However, when MCD is secondary to a paraneoplastic syndrome, the treatment of neoplasia should be considered (20). Kofman et al. reported that 18 of 13,992 cases of non-Hodgkin lymphoma showed MCD, and that relapse of MCD occurred more frequently in patients treated only by steroids (77.8%) than those receiving combined therapy with steroids and other chemotherapeutic agents (25%) (13). Just before GnP, the urine protein-to-creatinine ratio was 3.89 g/gCr in our case. The prognosis of MCD associated with neoplasia was poor. Moreover, for the remission of MCD with steroid treatment without chemotherapy, the relapse rate is high (3, 14). Thus, it was considered that the complete remission of MCD was difficult, regardless of chemotherapy. Since the effects of steroids may be insufficient (13), we considered that chemotherapy was more important than steroid therapy for MCD associated with a malignant tumor. Moreover, diuretics improved the bilateral lower limb edema in our case. Thus, chemotherapy was administered first, but steroids were planned to be introduced if the improvement of nephrotic syndrome was poor. In our case, since the GnP was effective for nephrotic syndrome, steroids were therefore not administered. The criteria considered as remission are as follows: resolution of edema, normalization of serum albumin (≥3.5 g/dL), and marked reduction in proteinuria. In adults, a complete remission is less than 0.3 g/day proteinuria, and a partial remission is less than 3.5 g/day proteinuria and a 50% reduction (21). To achieve proteinuria reduction normally requires several months of treatment in adults. In idiopathic MCD, the probability of remission is approximately 30% after 4 weeks and 80% after 16 weeks of steroid therapy (10, 22, 23). The criterion considered as relapse in adults is the recurrence of massive proteinuria (≥3.5 g/day) (21). In our case, a partial remission was achieved after 2 weeks of GnP therapy, and a complete remission was achieved after 5 weeks. Although the GnP regimen included a small amount of dexamethasone, it was very low compared to an MCD therapeutic dose. In addition, even though relapse of MCD occurred in 77.8% in patients with malignant diseases treated only by steroid (13), there was no relapse of MCD after switching to the TS-1 regimen in which steroids were not included in our case. Therefore, we considered that the GnP therapy was effective for both the pancreatic cancer and for the MCD. In summary, we herein presented a rare case of MCD associated with pancreatic cancer treated with GnP therapy. Since the prognosis of MCD associated with a malignant tumor is a poor outcome in cases in which the therapy for the malignant tumor is not effective, it is considered that aggressive therapy for the malignant tumor is preferable in patients with malignancy-associated MCD. The patient gave her informed consent for inclusion in the study. The authors state that they have no Conflict of Interest (COI).	DEXAMETHASONE, GEMCITABINE\GEMCITABINE HYDROCHLORIDE, PACLITAXEL	DrugsGivenReaction	CC BY-NC-ND	32963158	18,354,536	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arteriospasm coronary'.	Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient. A 19-year-old-man was admitted to our hospital with intermittent chest pain. The day before admission, he had been diagnosed with enteritis and prescribed clarithromycin. He had experienced severe chest pain three times after taking clarithromycin; thus, acute coronary syndrome (ACS) was suspected. Emergent coronary angiography showed normal coronary arteries; however, the result of a subsequent acetylcholine provocation test was positive. We diagnosed him to have ACS caused by coronary vasospasms and suspected clarithromycin-induced Kounis syndrome. Although more common in older patients, Kounis syndrome must be suspected and a thorough medication history should be taken whenever a patient complains of chest pain. Introduction Vasospastic angina (VSA) usually develops after middle age (1-3), however, it is extremely rare in adolescents (4,5). Kounis syndrome is commonly known as an allergic angina or an allergic myocardial infarction caused by coronary vasospasms (6), which may also occur in adolescence (7). It is often caused by antibiotics, including clarithromycin (7,8). Recently, several studies have reported an increased risk of cardiovascular mortality in patients taking clarithromycin (9-11). Based on these reports, the U. S. Food and Drug Administration has called attention to the risks involved when prescribing clarithromycin to patients with heart disease (12). In this case report, we present the case of a 19-year-old male patient suspected to have Kounis syndrome caused by clarithromycin in the development of acute coronary syndrome (ACS). Case Report A 19-year-old-man was admitted to our hospital with intermittent chest pain. He was previously healthy with no coronary risk factors for hyperlipidemia, diabetes mellitus, Kawasaki disease, family history of heart disease, or smoking and passive smoking history. On the day before admission, he had consulted a nearby hospital for fever and diarrhea. He was diagnosed with enteritis, and as a result, he was prescribed oral clarithromycin. At 4 AM, approximately 6 hours after taking clarithromycin, he felt severe chest pains that he had previously not experienced before. However, the symptoms disappeared spontaneously within 1 hour. He took clarithromycin again after breakfast, and similar chest pains recurred at 12:00 PM and continued for 1 hour. Once again, the patient took clarithromycin after dinner, and several hours later, he experienced chest pains; therefore, he visited the nearby hospital again. ACS was suspected, so he was transferred to our hospital. The chest pain had already disappeared when he arrived at our hospital. On physical examination, his level of consciousness was normal, blood pressure was 138/81 mmHg, pulse was 64 beats per minute, temperature was 37.6℃, and oxygen saturation was 100%. He had no cardiac murmur or wheezing on auscultation. No eruptions, decrease in blood pressure or asthmatic bronchial reaction were observed. There were no abnormal findings in all other parameters of the physical examination. An electrocardiogram revealed terminal T wave inversion in V1 to V4 (Fig. 1A). Laboratory tests showed elevated troponin I (10.93 ng/mL), creatine kinase (CK; 802 U/L) and CK-MB (54.8 ng/mL) levels; however, WBC was within normal limits (8,140 /μL). We suspected ACS; however, emergent coronary angiography showed normal coronary arteries (Fig. 2A). Subsequently, we performed an acetylcholine provocation test, wherein the administration of 50 μg acetylcholine into the right coronary artery induced chest pains similar to those that he had previously experienced. On an electrocardiogram, transient ST segment depression and negative T wave appeared in the inferior wall leads (Fig. 3). In addition, coronary vasospasms, which resulted in 99% stenosis in the ostium of the posterior descending artery, were observed during the test (Fig. 2B). Left ventriculography showed akinesis in the narrow area of the inferior wall (Fig. 4), and the patient was subsequently diagnosed with vasospastic angina. Combination therapy with nitric acid and calcium-channel blocker was commenced, and clarithromycin was stopped. An electrocardiogram conducted the following day revealed negative T waves without any QT interval prolongation in the inferior leads. These electrocardiographic abnormal findings gradually improved before discharge (Fig. 1C), however, the improvement in inferior wall motion on echocardiogram was limited. The CK levels were the highest on admission, which was 18 hours after first attack, and they decreased thereafter, normalizing 1.5 days later. The chest symptoms did not recur during hospitalization, and he was discharged 9 days later without any complications. He had never experienced any chest pain previously; however, severe chest pain due to coronary vasospasm occurred three times after he took clarithromycin. An association between taking clarithromycin and coronary vasospasms was suspected. The value of non-specific IgE on day 2 was very high (375 IU/mL, N: <87). Consequently, we performed a drug-induced lymphocyte stimulation test (DLST) for clarithromycin, and the results were strongly positive (stimulation index 449%; >180 was judged positive). As a result, we thought that the coronary spasm may have been induced by an allergic reaction to clarithromycin. Figure 1. An electrocardiogram. Terminal T wave inversion in V1 to V4 was found on admission (A). However, on the following day, negative T waves without a prolonged QT interval (QTc 410 ms) had developed in the inferior leads (B). The abnormal findings gradually improved before discharge (on day 7) (C), and only negative T wave in III lead remained at the time of admission for the second acetylcholine provocation test (D). Figure 2. Coronary angiograms before and after the administration of acetylcholine on emergency admission. Although there was no significant stenosis in the control (A), the administration of 50 μg acetylcholine triggered coronary vasospasms, inducing 99% stenosis in the ostium of the posterior descending artery (white arrow), with chest pains (B). Figure 3. The electrocardiograms before (A) and during (B) the administration of acetylcholine. ST segment depression and negative T wave appeared in the inferior wall leads. Figure 4. Left ventriculography on emergency admission. Akinesis in the narrow area of the inferior wall (white arrows) was noted (A: diastolic phase, B: systolic phase). After 3 months, coronary angiography with an acetylcholine provocation test was performed again. At this admission, the electrocardiographic findings were improved and only a negative T wave in the III lead remained (Fig. 1D), and the wall motion in the inferior wall improved to hypokinesis on an echocardiogram. He was admitted 2 days before the examination, and taking calcium-channel blockers and nitrate were discontinued more than 48 hours before the acetylcholine provocation test. This time, the administration of 50 μg acetylcholine did not induce significant vasospasms (Fig. 5), there were no chest pains, and electrocardiogram changes were also not observed. Therefore, the acetylcholine provocation test was judged to be negative. Accordingly, the patient was banned from taking clarithromycin and continued taking prophylactic calcium-channel blockers. Thereafter, the recurrent chest pain never occurred. Figure 5. Coronary angiograms before (A) and after (B) the administration of acetylcholine after 3 months. Significant vasospasms and chest pain were not induced by acetylcholine. The stenotic lesion in the proximal right coronary artery was thought to be a catheter-induced spasm. Discussion VSA is predominantly observed in patients over 40 years of age. The pathophysiology is thought to be vascular smooth muscle hyper-reactivity and endothelial dysfunction (1-3). Therefore, the incidence of VSA in young patients, especially in adolescents, is very rare (4,5). We encountered a rare case of a 19-year-old patient with VSA. He had never been aware of chest pain prior to this episode. However, severe chest pain occurred repeatedly several hours after he took clarithromycin, which caused ACS. We suspected the chest pain “storm” was related to clarithromycin. Clarithromycin is an antibiotic that is frequently prescribed in clinical practice in Japan. However, recently, the U. S. Food and Drug Administration warned about a potential increased risk of heart problems with clarithromycin use (12). The report advised prescribers to consider using other antibiotics in patients with heart disease. The CLARICOR trial, a prospective, randomized, multicenter trial, showed that short-term clarithromycin prescribed for patients with stable coronary disease caused significantly higher cardiovascular mortality during a 3-year follow-up period (9). A long term follow-up of the CLARICOR trial also showed that clarithromycin increased cardiovascular mortality by over 10 years in patients with coronary heart disease who were not on statins (10). Similarly, in a large population-based cohort study including 326,781 patients, clarithromycin increased the risk of myocardial infarction within 14 days after start of treatment compared to amoxicillin (11). The exact mechanism of how clarithromycin induces more adverse cardiovascular events remains unclear. A prolonged QT interval, caused by the potassium channel blocking effect of clarithromycin, was considered to be a possible cause (13). Kounis syndrome induced by clarithromycin might be a reason for the incidence of myocardial infarctions and increase in cardiovascular mortality. Angina and myocardial infarctions caused by allergic coronary vasospasms were first reported in 1991, and it is known as Kounis syndrome. Hypersensitive coronary disorders induced by various conditions, drugs, foods, and environmental exposures are suspected to cause Kounis syndrome (6-8). Of the drugs that often cause this syndrome, antibiotics were the most common triggers (7). In the PubMed database, our search uncovered 1 case report of 36-year-old patient with Kounis syndrome caused by clarithromycin (14). There are no standard criteria to diagnose Kounis syndrome, so it is based on clinical symptoms, laboratory, electrocardiograms, echocardiograms, or angiographic evidence. The main cause of Kounis syndrome is thought to be a type I allergic reaction (7). DLST is a method to determine whether the patient has a hypersensitivity reaction of T-cell. Because there are such T-cell responses in all types of allergic reactions, DLST has been found to be frequently positive not only in delayed hypersensitivity reactions but also in anaphylaxis (>50%) (15). We think that the high value of IgE and positive result of DLST for clarithromycin in our patient might suggest that he had some kind of allergy to clarithromycin, which thereby triggered coronary spasms, resulting in ACS. Takotsubo cardiomyopathy may be considered to be an important differential diagnosis in such cases (16). However, it is often triggered by emotional stress (17), and there was no episode of stress in our patient. Furthermore, the characteristic findings of takotsubo cardiomyopathy, such as apical ballooning of left ventricular motion and QT interval prolongation with giant negative T waves on electrocardiogram, were not observed (18). Myocarditis caused by bacteria or virus which were related to enteritis is another possibility when making a differential diagnosis. However, in the typical case of myocarditis, the systolic dysfunction is generally diffuse (19). We believe that segmental left ventricular wall akinesis and rapid normalization of cardiac enzymes after admission were more consistent with ACS caused by coronary vasospasms than takotsubo cardiomyopathy and myocarditis. Moreover, there might be a possibility that enteritis had caused coronary vasospasm. However, there was no such case report, as far as we could search. Because severe chest pain occurred repeatedly every time he took clarithromycin, we believed that clarithromycin-induced Kounis syndrome was the most likely cause of this episode. Continuation of taking calcium-channel blockers may not be essential. However, in consideration of the possibility of Kounis syndrome recurrence by some other allergen, we continued calcium-channel blockers with his own request. Conclusions We herein described the case of a 19-year-old male patient diagnosed with ACS caused by coronary vasospasms, where clarithromycin was suspected to be a contributing factor. We propose that even in case of an adolescent complaining of chest pain, it is necessary to consider Kounis syndrome and to take a detailed medication history. Moreover, when prescribing clarithromycin to patients with cardiovascular diseases, it is important to explain that if any chest discomfort occurs, they should visit the hospital immediately. The authors state that they have no Conflict of Interest (COI).	CLARITHROMYCIN	DrugsGivenReaction	CC BY-NC-ND	32963159	18,431,710	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Kounis syndrome'.	Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient. A 19-year-old-man was admitted to our hospital with intermittent chest pain. The day before admission, he had been diagnosed with enteritis and prescribed clarithromycin. He had experienced severe chest pain three times after taking clarithromycin; thus, acute coronary syndrome (ACS) was suspected. Emergent coronary angiography showed normal coronary arteries; however, the result of a subsequent acetylcholine provocation test was positive. We diagnosed him to have ACS caused by coronary vasospasms and suspected clarithromycin-induced Kounis syndrome. Although more common in older patients, Kounis syndrome must be suspected and a thorough medication history should be taken whenever a patient complains of chest pain. Introduction Vasospastic angina (VSA) usually develops after middle age (1-3), however, it is extremely rare in adolescents (4,5). Kounis syndrome is commonly known as an allergic angina or an allergic myocardial infarction caused by coronary vasospasms (6), which may also occur in adolescence (7). It is often caused by antibiotics, including clarithromycin (7,8). Recently, several studies have reported an increased risk of cardiovascular mortality in patients taking clarithromycin (9-11). Based on these reports, the U. S. Food and Drug Administration has called attention to the risks involved when prescribing clarithromycin to patients with heart disease (12). In this case report, we present the case of a 19-year-old male patient suspected to have Kounis syndrome caused by clarithromycin in the development of acute coronary syndrome (ACS). Case Report A 19-year-old-man was admitted to our hospital with intermittent chest pain. He was previously healthy with no coronary risk factors for hyperlipidemia, diabetes mellitus, Kawasaki disease, family history of heart disease, or smoking and passive smoking history. On the day before admission, he had consulted a nearby hospital for fever and diarrhea. He was diagnosed with enteritis, and as a result, he was prescribed oral clarithromycin. At 4 AM, approximately 6 hours after taking clarithromycin, he felt severe chest pains that he had previously not experienced before. However, the symptoms disappeared spontaneously within 1 hour. He took clarithromycin again after breakfast, and similar chest pains recurred at 12:00 PM and continued for 1 hour. Once again, the patient took clarithromycin after dinner, and several hours later, he experienced chest pains; therefore, he visited the nearby hospital again. ACS was suspected, so he was transferred to our hospital. The chest pain had already disappeared when he arrived at our hospital. On physical examination, his level of consciousness was normal, blood pressure was 138/81 mmHg, pulse was 64 beats per minute, temperature was 37.6℃, and oxygen saturation was 100%. He had no cardiac murmur or wheezing on auscultation. No eruptions, decrease in blood pressure or asthmatic bronchial reaction were observed. There were no abnormal findings in all other parameters of the physical examination. An electrocardiogram revealed terminal T wave inversion in V1 to V4 (Fig. 1A). Laboratory tests showed elevated troponin I (10.93 ng/mL), creatine kinase (CK; 802 U/L) and CK-MB (54.8 ng/mL) levels; however, WBC was within normal limits (8,140 /μL). We suspected ACS; however, emergent coronary angiography showed normal coronary arteries (Fig. 2A). Subsequently, we performed an acetylcholine provocation test, wherein the administration of 50 μg acetylcholine into the right coronary artery induced chest pains similar to those that he had previously experienced. On an electrocardiogram, transient ST segment depression and negative T wave appeared in the inferior wall leads (Fig. 3). In addition, coronary vasospasms, which resulted in 99% stenosis in the ostium of the posterior descending artery, were observed during the test (Fig. 2B). Left ventriculography showed akinesis in the narrow area of the inferior wall (Fig. 4), and the patient was subsequently diagnosed with vasospastic angina. Combination therapy with nitric acid and calcium-channel blocker was commenced, and clarithromycin was stopped. An electrocardiogram conducted the following day revealed negative T waves without any QT interval prolongation in the inferior leads. These electrocardiographic abnormal findings gradually improved before discharge (Fig. 1C), however, the improvement in inferior wall motion on echocardiogram was limited. The CK levels were the highest on admission, which was 18 hours after first attack, and they decreased thereafter, normalizing 1.5 days later. The chest symptoms did not recur during hospitalization, and he was discharged 9 days later without any complications. He had never experienced any chest pain previously; however, severe chest pain due to coronary vasospasm occurred three times after he took clarithromycin. An association between taking clarithromycin and coronary vasospasms was suspected. The value of non-specific IgE on day 2 was very high (375 IU/mL, N: <87). Consequently, we performed a drug-induced lymphocyte stimulation test (DLST) for clarithromycin, and the results were strongly positive (stimulation index 449%; >180 was judged positive). As a result, we thought that the coronary spasm may have been induced by an allergic reaction to clarithromycin. Figure 1. An electrocardiogram. Terminal T wave inversion in V1 to V4 was found on admission (A). However, on the following day, negative T waves without a prolonged QT interval (QTc 410 ms) had developed in the inferior leads (B). The abnormal findings gradually improved before discharge (on day 7) (C), and only negative T wave in III lead remained at the time of admission for the second acetylcholine provocation test (D). Figure 2. Coronary angiograms before and after the administration of acetylcholine on emergency admission. Although there was no significant stenosis in the control (A), the administration of 50 μg acetylcholine triggered coronary vasospasms, inducing 99% stenosis in the ostium of the posterior descending artery (white arrow), with chest pains (B). Figure 3. The electrocardiograms before (A) and during (B) the administration of acetylcholine. ST segment depression and negative T wave appeared in the inferior wall leads. Figure 4. Left ventriculography on emergency admission. Akinesis in the narrow area of the inferior wall (white arrows) was noted (A: diastolic phase, B: systolic phase). After 3 months, coronary angiography with an acetylcholine provocation test was performed again. At this admission, the electrocardiographic findings were improved and only a negative T wave in the III lead remained (Fig. 1D), and the wall motion in the inferior wall improved to hypokinesis on an echocardiogram. He was admitted 2 days before the examination, and taking calcium-channel blockers and nitrate were discontinued more than 48 hours before the acetylcholine provocation test. This time, the administration of 50 μg acetylcholine did not induce significant vasospasms (Fig. 5), there were no chest pains, and electrocardiogram changes were also not observed. Therefore, the acetylcholine provocation test was judged to be negative. Accordingly, the patient was banned from taking clarithromycin and continued taking prophylactic calcium-channel blockers. Thereafter, the recurrent chest pain never occurred. Figure 5. Coronary angiograms before (A) and after (B) the administration of acetylcholine after 3 months. Significant vasospasms and chest pain were not induced by acetylcholine. The stenotic lesion in the proximal right coronary artery was thought to be a catheter-induced spasm. Discussion VSA is predominantly observed in patients over 40 years of age. The pathophysiology is thought to be vascular smooth muscle hyper-reactivity and endothelial dysfunction (1-3). Therefore, the incidence of VSA in young patients, especially in adolescents, is very rare (4,5). We encountered a rare case of a 19-year-old patient with VSA. He had never been aware of chest pain prior to this episode. However, severe chest pain occurred repeatedly several hours after he took clarithromycin, which caused ACS. We suspected the chest pain “storm” was related to clarithromycin. Clarithromycin is an antibiotic that is frequently prescribed in clinical practice in Japan. However, recently, the U. S. Food and Drug Administration warned about a potential increased risk of heart problems with clarithromycin use (12). The report advised prescribers to consider using other antibiotics in patients with heart disease. The CLARICOR trial, a prospective, randomized, multicenter trial, showed that short-term clarithromycin prescribed for patients with stable coronary disease caused significantly higher cardiovascular mortality during a 3-year follow-up period (9). A long term follow-up of the CLARICOR trial also showed that clarithromycin increased cardiovascular mortality by over 10 years in patients with coronary heart disease who were not on statins (10). Similarly, in a large population-based cohort study including 326,781 patients, clarithromycin increased the risk of myocardial infarction within 14 days after start of treatment compared to amoxicillin (11). The exact mechanism of how clarithromycin induces more adverse cardiovascular events remains unclear. A prolonged QT interval, caused by the potassium channel blocking effect of clarithromycin, was considered to be a possible cause (13). Kounis syndrome induced by clarithromycin might be a reason for the incidence of myocardial infarctions and increase in cardiovascular mortality. Angina and myocardial infarctions caused by allergic coronary vasospasms were first reported in 1991, and it is known as Kounis syndrome. Hypersensitive coronary disorders induced by various conditions, drugs, foods, and environmental exposures are suspected to cause Kounis syndrome (6-8). Of the drugs that often cause this syndrome, antibiotics were the most common triggers (7). In the PubMed database, our search uncovered 1 case report of 36-year-old patient with Kounis syndrome caused by clarithromycin (14). There are no standard criteria to diagnose Kounis syndrome, so it is based on clinical symptoms, laboratory, electrocardiograms, echocardiograms, or angiographic evidence. The main cause of Kounis syndrome is thought to be a type I allergic reaction (7). DLST is a method to determine whether the patient has a hypersensitivity reaction of T-cell. Because there are such T-cell responses in all types of allergic reactions, DLST has been found to be frequently positive not only in delayed hypersensitivity reactions but also in anaphylaxis (>50%) (15). We think that the high value of IgE and positive result of DLST for clarithromycin in our patient might suggest that he had some kind of allergy to clarithromycin, which thereby triggered coronary spasms, resulting in ACS. Takotsubo cardiomyopathy may be considered to be an important differential diagnosis in such cases (16). However, it is often triggered by emotional stress (17), and there was no episode of stress in our patient. Furthermore, the characteristic findings of takotsubo cardiomyopathy, such as apical ballooning of left ventricular motion and QT interval prolongation with giant negative T waves on electrocardiogram, were not observed (18). Myocarditis caused by bacteria or virus which were related to enteritis is another possibility when making a differential diagnosis. However, in the typical case of myocarditis, the systolic dysfunction is generally diffuse (19). We believe that segmental left ventricular wall akinesis and rapid normalization of cardiac enzymes after admission were more consistent with ACS caused by coronary vasospasms than takotsubo cardiomyopathy and myocarditis. Moreover, there might be a possibility that enteritis had caused coronary vasospasm. However, there was no such case report, as far as we could search. Because severe chest pain occurred repeatedly every time he took clarithromycin, we believed that clarithromycin-induced Kounis syndrome was the most likely cause of this episode. Continuation of taking calcium-channel blockers may not be essential. However, in consideration of the possibility of Kounis syndrome recurrence by some other allergen, we continued calcium-channel blockers with his own request. Conclusions We herein described the case of a 19-year-old male patient diagnosed with ACS caused by coronary vasospasms, where clarithromycin was suspected to be a contributing factor. We propose that even in case of an adolescent complaining of chest pain, it is necessary to consider Kounis syndrome and to take a detailed medication history. Moreover, when prescribing clarithromycin to patients with cardiovascular diseases, it is important to explain that if any chest discomfort occurs, they should visit the hospital immediately. The authors state that they have no Conflict of Interest (COI).	CLARITHROMYCIN	DrugsGivenReaction	CC BY-NC-ND	32963159	18,386,094	2021-01-15
What was the administration route of drug 'CLARITHROMYCIN'?	Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient. A 19-year-old-man was admitted to our hospital with intermittent chest pain. The day before admission, he had been diagnosed with enteritis and prescribed clarithromycin. He had experienced severe chest pain three times after taking clarithromycin; thus, acute coronary syndrome (ACS) was suspected. Emergent coronary angiography showed normal coronary arteries; however, the result of a subsequent acetylcholine provocation test was positive. We diagnosed him to have ACS caused by coronary vasospasms and suspected clarithromycin-induced Kounis syndrome. Although more common in older patients, Kounis syndrome must be suspected and a thorough medication history should be taken whenever a patient complains of chest pain. Introduction Vasospastic angina (VSA) usually develops after middle age (1-3), however, it is extremely rare in adolescents (4,5). Kounis syndrome is commonly known as an allergic angina or an allergic myocardial infarction caused by coronary vasospasms (6), which may also occur in adolescence (7). It is often caused by antibiotics, including clarithromycin (7,8). Recently, several studies have reported an increased risk of cardiovascular mortality in patients taking clarithromycin (9-11). Based on these reports, the U. S. Food and Drug Administration has called attention to the risks involved when prescribing clarithromycin to patients with heart disease (12). In this case report, we present the case of a 19-year-old male patient suspected to have Kounis syndrome caused by clarithromycin in the development of acute coronary syndrome (ACS). Case Report A 19-year-old-man was admitted to our hospital with intermittent chest pain. He was previously healthy with no coronary risk factors for hyperlipidemia, diabetes mellitus, Kawasaki disease, family history of heart disease, or smoking and passive smoking history. On the day before admission, he had consulted a nearby hospital for fever and diarrhea. He was diagnosed with enteritis, and as a result, he was prescribed oral clarithromycin. At 4 AM, approximately 6 hours after taking clarithromycin, he felt severe chest pains that he had previously not experienced before. However, the symptoms disappeared spontaneously within 1 hour. He took clarithromycin again after breakfast, and similar chest pains recurred at 12:00 PM and continued for 1 hour. Once again, the patient took clarithromycin after dinner, and several hours later, he experienced chest pains; therefore, he visited the nearby hospital again. ACS was suspected, so he was transferred to our hospital. The chest pain had already disappeared when he arrived at our hospital. On physical examination, his level of consciousness was normal, blood pressure was 138/81 mmHg, pulse was 64 beats per minute, temperature was 37.6℃, and oxygen saturation was 100%. He had no cardiac murmur or wheezing on auscultation. No eruptions, decrease in blood pressure or asthmatic bronchial reaction were observed. There were no abnormal findings in all other parameters of the physical examination. An electrocardiogram revealed terminal T wave inversion in V1 to V4 (Fig. 1A). Laboratory tests showed elevated troponin I (10.93 ng/mL), creatine kinase (CK; 802 U/L) and CK-MB (54.8 ng/mL) levels; however, WBC was within normal limits (8,140 /μL). We suspected ACS; however, emergent coronary angiography showed normal coronary arteries (Fig. 2A). Subsequently, we performed an acetylcholine provocation test, wherein the administration of 50 μg acetylcholine into the right coronary artery induced chest pains similar to those that he had previously experienced. On an electrocardiogram, transient ST segment depression and negative T wave appeared in the inferior wall leads (Fig. 3). In addition, coronary vasospasms, which resulted in 99% stenosis in the ostium of the posterior descending artery, were observed during the test (Fig. 2B). Left ventriculography showed akinesis in the narrow area of the inferior wall (Fig. 4), and the patient was subsequently diagnosed with vasospastic angina. Combination therapy with nitric acid and calcium-channel blocker was commenced, and clarithromycin was stopped. An electrocardiogram conducted the following day revealed negative T waves without any QT interval prolongation in the inferior leads. These electrocardiographic abnormal findings gradually improved before discharge (Fig. 1C), however, the improvement in inferior wall motion on echocardiogram was limited. The CK levels were the highest on admission, which was 18 hours after first attack, and they decreased thereafter, normalizing 1.5 days later. The chest symptoms did not recur during hospitalization, and he was discharged 9 days later without any complications. He had never experienced any chest pain previously; however, severe chest pain due to coronary vasospasm occurred three times after he took clarithromycin. An association between taking clarithromycin and coronary vasospasms was suspected. The value of non-specific IgE on day 2 was very high (375 IU/mL, N: <87). Consequently, we performed a drug-induced lymphocyte stimulation test (DLST) for clarithromycin, and the results were strongly positive (stimulation index 449%; >180 was judged positive). As a result, we thought that the coronary spasm may have been induced by an allergic reaction to clarithromycin. Figure 1. An electrocardiogram. Terminal T wave inversion in V1 to V4 was found on admission (A). However, on the following day, negative T waves without a prolonged QT interval (QTc 410 ms) had developed in the inferior leads (B). The abnormal findings gradually improved before discharge (on day 7) (C), and only negative T wave in III lead remained at the time of admission for the second acetylcholine provocation test (D). Figure 2. Coronary angiograms before and after the administration of acetylcholine on emergency admission. Although there was no significant stenosis in the control (A), the administration of 50 μg acetylcholine triggered coronary vasospasms, inducing 99% stenosis in the ostium of the posterior descending artery (white arrow), with chest pains (B). Figure 3. The electrocardiograms before (A) and during (B) the administration of acetylcholine. ST segment depression and negative T wave appeared in the inferior wall leads. Figure 4. Left ventriculography on emergency admission. Akinesis in the narrow area of the inferior wall (white arrows) was noted (A: diastolic phase, B: systolic phase). After 3 months, coronary angiography with an acetylcholine provocation test was performed again. At this admission, the electrocardiographic findings were improved and only a negative T wave in the III lead remained (Fig. 1D), and the wall motion in the inferior wall improved to hypokinesis on an echocardiogram. He was admitted 2 days before the examination, and taking calcium-channel blockers and nitrate were discontinued more than 48 hours before the acetylcholine provocation test. This time, the administration of 50 μg acetylcholine did not induce significant vasospasms (Fig. 5), there were no chest pains, and electrocardiogram changes were also not observed. Therefore, the acetylcholine provocation test was judged to be negative. Accordingly, the patient was banned from taking clarithromycin and continued taking prophylactic calcium-channel blockers. Thereafter, the recurrent chest pain never occurred. Figure 5. Coronary angiograms before (A) and after (B) the administration of acetylcholine after 3 months. Significant vasospasms and chest pain were not induced by acetylcholine. The stenotic lesion in the proximal right coronary artery was thought to be a catheter-induced spasm. Discussion VSA is predominantly observed in patients over 40 years of age. The pathophysiology is thought to be vascular smooth muscle hyper-reactivity and endothelial dysfunction (1-3). Therefore, the incidence of VSA in young patients, especially in adolescents, is very rare (4,5). We encountered a rare case of a 19-year-old patient with VSA. He had never been aware of chest pain prior to this episode. However, severe chest pain occurred repeatedly several hours after he took clarithromycin, which caused ACS. We suspected the chest pain “storm” was related to clarithromycin. Clarithromycin is an antibiotic that is frequently prescribed in clinical practice in Japan. However, recently, the U. S. Food and Drug Administration warned about a potential increased risk of heart problems with clarithromycin use (12). The report advised prescribers to consider using other antibiotics in patients with heart disease. The CLARICOR trial, a prospective, randomized, multicenter trial, showed that short-term clarithromycin prescribed for patients with stable coronary disease caused significantly higher cardiovascular mortality during a 3-year follow-up period (9). A long term follow-up of the CLARICOR trial also showed that clarithromycin increased cardiovascular mortality by over 10 years in patients with coronary heart disease who were not on statins (10). Similarly, in a large population-based cohort study including 326,781 patients, clarithromycin increased the risk of myocardial infarction within 14 days after start of treatment compared to amoxicillin (11). The exact mechanism of how clarithromycin induces more adverse cardiovascular events remains unclear. A prolonged QT interval, caused by the potassium channel blocking effect of clarithromycin, was considered to be a possible cause (13). Kounis syndrome induced by clarithromycin might be a reason for the incidence of myocardial infarctions and increase in cardiovascular mortality. Angina and myocardial infarctions caused by allergic coronary vasospasms were first reported in 1991, and it is known as Kounis syndrome. Hypersensitive coronary disorders induced by various conditions, drugs, foods, and environmental exposures are suspected to cause Kounis syndrome (6-8). Of the drugs that often cause this syndrome, antibiotics were the most common triggers (7). In the PubMed database, our search uncovered 1 case report of 36-year-old patient with Kounis syndrome caused by clarithromycin (14). There are no standard criteria to diagnose Kounis syndrome, so it is based on clinical symptoms, laboratory, electrocardiograms, echocardiograms, or angiographic evidence. The main cause of Kounis syndrome is thought to be a type I allergic reaction (7). DLST is a method to determine whether the patient has a hypersensitivity reaction of T-cell. Because there are such T-cell responses in all types of allergic reactions, DLST has been found to be frequently positive not only in delayed hypersensitivity reactions but also in anaphylaxis (>50%) (15). We think that the high value of IgE and positive result of DLST for clarithromycin in our patient might suggest that he had some kind of allergy to clarithromycin, which thereby triggered coronary spasms, resulting in ACS. Takotsubo cardiomyopathy may be considered to be an important differential diagnosis in such cases (16). However, it is often triggered by emotional stress (17), and there was no episode of stress in our patient. Furthermore, the characteristic findings of takotsubo cardiomyopathy, such as apical ballooning of left ventricular motion and QT interval prolongation with giant negative T waves on electrocardiogram, were not observed (18). Myocarditis caused by bacteria or virus which were related to enteritis is another possibility when making a differential diagnosis. However, in the typical case of myocarditis, the systolic dysfunction is generally diffuse (19). We believe that segmental left ventricular wall akinesis and rapid normalization of cardiac enzymes after admission were more consistent with ACS caused by coronary vasospasms than takotsubo cardiomyopathy and myocarditis. Moreover, there might be a possibility that enteritis had caused coronary vasospasm. However, there was no such case report, as far as we could search. Because severe chest pain occurred repeatedly every time he took clarithromycin, we believed that clarithromycin-induced Kounis syndrome was the most likely cause of this episode. Continuation of taking calcium-channel blockers may not be essential. However, in consideration of the possibility of Kounis syndrome recurrence by some other allergen, we continued calcium-channel blockers with his own request. Conclusions We herein described the case of a 19-year-old male patient diagnosed with ACS caused by coronary vasospasms, where clarithromycin was suspected to be a contributing factor. We propose that even in case of an adolescent complaining of chest pain, it is necessary to consider Kounis syndrome and to take a detailed medication history. Moreover, when prescribing clarithromycin to patients with cardiovascular diseases, it is important to explain that if any chest discomfort occurs, they should visit the hospital immediately. The authors state that they have no Conflict of Interest (COI).	Oral	DrugAdministrationRoute	CC BY-NC-ND	32963159	18,386,094	2021-01-15
What was the outcome of reaction 'Arteriospasm coronary'?	Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient. A 19-year-old-man was admitted to our hospital with intermittent chest pain. The day before admission, he had been diagnosed with enteritis and prescribed clarithromycin. He had experienced severe chest pain three times after taking clarithromycin; thus, acute coronary syndrome (ACS) was suspected. Emergent coronary angiography showed normal coronary arteries; however, the result of a subsequent acetylcholine provocation test was positive. We diagnosed him to have ACS caused by coronary vasospasms and suspected clarithromycin-induced Kounis syndrome. Although more common in older patients, Kounis syndrome must be suspected and a thorough medication history should be taken whenever a patient complains of chest pain. Introduction Vasospastic angina (VSA) usually develops after middle age (1-3), however, it is extremely rare in adolescents (4,5). Kounis syndrome is commonly known as an allergic angina or an allergic myocardial infarction caused by coronary vasospasms (6), which may also occur in adolescence (7). It is often caused by antibiotics, including clarithromycin (7,8). Recently, several studies have reported an increased risk of cardiovascular mortality in patients taking clarithromycin (9-11). Based on these reports, the U. S. Food and Drug Administration has called attention to the risks involved when prescribing clarithromycin to patients with heart disease (12). In this case report, we present the case of a 19-year-old male patient suspected to have Kounis syndrome caused by clarithromycin in the development of acute coronary syndrome (ACS). Case Report A 19-year-old-man was admitted to our hospital with intermittent chest pain. He was previously healthy with no coronary risk factors for hyperlipidemia, diabetes mellitus, Kawasaki disease, family history of heart disease, or smoking and passive smoking history. On the day before admission, he had consulted a nearby hospital for fever and diarrhea. He was diagnosed with enteritis, and as a result, he was prescribed oral clarithromycin. At 4 AM, approximately 6 hours after taking clarithromycin, he felt severe chest pains that he had previously not experienced before. However, the symptoms disappeared spontaneously within 1 hour. He took clarithromycin again after breakfast, and similar chest pains recurred at 12:00 PM and continued for 1 hour. Once again, the patient took clarithromycin after dinner, and several hours later, he experienced chest pains; therefore, he visited the nearby hospital again. ACS was suspected, so he was transferred to our hospital. The chest pain had already disappeared when he arrived at our hospital. On physical examination, his level of consciousness was normal, blood pressure was 138/81 mmHg, pulse was 64 beats per minute, temperature was 37.6℃, and oxygen saturation was 100%. He had no cardiac murmur or wheezing on auscultation. No eruptions, decrease in blood pressure or asthmatic bronchial reaction were observed. There were no abnormal findings in all other parameters of the physical examination. An electrocardiogram revealed terminal T wave inversion in V1 to V4 (Fig. 1A). Laboratory tests showed elevated troponin I (10.93 ng/mL), creatine kinase (CK; 802 U/L) and CK-MB (54.8 ng/mL) levels; however, WBC was within normal limits (8,140 /μL). We suspected ACS; however, emergent coronary angiography showed normal coronary arteries (Fig. 2A). Subsequently, we performed an acetylcholine provocation test, wherein the administration of 50 μg acetylcholine into the right coronary artery induced chest pains similar to those that he had previously experienced. On an electrocardiogram, transient ST segment depression and negative T wave appeared in the inferior wall leads (Fig. 3). In addition, coronary vasospasms, which resulted in 99% stenosis in the ostium of the posterior descending artery, were observed during the test (Fig. 2B). Left ventriculography showed akinesis in the narrow area of the inferior wall (Fig. 4), and the patient was subsequently diagnosed with vasospastic angina. Combination therapy with nitric acid and calcium-channel blocker was commenced, and clarithromycin was stopped. An electrocardiogram conducted the following day revealed negative T waves without any QT interval prolongation in the inferior leads. These electrocardiographic abnormal findings gradually improved before discharge (Fig. 1C), however, the improvement in inferior wall motion on echocardiogram was limited. The CK levels were the highest on admission, which was 18 hours after first attack, and they decreased thereafter, normalizing 1.5 days later. The chest symptoms did not recur during hospitalization, and he was discharged 9 days later without any complications. He had never experienced any chest pain previously; however, severe chest pain due to coronary vasospasm occurred three times after he took clarithromycin. An association between taking clarithromycin and coronary vasospasms was suspected. The value of non-specific IgE on day 2 was very high (375 IU/mL, N: <87). Consequently, we performed a drug-induced lymphocyte stimulation test (DLST) for clarithromycin, and the results were strongly positive (stimulation index 449%; >180 was judged positive). As a result, we thought that the coronary spasm may have been induced by an allergic reaction to clarithromycin. Figure 1. An electrocardiogram. Terminal T wave inversion in V1 to V4 was found on admission (A). However, on the following day, negative T waves without a prolonged QT interval (QTc 410 ms) had developed in the inferior leads (B). The abnormal findings gradually improved before discharge (on day 7) (C), and only negative T wave in III lead remained at the time of admission for the second acetylcholine provocation test (D). Figure 2. Coronary angiograms before and after the administration of acetylcholine on emergency admission. Although there was no significant stenosis in the control (A), the administration of 50 μg acetylcholine triggered coronary vasospasms, inducing 99% stenosis in the ostium of the posterior descending artery (white arrow), with chest pains (B). Figure 3. The electrocardiograms before (A) and during (B) the administration of acetylcholine. ST segment depression and negative T wave appeared in the inferior wall leads. Figure 4. Left ventriculography on emergency admission. Akinesis in the narrow area of the inferior wall (white arrows) was noted (A: diastolic phase, B: systolic phase). After 3 months, coronary angiography with an acetylcholine provocation test was performed again. At this admission, the electrocardiographic findings were improved and only a negative T wave in the III lead remained (Fig. 1D), and the wall motion in the inferior wall improved to hypokinesis on an echocardiogram. He was admitted 2 days before the examination, and taking calcium-channel blockers and nitrate were discontinued more than 48 hours before the acetylcholine provocation test. This time, the administration of 50 μg acetylcholine did not induce significant vasospasms (Fig. 5), there were no chest pains, and electrocardiogram changes were also not observed. Therefore, the acetylcholine provocation test was judged to be negative. Accordingly, the patient was banned from taking clarithromycin and continued taking prophylactic calcium-channel blockers. Thereafter, the recurrent chest pain never occurred. Figure 5. Coronary angiograms before (A) and after (B) the administration of acetylcholine after 3 months. Significant vasospasms and chest pain were not induced by acetylcholine. The stenotic lesion in the proximal right coronary artery was thought to be a catheter-induced spasm. Discussion VSA is predominantly observed in patients over 40 years of age. The pathophysiology is thought to be vascular smooth muscle hyper-reactivity and endothelial dysfunction (1-3). Therefore, the incidence of VSA in young patients, especially in adolescents, is very rare (4,5). We encountered a rare case of a 19-year-old patient with VSA. He had never been aware of chest pain prior to this episode. However, severe chest pain occurred repeatedly several hours after he took clarithromycin, which caused ACS. We suspected the chest pain “storm” was related to clarithromycin. Clarithromycin is an antibiotic that is frequently prescribed in clinical practice in Japan. However, recently, the U. S. Food and Drug Administration warned about a potential increased risk of heart problems with clarithromycin use (12). The report advised prescribers to consider using other antibiotics in patients with heart disease. The CLARICOR trial, a prospective, randomized, multicenter trial, showed that short-term clarithromycin prescribed for patients with stable coronary disease caused significantly higher cardiovascular mortality during a 3-year follow-up period (9). A long term follow-up of the CLARICOR trial also showed that clarithromycin increased cardiovascular mortality by over 10 years in patients with coronary heart disease who were not on statins (10). Similarly, in a large population-based cohort study including 326,781 patients, clarithromycin increased the risk of myocardial infarction within 14 days after start of treatment compared to amoxicillin (11). The exact mechanism of how clarithromycin induces more adverse cardiovascular events remains unclear. A prolonged QT interval, caused by the potassium channel blocking effect of clarithromycin, was considered to be a possible cause (13). Kounis syndrome induced by clarithromycin might be a reason for the incidence of myocardial infarctions and increase in cardiovascular mortality. Angina and myocardial infarctions caused by allergic coronary vasospasms were first reported in 1991, and it is known as Kounis syndrome. Hypersensitive coronary disorders induced by various conditions, drugs, foods, and environmental exposures are suspected to cause Kounis syndrome (6-8). Of the drugs that often cause this syndrome, antibiotics were the most common triggers (7). In the PubMed database, our search uncovered 1 case report of 36-year-old patient with Kounis syndrome caused by clarithromycin (14). There are no standard criteria to diagnose Kounis syndrome, so it is based on clinical symptoms, laboratory, electrocardiograms, echocardiograms, or angiographic evidence. The main cause of Kounis syndrome is thought to be a type I allergic reaction (7). DLST is a method to determine whether the patient has a hypersensitivity reaction of T-cell. Because there are such T-cell responses in all types of allergic reactions, DLST has been found to be frequently positive not only in delayed hypersensitivity reactions but also in anaphylaxis (>50%) (15). We think that the high value of IgE and positive result of DLST for clarithromycin in our patient might suggest that he had some kind of allergy to clarithromycin, which thereby triggered coronary spasms, resulting in ACS. Takotsubo cardiomyopathy may be considered to be an important differential diagnosis in such cases (16). However, it is often triggered by emotional stress (17), and there was no episode of stress in our patient. Furthermore, the characteristic findings of takotsubo cardiomyopathy, such as apical ballooning of left ventricular motion and QT interval prolongation with giant negative T waves on electrocardiogram, were not observed (18). Myocarditis caused by bacteria or virus which were related to enteritis is another possibility when making a differential diagnosis. However, in the typical case of myocarditis, the systolic dysfunction is generally diffuse (19). We believe that segmental left ventricular wall akinesis and rapid normalization of cardiac enzymes after admission were more consistent with ACS caused by coronary vasospasms than takotsubo cardiomyopathy and myocarditis. Moreover, there might be a possibility that enteritis had caused coronary vasospasm. However, there was no such case report, as far as we could search. Because severe chest pain occurred repeatedly every time he took clarithromycin, we believed that clarithromycin-induced Kounis syndrome was the most likely cause of this episode. Continuation of taking calcium-channel blockers may not be essential. However, in consideration of the possibility of Kounis syndrome recurrence by some other allergen, we continued calcium-channel blockers with his own request. Conclusions We herein described the case of a 19-year-old male patient diagnosed with ACS caused by coronary vasospasms, where clarithromycin was suspected to be a contributing factor. We propose that even in case of an adolescent complaining of chest pain, it is necessary to consider Kounis syndrome and to take a detailed medication history. Moreover, when prescribing clarithromycin to patients with cardiovascular diseases, it is important to explain that if any chest discomfort occurs, they should visit the hospital immediately. The authors state that they have no Conflict of Interest (COI).	Recovered	ReactionOutcome	CC BY-NC-ND	32963159	18,431,710	2021-01-15
What was the outcome of reaction 'Kounis syndrome'?	Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient. A 19-year-old-man was admitted to our hospital with intermittent chest pain. The day before admission, he had been diagnosed with enteritis and prescribed clarithromycin. He had experienced severe chest pain three times after taking clarithromycin; thus, acute coronary syndrome (ACS) was suspected. Emergent coronary angiography showed normal coronary arteries; however, the result of a subsequent acetylcholine provocation test was positive. We diagnosed him to have ACS caused by coronary vasospasms and suspected clarithromycin-induced Kounis syndrome. Although more common in older patients, Kounis syndrome must be suspected and a thorough medication history should be taken whenever a patient complains of chest pain. Introduction Vasospastic angina (VSA) usually develops after middle age (1-3), however, it is extremely rare in adolescents (4,5). Kounis syndrome is commonly known as an allergic angina or an allergic myocardial infarction caused by coronary vasospasms (6), which may also occur in adolescence (7). It is often caused by antibiotics, including clarithromycin (7,8). Recently, several studies have reported an increased risk of cardiovascular mortality in patients taking clarithromycin (9-11). Based on these reports, the U. S. Food and Drug Administration has called attention to the risks involved when prescribing clarithromycin to patients with heart disease (12). In this case report, we present the case of a 19-year-old male patient suspected to have Kounis syndrome caused by clarithromycin in the development of acute coronary syndrome (ACS). Case Report A 19-year-old-man was admitted to our hospital with intermittent chest pain. He was previously healthy with no coronary risk factors for hyperlipidemia, diabetes mellitus, Kawasaki disease, family history of heart disease, or smoking and passive smoking history. On the day before admission, he had consulted a nearby hospital for fever and diarrhea. He was diagnosed with enteritis, and as a result, he was prescribed oral clarithromycin. At 4 AM, approximately 6 hours after taking clarithromycin, he felt severe chest pains that he had previously not experienced before. However, the symptoms disappeared spontaneously within 1 hour. He took clarithromycin again after breakfast, and similar chest pains recurred at 12:00 PM and continued for 1 hour. Once again, the patient took clarithromycin after dinner, and several hours later, he experienced chest pains; therefore, he visited the nearby hospital again. ACS was suspected, so he was transferred to our hospital. The chest pain had already disappeared when he arrived at our hospital. On physical examination, his level of consciousness was normal, blood pressure was 138/81 mmHg, pulse was 64 beats per minute, temperature was 37.6℃, and oxygen saturation was 100%. He had no cardiac murmur or wheezing on auscultation. No eruptions, decrease in blood pressure or asthmatic bronchial reaction were observed. There were no abnormal findings in all other parameters of the physical examination. An electrocardiogram revealed terminal T wave inversion in V1 to V4 (Fig. 1A). Laboratory tests showed elevated troponin I (10.93 ng/mL), creatine kinase (CK; 802 U/L) and CK-MB (54.8 ng/mL) levels; however, WBC was within normal limits (8,140 /μL). We suspected ACS; however, emergent coronary angiography showed normal coronary arteries (Fig. 2A). Subsequently, we performed an acetylcholine provocation test, wherein the administration of 50 μg acetylcholine into the right coronary artery induced chest pains similar to those that he had previously experienced. On an electrocardiogram, transient ST segment depression and negative T wave appeared in the inferior wall leads (Fig. 3). In addition, coronary vasospasms, which resulted in 99% stenosis in the ostium of the posterior descending artery, were observed during the test (Fig. 2B). Left ventriculography showed akinesis in the narrow area of the inferior wall (Fig. 4), and the patient was subsequently diagnosed with vasospastic angina. Combination therapy with nitric acid and calcium-channel blocker was commenced, and clarithromycin was stopped. An electrocardiogram conducted the following day revealed negative T waves without any QT interval prolongation in the inferior leads. These electrocardiographic abnormal findings gradually improved before discharge (Fig. 1C), however, the improvement in inferior wall motion on echocardiogram was limited. The CK levels were the highest on admission, which was 18 hours after first attack, and they decreased thereafter, normalizing 1.5 days later. The chest symptoms did not recur during hospitalization, and he was discharged 9 days later without any complications. He had never experienced any chest pain previously; however, severe chest pain due to coronary vasospasm occurred three times after he took clarithromycin. An association between taking clarithromycin and coronary vasospasms was suspected. The value of non-specific IgE on day 2 was very high (375 IU/mL, N: <87). Consequently, we performed a drug-induced lymphocyte stimulation test (DLST) for clarithromycin, and the results were strongly positive (stimulation index 449%; >180 was judged positive). As a result, we thought that the coronary spasm may have been induced by an allergic reaction to clarithromycin. Figure 1. An electrocardiogram. Terminal T wave inversion in V1 to V4 was found on admission (A). However, on the following day, negative T waves without a prolonged QT interval (QTc 410 ms) had developed in the inferior leads (B). The abnormal findings gradually improved before discharge (on day 7) (C), and only negative T wave in III lead remained at the time of admission for the second acetylcholine provocation test (D). Figure 2. Coronary angiograms before and after the administration of acetylcholine on emergency admission. Although there was no significant stenosis in the control (A), the administration of 50 μg acetylcholine triggered coronary vasospasms, inducing 99% stenosis in the ostium of the posterior descending artery (white arrow), with chest pains (B). Figure 3. The electrocardiograms before (A) and during (B) the administration of acetylcholine. ST segment depression and negative T wave appeared in the inferior wall leads. Figure 4. Left ventriculography on emergency admission. Akinesis in the narrow area of the inferior wall (white arrows) was noted (A: diastolic phase, B: systolic phase). After 3 months, coronary angiography with an acetylcholine provocation test was performed again. At this admission, the electrocardiographic findings were improved and only a negative T wave in the III lead remained (Fig. 1D), and the wall motion in the inferior wall improved to hypokinesis on an echocardiogram. He was admitted 2 days before the examination, and taking calcium-channel blockers and nitrate were discontinued more than 48 hours before the acetylcholine provocation test. This time, the administration of 50 μg acetylcholine did not induce significant vasospasms (Fig. 5), there were no chest pains, and electrocardiogram changes were also not observed. Therefore, the acetylcholine provocation test was judged to be negative. Accordingly, the patient was banned from taking clarithromycin and continued taking prophylactic calcium-channel blockers. Thereafter, the recurrent chest pain never occurred. Figure 5. Coronary angiograms before (A) and after (B) the administration of acetylcholine after 3 months. Significant vasospasms and chest pain were not induced by acetylcholine. The stenotic lesion in the proximal right coronary artery was thought to be a catheter-induced spasm. Discussion VSA is predominantly observed in patients over 40 years of age. The pathophysiology is thought to be vascular smooth muscle hyper-reactivity and endothelial dysfunction (1-3). Therefore, the incidence of VSA in young patients, especially in adolescents, is very rare (4,5). We encountered a rare case of a 19-year-old patient with VSA. He had never been aware of chest pain prior to this episode. However, severe chest pain occurred repeatedly several hours after he took clarithromycin, which caused ACS. We suspected the chest pain “storm” was related to clarithromycin. Clarithromycin is an antibiotic that is frequently prescribed in clinical practice in Japan. However, recently, the U. S. Food and Drug Administration warned about a potential increased risk of heart problems with clarithromycin use (12). The report advised prescribers to consider using other antibiotics in patients with heart disease. The CLARICOR trial, a prospective, randomized, multicenter trial, showed that short-term clarithromycin prescribed for patients with stable coronary disease caused significantly higher cardiovascular mortality during a 3-year follow-up period (9). A long term follow-up of the CLARICOR trial also showed that clarithromycin increased cardiovascular mortality by over 10 years in patients with coronary heart disease who were not on statins (10). Similarly, in a large population-based cohort study including 326,781 patients, clarithromycin increased the risk of myocardial infarction within 14 days after start of treatment compared to amoxicillin (11). The exact mechanism of how clarithromycin induces more adverse cardiovascular events remains unclear. A prolonged QT interval, caused by the potassium channel blocking effect of clarithromycin, was considered to be a possible cause (13). Kounis syndrome induced by clarithromycin might be a reason for the incidence of myocardial infarctions and increase in cardiovascular mortality. Angina and myocardial infarctions caused by allergic coronary vasospasms were first reported in 1991, and it is known as Kounis syndrome. Hypersensitive coronary disorders induced by various conditions, drugs, foods, and environmental exposures are suspected to cause Kounis syndrome (6-8). Of the drugs that often cause this syndrome, antibiotics were the most common triggers (7). In the PubMed database, our search uncovered 1 case report of 36-year-old patient with Kounis syndrome caused by clarithromycin (14). There are no standard criteria to diagnose Kounis syndrome, so it is based on clinical symptoms, laboratory, electrocardiograms, echocardiograms, or angiographic evidence. The main cause of Kounis syndrome is thought to be a type I allergic reaction (7). DLST is a method to determine whether the patient has a hypersensitivity reaction of T-cell. Because there are such T-cell responses in all types of allergic reactions, DLST has been found to be frequently positive not only in delayed hypersensitivity reactions but also in anaphylaxis (>50%) (15). We think that the high value of IgE and positive result of DLST for clarithromycin in our patient might suggest that he had some kind of allergy to clarithromycin, which thereby triggered coronary spasms, resulting in ACS. Takotsubo cardiomyopathy may be considered to be an important differential diagnosis in such cases (16). However, it is often triggered by emotional stress (17), and there was no episode of stress in our patient. Furthermore, the characteristic findings of takotsubo cardiomyopathy, such as apical ballooning of left ventricular motion and QT interval prolongation with giant negative T waves on electrocardiogram, were not observed (18). Myocarditis caused by bacteria or virus which were related to enteritis is another possibility when making a differential diagnosis. However, in the typical case of myocarditis, the systolic dysfunction is generally diffuse (19). We believe that segmental left ventricular wall akinesis and rapid normalization of cardiac enzymes after admission were more consistent with ACS caused by coronary vasospasms than takotsubo cardiomyopathy and myocarditis. Moreover, there might be a possibility that enteritis had caused coronary vasospasm. However, there was no such case report, as far as we could search. Because severe chest pain occurred repeatedly every time he took clarithromycin, we believed that clarithromycin-induced Kounis syndrome was the most likely cause of this episode. Continuation of taking calcium-channel blockers may not be essential. However, in consideration of the possibility of Kounis syndrome recurrence by some other allergen, we continued calcium-channel blockers with his own request. Conclusions We herein described the case of a 19-year-old male patient diagnosed with ACS caused by coronary vasospasms, where clarithromycin was suspected to be a contributing factor. We propose that even in case of an adolescent complaining of chest pain, it is necessary to consider Kounis syndrome and to take a detailed medication history. Moreover, when prescribing clarithromycin to patients with cardiovascular diseases, it is important to explain that if any chest discomfort occurs, they should visit the hospital immediately. The authors state that they have no Conflict of Interest (COI).	Recovered	ReactionOutcome	CC BY-NC-ND	32963159	18,386,094	2021-01-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis B reactivation'.	Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation. Introduction Hepatitis B virus (HBV) reactivation has emerged as a major complication induced by long-term chemotherapy or immunosuppressive therapy (1). De novo hepatitis B, a form of HBV reactivation, can occur as a result of the reactivation of latent HBV infection in subjects who are negative for hepatitis B surface antigen (HBs-Ag), but positive for anti-hepatitis B core antibody (HBc-Ab), anti-HBs antibody (HBs-Ab) or both (2,3). It is well known that patients receiving chemotherapy, including rituximab and hematopoietic stem cell transplantation (HSCT), are at high risk of HBV reactivation (4-6). Among HSCT recipients with resolved HBV, the risk of HBV reactivation is higher with allogeneic HSCT (allo-HSCT) than with autologous HSCT (auto-HSCT) (7). HBV reactivation usually develops a few months after chemotherapy or immunosuppressive therapy. Long-term HBV-DNA monitoring after transplantation is recommended (4), because the time interval between HSCT and HBsAg-positive conversion can be long. However, currently, there is no definitive indication for how long the viral load should be monitored in such cases. We herein present the case of a patient who experienced HBV reactivation 55 months after chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT), and de novo hepatitis B improved with tenofovir alafenamide fumarate (TAF) therapy. Case Report A 54-year old woman presented to our hospital with a continuous low-grade fever. Her workup revealed stage IVB diffuse large B-cell lymphoma (DLBCL). Her laboratory findings were negative for HBs-Ag and HBV-DNA, but was positive for HBs-Ab and HBc-Ab. She had no family history of HBV infection. She underwent 4 courses of rituximab, cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (R-CHOP) therapy, 2 courses of rituximab, methotrexate, procarbazine, and VCR (R-MPV) therapy, 1 course of rituximab, CPM, doxorubicin, etoposide, vincristine, and prednisolone (R-CHOEP) therapy, and 2 courses of rituximab, CPM, high-dose cytarabine, dexametazone, and etoposide (R-CHASE) therapy. Furthermore, she underwent one course of rituximab, melphalan, CPM, etoposide, and dexametazone (R-LEED) therapy, and auto-PBSCT. She achieved complete remission. During the period of chemotherapy and auto-PBSCT, her serum level of HBV-DNA remained undetectable. After chemotherapy and auto-PBSCT, she was monitored regularly every 1-3 months and was not receiving immunosuppressive therapy. Her serum HBV-DNA levels became positive 55 months after the last treatment, increasing to 4.1 log IU/mL. HBs-Ag, hepatitis B envelope antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) also became positive without elevation of serum transaminase. The HBV genotype was group C (Table 1). She had no history of blood transfusion and was sexually inactive. We diagnosed her to have HBV reactivation. Although we recommended that she start nucleotide analogue therapy (NA), she refused and requested a reexamination one month later. Table 1. Laboratory Findings at 55 Months Following Chemotherapy and Auto-PBSCT. Variable Variable White blood cells (/µL) 4,140 Total bilirubin (mg/dL) 0.5 Red blood cells (104/µL) 355 AST (IU/L) 21 Hematocrit (%) 33.6 ALT (IU/L) 19 Hemoglobin (g/dL) 11.2 LDH (IU/L) 154 Platelets (104/µL) 28.0 ALP (IU/L) 240 PT-INR 1.01 GGT (IU/L) 41 PT (%) 97 HBsAg (IU/mL) 4.63 Total protein (g/dL) 6.9 HBV-DNA (log IU/mL) 4.1 Alubmin (g/dL) 3.8 HBeAg 11.4 C-reactive protein (mg/dL) 1.26 HBeAb (%) 0.1 BUN (mg/dL) 14 HBcrAg (log U/mL) 5.5 Creatinine (mg/dL) 0.45 HBV genotype C auto-PBSCT: autologous peripheral blood stem cell transplantation, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, HBsAg: hepatitis B surface antigen, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen One month later, elevated HBV-DNA (8.0 log IU/mL) and transaminase levels (AST 35 IU/L; ALT 37 IU/L) were found (Fig. 1). She was started on TAF. Her peak transaminase levels were observed 1 month after treatment initiation (AST 445 IU/L; ALT 640 IU/L). A liver biopsy revealed slight cross-linked fibrosis between portal veins and a lymphocyte infiltrate in the portal vein area, with a moderate degree of inflammation (Fig. 2). During the course of TAF therapy, the patient's transaminase and HBV-DNA levels gradually decreased. After five months, HBV-DNA, and HBs-Ag were no longer detectable, while the HBs-Ab became positive. However, HBcrAg remained detectable and this, TAF therapy continued. Figure 1. Clinical course of the patient’s condition. Solid thick black arrow indicates the time of liver biopsy. Solid think black arrows indicate the time of chemotherapy including rituximab and auto-PBSCT. auto-PBSCT: autologous peripheral blood stem cell transplantation Figure 2. Histological findings of the liver biopsy specimen. (A) Moderate lymphocytic infiltrate is observed in the portal areas of hepatic lobules with slightly piecemeal necrosis (Hematoxylin and Eosin staining; magnification, ×100) (B) Slight portal fibrosis with portal-to-portal bridging. (Masson’s trichrome staining; magnification, ×100). Discussion In this case, the patient developed hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. HBV reactivation is a common and potentially fatal complication in patients with past HBV infection undergoing immunosuppressive therapy (1-3). Patients receiving chemotherapy, including rituximab and auto-PBSCT, are at a high risk of HBV reactivation (4-6). To prevent HBV reactivation in patients receiving HSCT, the Japan Society of Hepatology (JSH) guidelines recommend that monthly HBV-DNA monitoring be performed during treatment and for at least 12 months after its completion. It also recommends long-term HBV-DNA monitoring after HSCT. HBV reactivation is not uncommon in HSCT recipients. In particular, patients undergoing allo-HSCT are at a very high risk of HBV reactivation, and the time interval between transplantation and HBs-Ag conversion can be long (8,9). The risk of HBV reactivation is lower with auto-HSCT than with allo-HSCT (7); however, the rate of reactivation is still 5.4-16.7% in patients with resolved HBV infection (7,10,11). Rare cases have been reported where HBV reactivation occurred more than 1 year after auto-HSCT (12,13) (Table 2). Auto-HSCT is accepted as a comparatively effective treatment for blood diseases, and the current protocol for patients receiving auto-HSCT therapy is to source stem cells from peripheral blood (14). Our patient developed de novo hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. This prompts us to question the current recommended timeframe of viral load monitoring in HSCT recipient. The prophylactic use of NA in HBs-Ag negative, HBc-Ab positive HSCT recipients is recommended by the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) guidelines (5,6), although the optimal duration of prophylaxis is not known. The incidence of HBV reactivation after HSCT in patients with resolved HBV infection is about 40% (9), suggesting that more than half of HSCT patients do not require NA prophylactic administration. Thus, NA prophylaxis for all patients may not be an economically sound option. Recently, it has been reported that an ultra-high sensitivity HBsAg assay can become an alternative method to diagnose HBV reactivation, because such an assay is quick, easy, and effective (15). As reported in this study, the ultra-high sensitivity HBsAg assay has been useful for long-term follow-ups. Table 2. Presenting Clinical Features of 3 Cases of HBV Reactivation in Resolved HBV Patients after Auto-HSCT and Our Patient. No Disease Sex Age Anti-HBs Period to reactivation Peak HBV DNA (log IU/mL) Peak ALT (IU/L) Treatment of reactivation Evolution Reference 1 HL M 68 Positive 18 months >8.2 ×2UNL TDF Resolved [12] 2 MM F 72 Negative 12 months 7.2 21 LMV Resolved [13] 3 MM M 60 Positive 20 months 6.7 261 No treatment Resolved [13] 4 DLBCL F 54 Positive 55 months 8.0 640 TAF Resolved Our case auto-HSCT: autologous hematopoietic stem cell transplantation, anti HBs: anti-hepatitis B surface, HL: hodgkin’s lymphoma, MM: multiple myeloma, DLBCL: diffuse large B-cell lymphoma, ULN: upper limited normal, TDF: tenofovir disoproxil fumarate, LMV: lamivudine, TAF: tenofovir alafenamide fumarate, HBV: hepatitis B virus As HBV reactivation is a well-known risk for patients receiving immunosuppressive therapy; most patients with past HBV infection are monitored for HBV markers carefully or receive anti-HBV prophylaxis. By adopting this strategy, there have been few reports of pathological HBV reactivation with severe acute fatal hepatitis (16-18). Although the timing of liver biopsy from the onset of de novo hepatitis is almost unchanged, fibrosis was more advanced than that observed in previous cases receiving immunosuppressive therapy for preventing graft-versus-host disease (17,18). The patient in this study did not require receive immunosuppressive therapy, reported to improve clinicopathologic findings for severe hepatitis (19), following the treatment. It has been reported that hepatic fibrosis does not progress after HBsAg seroclearance (20,21), and that fibrosis or chronic changes may sometimes occur before HBV seroclearance. Further study is needed regarding the histopathology, including the progression of liver fibrosis, in patients with HBV reactivation to address these issues. Certain virologic features have been linked to HBV reactivation. For instance, mutations in the core promoter region (A1762T and G1764A) and in the precore region (G1896A) are reported to be associated with HBV reactivation (22,23). Additionally, a recent study used next-generation sequencing and showed that mutation in the precore region (G1899A) are also associated with HBV reactivation (24). Further studies are required to elucidate the mechanisms that contribute to such virologic features in HBV reactivation. In the latest JSH, EASL, and AASLD guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF are recommended as first line anti-HBV treatments for prophylaxis against HBV reactivation (4-6). TAF has demonstrated safety and efficacy in achieving viral suppression in patients with chronic hepatitis B (25-27). In our patient, TAF was used effectively and safely against de novo hepatitis B. Tamori et al. (28) suggested that NA therapy can be discontinued in patients with HBV reactivation after the HBs-Ab test shows consistent positive results. In our patient, the HBs-Ab test was positive, but HBcr-Ag remained detectable. HBcr-Ag is considered a marker of intrahepatic HBV [covalently closed circular DNA (cccDNA)], and serum HBcrAg positivity is a risk factor for HBV reactivation in patients undergoing immunosuppressive therapy (29). As such, our findings suggest that TAF therapy should be continued until serum HBcrAg becomes undetectable. In conclusion, we herein described a case of HBV reactivation 55 months after chemotherapy including rituximab and auto-PBSCT. In such high-risk cases, the recommended guidelines should be followed, and careful long-term follow-ups, including the possibility of lifelong observation, are warranted. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to all members for the Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital.	CYCLOPHOSPHAMIDE, CYTARABINE, DEXAMETHASONE, DOXORUBICIN, ETOPOSIDE, MELPHALAN, METHOTREXATE SODIUM, PREDNISOLONE SODIUM SUCCINATE, PROCARBAZINE, RITUXIMAB, VINCRISTINE	DrugsGivenReaction	CC BY-NC-ND	32963163	18,381,225	2021-02-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis'.	Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation. Introduction Hepatitis B virus (HBV) reactivation has emerged as a major complication induced by long-term chemotherapy or immunosuppressive therapy (1). De novo hepatitis B, a form of HBV reactivation, can occur as a result of the reactivation of latent HBV infection in subjects who are negative for hepatitis B surface antigen (HBs-Ag), but positive for anti-hepatitis B core antibody (HBc-Ab), anti-HBs antibody (HBs-Ab) or both (2,3). It is well known that patients receiving chemotherapy, including rituximab and hematopoietic stem cell transplantation (HSCT), are at high risk of HBV reactivation (4-6). Among HSCT recipients with resolved HBV, the risk of HBV reactivation is higher with allogeneic HSCT (allo-HSCT) than with autologous HSCT (auto-HSCT) (7). HBV reactivation usually develops a few months after chemotherapy or immunosuppressive therapy. Long-term HBV-DNA monitoring after transplantation is recommended (4), because the time interval between HSCT and HBsAg-positive conversion can be long. However, currently, there is no definitive indication for how long the viral load should be monitored in such cases. We herein present the case of a patient who experienced HBV reactivation 55 months after chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT), and de novo hepatitis B improved with tenofovir alafenamide fumarate (TAF) therapy. Case Report A 54-year old woman presented to our hospital with a continuous low-grade fever. Her workup revealed stage IVB diffuse large B-cell lymphoma (DLBCL). Her laboratory findings were negative for HBs-Ag and HBV-DNA, but was positive for HBs-Ab and HBc-Ab. She had no family history of HBV infection. She underwent 4 courses of rituximab, cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (R-CHOP) therapy, 2 courses of rituximab, methotrexate, procarbazine, and VCR (R-MPV) therapy, 1 course of rituximab, CPM, doxorubicin, etoposide, vincristine, and prednisolone (R-CHOEP) therapy, and 2 courses of rituximab, CPM, high-dose cytarabine, dexametazone, and etoposide (R-CHASE) therapy. Furthermore, she underwent one course of rituximab, melphalan, CPM, etoposide, and dexametazone (R-LEED) therapy, and auto-PBSCT. She achieved complete remission. During the period of chemotherapy and auto-PBSCT, her serum level of HBV-DNA remained undetectable. After chemotherapy and auto-PBSCT, she was monitored regularly every 1-3 months and was not receiving immunosuppressive therapy. Her serum HBV-DNA levels became positive 55 months after the last treatment, increasing to 4.1 log IU/mL. HBs-Ag, hepatitis B envelope antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) also became positive without elevation of serum transaminase. The HBV genotype was group C (Table 1). She had no history of blood transfusion and was sexually inactive. We diagnosed her to have HBV reactivation. Although we recommended that she start nucleotide analogue therapy (NA), she refused and requested a reexamination one month later. Table 1. Laboratory Findings at 55 Months Following Chemotherapy and Auto-PBSCT. Variable Variable White blood cells (/µL) 4,140 Total bilirubin (mg/dL) 0.5 Red blood cells (104/µL) 355 AST (IU/L) 21 Hematocrit (%) 33.6 ALT (IU/L) 19 Hemoglobin (g/dL) 11.2 LDH (IU/L) 154 Platelets (104/µL) 28.0 ALP (IU/L) 240 PT-INR 1.01 GGT (IU/L) 41 PT (%) 97 HBsAg (IU/mL) 4.63 Total protein (g/dL) 6.9 HBV-DNA (log IU/mL) 4.1 Alubmin (g/dL) 3.8 HBeAg 11.4 C-reactive protein (mg/dL) 1.26 HBeAb (%) 0.1 BUN (mg/dL) 14 HBcrAg (log U/mL) 5.5 Creatinine (mg/dL) 0.45 HBV genotype C auto-PBSCT: autologous peripheral blood stem cell transplantation, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, HBsAg: hepatitis B surface antigen, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen One month later, elevated HBV-DNA (8.0 log IU/mL) and transaminase levels (AST 35 IU/L; ALT 37 IU/L) were found (Fig. 1). She was started on TAF. Her peak transaminase levels were observed 1 month after treatment initiation (AST 445 IU/L; ALT 640 IU/L). A liver biopsy revealed slight cross-linked fibrosis between portal veins and a lymphocyte infiltrate in the portal vein area, with a moderate degree of inflammation (Fig. 2). During the course of TAF therapy, the patient's transaminase and HBV-DNA levels gradually decreased. After five months, HBV-DNA, and HBs-Ag were no longer detectable, while the HBs-Ab became positive. However, HBcrAg remained detectable and this, TAF therapy continued. Figure 1. Clinical course of the patient’s condition. Solid thick black arrow indicates the time of liver biopsy. Solid think black arrows indicate the time of chemotherapy including rituximab and auto-PBSCT. auto-PBSCT: autologous peripheral blood stem cell transplantation Figure 2. Histological findings of the liver biopsy specimen. (A) Moderate lymphocytic infiltrate is observed in the portal areas of hepatic lobules with slightly piecemeal necrosis (Hematoxylin and Eosin staining; magnification, ×100) (B) Slight portal fibrosis with portal-to-portal bridging. (Masson’s trichrome staining; magnification, ×100). Discussion In this case, the patient developed hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. HBV reactivation is a common and potentially fatal complication in patients with past HBV infection undergoing immunosuppressive therapy (1-3). Patients receiving chemotherapy, including rituximab and auto-PBSCT, are at a high risk of HBV reactivation (4-6). To prevent HBV reactivation in patients receiving HSCT, the Japan Society of Hepatology (JSH) guidelines recommend that monthly HBV-DNA monitoring be performed during treatment and for at least 12 months after its completion. It also recommends long-term HBV-DNA monitoring after HSCT. HBV reactivation is not uncommon in HSCT recipients. In particular, patients undergoing allo-HSCT are at a very high risk of HBV reactivation, and the time interval between transplantation and HBs-Ag conversion can be long (8,9). The risk of HBV reactivation is lower with auto-HSCT than with allo-HSCT (7); however, the rate of reactivation is still 5.4-16.7% in patients with resolved HBV infection (7,10,11). Rare cases have been reported where HBV reactivation occurred more than 1 year after auto-HSCT (12,13) (Table 2). Auto-HSCT is accepted as a comparatively effective treatment for blood diseases, and the current protocol for patients receiving auto-HSCT therapy is to source stem cells from peripheral blood (14). Our patient developed de novo hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. This prompts us to question the current recommended timeframe of viral load monitoring in HSCT recipient. The prophylactic use of NA in HBs-Ag negative, HBc-Ab positive HSCT recipients is recommended by the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) guidelines (5,6), although the optimal duration of prophylaxis is not known. The incidence of HBV reactivation after HSCT in patients with resolved HBV infection is about 40% (9), suggesting that more than half of HSCT patients do not require NA prophylactic administration. Thus, NA prophylaxis for all patients may not be an economically sound option. Recently, it has been reported that an ultra-high sensitivity HBsAg assay can become an alternative method to diagnose HBV reactivation, because such an assay is quick, easy, and effective (15). As reported in this study, the ultra-high sensitivity HBsAg assay has been useful for long-term follow-ups. Table 2. Presenting Clinical Features of 3 Cases of HBV Reactivation in Resolved HBV Patients after Auto-HSCT and Our Patient. No Disease Sex Age Anti-HBs Period to reactivation Peak HBV DNA (log IU/mL) Peak ALT (IU/L) Treatment of reactivation Evolution Reference 1 HL M 68 Positive 18 months >8.2 ×2UNL TDF Resolved [12] 2 MM F 72 Negative 12 months 7.2 21 LMV Resolved [13] 3 MM M 60 Positive 20 months 6.7 261 No treatment Resolved [13] 4 DLBCL F 54 Positive 55 months 8.0 640 TAF Resolved Our case auto-HSCT: autologous hematopoietic stem cell transplantation, anti HBs: anti-hepatitis B surface, HL: hodgkin’s lymphoma, MM: multiple myeloma, DLBCL: diffuse large B-cell lymphoma, ULN: upper limited normal, TDF: tenofovir disoproxil fumarate, LMV: lamivudine, TAF: tenofovir alafenamide fumarate, HBV: hepatitis B virus As HBV reactivation is a well-known risk for patients receiving immunosuppressive therapy; most patients with past HBV infection are monitored for HBV markers carefully or receive anti-HBV prophylaxis. By adopting this strategy, there have been few reports of pathological HBV reactivation with severe acute fatal hepatitis (16-18). Although the timing of liver biopsy from the onset of de novo hepatitis is almost unchanged, fibrosis was more advanced than that observed in previous cases receiving immunosuppressive therapy for preventing graft-versus-host disease (17,18). The patient in this study did not require receive immunosuppressive therapy, reported to improve clinicopathologic findings for severe hepatitis (19), following the treatment. It has been reported that hepatic fibrosis does not progress after HBsAg seroclearance (20,21), and that fibrosis or chronic changes may sometimes occur before HBV seroclearance. Further study is needed regarding the histopathology, including the progression of liver fibrosis, in patients with HBV reactivation to address these issues. Certain virologic features have been linked to HBV reactivation. For instance, mutations in the core promoter region (A1762T and G1764A) and in the precore region (G1896A) are reported to be associated with HBV reactivation (22,23). Additionally, a recent study used next-generation sequencing and showed that mutation in the precore region (G1899A) are also associated with HBV reactivation (24). Further studies are required to elucidate the mechanisms that contribute to such virologic features in HBV reactivation. In the latest JSH, EASL, and AASLD guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF are recommended as first line anti-HBV treatments for prophylaxis against HBV reactivation (4-6). TAF has demonstrated safety and efficacy in achieving viral suppression in patients with chronic hepatitis B (25-27). In our patient, TAF was used effectively and safely against de novo hepatitis B. Tamori et al. (28) suggested that NA therapy can be discontinued in patients with HBV reactivation after the HBs-Ab test shows consistent positive results. In our patient, the HBs-Ab test was positive, but HBcr-Ag remained detectable. HBcr-Ag is considered a marker of intrahepatic HBV [covalently closed circular DNA (cccDNA)], and serum HBcrAg positivity is a risk factor for HBV reactivation in patients undergoing immunosuppressive therapy (29). As such, our findings suggest that TAF therapy should be continued until serum HBcrAg becomes undetectable. In conclusion, we herein described a case of HBV reactivation 55 months after chemotherapy including rituximab and auto-PBSCT. In such high-risk cases, the recommended guidelines should be followed, and careful long-term follow-ups, including the possibility of lifelong observation, are warranted. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to all members for the Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital.	CYCLOPHOSPHAMIDE, CYTARABINE, DEXAMETHASONE, DOXORUBICIN, ETOPOSIDE, MELPHALAN, METHOTREXATE SODIUM, PREDNISOLONE SODIUM SUCCINATE, PROCARBAZINE, RITUXIMAB, VINCRISTINE	DrugsGivenReaction	CC BY-NC-ND	32963163	18,381,225	2021-02-01
What was the dosage of drug 'MELPHALAN'?	Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation. Introduction Hepatitis B virus (HBV) reactivation has emerged as a major complication induced by long-term chemotherapy or immunosuppressive therapy (1). De novo hepatitis B, a form of HBV reactivation, can occur as a result of the reactivation of latent HBV infection in subjects who are negative for hepatitis B surface antigen (HBs-Ag), but positive for anti-hepatitis B core antibody (HBc-Ab), anti-HBs antibody (HBs-Ab) or both (2,3). It is well known that patients receiving chemotherapy, including rituximab and hematopoietic stem cell transplantation (HSCT), are at high risk of HBV reactivation (4-6). Among HSCT recipients with resolved HBV, the risk of HBV reactivation is higher with allogeneic HSCT (allo-HSCT) than with autologous HSCT (auto-HSCT) (7). HBV reactivation usually develops a few months after chemotherapy or immunosuppressive therapy. Long-term HBV-DNA monitoring after transplantation is recommended (4), because the time interval between HSCT and HBsAg-positive conversion can be long. However, currently, there is no definitive indication for how long the viral load should be monitored in such cases. We herein present the case of a patient who experienced HBV reactivation 55 months after chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT), and de novo hepatitis B improved with tenofovir alafenamide fumarate (TAF) therapy. Case Report A 54-year old woman presented to our hospital with a continuous low-grade fever. Her workup revealed stage IVB diffuse large B-cell lymphoma (DLBCL). Her laboratory findings were negative for HBs-Ag and HBV-DNA, but was positive for HBs-Ab and HBc-Ab. She had no family history of HBV infection. She underwent 4 courses of rituximab, cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (R-CHOP) therapy, 2 courses of rituximab, methotrexate, procarbazine, and VCR (R-MPV) therapy, 1 course of rituximab, CPM, doxorubicin, etoposide, vincristine, and prednisolone (R-CHOEP) therapy, and 2 courses of rituximab, CPM, high-dose cytarabine, dexametazone, and etoposide (R-CHASE) therapy. Furthermore, she underwent one course of rituximab, melphalan, CPM, etoposide, and dexametazone (R-LEED) therapy, and auto-PBSCT. She achieved complete remission. During the period of chemotherapy and auto-PBSCT, her serum level of HBV-DNA remained undetectable. After chemotherapy and auto-PBSCT, she was monitored regularly every 1-3 months and was not receiving immunosuppressive therapy. Her serum HBV-DNA levels became positive 55 months after the last treatment, increasing to 4.1 log IU/mL. HBs-Ag, hepatitis B envelope antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) also became positive without elevation of serum transaminase. The HBV genotype was group C (Table 1). She had no history of blood transfusion and was sexually inactive. We diagnosed her to have HBV reactivation. Although we recommended that she start nucleotide analogue therapy (NA), she refused and requested a reexamination one month later. Table 1. Laboratory Findings at 55 Months Following Chemotherapy and Auto-PBSCT. Variable Variable White blood cells (/µL) 4,140 Total bilirubin (mg/dL) 0.5 Red blood cells (104/µL) 355 AST (IU/L) 21 Hematocrit (%) 33.6 ALT (IU/L) 19 Hemoglobin (g/dL) 11.2 LDH (IU/L) 154 Platelets (104/µL) 28.0 ALP (IU/L) 240 PT-INR 1.01 GGT (IU/L) 41 PT (%) 97 HBsAg (IU/mL) 4.63 Total protein (g/dL) 6.9 HBV-DNA (log IU/mL) 4.1 Alubmin (g/dL) 3.8 HBeAg 11.4 C-reactive protein (mg/dL) 1.26 HBeAb (%) 0.1 BUN (mg/dL) 14 HBcrAg (log U/mL) 5.5 Creatinine (mg/dL) 0.45 HBV genotype C auto-PBSCT: autologous peripheral blood stem cell transplantation, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, HBsAg: hepatitis B surface antigen, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen One month later, elevated HBV-DNA (8.0 log IU/mL) and transaminase levels (AST 35 IU/L; ALT 37 IU/L) were found (Fig. 1). She was started on TAF. Her peak transaminase levels were observed 1 month after treatment initiation (AST 445 IU/L; ALT 640 IU/L). A liver biopsy revealed slight cross-linked fibrosis between portal veins and a lymphocyte infiltrate in the portal vein area, with a moderate degree of inflammation (Fig. 2). During the course of TAF therapy, the patient's transaminase and HBV-DNA levels gradually decreased. After five months, HBV-DNA, and HBs-Ag were no longer detectable, while the HBs-Ab became positive. However, HBcrAg remained detectable and this, TAF therapy continued. Figure 1. Clinical course of the patient’s condition. Solid thick black arrow indicates the time of liver biopsy. Solid think black arrows indicate the time of chemotherapy including rituximab and auto-PBSCT. auto-PBSCT: autologous peripheral blood stem cell transplantation Figure 2. Histological findings of the liver biopsy specimen. (A) Moderate lymphocytic infiltrate is observed in the portal areas of hepatic lobules with slightly piecemeal necrosis (Hematoxylin and Eosin staining; magnification, ×100) (B) Slight portal fibrosis with portal-to-portal bridging. (Masson’s trichrome staining; magnification, ×100). Discussion In this case, the patient developed hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. HBV reactivation is a common and potentially fatal complication in patients with past HBV infection undergoing immunosuppressive therapy (1-3). Patients receiving chemotherapy, including rituximab and auto-PBSCT, are at a high risk of HBV reactivation (4-6). To prevent HBV reactivation in patients receiving HSCT, the Japan Society of Hepatology (JSH) guidelines recommend that monthly HBV-DNA monitoring be performed during treatment and for at least 12 months after its completion. It also recommends long-term HBV-DNA monitoring after HSCT. HBV reactivation is not uncommon in HSCT recipients. In particular, patients undergoing allo-HSCT are at a very high risk of HBV reactivation, and the time interval between transplantation and HBs-Ag conversion can be long (8,9). The risk of HBV reactivation is lower with auto-HSCT than with allo-HSCT (7); however, the rate of reactivation is still 5.4-16.7% in patients with resolved HBV infection (7,10,11). Rare cases have been reported where HBV reactivation occurred more than 1 year after auto-HSCT (12,13) (Table 2). Auto-HSCT is accepted as a comparatively effective treatment for blood diseases, and the current protocol for patients receiving auto-HSCT therapy is to source stem cells from peripheral blood (14). Our patient developed de novo hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. This prompts us to question the current recommended timeframe of viral load monitoring in HSCT recipient. The prophylactic use of NA in HBs-Ag negative, HBc-Ab positive HSCT recipients is recommended by the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) guidelines (5,6), although the optimal duration of prophylaxis is not known. The incidence of HBV reactivation after HSCT in patients with resolved HBV infection is about 40% (9), suggesting that more than half of HSCT patients do not require NA prophylactic administration. Thus, NA prophylaxis for all patients may not be an economically sound option. Recently, it has been reported that an ultra-high sensitivity HBsAg assay can become an alternative method to diagnose HBV reactivation, because such an assay is quick, easy, and effective (15). As reported in this study, the ultra-high sensitivity HBsAg assay has been useful for long-term follow-ups. Table 2. Presenting Clinical Features of 3 Cases of HBV Reactivation in Resolved HBV Patients after Auto-HSCT and Our Patient. No Disease Sex Age Anti-HBs Period to reactivation Peak HBV DNA (log IU/mL) Peak ALT (IU/L) Treatment of reactivation Evolution Reference 1 HL M 68 Positive 18 months >8.2 ×2UNL TDF Resolved [12] 2 MM F 72 Negative 12 months 7.2 21 LMV Resolved [13] 3 MM M 60 Positive 20 months 6.7 261 No treatment Resolved [13] 4 DLBCL F 54 Positive 55 months 8.0 640 TAF Resolved Our case auto-HSCT: autologous hematopoietic stem cell transplantation, anti HBs: anti-hepatitis B surface, HL: hodgkin’s lymphoma, MM: multiple myeloma, DLBCL: diffuse large B-cell lymphoma, ULN: upper limited normal, TDF: tenofovir disoproxil fumarate, LMV: lamivudine, TAF: tenofovir alafenamide fumarate, HBV: hepatitis B virus As HBV reactivation is a well-known risk for patients receiving immunosuppressive therapy; most patients with past HBV infection are monitored for HBV markers carefully or receive anti-HBV prophylaxis. By adopting this strategy, there have been few reports of pathological HBV reactivation with severe acute fatal hepatitis (16-18). Although the timing of liver biopsy from the onset of de novo hepatitis is almost unchanged, fibrosis was more advanced than that observed in previous cases receiving immunosuppressive therapy for preventing graft-versus-host disease (17,18). The patient in this study did not require receive immunosuppressive therapy, reported to improve clinicopathologic findings for severe hepatitis (19), following the treatment. It has been reported that hepatic fibrosis does not progress after HBsAg seroclearance (20,21), and that fibrosis or chronic changes may sometimes occur before HBV seroclearance. Further study is needed regarding the histopathology, including the progression of liver fibrosis, in patients with HBV reactivation to address these issues. Certain virologic features have been linked to HBV reactivation. For instance, mutations in the core promoter region (A1762T and G1764A) and in the precore region (G1896A) are reported to be associated with HBV reactivation (22,23). Additionally, a recent study used next-generation sequencing and showed that mutation in the precore region (G1899A) are also associated with HBV reactivation (24). Further studies are required to elucidate the mechanisms that contribute to such virologic features in HBV reactivation. In the latest JSH, EASL, and AASLD guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF are recommended as first line anti-HBV treatments for prophylaxis against HBV reactivation (4-6). TAF has demonstrated safety and efficacy in achieving viral suppression in patients with chronic hepatitis B (25-27). In our patient, TAF was used effectively and safely against de novo hepatitis B. Tamori et al. (28) suggested that NA therapy can be discontinued in patients with HBV reactivation after the HBs-Ab test shows consistent positive results. In our patient, the HBs-Ab test was positive, but HBcr-Ag remained detectable. HBcr-Ag is considered a marker of intrahepatic HBV [covalently closed circular DNA (cccDNA)], and serum HBcrAg positivity is a risk factor for HBV reactivation in patients undergoing immunosuppressive therapy (29). As such, our findings suggest that TAF therapy should be continued until serum HBcrAg becomes undetectable. In conclusion, we herein described a case of HBV reactivation 55 months after chemotherapy including rituximab and auto-PBSCT. In such high-risk cases, the recommended guidelines should be followed, and careful long-term follow-ups, including the possibility of lifelong observation, are warranted. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to all members for the Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital.	UNK UNK, CYCLIC (1 COURSE OF R?LEED THERAPY)	DrugDosageText	CC BY-NC-ND	32963163	18,381,225	2021-02-01
What was the dosage of drug 'METHOTREXATE SODIUM'?	Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation. Introduction Hepatitis B virus (HBV) reactivation has emerged as a major complication induced by long-term chemotherapy or immunosuppressive therapy (1). De novo hepatitis B, a form of HBV reactivation, can occur as a result of the reactivation of latent HBV infection in subjects who are negative for hepatitis B surface antigen (HBs-Ag), but positive for anti-hepatitis B core antibody (HBc-Ab), anti-HBs antibody (HBs-Ab) or both (2,3). It is well known that patients receiving chemotherapy, including rituximab and hematopoietic stem cell transplantation (HSCT), are at high risk of HBV reactivation (4-6). Among HSCT recipients with resolved HBV, the risk of HBV reactivation is higher with allogeneic HSCT (allo-HSCT) than with autologous HSCT (auto-HSCT) (7). HBV reactivation usually develops a few months after chemotherapy or immunosuppressive therapy. Long-term HBV-DNA monitoring after transplantation is recommended (4), because the time interval between HSCT and HBsAg-positive conversion can be long. However, currently, there is no definitive indication for how long the viral load should be monitored in such cases. We herein present the case of a patient who experienced HBV reactivation 55 months after chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT), and de novo hepatitis B improved with tenofovir alafenamide fumarate (TAF) therapy. Case Report A 54-year old woman presented to our hospital with a continuous low-grade fever. Her workup revealed stage IVB diffuse large B-cell lymphoma (DLBCL). Her laboratory findings were negative for HBs-Ag and HBV-DNA, but was positive for HBs-Ab and HBc-Ab. She had no family history of HBV infection. She underwent 4 courses of rituximab, cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (R-CHOP) therapy, 2 courses of rituximab, methotrexate, procarbazine, and VCR (R-MPV) therapy, 1 course of rituximab, CPM, doxorubicin, etoposide, vincristine, and prednisolone (R-CHOEP) therapy, and 2 courses of rituximab, CPM, high-dose cytarabine, dexametazone, and etoposide (R-CHASE) therapy. Furthermore, she underwent one course of rituximab, melphalan, CPM, etoposide, and dexametazone (R-LEED) therapy, and auto-PBSCT. She achieved complete remission. During the period of chemotherapy and auto-PBSCT, her serum level of HBV-DNA remained undetectable. After chemotherapy and auto-PBSCT, she was monitored regularly every 1-3 months and was not receiving immunosuppressive therapy. Her serum HBV-DNA levels became positive 55 months after the last treatment, increasing to 4.1 log IU/mL. HBs-Ag, hepatitis B envelope antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) also became positive without elevation of serum transaminase. The HBV genotype was group C (Table 1). She had no history of blood transfusion and was sexually inactive. We diagnosed her to have HBV reactivation. Although we recommended that she start nucleotide analogue therapy (NA), she refused and requested a reexamination one month later. Table 1. Laboratory Findings at 55 Months Following Chemotherapy and Auto-PBSCT. Variable Variable White blood cells (/µL) 4,140 Total bilirubin (mg/dL) 0.5 Red blood cells (104/µL) 355 AST (IU/L) 21 Hematocrit (%) 33.6 ALT (IU/L) 19 Hemoglobin (g/dL) 11.2 LDH (IU/L) 154 Platelets (104/µL) 28.0 ALP (IU/L) 240 PT-INR 1.01 GGT (IU/L) 41 PT (%) 97 HBsAg (IU/mL) 4.63 Total protein (g/dL) 6.9 HBV-DNA (log IU/mL) 4.1 Alubmin (g/dL) 3.8 HBeAg 11.4 C-reactive protein (mg/dL) 1.26 HBeAb (%) 0.1 BUN (mg/dL) 14 HBcrAg (log U/mL) 5.5 Creatinine (mg/dL) 0.45 HBV genotype C auto-PBSCT: autologous peripheral blood stem cell transplantation, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, HBsAg: hepatitis B surface antigen, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen One month later, elevated HBV-DNA (8.0 log IU/mL) and transaminase levels (AST 35 IU/L; ALT 37 IU/L) were found (Fig. 1). She was started on TAF. Her peak transaminase levels were observed 1 month after treatment initiation (AST 445 IU/L; ALT 640 IU/L). A liver biopsy revealed slight cross-linked fibrosis between portal veins and a lymphocyte infiltrate in the portal vein area, with a moderate degree of inflammation (Fig. 2). During the course of TAF therapy, the patient's transaminase and HBV-DNA levels gradually decreased. After five months, HBV-DNA, and HBs-Ag were no longer detectable, while the HBs-Ab became positive. However, HBcrAg remained detectable and this, TAF therapy continued. Figure 1. Clinical course of the patient’s condition. Solid thick black arrow indicates the time of liver biopsy. Solid think black arrows indicate the time of chemotherapy including rituximab and auto-PBSCT. auto-PBSCT: autologous peripheral blood stem cell transplantation Figure 2. Histological findings of the liver biopsy specimen. (A) Moderate lymphocytic infiltrate is observed in the portal areas of hepatic lobules with slightly piecemeal necrosis (Hematoxylin and Eosin staining; magnification, ×100) (B) Slight portal fibrosis with portal-to-portal bridging. (Masson’s trichrome staining; magnification, ×100). Discussion In this case, the patient developed hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. HBV reactivation is a common and potentially fatal complication in patients with past HBV infection undergoing immunosuppressive therapy (1-3). Patients receiving chemotherapy, including rituximab and auto-PBSCT, are at a high risk of HBV reactivation (4-6). To prevent HBV reactivation in patients receiving HSCT, the Japan Society of Hepatology (JSH) guidelines recommend that monthly HBV-DNA monitoring be performed during treatment and for at least 12 months after its completion. It also recommends long-term HBV-DNA monitoring after HSCT. HBV reactivation is not uncommon in HSCT recipients. In particular, patients undergoing allo-HSCT are at a very high risk of HBV reactivation, and the time interval between transplantation and HBs-Ag conversion can be long (8,9). The risk of HBV reactivation is lower with auto-HSCT than with allo-HSCT (7); however, the rate of reactivation is still 5.4-16.7% in patients with resolved HBV infection (7,10,11). Rare cases have been reported where HBV reactivation occurred more than 1 year after auto-HSCT (12,13) (Table 2). Auto-HSCT is accepted as a comparatively effective treatment for blood diseases, and the current protocol for patients receiving auto-HSCT therapy is to source stem cells from peripheral blood (14). Our patient developed de novo hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. This prompts us to question the current recommended timeframe of viral load monitoring in HSCT recipient. The prophylactic use of NA in HBs-Ag negative, HBc-Ab positive HSCT recipients is recommended by the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) guidelines (5,6), although the optimal duration of prophylaxis is not known. The incidence of HBV reactivation after HSCT in patients with resolved HBV infection is about 40% (9), suggesting that more than half of HSCT patients do not require NA prophylactic administration. Thus, NA prophylaxis for all patients may not be an economically sound option. Recently, it has been reported that an ultra-high sensitivity HBsAg assay can become an alternative method to diagnose HBV reactivation, because such an assay is quick, easy, and effective (15). As reported in this study, the ultra-high sensitivity HBsAg assay has been useful for long-term follow-ups. Table 2. Presenting Clinical Features of 3 Cases of HBV Reactivation in Resolved HBV Patients after Auto-HSCT and Our Patient. No Disease Sex Age Anti-HBs Period to reactivation Peak HBV DNA (log IU/mL) Peak ALT (IU/L) Treatment of reactivation Evolution Reference 1 HL M 68 Positive 18 months >8.2 ×2UNL TDF Resolved [12] 2 MM F 72 Negative 12 months 7.2 21 LMV Resolved [13] 3 MM M 60 Positive 20 months 6.7 261 No treatment Resolved [13] 4 DLBCL F 54 Positive 55 months 8.0 640 TAF Resolved Our case auto-HSCT: autologous hematopoietic stem cell transplantation, anti HBs: anti-hepatitis B surface, HL: hodgkin’s lymphoma, MM: multiple myeloma, DLBCL: diffuse large B-cell lymphoma, ULN: upper limited normal, TDF: tenofovir disoproxil fumarate, LMV: lamivudine, TAF: tenofovir alafenamide fumarate, HBV: hepatitis B virus As HBV reactivation is a well-known risk for patients receiving immunosuppressive therapy; most patients with past HBV infection are monitored for HBV markers carefully or receive anti-HBV prophylaxis. By adopting this strategy, there have been few reports of pathological HBV reactivation with severe acute fatal hepatitis (16-18). Although the timing of liver biopsy from the onset of de novo hepatitis is almost unchanged, fibrosis was more advanced than that observed in previous cases receiving immunosuppressive therapy for preventing graft-versus-host disease (17,18). The patient in this study did not require receive immunosuppressive therapy, reported to improve clinicopathologic findings for severe hepatitis (19), following the treatment. It has been reported that hepatic fibrosis does not progress after HBsAg seroclearance (20,21), and that fibrosis or chronic changes may sometimes occur before HBV seroclearance. Further study is needed regarding the histopathology, including the progression of liver fibrosis, in patients with HBV reactivation to address these issues. Certain virologic features have been linked to HBV reactivation. For instance, mutations in the core promoter region (A1762T and G1764A) and in the precore region (G1896A) are reported to be associated with HBV reactivation (22,23). Additionally, a recent study used next-generation sequencing and showed that mutation in the precore region (G1899A) are also associated with HBV reactivation (24). Further studies are required to elucidate the mechanisms that contribute to such virologic features in HBV reactivation. In the latest JSH, EASL, and AASLD guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF are recommended as first line anti-HBV treatments for prophylaxis against HBV reactivation (4-6). TAF has demonstrated safety and efficacy in achieving viral suppression in patients with chronic hepatitis B (25-27). In our patient, TAF was used effectively and safely against de novo hepatitis B. Tamori et al. (28) suggested that NA therapy can be discontinued in patients with HBV reactivation after the HBs-Ab test shows consistent positive results. In our patient, the HBs-Ab test was positive, but HBcr-Ag remained detectable. HBcr-Ag is considered a marker of intrahepatic HBV [covalently closed circular DNA (cccDNA)], and serum HBcrAg positivity is a risk factor for HBV reactivation in patients undergoing immunosuppressive therapy (29). As such, our findings suggest that TAF therapy should be continued until serum HBcrAg becomes undetectable. In conclusion, we herein described a case of HBV reactivation 55 months after chemotherapy including rituximab and auto-PBSCT. In such high-risk cases, the recommended guidelines should be followed, and careful long-term follow-ups, including the possibility of lifelong observation, are warranted. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to all members for the Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital.	UNK UNK, CYCLIC (2 COURSES OF R?MPV THERAPY)	DrugDosageText	CC BY-NC-ND	32963163	18,381,225	2021-02-01
What was the dosage of drug 'PROCARBAZINE'?	Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation. Introduction Hepatitis B virus (HBV) reactivation has emerged as a major complication induced by long-term chemotherapy or immunosuppressive therapy (1). De novo hepatitis B, a form of HBV reactivation, can occur as a result of the reactivation of latent HBV infection in subjects who are negative for hepatitis B surface antigen (HBs-Ag), but positive for anti-hepatitis B core antibody (HBc-Ab), anti-HBs antibody (HBs-Ab) or both (2,3). It is well known that patients receiving chemotherapy, including rituximab and hematopoietic stem cell transplantation (HSCT), are at high risk of HBV reactivation (4-6). Among HSCT recipients with resolved HBV, the risk of HBV reactivation is higher with allogeneic HSCT (allo-HSCT) than with autologous HSCT (auto-HSCT) (7). HBV reactivation usually develops a few months after chemotherapy or immunosuppressive therapy. Long-term HBV-DNA monitoring after transplantation is recommended (4), because the time interval between HSCT and HBsAg-positive conversion can be long. However, currently, there is no definitive indication for how long the viral load should be monitored in such cases. We herein present the case of a patient who experienced HBV reactivation 55 months after chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT), and de novo hepatitis B improved with tenofovir alafenamide fumarate (TAF) therapy. Case Report A 54-year old woman presented to our hospital with a continuous low-grade fever. Her workup revealed stage IVB diffuse large B-cell lymphoma (DLBCL). Her laboratory findings were negative for HBs-Ag and HBV-DNA, but was positive for HBs-Ab and HBc-Ab. She had no family history of HBV infection. She underwent 4 courses of rituximab, cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (R-CHOP) therapy, 2 courses of rituximab, methotrexate, procarbazine, and VCR (R-MPV) therapy, 1 course of rituximab, CPM, doxorubicin, etoposide, vincristine, and prednisolone (R-CHOEP) therapy, and 2 courses of rituximab, CPM, high-dose cytarabine, dexametazone, and etoposide (R-CHASE) therapy. Furthermore, she underwent one course of rituximab, melphalan, CPM, etoposide, and dexametazone (R-LEED) therapy, and auto-PBSCT. She achieved complete remission. During the period of chemotherapy and auto-PBSCT, her serum level of HBV-DNA remained undetectable. After chemotherapy and auto-PBSCT, she was monitored regularly every 1-3 months and was not receiving immunosuppressive therapy. Her serum HBV-DNA levels became positive 55 months after the last treatment, increasing to 4.1 log IU/mL. HBs-Ag, hepatitis B envelope antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) also became positive without elevation of serum transaminase. The HBV genotype was group C (Table 1). She had no history of blood transfusion and was sexually inactive. We diagnosed her to have HBV reactivation. Although we recommended that she start nucleotide analogue therapy (NA), she refused and requested a reexamination one month later. Table 1. Laboratory Findings at 55 Months Following Chemotherapy and Auto-PBSCT. Variable Variable White blood cells (/µL) 4,140 Total bilirubin (mg/dL) 0.5 Red blood cells (104/µL) 355 AST (IU/L) 21 Hematocrit (%) 33.6 ALT (IU/L) 19 Hemoglobin (g/dL) 11.2 LDH (IU/L) 154 Platelets (104/µL) 28.0 ALP (IU/L) 240 PT-INR 1.01 GGT (IU/L) 41 PT (%) 97 HBsAg (IU/mL) 4.63 Total protein (g/dL) 6.9 HBV-DNA (log IU/mL) 4.1 Alubmin (g/dL) 3.8 HBeAg 11.4 C-reactive protein (mg/dL) 1.26 HBeAb (%) 0.1 BUN (mg/dL) 14 HBcrAg (log U/mL) 5.5 Creatinine (mg/dL) 0.45 HBV genotype C auto-PBSCT: autologous peripheral blood stem cell transplantation, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, HBsAg: hepatitis B surface antigen, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen One month later, elevated HBV-DNA (8.0 log IU/mL) and transaminase levels (AST 35 IU/L; ALT 37 IU/L) were found (Fig. 1). She was started on TAF. Her peak transaminase levels were observed 1 month after treatment initiation (AST 445 IU/L; ALT 640 IU/L). A liver biopsy revealed slight cross-linked fibrosis between portal veins and a lymphocyte infiltrate in the portal vein area, with a moderate degree of inflammation (Fig. 2). During the course of TAF therapy, the patient's transaminase and HBV-DNA levels gradually decreased. After five months, HBV-DNA, and HBs-Ag were no longer detectable, while the HBs-Ab became positive. However, HBcrAg remained detectable and this, TAF therapy continued. Figure 1. Clinical course of the patient’s condition. Solid thick black arrow indicates the time of liver biopsy. Solid think black arrows indicate the time of chemotherapy including rituximab and auto-PBSCT. auto-PBSCT: autologous peripheral blood stem cell transplantation Figure 2. Histological findings of the liver biopsy specimen. (A) Moderate lymphocytic infiltrate is observed in the portal areas of hepatic lobules with slightly piecemeal necrosis (Hematoxylin and Eosin staining; magnification, ×100) (B) Slight portal fibrosis with portal-to-portal bridging. (Masson’s trichrome staining; magnification, ×100). Discussion In this case, the patient developed hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. HBV reactivation is a common and potentially fatal complication in patients with past HBV infection undergoing immunosuppressive therapy (1-3). Patients receiving chemotherapy, including rituximab and auto-PBSCT, are at a high risk of HBV reactivation (4-6). To prevent HBV reactivation in patients receiving HSCT, the Japan Society of Hepatology (JSH) guidelines recommend that monthly HBV-DNA monitoring be performed during treatment and for at least 12 months after its completion. It also recommends long-term HBV-DNA monitoring after HSCT. HBV reactivation is not uncommon in HSCT recipients. In particular, patients undergoing allo-HSCT are at a very high risk of HBV reactivation, and the time interval between transplantation and HBs-Ag conversion can be long (8,9). The risk of HBV reactivation is lower with auto-HSCT than with allo-HSCT (7); however, the rate of reactivation is still 5.4-16.7% in patients with resolved HBV infection (7,10,11). Rare cases have been reported where HBV reactivation occurred more than 1 year after auto-HSCT (12,13) (Table 2). Auto-HSCT is accepted as a comparatively effective treatment for blood diseases, and the current protocol for patients receiving auto-HSCT therapy is to source stem cells from peripheral blood (14). Our patient developed de novo hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. This prompts us to question the current recommended timeframe of viral load monitoring in HSCT recipient. The prophylactic use of NA in HBs-Ag negative, HBc-Ab positive HSCT recipients is recommended by the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) guidelines (5,6), although the optimal duration of prophylaxis is not known. The incidence of HBV reactivation after HSCT in patients with resolved HBV infection is about 40% (9), suggesting that more than half of HSCT patients do not require NA prophylactic administration. Thus, NA prophylaxis for all patients may not be an economically sound option. Recently, it has been reported that an ultra-high sensitivity HBsAg assay can become an alternative method to diagnose HBV reactivation, because such an assay is quick, easy, and effective (15). As reported in this study, the ultra-high sensitivity HBsAg assay has been useful for long-term follow-ups. Table 2. Presenting Clinical Features of 3 Cases of HBV Reactivation in Resolved HBV Patients after Auto-HSCT and Our Patient. No Disease Sex Age Anti-HBs Period to reactivation Peak HBV DNA (log IU/mL) Peak ALT (IU/L) Treatment of reactivation Evolution Reference 1 HL M 68 Positive 18 months >8.2 ×2UNL TDF Resolved [12] 2 MM F 72 Negative 12 months 7.2 21 LMV Resolved [13] 3 MM M 60 Positive 20 months 6.7 261 No treatment Resolved [13] 4 DLBCL F 54 Positive 55 months 8.0 640 TAF Resolved Our case auto-HSCT: autologous hematopoietic stem cell transplantation, anti HBs: anti-hepatitis B surface, HL: hodgkin’s lymphoma, MM: multiple myeloma, DLBCL: diffuse large B-cell lymphoma, ULN: upper limited normal, TDF: tenofovir disoproxil fumarate, LMV: lamivudine, TAF: tenofovir alafenamide fumarate, HBV: hepatitis B virus As HBV reactivation is a well-known risk for patients receiving immunosuppressive therapy; most patients with past HBV infection are monitored for HBV markers carefully or receive anti-HBV prophylaxis. By adopting this strategy, there have been few reports of pathological HBV reactivation with severe acute fatal hepatitis (16-18). Although the timing of liver biopsy from the onset of de novo hepatitis is almost unchanged, fibrosis was more advanced than that observed in previous cases receiving immunosuppressive therapy for preventing graft-versus-host disease (17,18). The patient in this study did not require receive immunosuppressive therapy, reported to improve clinicopathologic findings for severe hepatitis (19), following the treatment. It has been reported that hepatic fibrosis does not progress after HBsAg seroclearance (20,21), and that fibrosis or chronic changes may sometimes occur before HBV seroclearance. Further study is needed regarding the histopathology, including the progression of liver fibrosis, in patients with HBV reactivation to address these issues. Certain virologic features have been linked to HBV reactivation. For instance, mutations in the core promoter region (A1762T and G1764A) and in the precore region (G1896A) are reported to be associated with HBV reactivation (22,23). Additionally, a recent study used next-generation sequencing and showed that mutation in the precore region (G1899A) are also associated with HBV reactivation (24). Further studies are required to elucidate the mechanisms that contribute to such virologic features in HBV reactivation. In the latest JSH, EASL, and AASLD guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF are recommended as first line anti-HBV treatments for prophylaxis against HBV reactivation (4-6). TAF has demonstrated safety and efficacy in achieving viral suppression in patients with chronic hepatitis B (25-27). In our patient, TAF was used effectively and safely against de novo hepatitis B. Tamori et al. (28) suggested that NA therapy can be discontinued in patients with HBV reactivation after the HBs-Ab test shows consistent positive results. In our patient, the HBs-Ab test was positive, but HBcr-Ag remained detectable. HBcr-Ag is considered a marker of intrahepatic HBV [covalently closed circular DNA (cccDNA)], and serum HBcrAg positivity is a risk factor for HBV reactivation in patients undergoing immunosuppressive therapy (29). As such, our findings suggest that TAF therapy should be continued until serum HBcrAg becomes undetectable. In conclusion, we herein described a case of HBV reactivation 55 months after chemotherapy including rituximab and auto-PBSCT. In such high-risk cases, the recommended guidelines should be followed, and careful long-term follow-ups, including the possibility of lifelong observation, are warranted. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to all members for the Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital.	UNK UNK, CYCLIC (2 COURSES OF R?MPV THERAPY)	DrugDosageText	CC BY-NC-ND	32963163	18,381,225	2021-02-01
What was the outcome of reaction 'Hepatitis B reactivation'?	Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation. Introduction Hepatitis B virus (HBV) reactivation has emerged as a major complication induced by long-term chemotherapy or immunosuppressive therapy (1). De novo hepatitis B, a form of HBV reactivation, can occur as a result of the reactivation of latent HBV infection in subjects who are negative for hepatitis B surface antigen (HBs-Ag), but positive for anti-hepatitis B core antibody (HBc-Ab), anti-HBs antibody (HBs-Ab) or both (2,3). It is well known that patients receiving chemotherapy, including rituximab and hematopoietic stem cell transplantation (HSCT), are at high risk of HBV reactivation (4-6). Among HSCT recipients with resolved HBV, the risk of HBV reactivation is higher with allogeneic HSCT (allo-HSCT) than with autologous HSCT (auto-HSCT) (7). HBV reactivation usually develops a few months after chemotherapy or immunosuppressive therapy. Long-term HBV-DNA monitoring after transplantation is recommended (4), because the time interval between HSCT and HBsAg-positive conversion can be long. However, currently, there is no definitive indication for how long the viral load should be monitored in such cases. We herein present the case of a patient who experienced HBV reactivation 55 months after chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT), and de novo hepatitis B improved with tenofovir alafenamide fumarate (TAF) therapy. Case Report A 54-year old woman presented to our hospital with a continuous low-grade fever. Her workup revealed stage IVB diffuse large B-cell lymphoma (DLBCL). Her laboratory findings were negative for HBs-Ag and HBV-DNA, but was positive for HBs-Ab and HBc-Ab. She had no family history of HBV infection. She underwent 4 courses of rituximab, cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (R-CHOP) therapy, 2 courses of rituximab, methotrexate, procarbazine, and VCR (R-MPV) therapy, 1 course of rituximab, CPM, doxorubicin, etoposide, vincristine, and prednisolone (R-CHOEP) therapy, and 2 courses of rituximab, CPM, high-dose cytarabine, dexametazone, and etoposide (R-CHASE) therapy. Furthermore, she underwent one course of rituximab, melphalan, CPM, etoposide, and dexametazone (R-LEED) therapy, and auto-PBSCT. She achieved complete remission. During the period of chemotherapy and auto-PBSCT, her serum level of HBV-DNA remained undetectable. After chemotherapy and auto-PBSCT, she was monitored regularly every 1-3 months and was not receiving immunosuppressive therapy. Her serum HBV-DNA levels became positive 55 months after the last treatment, increasing to 4.1 log IU/mL. HBs-Ag, hepatitis B envelope antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) also became positive without elevation of serum transaminase. The HBV genotype was group C (Table 1). She had no history of blood transfusion and was sexually inactive. We diagnosed her to have HBV reactivation. Although we recommended that she start nucleotide analogue therapy (NA), she refused and requested a reexamination one month later. Table 1. Laboratory Findings at 55 Months Following Chemotherapy and Auto-PBSCT. Variable Variable White blood cells (/µL) 4,140 Total bilirubin (mg/dL) 0.5 Red blood cells (104/µL) 355 AST (IU/L) 21 Hematocrit (%) 33.6 ALT (IU/L) 19 Hemoglobin (g/dL) 11.2 LDH (IU/L) 154 Platelets (104/µL) 28.0 ALP (IU/L) 240 PT-INR 1.01 GGT (IU/L) 41 PT (%) 97 HBsAg (IU/mL) 4.63 Total protein (g/dL) 6.9 HBV-DNA (log IU/mL) 4.1 Alubmin (g/dL) 3.8 HBeAg 11.4 C-reactive protein (mg/dL) 1.26 HBeAb (%) 0.1 BUN (mg/dL) 14 HBcrAg (log U/mL) 5.5 Creatinine (mg/dL) 0.45 HBV genotype C auto-PBSCT: autologous peripheral blood stem cell transplantation, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, HBsAg: hepatitis B surface antigen, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen One month later, elevated HBV-DNA (8.0 log IU/mL) and transaminase levels (AST 35 IU/L; ALT 37 IU/L) were found (Fig. 1). She was started on TAF. Her peak transaminase levels were observed 1 month after treatment initiation (AST 445 IU/L; ALT 640 IU/L). A liver biopsy revealed slight cross-linked fibrosis between portal veins and a lymphocyte infiltrate in the portal vein area, with a moderate degree of inflammation (Fig. 2). During the course of TAF therapy, the patient's transaminase and HBV-DNA levels gradually decreased. After five months, HBV-DNA, and HBs-Ag were no longer detectable, while the HBs-Ab became positive. However, HBcrAg remained detectable and this, TAF therapy continued. Figure 1. Clinical course of the patient’s condition. Solid thick black arrow indicates the time of liver biopsy. Solid think black arrows indicate the time of chemotherapy including rituximab and auto-PBSCT. auto-PBSCT: autologous peripheral blood stem cell transplantation Figure 2. Histological findings of the liver biopsy specimen. (A) Moderate lymphocytic infiltrate is observed in the portal areas of hepatic lobules with slightly piecemeal necrosis (Hematoxylin and Eosin staining; magnification, ×100) (B) Slight portal fibrosis with portal-to-portal bridging. (Masson’s trichrome staining; magnification, ×100). Discussion In this case, the patient developed hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. HBV reactivation is a common and potentially fatal complication in patients with past HBV infection undergoing immunosuppressive therapy (1-3). Patients receiving chemotherapy, including rituximab and auto-PBSCT, are at a high risk of HBV reactivation (4-6). To prevent HBV reactivation in patients receiving HSCT, the Japan Society of Hepatology (JSH) guidelines recommend that monthly HBV-DNA monitoring be performed during treatment and for at least 12 months after its completion. It also recommends long-term HBV-DNA monitoring after HSCT. HBV reactivation is not uncommon in HSCT recipients. In particular, patients undergoing allo-HSCT are at a very high risk of HBV reactivation, and the time interval between transplantation and HBs-Ag conversion can be long (8,9). The risk of HBV reactivation is lower with auto-HSCT than with allo-HSCT (7); however, the rate of reactivation is still 5.4-16.7% in patients with resolved HBV infection (7,10,11). Rare cases have been reported where HBV reactivation occurred more than 1 year after auto-HSCT (12,13) (Table 2). Auto-HSCT is accepted as a comparatively effective treatment for blood diseases, and the current protocol for patients receiving auto-HSCT therapy is to source stem cells from peripheral blood (14). Our patient developed de novo hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. This prompts us to question the current recommended timeframe of viral load monitoring in HSCT recipient. The prophylactic use of NA in HBs-Ag negative, HBc-Ab positive HSCT recipients is recommended by the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) guidelines (5,6), although the optimal duration of prophylaxis is not known. The incidence of HBV reactivation after HSCT in patients with resolved HBV infection is about 40% (9), suggesting that more than half of HSCT patients do not require NA prophylactic administration. Thus, NA prophylaxis for all patients may not be an economically sound option. Recently, it has been reported that an ultra-high sensitivity HBsAg assay can become an alternative method to diagnose HBV reactivation, because such an assay is quick, easy, and effective (15). As reported in this study, the ultra-high sensitivity HBsAg assay has been useful for long-term follow-ups. Table 2. Presenting Clinical Features of 3 Cases of HBV Reactivation in Resolved HBV Patients after Auto-HSCT and Our Patient. No Disease Sex Age Anti-HBs Period to reactivation Peak HBV DNA (log IU/mL) Peak ALT (IU/L) Treatment of reactivation Evolution Reference 1 HL M 68 Positive 18 months >8.2 ×2UNL TDF Resolved [12] 2 MM F 72 Negative 12 months 7.2 21 LMV Resolved [13] 3 MM M 60 Positive 20 months 6.7 261 No treatment Resolved [13] 4 DLBCL F 54 Positive 55 months 8.0 640 TAF Resolved Our case auto-HSCT: autologous hematopoietic stem cell transplantation, anti HBs: anti-hepatitis B surface, HL: hodgkin’s lymphoma, MM: multiple myeloma, DLBCL: diffuse large B-cell lymphoma, ULN: upper limited normal, TDF: tenofovir disoproxil fumarate, LMV: lamivudine, TAF: tenofovir alafenamide fumarate, HBV: hepatitis B virus As HBV reactivation is a well-known risk for patients receiving immunosuppressive therapy; most patients with past HBV infection are monitored for HBV markers carefully or receive anti-HBV prophylaxis. By adopting this strategy, there have been few reports of pathological HBV reactivation with severe acute fatal hepatitis (16-18). Although the timing of liver biopsy from the onset of de novo hepatitis is almost unchanged, fibrosis was more advanced than that observed in previous cases receiving immunosuppressive therapy for preventing graft-versus-host disease (17,18). The patient in this study did not require receive immunosuppressive therapy, reported to improve clinicopathologic findings for severe hepatitis (19), following the treatment. It has been reported that hepatic fibrosis does not progress after HBsAg seroclearance (20,21), and that fibrosis or chronic changes may sometimes occur before HBV seroclearance. Further study is needed regarding the histopathology, including the progression of liver fibrosis, in patients with HBV reactivation to address these issues. Certain virologic features have been linked to HBV reactivation. For instance, mutations in the core promoter region (A1762T and G1764A) and in the precore region (G1896A) are reported to be associated with HBV reactivation (22,23). Additionally, a recent study used next-generation sequencing and showed that mutation in the precore region (G1899A) are also associated with HBV reactivation (24). Further studies are required to elucidate the mechanisms that contribute to such virologic features in HBV reactivation. In the latest JSH, EASL, and AASLD guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF are recommended as first line anti-HBV treatments for prophylaxis against HBV reactivation (4-6). TAF has demonstrated safety and efficacy in achieving viral suppression in patients with chronic hepatitis B (25-27). In our patient, TAF was used effectively and safely against de novo hepatitis B. Tamori et al. (28) suggested that NA therapy can be discontinued in patients with HBV reactivation after the HBs-Ab test shows consistent positive results. In our patient, the HBs-Ab test was positive, but HBcr-Ag remained detectable. HBcr-Ag is considered a marker of intrahepatic HBV [covalently closed circular DNA (cccDNA)], and serum HBcrAg positivity is a risk factor for HBV reactivation in patients undergoing immunosuppressive therapy (29). As such, our findings suggest that TAF therapy should be continued until serum HBcrAg becomes undetectable. In conclusion, we herein described a case of HBV reactivation 55 months after chemotherapy including rituximab and auto-PBSCT. In such high-risk cases, the recommended guidelines should be followed, and careful long-term follow-ups, including the possibility of lifelong observation, are warranted. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to all members for the Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital.	Recovered	ReactionOutcome	CC BY-NC-ND	32963163	18,381,225	2021-02-01
What was the outcome of reaction 'Hepatitis'?	Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation. Introduction Hepatitis B virus (HBV) reactivation has emerged as a major complication induced by long-term chemotherapy or immunosuppressive therapy (1). De novo hepatitis B, a form of HBV reactivation, can occur as a result of the reactivation of latent HBV infection in subjects who are negative for hepatitis B surface antigen (HBs-Ag), but positive for anti-hepatitis B core antibody (HBc-Ab), anti-HBs antibody (HBs-Ab) or both (2,3). It is well known that patients receiving chemotherapy, including rituximab and hematopoietic stem cell transplantation (HSCT), are at high risk of HBV reactivation (4-6). Among HSCT recipients with resolved HBV, the risk of HBV reactivation is higher with allogeneic HSCT (allo-HSCT) than with autologous HSCT (auto-HSCT) (7). HBV reactivation usually develops a few months after chemotherapy or immunosuppressive therapy. Long-term HBV-DNA monitoring after transplantation is recommended (4), because the time interval between HSCT and HBsAg-positive conversion can be long. However, currently, there is no definitive indication for how long the viral load should be monitored in such cases. We herein present the case of a patient who experienced HBV reactivation 55 months after chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT), and de novo hepatitis B improved with tenofovir alafenamide fumarate (TAF) therapy. Case Report A 54-year old woman presented to our hospital with a continuous low-grade fever. Her workup revealed stage IVB diffuse large B-cell lymphoma (DLBCL). Her laboratory findings were negative for HBs-Ag and HBV-DNA, but was positive for HBs-Ab and HBc-Ab. She had no family history of HBV infection. She underwent 4 courses of rituximab, cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (R-CHOP) therapy, 2 courses of rituximab, methotrexate, procarbazine, and VCR (R-MPV) therapy, 1 course of rituximab, CPM, doxorubicin, etoposide, vincristine, and prednisolone (R-CHOEP) therapy, and 2 courses of rituximab, CPM, high-dose cytarabine, dexametazone, and etoposide (R-CHASE) therapy. Furthermore, she underwent one course of rituximab, melphalan, CPM, etoposide, and dexametazone (R-LEED) therapy, and auto-PBSCT. She achieved complete remission. During the period of chemotherapy and auto-PBSCT, her serum level of HBV-DNA remained undetectable. After chemotherapy and auto-PBSCT, she was monitored regularly every 1-3 months and was not receiving immunosuppressive therapy. Her serum HBV-DNA levels became positive 55 months after the last treatment, increasing to 4.1 log IU/mL. HBs-Ag, hepatitis B envelope antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) also became positive without elevation of serum transaminase. The HBV genotype was group C (Table 1). She had no history of blood transfusion and was sexually inactive. We diagnosed her to have HBV reactivation. Although we recommended that she start nucleotide analogue therapy (NA), she refused and requested a reexamination one month later. Table 1. Laboratory Findings at 55 Months Following Chemotherapy and Auto-PBSCT. Variable Variable White blood cells (/µL) 4,140 Total bilirubin (mg/dL) 0.5 Red blood cells (104/µL) 355 AST (IU/L) 21 Hematocrit (%) 33.6 ALT (IU/L) 19 Hemoglobin (g/dL) 11.2 LDH (IU/L) 154 Platelets (104/µL) 28.0 ALP (IU/L) 240 PT-INR 1.01 GGT (IU/L) 41 PT (%) 97 HBsAg (IU/mL) 4.63 Total protein (g/dL) 6.9 HBV-DNA (log IU/mL) 4.1 Alubmin (g/dL) 3.8 HBeAg 11.4 C-reactive protein (mg/dL) 1.26 HBeAb (%) 0.1 BUN (mg/dL) 14 HBcrAg (log U/mL) 5.5 Creatinine (mg/dL) 0.45 HBV genotype C auto-PBSCT: autologous peripheral blood stem cell transplantation, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, HBsAg: hepatitis B surface antigen, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen One month later, elevated HBV-DNA (8.0 log IU/mL) and transaminase levels (AST 35 IU/L; ALT 37 IU/L) were found (Fig. 1). She was started on TAF. Her peak transaminase levels were observed 1 month after treatment initiation (AST 445 IU/L; ALT 640 IU/L). A liver biopsy revealed slight cross-linked fibrosis between portal veins and a lymphocyte infiltrate in the portal vein area, with a moderate degree of inflammation (Fig. 2). During the course of TAF therapy, the patient's transaminase and HBV-DNA levels gradually decreased. After five months, HBV-DNA, and HBs-Ag were no longer detectable, while the HBs-Ab became positive. However, HBcrAg remained detectable and this, TAF therapy continued. Figure 1. Clinical course of the patient’s condition. Solid thick black arrow indicates the time of liver biopsy. Solid think black arrows indicate the time of chemotherapy including rituximab and auto-PBSCT. auto-PBSCT: autologous peripheral blood stem cell transplantation Figure 2. Histological findings of the liver biopsy specimen. (A) Moderate lymphocytic infiltrate is observed in the portal areas of hepatic lobules with slightly piecemeal necrosis (Hematoxylin and Eosin staining; magnification, ×100) (B) Slight portal fibrosis with portal-to-portal bridging. (Masson’s trichrome staining; magnification, ×100). Discussion In this case, the patient developed hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. HBV reactivation is a common and potentially fatal complication in patients with past HBV infection undergoing immunosuppressive therapy (1-3). Patients receiving chemotherapy, including rituximab and auto-PBSCT, are at a high risk of HBV reactivation (4-6). To prevent HBV reactivation in patients receiving HSCT, the Japan Society of Hepatology (JSH) guidelines recommend that monthly HBV-DNA monitoring be performed during treatment and for at least 12 months after its completion. It also recommends long-term HBV-DNA monitoring after HSCT. HBV reactivation is not uncommon in HSCT recipients. In particular, patients undergoing allo-HSCT are at a very high risk of HBV reactivation, and the time interval between transplantation and HBs-Ag conversion can be long (8,9). The risk of HBV reactivation is lower with auto-HSCT than with allo-HSCT (7); however, the rate of reactivation is still 5.4-16.7% in patients with resolved HBV infection (7,10,11). Rare cases have been reported where HBV reactivation occurred more than 1 year after auto-HSCT (12,13) (Table 2). Auto-HSCT is accepted as a comparatively effective treatment for blood diseases, and the current protocol for patients receiving auto-HSCT therapy is to source stem cells from peripheral blood (14). Our patient developed de novo hepatitis due to HBV reactivation 55 months after the end of chemotherapy and auto-PBSCT. This prompts us to question the current recommended timeframe of viral load monitoring in HSCT recipient. The prophylactic use of NA in HBs-Ag negative, HBc-Ab positive HSCT recipients is recommended by the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) guidelines (5,6), although the optimal duration of prophylaxis is not known. The incidence of HBV reactivation after HSCT in patients with resolved HBV infection is about 40% (9), suggesting that more than half of HSCT patients do not require NA prophylactic administration. Thus, NA prophylaxis for all patients may not be an economically sound option. Recently, it has been reported that an ultra-high sensitivity HBsAg assay can become an alternative method to diagnose HBV reactivation, because such an assay is quick, easy, and effective (15). As reported in this study, the ultra-high sensitivity HBsAg assay has been useful for long-term follow-ups. Table 2. Presenting Clinical Features of 3 Cases of HBV Reactivation in Resolved HBV Patients after Auto-HSCT and Our Patient. No Disease Sex Age Anti-HBs Period to reactivation Peak HBV DNA (log IU/mL) Peak ALT (IU/L) Treatment of reactivation Evolution Reference 1 HL M 68 Positive 18 months >8.2 ×2UNL TDF Resolved [12] 2 MM F 72 Negative 12 months 7.2 21 LMV Resolved [13] 3 MM M 60 Positive 20 months 6.7 261 No treatment Resolved [13] 4 DLBCL F 54 Positive 55 months 8.0 640 TAF Resolved Our case auto-HSCT: autologous hematopoietic stem cell transplantation, anti HBs: anti-hepatitis B surface, HL: hodgkin’s lymphoma, MM: multiple myeloma, DLBCL: diffuse large B-cell lymphoma, ULN: upper limited normal, TDF: tenofovir disoproxil fumarate, LMV: lamivudine, TAF: tenofovir alafenamide fumarate, HBV: hepatitis B virus As HBV reactivation is a well-known risk for patients receiving immunosuppressive therapy; most patients with past HBV infection are monitored for HBV markers carefully or receive anti-HBV prophylaxis. By adopting this strategy, there have been few reports of pathological HBV reactivation with severe acute fatal hepatitis (16-18). Although the timing of liver biopsy from the onset of de novo hepatitis is almost unchanged, fibrosis was more advanced than that observed in previous cases receiving immunosuppressive therapy for preventing graft-versus-host disease (17,18). The patient in this study did not require receive immunosuppressive therapy, reported to improve clinicopathologic findings for severe hepatitis (19), following the treatment. It has been reported that hepatic fibrosis does not progress after HBsAg seroclearance (20,21), and that fibrosis or chronic changes may sometimes occur before HBV seroclearance. Further study is needed regarding the histopathology, including the progression of liver fibrosis, in patients with HBV reactivation to address these issues. Certain virologic features have been linked to HBV reactivation. For instance, mutations in the core promoter region (A1762T and G1764A) and in the precore region (G1896A) are reported to be associated with HBV reactivation (22,23). Additionally, a recent study used next-generation sequencing and showed that mutation in the precore region (G1899A) are also associated with HBV reactivation (24). Further studies are required to elucidate the mechanisms that contribute to such virologic features in HBV reactivation. In the latest JSH, EASL, and AASLD guidelines, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF are recommended as first line anti-HBV treatments for prophylaxis against HBV reactivation (4-6). TAF has demonstrated safety and efficacy in achieving viral suppression in patients with chronic hepatitis B (25-27). In our patient, TAF was used effectively and safely against de novo hepatitis B. Tamori et al. (28) suggested that NA therapy can be discontinued in patients with HBV reactivation after the HBs-Ab test shows consistent positive results. In our patient, the HBs-Ab test was positive, but HBcr-Ag remained detectable. HBcr-Ag is considered a marker of intrahepatic HBV [covalently closed circular DNA (cccDNA)], and serum HBcrAg positivity is a risk factor for HBV reactivation in patients undergoing immunosuppressive therapy (29). As such, our findings suggest that TAF therapy should be continued until serum HBcrAg becomes undetectable. In conclusion, we herein described a case of HBV reactivation 55 months after chemotherapy including rituximab and auto-PBSCT. In such high-risk cases, the recommended guidelines should be followed, and careful long-term follow-ups, including the possibility of lifelong observation, are warranted. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to all members for the Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital.	Recovered	ReactionOutcome	CC BY-NC-ND	32963163	18,381,225	2021-02-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebrovascular accident'.	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	DALBAVANCIN, DAPTOMYCIN, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, VANCOMYCIN	DrugsGivenReaction	CC BY	32965641	19,165,851	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	AMOXICILLIN, LINEZOLID, MOXIFLOXACIN, RIFAMPIN	DrugsGivenReaction	CC BY	32965641	20,453,567	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug intolerance'.	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	AMOXICILLIN, LINEZOLID, MOXIFLOXACIN, RIFAMPIN	DrugsGivenReaction	CC BY	32965641	20,453,567	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypersensitivity'.	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	AMOXICILLIN, LINEZOLID, MOXIFLOXACIN, RIFAMPIN	DrugsGivenReaction	CC BY	32965641	20,453,567	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'.	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	AMOXICILLIN, LINEZOLID, MOXIFLOXACIN, RIFAMPIN	DrugsGivenReaction	CC BY	32965641	20,453,567	2021-02
What was the administration route of drug 'MOXIFLOXACIN'?	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	Oral	DrugAdministrationRoute	CC BY	32965641	20,453,567	2021-02
What was the administration route of drug 'PIPERACILLIN SODIUM\TAZOBACTAM SODIUM'?	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY	32965641	19,165,851	2021-02
What was the administration route of drug 'RIFAMPIN'?	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	Oral	DrugAdministrationRoute	CC BY	32965641	20,453,567	2021-02
What was the dosage of drug 'DAPTOMYCIN'?	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	10 MG/KG	DrugDosageText	CC BY	32965641	19,165,851	2021-02
What was the outcome of reaction 'Cerebrovascular accident'?	Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases. We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects. Introduction Long-term suppressive therapy is a last option in patients with chronic bacterial infections, consisting of substances that are well tolerated, have good oral bioavailability and antimicrobial activity. Unfortunately, in some cases not all of these options are available. This might either be due to resistance of the pathogens involved or side effects in patients. Dalbavancin is a lipoglycopeptide with an exceptional long terminal half-life that was licensed for the treatment of skin and soft tissue infections. It is not licensed for bacteremia, although it is broadly used for this specific indication [1, 2]. It has broad activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS, such as S. epidermidis, S. haemolyticus) and enterococci (E. faecalis and E. faecium). Its long half-life of more than 14 days allows weekly or biweekly infusions [3] making it an attractive choice for outpatient antibiotic treatment. We present a series of four patients with Gram-positive bacteremia due to an intravascular source, where dalbavancin was used as suppressive, indefinite therapy after prior intravenous therapy with different substances. Methods All patients were seen by an infectious diseases specialist before initiating dalbavancin treatment and in all cases oral suppressive therapy was deemed not feasible. In all four patients a broad interdisciplinary consensus for chronic suppressive therapy was established. Conventional therapy was mainly limited by comorbidities, side effects including allergies and a lack of other (non-antibiotic) options (e.g., surgery and appropriate focus control). All patients provided informed consent for dalbavancin off-label use. The health insurances involved were informed about the off-label use of dalbavancin and funding was requested and approved. Dalbavancin was started after clearance of bacteremia. In all cases dalbavancin was infused by the patients` general practitioner on an out-patient basis. The isolated organisms (including resistance patterns) are listed in Table 1 together with a short synopsis of the clinical course. Dalbavancin susceptibility testing was not available, but all pathogens involved were susceptible to glycopeptides (vancomycin).Table 1 Characteristics of patients with Dalbavancin suppressive therapy with resistance profiles of the isolated organisms Patient 1 Patient 2 Patient 3 Patient 4 Gender/Age M/81 ys M/59 ys M/67 ys M/80 ys Isolated pathogen in blood culture MRSA E. faecium E. faecalis E. faecalis Source of bacteremia Prosthetic valve endocarditis LVAD infection LVAD infection TAVI endocarditis Implantation of intravascular prothesis/device 2001 June 2018 January 2018 May 2016 Clinical events of note prior to the onset of the index bacteremia Admission to another hospital with fever and chills, MRSA bacteremia History of NEM Admission with bowel obstruction/laparotomy/adhesiolysis; C. diff. colitis History of hairy cell leukemia Admission with fever and chills, E. faecalis bacteremia (unknown source) Several admissions with E. faecalis bacteremia, diagnosis of TAVI endocarditis (TEE initially negative) Index bacteremia (calendar date = d1) May 2018 (d1) October 2018 (d1) May 2019 (d1) August 2019 (d1) Initial management of index bacteremia and events up to initiation of dalbavancin Vancomycin plus rifampicin, later daptomycin plus rifampicin for 6 weeks, cessation of antibiotic therapy on d50 Vancomycin/daptomycin, then switch to dalbavancin Vancomycin, due to severe penicillin allergy; then chronic suppressive therapy with dalbavancin Vancomycin and piperacillin (ampicillin/amoxicillin allergy) Complications/side effects Readmission on d63 with recurrence of MRSA bacteremia, treatment with vancomycin, then switch to linezolid p.o., followed by dalbavancin C. diff. colitis with acute renal failure, no recurrence despite continuation of dalbavancin, No relevant side effects Recurrence of E. faecalis bacteremia on d161, treatment with vancomycin and then again switch to dalbavancin Recurrence of bacteremia under oral suppressive therapy with moxifloxacin/rifampicin Mild rash (association to dalbavancin debatable) Start/end Dalbavancin d123/d130 (given only twice) d41/still ongoing d28/d210 d98/d213 Follow up / outcome Death on about d135 due to heart failure Dalbavancin still ongoing Readmission on d214 with stroke, BC sterile, death due to complications of stroke on d228 Due to general worsening of condition treatment change to best supportive care Death on d223 Dalbavancin regimen LD 1000 mg, 375 mg weekly LD 1000 mg, 500 mg weekly LD 1000 mg, 500 mg weekly LD 1500 mg, 1000 mg biweekly Susceptibility testing [MIC (mg/L)] Ampicillin R R [> 8] S [< = 2] S [< = 2] Amox./Clav R R S S Ceftriaxone R R R R Pip/Taz R R S S Meropenem R R R R Ciprofloxacin R [4] X [0.5] Moxifloxacin R [1] X [1] Rifampicin R [> 1] R Cotrimoxazol R [> 4/76] R R R Clindamycin R [1] R R S [1] Linezolid S [< 0.5] S [1] S [2] S [1] Vancomycin S [1] S [1] S [1] S [< = 0.5] Daptomycin R [2] S [4] S [4] Tetracyclin I [2] The SIR category of antimicrobial agents without MIC value is inferred from an indicator substance or represents intrinsic resistance M male, ys years, LVAD left ventricular assist device, TAVI transcatheter aortic valve implantation, NEN neuroendocrine neoplasm, LD loading dose, MIC minimal inhibitory concentration, S susceptible, R resistant X no EUCAST break-points available, breakpoints were derived from the POET study [12] Patient 1 An 81-year-old male patient was transferred to our hospital in June 2018 with methicillin-resistant S. aureus (MRSA) bacteremia and a previous history of prosthetic aortic valve replacement in 2001. Transesophageal echocardiography (TEE) showed endocardial vegetations (8 × 5 mm, aortic valve) leading to the diagnosis of prosthetic valve endocarditis (two major DUKE criteria positive). After initial treatment with vancomycin antibiotic therapy was switched to daptomycin (8 mg/kg) plus rifampicin (2 × 450 mg) and i.v. treatment was continued for 6 weeks. Blood cultures (BC) cleared within several days, no complications arose during the hospital stay. Twelve days after discharge the patient was readmitted to a different hospital and BC grew MRSA again. The resistance profile showed that linezolid would be the only oral treatment option available. The patient was transferred to our hospital where cardiothoracic surgeons judged major cardiac surgery not feasible because of comorbidities and the patient’s general condition. The patient was treated with linezolid initially for several days before dalbavancin was administered once weekly (loading dose 1000 mg, followed by 350 mg weekly—dose adjusted for renal insufficiency—GFR CKD-EPI 23 ml/min/1.73qm). The patient received dalbavancin only twice, before he was readmitted in the beginning of October 2018 with acute decompensated heart failure and transferred to another hospital. He died in November 2018 due to heart failure and kidney failure. There was no clinical suspicion of relapse of MRSA bacteremia, but no BCs were obtained. Patient 2 A 59-year-old male patient was admitted to an intensive care unit in our hospital with acute bowel obstruction in September 2018. The patient had a previous history of neuroendocrine neoplasm (NEN). Due to end-stage heart failure (dilated cardiomyopathy (DCM)), a left ventricular assist device (LVAD) had been implanted in June 2018. After laparotomy and adhesiolysis, the patient recovered but then developed an episode of Clostridioides difficile infection (CDI) after broad spectrum antibiotic therapy. During treatment with oral vancomycin, the patient developed fever and Enterococcus faecium (E. faecium) as well as two different species of coagulase-negative staphylococci (S. epidermidis and S. haemolyticus) were isolated from his blood, all of them in several different BC sets. The patient was treated with intravenous vancomycin (target trough serum concentration: 15–20 mcg/ml) and later switched to daptomycin (10 mg/kg once daily). Subsequent BCs remained sterile under intravenous therapy. A PET/CT was performed where an infection of the LVAD was suspected. Owing to his general clinical condition and his history of NEN the patient was neither considered a candidate for heart transplantation nor for LVAD exchange. Dalbavancin was offered as salvage therapy. The once weekly infusion was performed by the general practitioner of the patient (loading dose 1000 mg, followed by 500 mg weekly). He was readmitted several times during the following year (for different reasons: recurrent CDI, acute renal failure; both under dalbavancin therapy, both resolved despite continued dalbavancin infusions). There was no recurrence of bacteremia. A PET/CT performed nearly 1 year after initiating dalbavancin showed evidence of still active LVAD infection and dalbavancin therapy was continued. At the latest follow-up (more than 1 year of dalbavancin treatment) the patient was in stable condition. Patient 3 A 67-year-old male patient was admitted with fever and chills to our hospital in May 2019. He had a history of hairy cell leukemia and toxic cardiomyopathy (gladribine-induced) with LVAD implanted January 2019. After admission treatment with vancomycin and piperacillin/tazobactam was started. Two days later, two BCs taken at admission grew Enterococcus faecalis (E. faecalis). I.v. therapy with piperacillin/tazobactam had to be stopped due to an allergic reaction (rash). Vancomycin was continued and lead to clearance of bacteremia. Again, like in the previously described patient neither heart transplantation nor LVAD exchange (with high surgical risk) was a suitable option for this patient according to an interdisciplinary consensus. With E. faecalis bacteremia in this penicillin-allergic patient dalbavancin chronic suppressive palliative therapy was offered to the patient and started in the end of May 2019 (loading 1000 mg, followed by 500 mg weekly). Since no other focus could be established the LVAD was considered to be the most likely source of bacteremia. The patients did fine on an outpatient revisit two months later. He was, however, readmitted in October 2019 with sepsis and E. faecalis breakthrough bacteremia despite continued dalbavancin therapy (500 mg weekly). He was again treated with vancomycin and cleared bacteremia. Since there were no other options available, dalbavancin was re-administered (loading 1000 mg, followed by 500 mg weekly) and the patient was discharged from our hospital. He was again re-admitted in the end of November 2019 with (most likely LVAD associated ischemic) stroke. BCs, however, were negative at admission and during his hospital stay. He died in December 2019 due to complications of stroke. Patient 4 An 80-year-old male patient was admitted with fever in September 2019. He had a previous history of transcatheter aortic valve implantation (TAVI) due to aortic valve stenosis in May 2016 and several other chronic conditions (chronic renal failure, diabetes, chronic osteomyelitis of the calcaneus, total knee endoprosthesis, early stages of dementia). He was in reduced general condition due to age and comorbidities. BCs grew E. faecalis. During the hospital stay, a thorough work-up was repeated. TEE showed no vegetations on the aortic valve. CT scan, however, revealed septic emboli in kidneys, spleen and brain, leading to the diagnosis of TAVI endocarditis (based on one major and three minor DUKE criteria). The calcaneus was evaluated by orthopedic surgeons and surgery with amputation was recommended. The patient, however, refused both heart surgery and amputation. Simultaneously, he was deemed not operable owing to his age and comorbidities. Unfortunately, he had an amoxicillin allergy (rash); amoxicillin re-exposure was tried during the hospital stay, but again, he developed a severe generalized rash. An oral treatment with moxifloxacin 1 × 400 mg and rifampicin 1 × 600 mg was attempted after several weeks of intravenous therapy (and negative BCs). Although doing well initially under oral therapy, the patient was seen on an outpatient appointment (in October 2019) and relapse of E. faecalis bacteremia could be documented. A short treatment course with linezolid over only several days failed due to poor tolerability (nausea). The patient was readmitted and treated with vancomycin intravenously (and piperacillin, which he tolerated despite his amoxicillin allergy) leading to clearance of bacteremia. After 4 weeks of treatment, the patient was discharged from the hospital (at the beginning of December 2019) with dalbavancin therapy (1500 mg loading, followed by 1000 mg biweekly). Until March 2020 there was still no clinical sign of bacteremia. A minor rash after the administration of dalbavancin did not lead to discontinuation of the drug. However, his general condition worsened, and the treatment protocol was changed to best supportive care. The patient died in April 2020. Discussion We present four patients with bacteremia caused by Gram-positive cocci due to an intravascular source. All patients had cardiovascular foreign bodies implanted and finally received (or continue to receive) indefinite suppressive therapy with dalbavancin after prior intravenous therapy with other substances. Patient 1 was treated with dalbavancin only twice, but he could be discharged home and was stable for roughly 4 weeks (2 weeks linezolid and 2 weeks dalbavancin combined), before he was readmitted. Although dalbavancin therapy was not effective in preventing relapse of infection in patient 3, he did fine for several months after the initial diagnosis of bacteremia and was able to stay at home most of the time after discharge (more than 5 months) which can be considered as a success of suppressive therapy. The possibility exists, that patient 2 does not have true LVAD infection, but several BC sets were repeatedly positive for different pathogens and PET/CT was suggestive for LVAD infection. On the other hand, antibiotic therapy was never stopped to document recurrence of bacteremia since this was judged be too high of a risk in a patient with severe heart failure. He was also the only patient of our small series, where dalbavancin was started right after the cessation of the previous intravenous therapy (with no oral treatment in between). Patient 4 also received dalbavancin and the treatment was effective for several months. The only other option for this patient would have been continued vancomycin treatment (due to his renal insufficiency once daily), but implementation would have been much more complicated in an outpatient setting. These four patients share some unique features:1. All had bacterial infection of a prosthetic device and a curative approach (surgical removal) was not possible. 2. There was always broad interdisciplinary consensus that a relapse of bacteremia would inevitably happen if antibiotics were stopped. 3. Oral substances for chronic suppressive therapy were not available, not feasible or not effective and an intravenous therapy offered the advantage of higher drug levels in the blood. The long half-life of dalbavancin offers the further advantage of a nearly comfortable dosing interval, even in an outpatient setting. All isolated pathogens were also susceptible to linezolid. However, problems with myelotoxicity in long-term use are well described in the literature [4] and reflect our own clinical experience. Furthermore, linezolid lacks bactericidal activity of dalbavancin. Outpatient parenteral antimicrobial therapy (OPAT) is not well established in our region and problems arise frequently especially during weekends and on holidays. A once weekly or biweekly infusion is preferable, and implementation is easier. Patients have been treated with dalbavancin for endocarditis before [1, 5] and a case report describes the (successful) suppressive therapy of MRSA prosthetic valve endocarditis [6]. Dalbavancin was also effective as suppressive therapy in a patient with MRSA LVAD infection (however this patient was not bacteremic) [7]. In a letter to the editor Cicullo et al. describe the case of a patient with MRSA bacteremia and an abdominal aortic prothesis, where dalbavancin was used and resulted in cure of infection [8]. Dalbavancin may also be effective in biofilm-forming infections, as previous in-vitro studies suggest [9]. On the other side dalbavancin treatment in chronic osteomyelitis resulted in poor outcomes (cure rate of less than 40%) [10]. Overall, off label use of dalbavancin is common and the substance seems to be an acceptable safe alternative to other intravenous options even in patients with bacteremia. The ideal dosing regimen for dalbavancin in this setting is still unclear. Several different regimens are published in the literature:1. 1000 mg loading dose, followed by 500 mg weekly [1]. 2. 1500 mg loading dose, followed by 1000my biweekly [4]. 3. 1500 mg weekly [7]. Wunsch et al. describe 25 patients with endocarditis and a third of these patients were treated with the same regime as the patients from our series (36% received dalbavancin only once) [1]. Most (63%), but not all patients with endocarditis in the retrospective study of Tobudic et al. were treated with the biweekly regimen [5]. Patients with endocarditis in the Spanish DALBACEN cohort were treated with both dosing regimens also [11]. A completely different approach was applied by Spaziante et al., where serum dalbavancin concentrations were monitored and dosing was managed via drug monitoring [6]. The authors note, however, that the appropriate target concentration for guiding dalbavancin dosing intervals is not yet established. Although we used the weekly regimen in three of our patients, we do see the benefit in the biweekly approach (meaning less frequent infusions). Drug monitoring would be the optimal approach for monitoring of dalbavancin in our opinion. Within our limited experience we could not see any relevant side effects of long-term dalbavancin treatment. Two of our patients (No. 2 and 3) received dalbavancin for several months without any documented problems. Patient No. 4 developed a mild rash, which did not lead to discontinuation of the substance. Other studies also documented a low rate of side effects: in one study 5% of patients receiving dalbavancin did experience nausea or rash [10]. Long-term, even indefinite suppressive therapy is a decision on a case-by-case basis and needs to be discussed with the patient and all people involved in patient management (relatives, general practitioner, nursing service, etc.). Long-term side effects of dalbavancin therapy cannot be ruled out with the data of our small case series and patients must be followed closely. Overall tolerance, however, was good in our patients. Conclusions Dalbavancin is an attractive option for outpatient antibiotic therapy including patients in need for a long-term suppressive therapy. Therapy with dalbavancin might be considered in patients with Gram-positive bacteremia due to an intravascular source as a salvage option when other options (such as oral antibiotics) are not available or not feasible. Long-term therapy seems to be well tolerated in these patients with few side effects. Although only once weekly or biweekly application is necessary long-term suppressive therapy still requires a huge effort on several sides (general practitioner, patient, health insurance, nursing service, etc.). Of note, the optimal dosing strategy is still a matter of debate and might depend on several factors. Drug monitoring might possibly be helpful to monitor drug levels and prevent long-term drug accumulation. Author contribution All authors contributed to the design of the case series. Data collection and analysis were performed by FHi, AM and FH. The first draft of the manuscript was written by FHi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest Hitzenbichler: travel grants from Gilead Sciences, lecture fees from MSD. Mohr: travel grants from Gilead Sciences. Camboni: no conflicts of interest. Simon: lecture fees from Becton Dickinson, grants from Pfizer. Salzberger: advisory and lecture fees from Falk Foundation, GSK, Roche, Sanofi; research grants from Bosch-Stiftung, GSK, Biochryst. Hanses: advisory and lecture fees from Correvio. Ethical approval The study was reviewed and approved by the local ethics committee of the University of Regensburg (number 19-1257-101).	Fatal	ReactionOutcome	CC BY	32965641	19,165,851	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastroenteritis radiation'.	Acute Ileal Perforation Caused by Radiation Enteritis After Restoration. Few radiation-induced bowel perforations have been reported to date. Furthermore, perforation after ileal restoration in asymptomatic patients is rare. We report the case of a 61-year-old man who was administered preoperative chemoradiotherapy for advanced rectal cancer. The patient underwent ultra-low anterior resection with ileal diversion, followed by ileal restoration. Perforation was detected 9 days after restoration, and he underwent a right hemicolectomy. The histologic evaluation indicated ileal perforation caused by acute radiation enteritis. INTRODUCTION In recent years, preoperative chemoradiotherapy (CRT) combined with total mesorectal excision has become a well-established approach for the reduction of local recurrence following the treatment of advanced rectal cancer [1]. As many rectal cancer patients undergo preoperative CRT, the complications associated with radiation should not be overlooked. Gastrointestinal symptoms following radiotherapy can be caused by intestinal strictures, intestinal fistula, de novo or recurrent neoplasia, small bowel bacterial overgrowth, bile salt malabsorption, fat or carbohydrate malabsorption, inflammatory bowel disease, pancreatic insufficiency, or irritable bowel syndrome, presenting with variable degrees [2]. In addition, rare cases of perforation, which can lead to generalized peritonitis and sometimes mortality, have been reported [3]. Herein, we report a rare complication of radiation enteritis, namely ileal perforation, after ileal restoration in a patient who underwent preoperative CRT. CASE REPORT This study was reviewed and approved by the Institutional Review Board of the Asan Medical Center in Seoul, Korea (No. 2020-0846). Written informed consent was obtained for publication of this case report and accompanying images. A 61-year-old man visited the hospital with pathologically confirmed rectal cancer 3 cm from the anal margin, identified using colonoscopy. Magnetic resonance imaging (MRI) scan revealed a tumor with perirectal fat infiltration. Preoperative CRT with capecitabine was administered at a cumulative dose of 5,040 cGY, divided into 28 cycles. Following preoperative CRT, sigmoidoscopy revealed the mass size to have decreased. MRI scan also revealed a decrease in the mass size, and the residual lesion contained more fibrous than tumor tissue. In addition, contrast-enhanced computed tomography (CT) scan showed diffuse wall thickening in a distal ileal segment located in the pelvis, indicating probable radiation enteritis (Fig. 1A). Eight weeks after the completion of preoperative CRT, the patient underwent robot-assisted ultra-low anterior resection with ileal diversion. The patient recovered uneventfully and was discharged 7 days after the surgery. Postoperative histologic staging was ypT3N0, and 6 cycles of adjuvant chemotherapy with capecitabine were administered thereafter. The patient was admitted again for ileal restoration 6 months after the operation. A small incision for ileal restoration did not permit accurate evaluation of the stricture and wall thickening or perfusion along the entire ileum. Functional end-to-end anastomosis was performed using a linear cutting stapler. Two days after the surgery, the patient’s progress was unremarkable, other than several episodes of diarrhea. However, 5 days after the surgery, a sudden episode of fever (38.7°C) developed, along with abdominal distension and mild tenderness. CT images suggested segmental diffuse edema in the terminal ileum, resulting in small bowel stricture and some uncomplicated reactive ascites. Although the patient was treated conservatively with fasting and antibiotics, the fever did not subside, and the abdominal distension and tenderness worsened. Percutaneous catheter drainage (PCD) was performed 8 days after the surgery; 550 mL of fluid was drained, which was clear and serous. After drainage, the patient’s distension and tenderness showed some improvement. However, 9 days after surgery, the patient exhibited aggravated symptoms, and the PCD appeared green in color and turbid in nature. In addition, an erect simple abdominal radiograph confirmed the presence of free air. CT images suggested peritonitis associated with bowel perforation, including free air, ascites, peritoneal infiltration, and thickening with enhancement (Fig. 1B, C). There was also a persistence of the previously noted diffuse segmental mural thickening in the distal ileum (i.e., presumed radiation enteritis), causing small bowel stricture with proximal dilatation (Fig. 1B, C). Considering the CT findings and the nature of the drainage fluid, emergency surgery was planned. Surgical findings showed that the previous anastomosis was intact, and a pinpoint perforation was confirmed on the sidewall of the anastomosis (Fig. 2A). As the perforation site was identified at some distance from the PCD, the possibility of iatrogenic perforation following PCD insertion was less likely. A stricture, caused by radiation enteritis, was detected 10 cm in length in the distal bowel segment 5 cm above the crotch of restoration anastomosis. A limited right hemicolectomy with ileal resection (length, 42 cm), including the previous stomal restoration site, was subsequently performed. Postoperative histology revealed the perforation site with a transmural tissue defect and acute fibrinous inflammation (Fig. 2B). In addition, the affected mucosa showed marked crypt dissipation, stromal hyalinization, and telangiectasia (Fig. 2C, D). Taken together, these pathologic features are consistent with perforated severe radiation enteritis. Subsequent culture of the ascites fluid confirmed enteric aerobic and anaerobic microbes; however, the clostridium difficile toxin assay was negative. The patient was discharged without the occurrence of any subsequent events other than a few episodes of diarrhea 11 days after surgery. DISCUSSION Gastrointestinal adverse events following radiation therapy can occur when gastrointestinal structures are included in the radiation field. The incidence and severity of radiation enteritis depend on the dose of radiotherapy. Additional aggravating factors include age, presence of comorbidities, prior operation, tobacco abuse, and concurrent chemotherapy [3]. Enteral epithelium is affected by chemotherapy as well as radiation because of its highly proliferative potential [4]. Mucosal atrophy with atypical hyperplastic glands and intestinal wall fibrosis, and telangiectasias can be typical histologic changes [5]. Otherwise, mucosal ulceration can also occur, sometimes developing abscess, fistula, and perforation. Fibrosis occurs as part of the healing process of the ulcer, which unfortunately produces narrowing of the enteral lumen causing stricture and even obstruction [5]. The patient did not have any comorbidities and history of surgery except for rectal cancer operation. He had a 30-pack-year smoking history, but quit smoking approximately a year before the rectal cancer diagnosis. Considering the pathogenesis of the patient, stricture caused by radiation enteritis led to obstruction and small bowel bacterial overgrowth caused by stasis, leading to stercoral enteritis and perforation caused by high pressure. In general, the complication of radiation can be divided into acute and late, depending on the timing. Late complication is less frequent than acute complication, but it can occur in up to 40% of patients receiving radiation in the abdominopelvic area three to 6 years after radiation [3]. Complications can be graded from 0 to 5 according to the Radiation Therapy Oncology Group morbidity grading scale [3]. Depending on the severity, there are various clinical features such as enteritis, bleeding, narrowing, perforation, fistula, etc. Enteral perforation is a very uncommon complication compared with bleeding and obstruction [6]. Diagnosis should be based on a combination of the patient’s clinical symptoms, history, laboratory result, imaging finding, and physical examination. The possibility of recurrent neoplasia should not be ruled out during diagnostic workup [7]. Management of chronic radiation enteritis is primarily focused on symptomatic improvement. Additionally, nutritional support should not be omitted. Symptomatic treatments include antidiarrheal agents, antiinflammatories, probiotics and antibiotics, cholestyramine, pentoxifylline and tocopherol, and hyperbaric oxygen, based on the individual status [2]. If the response to medical treatment does not meet the expectations, endoscopic therapy, including coagulation therapy and balloon dilatation, and further surgery needs to be considered [2]. This report describes a rare case of ileal perforation caused by intractable radiation enteritis after ileal restoration. In conclusion, when radiation enteritis continues to be intractable, concurrent with relevant physical, laboratory, and abdominopelvic CT findings, timely surgical intervention needs to be considered, or an irradiated bowel resection should be performed during ileal restoration. Fig. 1. Abdominal computed tomography scans. (A) Diffuse wall thickening in the distal ileal segment located in the pelvis 8 weeks after the preoperative chemoradiotherapy. (B) Small bowel obstruction following a persistent distal ileal stricture (white arrow). (C) Dilated proximal small bowel. Fig. 2. Gross and histologic findings. (A) Pinpoint perforation of the sidewall of the anastomosis. (B) Perforation with acute fibrinous inflammation of the left side of the bowel wall (H&E, ×40). (C) Marked crypt dropout in the mucosa (H&E, ×100). (D) Stromal hyalinization and telangiectasia at high magnification (H&E, ×200). No potential conflict of interest relevant to this article was reported.	CAPECITABINE	DrugsGivenReaction	CC BY-NC	32972095	19,962,131	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ileal perforation'.	Acute Ileal Perforation Caused by Radiation Enteritis After Restoration. Few radiation-induced bowel perforations have been reported to date. Furthermore, perforation after ileal restoration in asymptomatic patients is rare. We report the case of a 61-year-old man who was administered preoperative chemoradiotherapy for advanced rectal cancer. The patient underwent ultra-low anterior resection with ileal diversion, followed by ileal restoration. Perforation was detected 9 days after restoration, and he underwent a right hemicolectomy. The histologic evaluation indicated ileal perforation caused by acute radiation enteritis. INTRODUCTION In recent years, preoperative chemoradiotherapy (CRT) combined with total mesorectal excision has become a well-established approach for the reduction of local recurrence following the treatment of advanced rectal cancer [1]. As many rectal cancer patients undergo preoperative CRT, the complications associated with radiation should not be overlooked. Gastrointestinal symptoms following radiotherapy can be caused by intestinal strictures, intestinal fistula, de novo or recurrent neoplasia, small bowel bacterial overgrowth, bile salt malabsorption, fat or carbohydrate malabsorption, inflammatory bowel disease, pancreatic insufficiency, or irritable bowel syndrome, presenting with variable degrees [2]. In addition, rare cases of perforation, which can lead to generalized peritonitis and sometimes mortality, have been reported [3]. Herein, we report a rare complication of radiation enteritis, namely ileal perforation, after ileal restoration in a patient who underwent preoperative CRT. CASE REPORT This study was reviewed and approved by the Institutional Review Board of the Asan Medical Center in Seoul, Korea (No. 2020-0846). Written informed consent was obtained for publication of this case report and accompanying images. A 61-year-old man visited the hospital with pathologically confirmed rectal cancer 3 cm from the anal margin, identified using colonoscopy. Magnetic resonance imaging (MRI) scan revealed a tumor with perirectal fat infiltration. Preoperative CRT with capecitabine was administered at a cumulative dose of 5,040 cGY, divided into 28 cycles. Following preoperative CRT, sigmoidoscopy revealed the mass size to have decreased. MRI scan also revealed a decrease in the mass size, and the residual lesion contained more fibrous than tumor tissue. In addition, contrast-enhanced computed tomography (CT) scan showed diffuse wall thickening in a distal ileal segment located in the pelvis, indicating probable radiation enteritis (Fig. 1A). Eight weeks after the completion of preoperative CRT, the patient underwent robot-assisted ultra-low anterior resection with ileal diversion. The patient recovered uneventfully and was discharged 7 days after the surgery. Postoperative histologic staging was ypT3N0, and 6 cycles of adjuvant chemotherapy with capecitabine were administered thereafter. The patient was admitted again for ileal restoration 6 months after the operation. A small incision for ileal restoration did not permit accurate evaluation of the stricture and wall thickening or perfusion along the entire ileum. Functional end-to-end anastomosis was performed using a linear cutting stapler. Two days after the surgery, the patient’s progress was unremarkable, other than several episodes of diarrhea. However, 5 days after the surgery, a sudden episode of fever (38.7°C) developed, along with abdominal distension and mild tenderness. CT images suggested segmental diffuse edema in the terminal ileum, resulting in small bowel stricture and some uncomplicated reactive ascites. Although the patient was treated conservatively with fasting and antibiotics, the fever did not subside, and the abdominal distension and tenderness worsened. Percutaneous catheter drainage (PCD) was performed 8 days after the surgery; 550 mL of fluid was drained, which was clear and serous. After drainage, the patient’s distension and tenderness showed some improvement. However, 9 days after surgery, the patient exhibited aggravated symptoms, and the PCD appeared green in color and turbid in nature. In addition, an erect simple abdominal radiograph confirmed the presence of free air. CT images suggested peritonitis associated with bowel perforation, including free air, ascites, peritoneal infiltration, and thickening with enhancement (Fig. 1B, C). There was also a persistence of the previously noted diffuse segmental mural thickening in the distal ileum (i.e., presumed radiation enteritis), causing small bowel stricture with proximal dilatation (Fig. 1B, C). Considering the CT findings and the nature of the drainage fluid, emergency surgery was planned. Surgical findings showed that the previous anastomosis was intact, and a pinpoint perforation was confirmed on the sidewall of the anastomosis (Fig. 2A). As the perforation site was identified at some distance from the PCD, the possibility of iatrogenic perforation following PCD insertion was less likely. A stricture, caused by radiation enteritis, was detected 10 cm in length in the distal bowel segment 5 cm above the crotch of restoration anastomosis. A limited right hemicolectomy with ileal resection (length, 42 cm), including the previous stomal restoration site, was subsequently performed. Postoperative histology revealed the perforation site with a transmural tissue defect and acute fibrinous inflammation (Fig. 2B). In addition, the affected mucosa showed marked crypt dissipation, stromal hyalinization, and telangiectasia (Fig. 2C, D). Taken together, these pathologic features are consistent with perforated severe radiation enteritis. Subsequent culture of the ascites fluid confirmed enteric aerobic and anaerobic microbes; however, the clostridium difficile toxin assay was negative. The patient was discharged without the occurrence of any subsequent events other than a few episodes of diarrhea 11 days after surgery. DISCUSSION Gastrointestinal adverse events following radiation therapy can occur when gastrointestinal structures are included in the radiation field. The incidence and severity of radiation enteritis depend on the dose of radiotherapy. Additional aggravating factors include age, presence of comorbidities, prior operation, tobacco abuse, and concurrent chemotherapy [3]. Enteral epithelium is affected by chemotherapy as well as radiation because of its highly proliferative potential [4]. Mucosal atrophy with atypical hyperplastic glands and intestinal wall fibrosis, and telangiectasias can be typical histologic changes [5]. Otherwise, mucosal ulceration can also occur, sometimes developing abscess, fistula, and perforation. Fibrosis occurs as part of the healing process of the ulcer, which unfortunately produces narrowing of the enteral lumen causing stricture and even obstruction [5]. The patient did not have any comorbidities and history of surgery except for rectal cancer operation. He had a 30-pack-year smoking history, but quit smoking approximately a year before the rectal cancer diagnosis. Considering the pathogenesis of the patient, stricture caused by radiation enteritis led to obstruction and small bowel bacterial overgrowth caused by stasis, leading to stercoral enteritis and perforation caused by high pressure. In general, the complication of radiation can be divided into acute and late, depending on the timing. Late complication is less frequent than acute complication, but it can occur in up to 40% of patients receiving radiation in the abdominopelvic area three to 6 years after radiation [3]. Complications can be graded from 0 to 5 according to the Radiation Therapy Oncology Group morbidity grading scale [3]. Depending on the severity, there are various clinical features such as enteritis, bleeding, narrowing, perforation, fistula, etc. Enteral perforation is a very uncommon complication compared with bleeding and obstruction [6]. Diagnosis should be based on a combination of the patient’s clinical symptoms, history, laboratory result, imaging finding, and physical examination. The possibility of recurrent neoplasia should not be ruled out during diagnostic workup [7]. Management of chronic radiation enteritis is primarily focused on symptomatic improvement. Additionally, nutritional support should not be omitted. Symptomatic treatments include antidiarrheal agents, antiinflammatories, probiotics and antibiotics, cholestyramine, pentoxifylline and tocopherol, and hyperbaric oxygen, based on the individual status [2]. If the response to medical treatment does not meet the expectations, endoscopic therapy, including coagulation therapy and balloon dilatation, and further surgery needs to be considered [2]. This report describes a rare case of ileal perforation caused by intractable radiation enteritis after ileal restoration. In conclusion, when radiation enteritis continues to be intractable, concurrent with relevant physical, laboratory, and abdominopelvic CT findings, timely surgical intervention needs to be considered, or an irradiated bowel resection should be performed during ileal restoration. Fig. 1. Abdominal computed tomography scans. (A) Diffuse wall thickening in the distal ileal segment located in the pelvis 8 weeks after the preoperative chemoradiotherapy. (B) Small bowel obstruction following a persistent distal ileal stricture (white arrow). (C) Dilated proximal small bowel. Fig. 2. Gross and histologic findings. (A) Pinpoint perforation of the sidewall of the anastomosis. (B) Perforation with acute fibrinous inflammation of the left side of the bowel wall (H&E, ×40). (C) Marked crypt dropout in the mucosa (H&E, ×100). (D) Stromal hyalinization and telangiectasia at high magnification (H&E, ×200). No potential conflict of interest relevant to this article was reported.	CAPECITABINE	DrugsGivenReaction	CC BY-NC	32972095	19,962,131	2021-07
What was the dosage of drug 'CAPECITABINE'?	Acute Ileal Perforation Caused by Radiation Enteritis After Restoration. Few radiation-induced bowel perforations have been reported to date. Furthermore, perforation after ileal restoration in asymptomatic patients is rare. We report the case of a 61-year-old man who was administered preoperative chemoradiotherapy for advanced rectal cancer. The patient underwent ultra-low anterior resection with ileal diversion, followed by ileal restoration. Perforation was detected 9 days after restoration, and he underwent a right hemicolectomy. The histologic evaluation indicated ileal perforation caused by acute radiation enteritis. INTRODUCTION In recent years, preoperative chemoradiotherapy (CRT) combined with total mesorectal excision has become a well-established approach for the reduction of local recurrence following the treatment of advanced rectal cancer [1]. As many rectal cancer patients undergo preoperative CRT, the complications associated with radiation should not be overlooked. Gastrointestinal symptoms following radiotherapy can be caused by intestinal strictures, intestinal fistula, de novo or recurrent neoplasia, small bowel bacterial overgrowth, bile salt malabsorption, fat or carbohydrate malabsorption, inflammatory bowel disease, pancreatic insufficiency, or irritable bowel syndrome, presenting with variable degrees [2]. In addition, rare cases of perforation, which can lead to generalized peritonitis and sometimes mortality, have been reported [3]. Herein, we report a rare complication of radiation enteritis, namely ileal perforation, after ileal restoration in a patient who underwent preoperative CRT. CASE REPORT This study was reviewed and approved by the Institutional Review Board of the Asan Medical Center in Seoul, Korea (No. 2020-0846). Written informed consent was obtained for publication of this case report and accompanying images. A 61-year-old man visited the hospital with pathologically confirmed rectal cancer 3 cm from the anal margin, identified using colonoscopy. Magnetic resonance imaging (MRI) scan revealed a tumor with perirectal fat infiltration. Preoperative CRT with capecitabine was administered at a cumulative dose of 5,040 cGY, divided into 28 cycles. Following preoperative CRT, sigmoidoscopy revealed the mass size to have decreased. MRI scan also revealed a decrease in the mass size, and the residual lesion contained more fibrous than tumor tissue. In addition, contrast-enhanced computed tomography (CT) scan showed diffuse wall thickening in a distal ileal segment located in the pelvis, indicating probable radiation enteritis (Fig. 1A). Eight weeks after the completion of preoperative CRT, the patient underwent robot-assisted ultra-low anterior resection with ileal diversion. The patient recovered uneventfully and was discharged 7 days after the surgery. Postoperative histologic staging was ypT3N0, and 6 cycles of adjuvant chemotherapy with capecitabine were administered thereafter. The patient was admitted again for ileal restoration 6 months after the operation. A small incision for ileal restoration did not permit accurate evaluation of the stricture and wall thickening or perfusion along the entire ileum. Functional end-to-end anastomosis was performed using a linear cutting stapler. Two days after the surgery, the patient’s progress was unremarkable, other than several episodes of diarrhea. However, 5 days after the surgery, a sudden episode of fever (38.7°C) developed, along with abdominal distension and mild tenderness. CT images suggested segmental diffuse edema in the terminal ileum, resulting in small bowel stricture and some uncomplicated reactive ascites. Although the patient was treated conservatively with fasting and antibiotics, the fever did not subside, and the abdominal distension and tenderness worsened. Percutaneous catheter drainage (PCD) was performed 8 days after the surgery; 550 mL of fluid was drained, which was clear and serous. After drainage, the patient’s distension and tenderness showed some improvement. However, 9 days after surgery, the patient exhibited aggravated symptoms, and the PCD appeared green in color and turbid in nature. In addition, an erect simple abdominal radiograph confirmed the presence of free air. CT images suggested peritonitis associated with bowel perforation, including free air, ascites, peritoneal infiltration, and thickening with enhancement (Fig. 1B, C). There was also a persistence of the previously noted diffuse segmental mural thickening in the distal ileum (i.e., presumed radiation enteritis), causing small bowel stricture with proximal dilatation (Fig. 1B, C). Considering the CT findings and the nature of the drainage fluid, emergency surgery was planned. Surgical findings showed that the previous anastomosis was intact, and a pinpoint perforation was confirmed on the sidewall of the anastomosis (Fig. 2A). As the perforation site was identified at some distance from the PCD, the possibility of iatrogenic perforation following PCD insertion was less likely. A stricture, caused by radiation enteritis, was detected 10 cm in length in the distal bowel segment 5 cm above the crotch of restoration anastomosis. A limited right hemicolectomy with ileal resection (length, 42 cm), including the previous stomal restoration site, was subsequently performed. Postoperative histology revealed the perforation site with a transmural tissue defect and acute fibrinous inflammation (Fig. 2B). In addition, the affected mucosa showed marked crypt dissipation, stromal hyalinization, and telangiectasia (Fig. 2C, D). Taken together, these pathologic features are consistent with perforated severe radiation enteritis. Subsequent culture of the ascites fluid confirmed enteric aerobic and anaerobic microbes; however, the clostridium difficile toxin assay was negative. The patient was discharged without the occurrence of any subsequent events other than a few episodes of diarrhea 11 days after surgery. DISCUSSION Gastrointestinal adverse events following radiation therapy can occur when gastrointestinal structures are included in the radiation field. The incidence and severity of radiation enteritis depend on the dose of radiotherapy. Additional aggravating factors include age, presence of comorbidities, prior operation, tobacco abuse, and concurrent chemotherapy [3]. Enteral epithelium is affected by chemotherapy as well as radiation because of its highly proliferative potential [4]. Mucosal atrophy with atypical hyperplastic glands and intestinal wall fibrosis, and telangiectasias can be typical histologic changes [5]. Otherwise, mucosal ulceration can also occur, sometimes developing abscess, fistula, and perforation. Fibrosis occurs as part of the healing process of the ulcer, which unfortunately produces narrowing of the enteral lumen causing stricture and even obstruction [5]. The patient did not have any comorbidities and history of surgery except for rectal cancer operation. He had a 30-pack-year smoking history, but quit smoking approximately a year before the rectal cancer diagnosis. Considering the pathogenesis of the patient, stricture caused by radiation enteritis led to obstruction and small bowel bacterial overgrowth caused by stasis, leading to stercoral enteritis and perforation caused by high pressure. In general, the complication of radiation can be divided into acute and late, depending on the timing. Late complication is less frequent than acute complication, but it can occur in up to 40% of patients receiving radiation in the abdominopelvic area three to 6 years after radiation [3]. Complications can be graded from 0 to 5 according to the Radiation Therapy Oncology Group morbidity grading scale [3]. Depending on the severity, there are various clinical features such as enteritis, bleeding, narrowing, perforation, fistula, etc. Enteral perforation is a very uncommon complication compared with bleeding and obstruction [6]. Diagnosis should be based on a combination of the patient’s clinical symptoms, history, laboratory result, imaging finding, and physical examination. The possibility of recurrent neoplasia should not be ruled out during diagnostic workup [7]. Management of chronic radiation enteritis is primarily focused on symptomatic improvement. Additionally, nutritional support should not be omitted. Symptomatic treatments include antidiarrheal agents, antiinflammatories, probiotics and antibiotics, cholestyramine, pentoxifylline and tocopherol, and hyperbaric oxygen, based on the individual status [2]. If the response to medical treatment does not meet the expectations, endoscopic therapy, including coagulation therapy and balloon dilatation, and further surgery needs to be considered [2]. This report describes a rare case of ileal perforation caused by intractable radiation enteritis after ileal restoration. In conclusion, when radiation enteritis continues to be intractable, concurrent with relevant physical, laboratory, and abdominopelvic CT findings, timely surgical intervention needs to be considered, or an irradiated bowel resection should be performed during ileal restoration. Fig. 1. Abdominal computed tomography scans. (A) Diffuse wall thickening in the distal ileal segment located in the pelvis 8 weeks after the preoperative chemoradiotherapy. (B) Small bowel obstruction following a persistent distal ileal stricture (white arrow). (C) Dilated proximal small bowel. Fig. 2. Gross and histologic findings. (A) Pinpoint perforation of the sidewall of the anastomosis. (B) Perforation with acute fibrinous inflammation of the left side of the bowel wall (H&E, ×40). (C) Marked crypt dropout in the mucosa (H&E, ×100). (D) Stromal hyalinization and telangiectasia at high magnification (H&E, ×200). No potential conflict of interest relevant to this article was reported.	CUMULATIVE DOSE OF 5,040 CGY, DIVIDED INTO 28 CYCLES	DrugDosageText	CC BY-NC	32972095	19,962,131	2021-07
What was the outcome of reaction 'Gastroenteritis radiation'?	Acute Ileal Perforation Caused by Radiation Enteritis After Restoration. Few radiation-induced bowel perforations have been reported to date. Furthermore, perforation after ileal restoration in asymptomatic patients is rare. We report the case of a 61-year-old man who was administered preoperative chemoradiotherapy for advanced rectal cancer. The patient underwent ultra-low anterior resection with ileal diversion, followed by ileal restoration. Perforation was detected 9 days after restoration, and he underwent a right hemicolectomy. The histologic evaluation indicated ileal perforation caused by acute radiation enteritis. INTRODUCTION In recent years, preoperative chemoradiotherapy (CRT) combined with total mesorectal excision has become a well-established approach for the reduction of local recurrence following the treatment of advanced rectal cancer [1]. As many rectal cancer patients undergo preoperative CRT, the complications associated with radiation should not be overlooked. Gastrointestinal symptoms following radiotherapy can be caused by intestinal strictures, intestinal fistula, de novo or recurrent neoplasia, small bowel bacterial overgrowth, bile salt malabsorption, fat or carbohydrate malabsorption, inflammatory bowel disease, pancreatic insufficiency, or irritable bowel syndrome, presenting with variable degrees [2]. In addition, rare cases of perforation, which can lead to generalized peritonitis and sometimes mortality, have been reported [3]. Herein, we report a rare complication of radiation enteritis, namely ileal perforation, after ileal restoration in a patient who underwent preoperative CRT. CASE REPORT This study was reviewed and approved by the Institutional Review Board of the Asan Medical Center in Seoul, Korea (No. 2020-0846). Written informed consent was obtained for publication of this case report and accompanying images. A 61-year-old man visited the hospital with pathologically confirmed rectal cancer 3 cm from the anal margin, identified using colonoscopy. Magnetic resonance imaging (MRI) scan revealed a tumor with perirectal fat infiltration. Preoperative CRT with capecitabine was administered at a cumulative dose of 5,040 cGY, divided into 28 cycles. Following preoperative CRT, sigmoidoscopy revealed the mass size to have decreased. MRI scan also revealed a decrease in the mass size, and the residual lesion contained more fibrous than tumor tissue. In addition, contrast-enhanced computed tomography (CT) scan showed diffuse wall thickening in a distal ileal segment located in the pelvis, indicating probable radiation enteritis (Fig. 1A). Eight weeks after the completion of preoperative CRT, the patient underwent robot-assisted ultra-low anterior resection with ileal diversion. The patient recovered uneventfully and was discharged 7 days after the surgery. Postoperative histologic staging was ypT3N0, and 6 cycles of adjuvant chemotherapy with capecitabine were administered thereafter. The patient was admitted again for ileal restoration 6 months after the operation. A small incision for ileal restoration did not permit accurate evaluation of the stricture and wall thickening or perfusion along the entire ileum. Functional end-to-end anastomosis was performed using a linear cutting stapler. Two days after the surgery, the patient’s progress was unremarkable, other than several episodes of diarrhea. However, 5 days after the surgery, a sudden episode of fever (38.7°C) developed, along with abdominal distension and mild tenderness. CT images suggested segmental diffuse edema in the terminal ileum, resulting in small bowel stricture and some uncomplicated reactive ascites. Although the patient was treated conservatively with fasting and antibiotics, the fever did not subside, and the abdominal distension and tenderness worsened. Percutaneous catheter drainage (PCD) was performed 8 days after the surgery; 550 mL of fluid was drained, which was clear and serous. After drainage, the patient’s distension and tenderness showed some improvement. However, 9 days after surgery, the patient exhibited aggravated symptoms, and the PCD appeared green in color and turbid in nature. In addition, an erect simple abdominal radiograph confirmed the presence of free air. CT images suggested peritonitis associated with bowel perforation, including free air, ascites, peritoneal infiltration, and thickening with enhancement (Fig. 1B, C). There was also a persistence of the previously noted diffuse segmental mural thickening in the distal ileum (i.e., presumed radiation enteritis), causing small bowel stricture with proximal dilatation (Fig. 1B, C). Considering the CT findings and the nature of the drainage fluid, emergency surgery was planned. Surgical findings showed that the previous anastomosis was intact, and a pinpoint perforation was confirmed on the sidewall of the anastomosis (Fig. 2A). As the perforation site was identified at some distance from the PCD, the possibility of iatrogenic perforation following PCD insertion was less likely. A stricture, caused by radiation enteritis, was detected 10 cm in length in the distal bowel segment 5 cm above the crotch of restoration anastomosis. A limited right hemicolectomy with ileal resection (length, 42 cm), including the previous stomal restoration site, was subsequently performed. Postoperative histology revealed the perforation site with a transmural tissue defect and acute fibrinous inflammation (Fig. 2B). In addition, the affected mucosa showed marked crypt dissipation, stromal hyalinization, and telangiectasia (Fig. 2C, D). Taken together, these pathologic features are consistent with perforated severe radiation enteritis. Subsequent culture of the ascites fluid confirmed enteric aerobic and anaerobic microbes; however, the clostridium difficile toxin assay was negative. The patient was discharged without the occurrence of any subsequent events other than a few episodes of diarrhea 11 days after surgery. DISCUSSION Gastrointestinal adverse events following radiation therapy can occur when gastrointestinal structures are included in the radiation field. The incidence and severity of radiation enteritis depend on the dose of radiotherapy. Additional aggravating factors include age, presence of comorbidities, prior operation, tobacco abuse, and concurrent chemotherapy [3]. Enteral epithelium is affected by chemotherapy as well as radiation because of its highly proliferative potential [4]. Mucosal atrophy with atypical hyperplastic glands and intestinal wall fibrosis, and telangiectasias can be typical histologic changes [5]. Otherwise, mucosal ulceration can also occur, sometimes developing abscess, fistula, and perforation. Fibrosis occurs as part of the healing process of the ulcer, which unfortunately produces narrowing of the enteral lumen causing stricture and even obstruction [5]. The patient did not have any comorbidities and history of surgery except for rectal cancer operation. He had a 30-pack-year smoking history, but quit smoking approximately a year before the rectal cancer diagnosis. Considering the pathogenesis of the patient, stricture caused by radiation enteritis led to obstruction and small bowel bacterial overgrowth caused by stasis, leading to stercoral enteritis and perforation caused by high pressure. In general, the complication of radiation can be divided into acute and late, depending on the timing. Late complication is less frequent than acute complication, but it can occur in up to 40% of patients receiving radiation in the abdominopelvic area three to 6 years after radiation [3]. Complications can be graded from 0 to 5 according to the Radiation Therapy Oncology Group morbidity grading scale [3]. Depending on the severity, there are various clinical features such as enteritis, bleeding, narrowing, perforation, fistula, etc. Enteral perforation is a very uncommon complication compared with bleeding and obstruction [6]. Diagnosis should be based on a combination of the patient’s clinical symptoms, history, laboratory result, imaging finding, and physical examination. The possibility of recurrent neoplasia should not be ruled out during diagnostic workup [7]. Management of chronic radiation enteritis is primarily focused on symptomatic improvement. Additionally, nutritional support should not be omitted. Symptomatic treatments include antidiarrheal agents, antiinflammatories, probiotics and antibiotics, cholestyramine, pentoxifylline and tocopherol, and hyperbaric oxygen, based on the individual status [2]. If the response to medical treatment does not meet the expectations, endoscopic therapy, including coagulation therapy and balloon dilatation, and further surgery needs to be considered [2]. This report describes a rare case of ileal perforation caused by intractable radiation enteritis after ileal restoration. In conclusion, when radiation enteritis continues to be intractable, concurrent with relevant physical, laboratory, and abdominopelvic CT findings, timely surgical intervention needs to be considered, or an irradiated bowel resection should be performed during ileal restoration. Fig. 1. Abdominal computed tomography scans. (A) Diffuse wall thickening in the distal ileal segment located in the pelvis 8 weeks after the preoperative chemoradiotherapy. (B) Small bowel obstruction following a persistent distal ileal stricture (white arrow). (C) Dilated proximal small bowel. Fig. 2. Gross and histologic findings. (A) Pinpoint perforation of the sidewall of the anastomosis. (B) Perforation with acute fibrinous inflammation of the left side of the bowel wall (H&E, ×40). (C) Marked crypt dropout in the mucosa (H&E, ×100). (D) Stromal hyalinization and telangiectasia at high magnification (H&E, ×200). No potential conflict of interest relevant to this article was reported.	Recovered	ReactionOutcome	CC BY-NC	32972095	19,962,131	2021-07
What was the outcome of reaction 'Ileal perforation'?	Acute Ileal Perforation Caused by Radiation Enteritis After Restoration. Few radiation-induced bowel perforations have been reported to date. Furthermore, perforation after ileal restoration in asymptomatic patients is rare. We report the case of a 61-year-old man who was administered preoperative chemoradiotherapy for advanced rectal cancer. The patient underwent ultra-low anterior resection with ileal diversion, followed by ileal restoration. Perforation was detected 9 days after restoration, and he underwent a right hemicolectomy. The histologic evaluation indicated ileal perforation caused by acute radiation enteritis. INTRODUCTION In recent years, preoperative chemoradiotherapy (CRT) combined with total mesorectal excision has become a well-established approach for the reduction of local recurrence following the treatment of advanced rectal cancer [1]. As many rectal cancer patients undergo preoperative CRT, the complications associated with radiation should not be overlooked. Gastrointestinal symptoms following radiotherapy can be caused by intestinal strictures, intestinal fistula, de novo or recurrent neoplasia, small bowel bacterial overgrowth, bile salt malabsorption, fat or carbohydrate malabsorption, inflammatory bowel disease, pancreatic insufficiency, or irritable bowel syndrome, presenting with variable degrees [2]. In addition, rare cases of perforation, which can lead to generalized peritonitis and sometimes mortality, have been reported [3]. Herein, we report a rare complication of radiation enteritis, namely ileal perforation, after ileal restoration in a patient who underwent preoperative CRT. CASE REPORT This study was reviewed and approved by the Institutional Review Board of the Asan Medical Center in Seoul, Korea (No. 2020-0846). Written informed consent was obtained for publication of this case report and accompanying images. A 61-year-old man visited the hospital with pathologically confirmed rectal cancer 3 cm from the anal margin, identified using colonoscopy. Magnetic resonance imaging (MRI) scan revealed a tumor with perirectal fat infiltration. Preoperative CRT with capecitabine was administered at a cumulative dose of 5,040 cGY, divided into 28 cycles. Following preoperative CRT, sigmoidoscopy revealed the mass size to have decreased. MRI scan also revealed a decrease in the mass size, and the residual lesion contained more fibrous than tumor tissue. In addition, contrast-enhanced computed tomography (CT) scan showed diffuse wall thickening in a distal ileal segment located in the pelvis, indicating probable radiation enteritis (Fig. 1A). Eight weeks after the completion of preoperative CRT, the patient underwent robot-assisted ultra-low anterior resection with ileal diversion. The patient recovered uneventfully and was discharged 7 days after the surgery. Postoperative histologic staging was ypT3N0, and 6 cycles of adjuvant chemotherapy with capecitabine were administered thereafter. The patient was admitted again for ileal restoration 6 months after the operation. A small incision for ileal restoration did not permit accurate evaluation of the stricture and wall thickening or perfusion along the entire ileum. Functional end-to-end anastomosis was performed using a linear cutting stapler. Two days after the surgery, the patient’s progress was unremarkable, other than several episodes of diarrhea. However, 5 days after the surgery, a sudden episode of fever (38.7°C) developed, along with abdominal distension and mild tenderness. CT images suggested segmental diffuse edema in the terminal ileum, resulting in small bowel stricture and some uncomplicated reactive ascites. Although the patient was treated conservatively with fasting and antibiotics, the fever did not subside, and the abdominal distension and tenderness worsened. Percutaneous catheter drainage (PCD) was performed 8 days after the surgery; 550 mL of fluid was drained, which was clear and serous. After drainage, the patient’s distension and tenderness showed some improvement. However, 9 days after surgery, the patient exhibited aggravated symptoms, and the PCD appeared green in color and turbid in nature. In addition, an erect simple abdominal radiograph confirmed the presence of free air. CT images suggested peritonitis associated with bowel perforation, including free air, ascites, peritoneal infiltration, and thickening with enhancement (Fig. 1B, C). There was also a persistence of the previously noted diffuse segmental mural thickening in the distal ileum (i.e., presumed radiation enteritis), causing small bowel stricture with proximal dilatation (Fig. 1B, C). Considering the CT findings and the nature of the drainage fluid, emergency surgery was planned. Surgical findings showed that the previous anastomosis was intact, and a pinpoint perforation was confirmed on the sidewall of the anastomosis (Fig. 2A). As the perforation site was identified at some distance from the PCD, the possibility of iatrogenic perforation following PCD insertion was less likely. A stricture, caused by radiation enteritis, was detected 10 cm in length in the distal bowel segment 5 cm above the crotch of restoration anastomosis. A limited right hemicolectomy with ileal resection (length, 42 cm), including the previous stomal restoration site, was subsequently performed. Postoperative histology revealed the perforation site with a transmural tissue defect and acute fibrinous inflammation (Fig. 2B). In addition, the affected mucosa showed marked crypt dissipation, stromal hyalinization, and telangiectasia (Fig. 2C, D). Taken together, these pathologic features are consistent with perforated severe radiation enteritis. Subsequent culture of the ascites fluid confirmed enteric aerobic and anaerobic microbes; however, the clostridium difficile toxin assay was negative. The patient was discharged without the occurrence of any subsequent events other than a few episodes of diarrhea 11 days after surgery. DISCUSSION Gastrointestinal adverse events following radiation therapy can occur when gastrointestinal structures are included in the radiation field. The incidence and severity of radiation enteritis depend on the dose of radiotherapy. Additional aggravating factors include age, presence of comorbidities, prior operation, tobacco abuse, and concurrent chemotherapy [3]. Enteral epithelium is affected by chemotherapy as well as radiation because of its highly proliferative potential [4]. Mucosal atrophy with atypical hyperplastic glands and intestinal wall fibrosis, and telangiectasias can be typical histologic changes [5]. Otherwise, mucosal ulceration can also occur, sometimes developing abscess, fistula, and perforation. Fibrosis occurs as part of the healing process of the ulcer, which unfortunately produces narrowing of the enteral lumen causing stricture and even obstruction [5]. The patient did not have any comorbidities and history of surgery except for rectal cancer operation. He had a 30-pack-year smoking history, but quit smoking approximately a year before the rectal cancer diagnosis. Considering the pathogenesis of the patient, stricture caused by radiation enteritis led to obstruction and small bowel bacterial overgrowth caused by stasis, leading to stercoral enteritis and perforation caused by high pressure. In general, the complication of radiation can be divided into acute and late, depending on the timing. Late complication is less frequent than acute complication, but it can occur in up to 40% of patients receiving radiation in the abdominopelvic area three to 6 years after radiation [3]. Complications can be graded from 0 to 5 according to the Radiation Therapy Oncology Group morbidity grading scale [3]. Depending on the severity, there are various clinical features such as enteritis, bleeding, narrowing, perforation, fistula, etc. Enteral perforation is a very uncommon complication compared with bleeding and obstruction [6]. Diagnosis should be based on a combination of the patient’s clinical symptoms, history, laboratory result, imaging finding, and physical examination. The possibility of recurrent neoplasia should not be ruled out during diagnostic workup [7]. Management of chronic radiation enteritis is primarily focused on symptomatic improvement. Additionally, nutritional support should not be omitted. Symptomatic treatments include antidiarrheal agents, antiinflammatories, probiotics and antibiotics, cholestyramine, pentoxifylline and tocopherol, and hyperbaric oxygen, based on the individual status [2]. If the response to medical treatment does not meet the expectations, endoscopic therapy, including coagulation therapy and balloon dilatation, and further surgery needs to be considered [2]. This report describes a rare case of ileal perforation caused by intractable radiation enteritis after ileal restoration. In conclusion, when radiation enteritis continues to be intractable, concurrent with relevant physical, laboratory, and abdominopelvic CT findings, timely surgical intervention needs to be considered, or an irradiated bowel resection should be performed during ileal restoration. Fig. 1. Abdominal computed tomography scans. (A) Diffuse wall thickening in the distal ileal segment located in the pelvis 8 weeks after the preoperative chemoradiotherapy. (B) Small bowel obstruction following a persistent distal ileal stricture (white arrow). (C) Dilated proximal small bowel. Fig. 2. Gross and histologic findings. (A) Pinpoint perforation of the sidewall of the anastomosis. (B) Perforation with acute fibrinous inflammation of the left side of the bowel wall (H&E, ×40). (C) Marked crypt dropout in the mucosa (H&E, ×100). (D) Stromal hyalinization and telangiectasia at high magnification (H&E, ×200). No potential conflict of interest relevant to this article was reported.	Recovered	ReactionOutcome	CC BY-NC	32972095	19,962,131	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaphylactic reaction'.	Mycophenolate mofetil for methotrexate-resistant juvenile localized scleroderma. To investigate safety and efficacy of MMF in patients with severe or MTX-refractory juvenile localized scleroderma. Consecutive juvenile localized scleroderma patients undergoing systemic treatment were included in a retrospective longitudinal study. Patients treated with MMF because they were refractory or intolerant to MTX (MMF-group) were compared with responders to MTX (MTX-group). Disease activity was assessed by Localized Scleroderma Cutaneous Assessment Tool and thermography. Disease course was established on the number of relapses and treatment changes. Relapse-free survival was examined by Kaplan-Meier analysis. MMF and MTX groups included 22 and 47 patients, respectively. No significant difference in demographics, follow-up duration and treatment before diagnosis was observed between groups. The most represented clinical subtypes in the MMF-group were pansclerotic morphea and mixed subtype (P = 0.008 and P = 0.029, respectively), and linear scleroderma of the face in the MTX-group (P = 0.048). MMF was started because of MTX resistance (18 patients), relapse during MTX tapering/withdrawal (3 patients) and anaphylaxis to MTX (1 patient). After mean 9.4 years of follow-up, 90.9% of patients on MMF and 100% of those on MTX had inactive disease. No significant difference in relapse-free survival between the groups was found (P = 0.066, log-rank test), although MMF likely induced more persistent remission. MMF was well tolerated and combination of MMF and MTX did not increase its efficacy. The present study adds strong evidence on the efficacy and tolerance of MMF in severe and/or MTX-refractory juvenile localized scleroderma. Further controlled studies are needed to prove its efficacy as first line treatment. Rheumatology key messages Most patients with MTX-refractory juvenile localized scleroderma achieve sustained remission with MMF. MMF is well tolerated and equally effective in monotherapy or combined with MTX. Introduction Juvenile localized scleroderma (JLS) is a spectrum of disorders characterized by inflammation followed by thickening and sclerosis of skin and underlying tissues such as subcutaneous fat, muscle, fascia and bone, potentially leading to functional disability and cosmetic problems [1, 2]. While it is believed that most patients will enter spontaneous remission after 3–5 years of disease activity, those with more extensive deep tissue involvement, such as linear subtype and pansclerotic morphea, present considerable risk of severe course with persistent activity into adulthood and development of physical disability [1, 2]. Since the early 2000s a combination of MTX and CS has been reported as successful and safe treatment for JLS and chosen as first-choice therapy for patients with active disease [3–5]. Nevertheless, about 30% of patients do not respond to this therapy or do not tolerate it [3–5]. As alternatives to MTX, various other drugs have been used, and even biological agents such as abatacept and tocilizumab [6–8]. MMF has been suggested as potential treatment of JLS but up to now data are partial and incomplete, as only two case collections have been published so far [9, 10]. We conducted a retrospective, longitudinal study aimed to provide more evidence on MMF efficacy in reducing disease activity in MTX-resistant JLS, as well as to evaluate its safety profile. Methods Consecutive patients attending the Paediatric Rheumatology Unit of the Department of Woman and Child Health of Padova University, fulfilling diagnostic criteria for JLS and undergoing systemic treatment from 2000 to 2018, were included in the study and their charts were retrospectively reviewed [11]. The MMF-group included patients treated with MMF for at least 6 months, alone or in association with MTX and/or steroids, while the MTX-group included patients treated with MTX and steroids only. Institutional review board approval was not needed as the study included retrospective analysis of data. Written informed consent was obtained from parents of all subjects taking part in the study. Data collection included: demographics (age, gender, personal or family history of autoimmune diseases), clinical data (age at disease onset, age at diagnosis, follow-up duration, presence of extracutaneous manifestations, ANA considered positive if ≥1:160, treatment history (start and duration of treatment with MTX and/or MMF eventually associated with oral or i.v. CS, current treatment at last evaluation) and disease course (disease relapses defined as a disease reactivation during treatment and/or tapering and/or after withdrawal). All patients underwent periodic clinical evaluation including physical examination, laboratory work-up including complete blood cell counts, ESR, CRP and liver function tests; in patients taking MMF, levels of IgG, IgM and IgA were also routinely tested. Disease activity was monitored by clinical evaluation combined with infrared thermography (IRT). IRT examination was performed with an infrared camera (ThermaCAM PM695, FLIR Systems AB, Stockholm, Sweden) at a room temperature, after 20 min of acclimatization, wearing underwear. Lesions were considered positive to IRT when >0.5°C warmer than surrounding area or the contralateral side [12]. Long-term outcome was analysed by evaluation of disease activity at last visit including only patients with at least 6 months’ treatment duration. Disease activity was assessed by using the modified Localized Scleroderma Skin Severity Index (mLoSSI) combined with IRT [12, 13]. mLoSSI is part of Localized Scleroderma Cutaneous Assessment Tool and evaluates disease activity by grading of three domains: new lesion/lesion extension, erythema and skin thickness. Each lesion was examined and, in presence of multiple lesions, the most severe was considered. Combining mLoSSI and IRT, disease course was classified as follows: active disease: presence of new lesions and/or enlargement of an existing lesion within the past month, presence of erythema and/or skin thickening (equating to mLoSSI ≥1) and/or significant hyperthermia (>0.5°C) on thermography; clinical remission on medication (CRM): absence of new lesions and/or enlargement of existing lesions and signs of activity (equating to mLoSSI = 0, significant hyperthermia on thermography) during treatment; clinical remission off treatment: absence of new lesions and/or enlargement of existing lesions and signs of activity (as for CRM) for <2 years from treatment discontinuation; and complete clinical remission: absence of new lesions and enlargement of existing lesions and signs of activity (as for CRM) after ≥2 years from treatment discontinuation. Statistical analysis Descriptive statistics for each variable included in data collection was applied to analyse patient characteristics. For quantitative variables, the main indicators of centrality and variability were calculated. Association between categorical variables was investigated by Pearson’s χ2-test and Fisher’s exact test, and also in the extended Fisher–Freeman–Halton test version. Mann–Whitney test was used to evaluate differences between two groups, after verification of the non-normality distribution of variables considered in the analysis. Kaplan–Meier analysis with log-rank test was performed for relapse-free survival comparing the two groups of patients (MMF vs MTX) and, within the MMF-group, comparing patients treated with MMF in monotherapy and those in combination with MTX. A P-value of <0.05 (two-tailed test) was considered statistically significant. All analyses were performed using the IBM (New York, USA) SPSS statistical software (Version 18.0). Results Patients Twenty-two patients were included in MMF-group (9 males, 13 females) and 47 in MTX-group (20 males and 27 females). Clinical features of patients are summarized in Table 1. No significant difference was observed in the groups with regard to gender, age at diagnosis, diagnostic delay, family and/or personal history of autoimmune diseases, ANA and ENA positivity, follow-up duration and treatment received before diagnosis. In the MMF-group, pansclerotic morphea and mixed subtype were more frequent (P = 0.008 and P = 0.029, respectively) than in the MTX-group, where linear scleroderma of the face was slightly more represented (P = 0.048). Table 1 Clinical characteristics of patients Characteristics MMF group (22 pts) MTX group (47 pts) P-value F 13 (59.1) 27 (57.4) n.s M 9 (40.9) 20 (42.6) n.s. F:M ratio 1.4:1 1.35:1 n.s. Age at diagnosis, yearsa 8.3 (5.6) 7.1 (3.6) n.s. Diagnostic delay, monthsa 10 (8) 16 (17) n.s. Duration of follow-up, yearsa 9.4 (4.5) 9 (3.9) n.s. Disease subtype LiS of the trunk/limbs 4 (18.2) 13 (27.7) n.s. LiS of face 4 (18.2) 20 (42.6) 0.048 MS 7 (31.8) 4 (8.5) 0.029 GM 2 (9.1) 6 (12.8) n.s. PM 4 (18.2) 0 (0.0) 0.008 CM 1 (4.5) 4 (8.5) n.s. Data presented as n (%) unless stated. aMean (s.d.). F: female; M: male; LiS: linear scleroderma; MS: mixed subtype; PM: pansclerotic morphea; GM: generalized morphea; CM: circumscribed morphea; n.s.: not significant. No significant difference was found for extracutaneous manifestations (ECM): in MMF- and MTX-groups CNS abnormalities on MRI (not clinically significant) and mild dental abnormalities were present in one and two patients and in two and five patients, respectively. Prior to MMF, 14 patients (63.6%) received a combination of MTX and oral prednisone (oPDN), 7 (31.8%) MTX with three consecutive i.v. pulses of methylprednisolone followed by oPDN, while 1 patient was started on MMF because of anaphylactic reaction to MTX. MTX full dosage was 15–17 mg/m2/week. In the MTX-group 31 patients (66%) received MTX–oPDN and 16 (34%) MTX–methylprednisolone–oPDN. No significant differences in CS and MTX dosages and treatment duration were observed between the two groups. MMF was started because of persistent activity on full dose of MTX in 18/21 patients (85.7%), and relapse during MTX tapering/withdrawal in 3/21 (14.3%). Mean treatment duration in the MMF- and the MTX-group was similar (mean 39.5 and 39.4 months, respectively). MMF dosage was 700–1000 mg/m2/day and was used in combination with MTX in 12 (54.5%) patients. Minor side effects were recorded in 12 patients of the MMF-group: headache (22.7%), mild transaminases increase (18.2%), nausea/vomiting (9.1%) and fatigue (9.1%), with no treatment discontinuation because of side effects. Disease course and outcome During the follow-up period 10/22 (45.4%) patients in the MMF-group and 11/47 (23.4%) in the MTX-group presented at least one disease reactivation (P = not significant). Average time from treatment start to relapse was 31 months (median 37.3, 21 s.d.) in the MMF-group and 26.2 months (median 13, 32.4 s.d.) in the MTX-group (P = not significant). Moreover, the relapse-free survival analysis comparing the two groups of patients revealed no significant difference, as shown by Kaplan–Meier survival estimates of time to disease relapse (P = 0.066, log-rank test, Fig. 1A), although MMF likely induced a more persistent remission. In fact, from this analysis 50% of patients reactivated after 68 months in the MMF-group and after 22 months in the MTX-group. Fig. 1 Relapse-free survival analysis by Kaplan–Meier survival estimates of time to disease relapse In this analysis, patients in the MMF-group (dashed line) were compared with those in the MTX-group (continuous line) (P = 0.066, log-rank test) (A), and patients treated with MMF alone (close dots) with those treated with MMF in combination with MTX (spaced dots, P = not significant) (B). Of interest, association of MMF with MTX did not increase the efficacy of therapy, as relapses occurred in 5/10 patients treated with MMF monotherapy and in 5/12 with both agents (P = not significant). Average time from start of treatment to relapse was 30.9 months (median 40.9, 17.7 s.d.) with MMF monotherapy and 31.0 months (median 34.3, 26.0 s.d.) with MMF + MTX combination (P = not significant), respectively. Indeed, these results were confirmed by relapse-free survival analysis (Fig. 1B). As for clinical subtype, 60% of all disease relapses in the MMF-group occurred in patients with mixed subtype and with pansclerotic morphea. As for the long-term outcome, no significant difference in clinical course was observed in the two groups, as 90.9 and 100% of patients in the MMF- and MTX-group, respectively, had inactive disease at last evaluation. In particular, in the MMF-group 10 patients (50.0%) were in CRM, 3 (15%) in clinical remission off treatment and 7 (35%) in complete clinical remission. Furthermore, no significant difference in disease activity was found between patients treated with MMF alone and those with MMF + MTX. Discussion Localized scleroderma is characterized by early clinical inflammatory manifestations that are associated with extension of fibrotic lesions [14, 15]. Therefore, the aim of therapy is to cool down the inflammatory process in order to prevent progression to the fibrotic stage, thus reducing tissue damage [3]. A combination of MTX and CS is the recommended first-choice systemic treatment for JLS, but other agents such as abatacept and tocilizumab have been tried in severe cases [4–8]. In a previous report, we showed that MMF resulted in significant clinical improvement that allowed decrease and discontinuation of CS and MTX in 10 children with JLS refractory to MTX [9]. More recently, another study confirmed good response and tolerability with MMF in seven patients with difficult-to-treat localized scleroderma [10]. Although having the limitation of being retrospective, the present study is the largest to date on the use of MMF in JLS, and strengthens the evidence of its safety and efficacy in suppressing the inflammatory–fibrotic process. The comparison of the two patient cohorts, followed for 9 years on average, showed comparable efficacy between MMF and MTX. At the latest assessment, all patients in the MTX-group and 90.9% of those in the MMF-group had inactive disease. This comparable efficacy is particularly impressive in view of the composition of the MMF-group being patients that had been previously refractory or intolerant to MTX. Therefore, the result obtained further underlines the remarkable efficacy of MMF in seriously ill patients. MMF exerts immunosuppressive effects by inhibiting lymphocytes activation and proliferation. Therefore, it has been extensively used in prevention of kidney and lung transplantation rejection and for disease-modifying treatment in adults and children with SLE [16]. The rationale for using MMF in sclerodermatous conditions, such as JLS and SSc, came from observation of its in vitro inhibitory effect on smooth muscle cells and fibroblasts differentiation, thus decreasing the production and exaggerated accumulation of collagen and other extracellular matrix proteins [17]. More recently, in patients with SSc treated with MMF a reduction of monocyte chemoattractant protein-2 (CCL2) mRNA expression has been observed in skin [18]. CCL2 is a myeloid cell chemoattractant with an important role in SSc disease initiation, thus its inhibition by MMF was speculated to be the key responsible of skin induration improvement during treatment. A randomized controlled trial in adult SSc showed that MMF significantly improved skin thickening and involvement as measured by modified Rodnan Skin Score, and this effect was maintained throughout the 12-month follow-up [19]. More recently, a post hoc analysis has been performed from two randomized placebo-controlled trials in patients with diffuse SSc in which modified Rodnan Skin Score was regularly measured by expert physicians, and this study confirmed that MMF was as effective as CYC in leading to significant improvement of modified Rodnan Skin Score but was better tolerated [20]. In our previous report 6/10 patients received both MMF and MTX, therefore we were not able to demonstrate that MMF was the only agent responsible for clinical improvement. Conversely, in the present study MMF was equally effective when used as monotherapy or combined with MTX. This observation, although based on small numbers, is important for clinicians in order to reduce the risk of a severe immunosuppressive effect stemming from the contemporary use of two agents. MMF has a favourable safety profile and our study confirmed it: in fact, no discontinuation due to side effects was observed. In conclusion, the results presented here strengthen the evidence of the efficacy of MMF in achieving disease inactivity in children with severe MTX-refractory JLS. These results also suggest that a substantial proportion of patients treated with MMF maintain persistent control of disease activity, as shown by the longer time from treatment start to relapse. Further studies in larger cohorts of patients are needed to confirm these preliminary results and may clarify whether use of MMF as first-line agent, rather than only in MTX-refractory patients, likely provides better outcomes in patients with severe and extensive JLS forms. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. Supplementary Material keaa392_Supplementary_Data Click here for additional data file.	METHOTREXATE	DrugsGivenReaction	CC BY-NC	32978631	18,385,849	2021-03-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'.	Mycophenolate mofetil for methotrexate-resistant juvenile localized scleroderma. To investigate safety and efficacy of MMF in patients with severe or MTX-refractory juvenile localized scleroderma. Consecutive juvenile localized scleroderma patients undergoing systemic treatment were included in a retrospective longitudinal study. Patients treated with MMF because they were refractory or intolerant to MTX (MMF-group) were compared with responders to MTX (MTX-group). Disease activity was assessed by Localized Scleroderma Cutaneous Assessment Tool and thermography. Disease course was established on the number of relapses and treatment changes. Relapse-free survival was examined by Kaplan-Meier analysis. MMF and MTX groups included 22 and 47 patients, respectively. No significant difference in demographics, follow-up duration and treatment before diagnosis was observed between groups. The most represented clinical subtypes in the MMF-group were pansclerotic morphea and mixed subtype (P = 0.008 and P = 0.029, respectively), and linear scleroderma of the face in the MTX-group (P = 0.048). MMF was started because of MTX resistance (18 patients), relapse during MTX tapering/withdrawal (3 patients) and anaphylaxis to MTX (1 patient). After mean 9.4 years of follow-up, 90.9% of patients on MMF and 100% of those on MTX had inactive disease. No significant difference in relapse-free survival between the groups was found (P = 0.066, log-rank test), although MMF likely induced more persistent remission. MMF was well tolerated and combination of MMF and MTX did not increase its efficacy. The present study adds strong evidence on the efficacy and tolerance of MMF in severe and/or MTX-refractory juvenile localized scleroderma. Further controlled studies are needed to prove its efficacy as first line treatment. Rheumatology key messages Most patients with MTX-refractory juvenile localized scleroderma achieve sustained remission with MMF. MMF is well tolerated and equally effective in monotherapy or combined with MTX. Introduction Juvenile localized scleroderma (JLS) is a spectrum of disorders characterized by inflammation followed by thickening and sclerosis of skin and underlying tissues such as subcutaneous fat, muscle, fascia and bone, potentially leading to functional disability and cosmetic problems [1, 2]. While it is believed that most patients will enter spontaneous remission after 3–5 years of disease activity, those with more extensive deep tissue involvement, such as linear subtype and pansclerotic morphea, present considerable risk of severe course with persistent activity into adulthood and development of physical disability [1, 2]. Since the early 2000s a combination of MTX and CS has been reported as successful and safe treatment for JLS and chosen as first-choice therapy for patients with active disease [3–5]. Nevertheless, about 30% of patients do not respond to this therapy or do not tolerate it [3–5]. As alternatives to MTX, various other drugs have been used, and even biological agents such as abatacept and tocilizumab [6–8]. MMF has been suggested as potential treatment of JLS but up to now data are partial and incomplete, as only two case collections have been published so far [9, 10]. We conducted a retrospective, longitudinal study aimed to provide more evidence on MMF efficacy in reducing disease activity in MTX-resistant JLS, as well as to evaluate its safety profile. Methods Consecutive patients attending the Paediatric Rheumatology Unit of the Department of Woman and Child Health of Padova University, fulfilling diagnostic criteria for JLS and undergoing systemic treatment from 2000 to 2018, were included in the study and their charts were retrospectively reviewed [11]. The MMF-group included patients treated with MMF for at least 6 months, alone or in association with MTX and/or steroids, while the MTX-group included patients treated with MTX and steroids only. Institutional review board approval was not needed as the study included retrospective analysis of data. Written informed consent was obtained from parents of all subjects taking part in the study. Data collection included: demographics (age, gender, personal or family history of autoimmune diseases), clinical data (age at disease onset, age at diagnosis, follow-up duration, presence of extracutaneous manifestations, ANA considered positive if ≥1:160, treatment history (start and duration of treatment with MTX and/or MMF eventually associated with oral or i.v. CS, current treatment at last evaluation) and disease course (disease relapses defined as a disease reactivation during treatment and/or tapering and/or after withdrawal). All patients underwent periodic clinical evaluation including physical examination, laboratory work-up including complete blood cell counts, ESR, CRP and liver function tests; in patients taking MMF, levels of IgG, IgM and IgA were also routinely tested. Disease activity was monitored by clinical evaluation combined with infrared thermography (IRT). IRT examination was performed with an infrared camera (ThermaCAM PM695, FLIR Systems AB, Stockholm, Sweden) at a room temperature, after 20 min of acclimatization, wearing underwear. Lesions were considered positive to IRT when >0.5°C warmer than surrounding area or the contralateral side [12]. Long-term outcome was analysed by evaluation of disease activity at last visit including only patients with at least 6 months’ treatment duration. Disease activity was assessed by using the modified Localized Scleroderma Skin Severity Index (mLoSSI) combined with IRT [12, 13]. mLoSSI is part of Localized Scleroderma Cutaneous Assessment Tool and evaluates disease activity by grading of three domains: new lesion/lesion extension, erythema and skin thickness. Each lesion was examined and, in presence of multiple lesions, the most severe was considered. Combining mLoSSI and IRT, disease course was classified as follows: active disease: presence of new lesions and/or enlargement of an existing lesion within the past month, presence of erythema and/or skin thickening (equating to mLoSSI ≥1) and/or significant hyperthermia (>0.5°C) on thermography; clinical remission on medication (CRM): absence of new lesions and/or enlargement of existing lesions and signs of activity (equating to mLoSSI = 0, significant hyperthermia on thermography) during treatment; clinical remission off treatment: absence of new lesions and/or enlargement of existing lesions and signs of activity (as for CRM) for <2 years from treatment discontinuation; and complete clinical remission: absence of new lesions and enlargement of existing lesions and signs of activity (as for CRM) after ≥2 years from treatment discontinuation. Statistical analysis Descriptive statistics for each variable included in data collection was applied to analyse patient characteristics. For quantitative variables, the main indicators of centrality and variability were calculated. Association between categorical variables was investigated by Pearson’s χ2-test and Fisher’s exact test, and also in the extended Fisher–Freeman–Halton test version. Mann–Whitney test was used to evaluate differences between two groups, after verification of the non-normality distribution of variables considered in the analysis. Kaplan–Meier analysis with log-rank test was performed for relapse-free survival comparing the two groups of patients (MMF vs MTX) and, within the MMF-group, comparing patients treated with MMF in monotherapy and those in combination with MTX. A P-value of <0.05 (two-tailed test) was considered statistically significant. All analyses were performed using the IBM (New York, USA) SPSS statistical software (Version 18.0). Results Patients Twenty-two patients were included in MMF-group (9 males, 13 females) and 47 in MTX-group (20 males and 27 females). Clinical features of patients are summarized in Table 1. No significant difference was observed in the groups with regard to gender, age at diagnosis, diagnostic delay, family and/or personal history of autoimmune diseases, ANA and ENA positivity, follow-up duration and treatment received before diagnosis. In the MMF-group, pansclerotic morphea and mixed subtype were more frequent (P = 0.008 and P = 0.029, respectively) than in the MTX-group, where linear scleroderma of the face was slightly more represented (P = 0.048). Table 1 Clinical characteristics of patients Characteristics MMF group (22 pts) MTX group (47 pts) P-value F 13 (59.1) 27 (57.4) n.s M 9 (40.9) 20 (42.6) n.s. F:M ratio 1.4:1 1.35:1 n.s. Age at diagnosis, yearsa 8.3 (5.6) 7.1 (3.6) n.s. Diagnostic delay, monthsa 10 (8) 16 (17) n.s. Duration of follow-up, yearsa 9.4 (4.5) 9 (3.9) n.s. Disease subtype LiS of the trunk/limbs 4 (18.2) 13 (27.7) n.s. LiS of face 4 (18.2) 20 (42.6) 0.048 MS 7 (31.8) 4 (8.5) 0.029 GM 2 (9.1) 6 (12.8) n.s. PM 4 (18.2) 0 (0.0) 0.008 CM 1 (4.5) 4 (8.5) n.s. Data presented as n (%) unless stated. aMean (s.d.). F: female; M: male; LiS: linear scleroderma; MS: mixed subtype; PM: pansclerotic morphea; GM: generalized morphea; CM: circumscribed morphea; n.s.: not significant. No significant difference was found for extracutaneous manifestations (ECM): in MMF- and MTX-groups CNS abnormalities on MRI (not clinically significant) and mild dental abnormalities were present in one and two patients and in two and five patients, respectively. Prior to MMF, 14 patients (63.6%) received a combination of MTX and oral prednisone (oPDN), 7 (31.8%) MTX with three consecutive i.v. pulses of methylprednisolone followed by oPDN, while 1 patient was started on MMF because of anaphylactic reaction to MTX. MTX full dosage was 15–17 mg/m2/week. In the MTX-group 31 patients (66%) received MTX–oPDN and 16 (34%) MTX–methylprednisolone–oPDN. No significant differences in CS and MTX dosages and treatment duration were observed between the two groups. MMF was started because of persistent activity on full dose of MTX in 18/21 patients (85.7%), and relapse during MTX tapering/withdrawal in 3/21 (14.3%). Mean treatment duration in the MMF- and the MTX-group was similar (mean 39.5 and 39.4 months, respectively). MMF dosage was 700–1000 mg/m2/day and was used in combination with MTX in 12 (54.5%) patients. Minor side effects were recorded in 12 patients of the MMF-group: headache (22.7%), mild transaminases increase (18.2%), nausea/vomiting (9.1%) and fatigue (9.1%), with no treatment discontinuation because of side effects. Disease course and outcome During the follow-up period 10/22 (45.4%) patients in the MMF-group and 11/47 (23.4%) in the MTX-group presented at least one disease reactivation (P = not significant). Average time from treatment start to relapse was 31 months (median 37.3, 21 s.d.) in the MMF-group and 26.2 months (median 13, 32.4 s.d.) in the MTX-group (P = not significant). Moreover, the relapse-free survival analysis comparing the two groups of patients revealed no significant difference, as shown by Kaplan–Meier survival estimates of time to disease relapse (P = 0.066, log-rank test, Fig. 1A), although MMF likely induced a more persistent remission. In fact, from this analysis 50% of patients reactivated after 68 months in the MMF-group and after 22 months in the MTX-group. Fig. 1 Relapse-free survival analysis by Kaplan–Meier survival estimates of time to disease relapse In this analysis, patients in the MMF-group (dashed line) were compared with those in the MTX-group (continuous line) (P = 0.066, log-rank test) (A), and patients treated with MMF alone (close dots) with those treated with MMF in combination with MTX (spaced dots, P = not significant) (B). Of interest, association of MMF with MTX did not increase the efficacy of therapy, as relapses occurred in 5/10 patients treated with MMF monotherapy and in 5/12 with both agents (P = not significant). Average time from start of treatment to relapse was 30.9 months (median 40.9, 17.7 s.d.) with MMF monotherapy and 31.0 months (median 34.3, 26.0 s.d.) with MMF + MTX combination (P = not significant), respectively. Indeed, these results were confirmed by relapse-free survival analysis (Fig. 1B). As for clinical subtype, 60% of all disease relapses in the MMF-group occurred in patients with mixed subtype and with pansclerotic morphea. As for the long-term outcome, no significant difference in clinical course was observed in the two groups, as 90.9 and 100% of patients in the MMF- and MTX-group, respectively, had inactive disease at last evaluation. In particular, in the MMF-group 10 patients (50.0%) were in CRM, 3 (15%) in clinical remission off treatment and 7 (35%) in complete clinical remission. Furthermore, no significant difference in disease activity was found between patients treated with MMF alone and those with MMF + MTX. Discussion Localized scleroderma is characterized by early clinical inflammatory manifestations that are associated with extension of fibrotic lesions [14, 15]. Therefore, the aim of therapy is to cool down the inflammatory process in order to prevent progression to the fibrotic stage, thus reducing tissue damage [3]. A combination of MTX and CS is the recommended first-choice systemic treatment for JLS, but other agents such as abatacept and tocilizumab have been tried in severe cases [4–8]. In a previous report, we showed that MMF resulted in significant clinical improvement that allowed decrease and discontinuation of CS and MTX in 10 children with JLS refractory to MTX [9]. More recently, another study confirmed good response and tolerability with MMF in seven patients with difficult-to-treat localized scleroderma [10]. Although having the limitation of being retrospective, the present study is the largest to date on the use of MMF in JLS, and strengthens the evidence of its safety and efficacy in suppressing the inflammatory–fibrotic process. The comparison of the two patient cohorts, followed for 9 years on average, showed comparable efficacy between MMF and MTX. At the latest assessment, all patients in the MTX-group and 90.9% of those in the MMF-group had inactive disease. This comparable efficacy is particularly impressive in view of the composition of the MMF-group being patients that had been previously refractory or intolerant to MTX. Therefore, the result obtained further underlines the remarkable efficacy of MMF in seriously ill patients. MMF exerts immunosuppressive effects by inhibiting lymphocytes activation and proliferation. Therefore, it has been extensively used in prevention of kidney and lung transplantation rejection and for disease-modifying treatment in adults and children with SLE [16]. The rationale for using MMF in sclerodermatous conditions, such as JLS and SSc, came from observation of its in vitro inhibitory effect on smooth muscle cells and fibroblasts differentiation, thus decreasing the production and exaggerated accumulation of collagen and other extracellular matrix proteins [17]. More recently, in patients with SSc treated with MMF a reduction of monocyte chemoattractant protein-2 (CCL2) mRNA expression has been observed in skin [18]. CCL2 is a myeloid cell chemoattractant with an important role in SSc disease initiation, thus its inhibition by MMF was speculated to be the key responsible of skin induration improvement during treatment. A randomized controlled trial in adult SSc showed that MMF significantly improved skin thickening and involvement as measured by modified Rodnan Skin Score, and this effect was maintained throughout the 12-month follow-up [19]. More recently, a post hoc analysis has been performed from two randomized placebo-controlled trials in patients with diffuse SSc in which modified Rodnan Skin Score was regularly measured by expert physicians, and this study confirmed that MMF was as effective as CYC in leading to significant improvement of modified Rodnan Skin Score but was better tolerated [20]. In our previous report 6/10 patients received both MMF and MTX, therefore we were not able to demonstrate that MMF was the only agent responsible for clinical improvement. Conversely, in the present study MMF was equally effective when used as monotherapy or combined with MTX. This observation, although based on small numbers, is important for clinicians in order to reduce the risk of a severe immunosuppressive effect stemming from the contemporary use of two agents. MMF has a favourable safety profile and our study confirmed it: in fact, no discontinuation due to side effects was observed. In conclusion, the results presented here strengthen the evidence of the efficacy of MMF in achieving disease inactivity in children with severe MTX-refractory JLS. These results also suggest that a substantial proportion of patients treated with MMF maintain persistent control of disease activity, as shown by the longer time from treatment start to relapse. Further studies in larger cohorts of patients are needed to confirm these preliminary results and may clarify whether use of MMF as first-line agent, rather than only in MTX-refractory patients, likely provides better outcomes in patients with severe and extensive JLS forms. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. Supplementary Material keaa392_Supplementary_Data Click here for additional data file.	METHOTREXATE	DrugsGivenReaction	CC BY-NC	32978631	18,385,849	2021-03-02

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