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Abstract Background Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC). Methods This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3 −) to nitrite (NO2 −) with nitrate reductase, followed by quantitation of NO2 − based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE. Results After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of

Abstract Background Transarterial chemoembolization (TACE) is the standard treatment for intermediate stage hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC] B). However, it often leads to a poor prognosis and decreased hepatic function especially in patients with BCLC substage B2. Lenvatinib (LEN) was demonstrated to be efficacious in these patients in the REFLECT phase 3 trial. We therefore aimed to evaluate the efficacy and safety of LEN as a first-line treatment for the patients with HCC at BCLC substage B2. Methods This prospective observational study used LEN in TACE-naïve patients with HCC at BCLC substage B2 and preserved hepatic function. The primary endpoint was overall survival. A one-year survival rate threshold of 60% and an expected survival rate of 78%, based on previous reports of TACE, was assumed for setting the sample size. With a one-sided α-type error of 5% and 70% detection power, 25 patients were required over a 2-year enrollment period and 10-month follow-up period. Results Thirty-one patients were enrolled in this study from June 2018 to June 2020. The 1-year survival rate was 71.0% (90% confidence interval, 68.4–73.6%). Median overall and progression-free survival periods were 17.0 and 10.4 months, and the objective response rates according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 and modified RECIST criteria were 22.6% and 70.0%, respectively. Common adverse events (AEs) were fatigue (68%), hypertension (65%), anorexia (61%), palmar-plantar erythrodysesthesia (39%), and thrombocytopenia (32%) of any grade; aspartate aminotransferase increased (23%), alanine aminotransferase increased (16%), and grade ≥ 3 proteinuria (13%). Treatment interruption and dose reduction were required in 61% and 81% of patients, respectively. LEN was discontinued in 29 patients due to disease progression (n = 17), AEs (n = 9), conversion to curative treatments (n = 2), and sudden death (n = 1), whereas post-LEN treatments were administered in 18 patients, including systemic chemotherapy (n = 11), TACE (n = 6), transarterial infusion (n = 1) and clinical trial (n = 1). Conclusions The results suggest that LEN provides treatment benefits as an initial therapeutic in patients with BCLC substage B2 HCC with a safety profile comparable to that previously reported.

Abstract Background Bleeding can be a serious adverse event of endoscopic sphincterotomy (EST). However, the risk of EST bleeding between direct oral anticoagulant (DOAC) users and those who received no antithrombotic agents has not been clarified. This study analyzed the risk factors for bleeding after EST in patients on DOAC and evaluated the Japan Gastroenterological Endoscopy Society (JGES) guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Methods We retrospectively analyzed 524 patients treated with EST who received DOAC or no antithrombotic drug from May 2016 to August 2019. We investigated the risk factors for bleeding. DOAC was typically discontinued for ≤ 1-day based on the JGES guideline. Although DOAC therapy recommenced the next morning after EST in principle, the duration of DOAC cessation and heparin replacement were determined by the attending physician based on each patient’s status. Results The number of patients on DOAC (DOAC group) and those not on antithrombotic drug (no-drug group) was 42 (8.0%) and 482 (92.0%), respectively. DOAC was discontinued for ≤ 1-day in 17 (40.0%) patients and for > 1-day in 25 (60.0%). Of the 524 patients, 21 (4.0%) had EST bleeding. The bleeding rate was higher in the DOAC group (14.0%) (p = 0.004). Multivariate analysis showed that bleeding occurred more frequently in patients on DOAC (odds ratio [OR] 3.95, 95% confidence interval [CI] 1.37–11.4, p = 0.011), patients with low platelet counts ( 80 years old) (OR 3.36, 95%CI 1.17–9.65, p = 0.024). Conclusions DOAC treatment, low platelet count, and old age (> 80 years old) are risk factors for EST bleeding. Although the bleeding incidence increased in patients on DOAC who received antithrombotic therapy according to the JGES guidelines, successful hemostasis was achieved with endoscopy in all cases, and no thrombotic events occurred after cessation of DOAC. Thus, the JGES guidelines are acceptable.

Abstract Background Methotrexate, an immunosuppressant, is widely used as the standard therapeutic drug for rheumatoid arthritis. With the increasing frequency of use of methotrexate, adverse effects of methotrexate have been reported, one of which is known as methotrexate-associated lymphoproliferative disorders. The etiology of hepatic methotrexate-associated lymphoproliferative disorders remains largely unknown. To date, there have only been ten cases of hepatic methotrexate-associated lymphoproliferative disorders reported in the English literature and a case report is very rare. Case presentation An 82-year-old Japanese man with rheumatoid arthritis treated with methotrexate presented with fever. Contrast-enhanced computed tomography showed multiple hypovascular nodules in his liver, spleen, and lung, and para-aortic lesions. Endoscopic ultrasound-guided fine-needle aspiration biopsy for liver tumors was performed, and pathological results identified cluster of differentiation 20-positive lymphocytes. Discontinuance of methotrexate led to regression of the nodules and a final definitive diagnosis of methotrexate-associated lymphoproliferative disorders was made. Conclusions We review 11 reported cases of hepatic methotrexate-associated lymphoproliferative disorders including the present case. Physicians should discontinue methotrexate in patients with rheumatoid arthritis treated with methotrexate when elevated soluble interleukin-2 receptor and hypovascular lesions in contrast-enhanced computed tomography are confirmed considering the possibility of methotrexate-associated lymphoproliferative disorders.

Abstract Introduction Sepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies. Chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for Clostridium perfringens sepsis. Therefore, Clostridium perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. This case report focuses on findings characteristic of an intravascular hemolysis due to Clostridium perfringens after transhepatic arterial chemoembolization. Case presentation An 83-year-old Japanese man presented to our hospital because of a third recurrence of hepatocellular carcinoma. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation and transhepatic arterial chemoembolization therapy for hepatocellular carcinoma of S4/S8 and S2. He had a medical history of pancreatic carcinoma and underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. Because follow-up computed tomography showed a recurrence of the hepatocellular carcinoma, he underwent transhepatic arterial chemoembolization with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil). On the sixth day after the procedure, he complained of fever and hematuria with jaundice. Laboratory findings indicated hemolysis and increased inflammatory response. Although we initiated antibiotic therapy combined with surgical debridement for infection after transhepatic arterial chemoembolization, he died within 6 hours. The autopsy showed a 4-cm local necrotic hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion. In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed. The culture obtained by fluid aspiration from the hepatic abscess revealed Clostridium perfringens. Although the role of Clostridium perfringens was never established during the life of this patient, based on the clinical course and the culture from the hepatic abscess at postmortem, intravascular hemolysis secondary to Clostridium perfringens sepsis was suspected. Conclusion Intravascular hemolysis secondary to Clostridium perfringens should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. Biliary reconstruction is an especially important risk factor for infection.

Abstract Background It remains unclear whether hepatitis C virus (HCV)-infected Japanese patients on hemodialysis (HD) have an altered viral response to glecaprevir (GLE) and pibrentasvir (PIB) combination therapy and whether this treatment is safe for this patient group. Therefore, we investigated the characteristics associated with virological response to GLE and PIB combination therapy for HCV in Japanese patients undergoing HD. This study aimed to evaluate the safety and efficacy of GLE and PIB combination therapy in HCV-infected Japanese patients on HD. Methods This multicenter, single-arm, open-label, and prospective study was conducted at four centers in Japan and enrolled Japanese patients with chronic HCV genotype 1b, 2a, and 2b infections. Enrolled patients received 300 mg GLE in combination with 120 mg PIB once daily for either 8 or 12 weeks. The primary endpoint of this trial was the rate of sustained virological response at 12 weeks after treatment (SVR12). Furthermore, pharmacological effects and adverse events associated with combination therapy were evaluated. Results A total of 18 HD patients with HCV infection were enrolled in this study. Of these patients, 17 (94.4%) achieved SVR12. Among patients receiving combination therapy for 8 weeks, only one experienced a virological relapse at week 12 after the end of treatment. Despite the absence of treatment-related deaths, adverse events were observed in 9 patients (50.0%) during treatment. The most frequent adverse event was pruritus, which occurred in 7 patients (38.9%). Conclusions GLE and PIB combination therapy was effective and tolerable in Japanese HD patients with chronic HCV genotype 1b, 2a, and 2b infections. Trial registration This study was registered at the UMIN Clinical Trials Registry as UMIN000029781 (registered 21 November 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034026).