Search

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.

Introduction Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. Methods A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. Results The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child–Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5–13). The albumin–bilirubin (ALBI) score ranged from − 3.01 to − 0.45 (median − 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child–Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child–Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10−4 and 2.42 × 10−4, respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. Conclusion Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications. Trial Registration UMIN registration no, 000038587. Electronic supplementary material The online version of this article (10.1007/s40121-020-00329-y) contains supplementary material, which is available to authorized users.

Pancreatic pseudocyst and portal vein thrombosis are common conditions resulting from acute and chronic pancreatitis. However, pancreatic pseudocyst-portal vein fistula (PPVF) is a rare and life-threatening complication. In PPVF patients, drainage or operative therapy is necessary under certain conditions, including communication between the pseudocyst and pancreatic duct, pancreatic duct stricture, pancreatic duct stone, and infection that is difficult to control with antibiotics. We describe the case of a 78-year-old woman who presented with an infected pancreatic pseudocyst invading the portal venous system with obstruction due to thromboembolization. Conservative therapy with antibiotics was insufficient. We, therefore, performed endoscopic ultrasound-guided cyst-drainage (EUS-CD). During EUS-CD, PPVF and pseudocyst-pancreatic duct fistula were confirmed by contrast medium injection. Despite the presence of the pseudocyst-pancreatic duct fistula, the pancreatic duct was not visualized in the pancreatic head, suggesting stricture in the main pancreatic duct. We, therefore, performed endoscopic retrograde pancreatography, which revealed pancreatic stone in the main pancreatic duct. Then, we added a 7-Fr pancreatic stent. She was discharged after 89 days of hospitalization. We reviewed the literature on the management of PPVF formation, and EUS-CD is considered to be a good treatment option for PPVF patients without portal vein patency.

Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naive patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10–5; genotype 2 vs. 3, p = 3.28 × 10–5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1–3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4–5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512–148.550), p value (p = 4.06 × 10–5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153–13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4–5 (41.6% [79/190]) than CKD stage 1–3 (26.1% [319/1220]) patients (p = 2.00 × 10–5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10–18) patients. G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

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 (p = 0.001), and elderly patients (> 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.

A 72-year-old man who had been on continuous ambulatory peritoneal dialysis treatment for 10 years underwent cardiopulmonary bypass for aortic valve replacement due to aortic valve stenosis. After surgery, he experienced pancreatitis, and rupture of a splenic artery aneurysm. He went into cardiopulmonary arrest but was successfully treated by transcatheter arterial embolization (TAE) with cardiopulmonary resuscitation. At three weeks after TAE, CT showed heterogeneous enhancement and the accumulation of pancreatic fluid in the pancreatic tail. At 4 months after TAE, he had sepsis and CT showed greater fluid collection with emphysema in comparison to 3 months previously. We diagnosed infected walled-off necrosis (WON). Conservative therapy with antibiotics was not sufficiently effective; thus, we performed endoscopic ultrasound-guided drainage (EUS-D). Contrast imaging revealed WON with colonic fistula. The WON remarkably decreased in size on CT after EUS-D. We experienced a rare case of ischemic acute pancreatitis (AP) caused by cardiopulmonary bypass complicated with infected WON with a colonic fistula. Ischemic AP more frequently shows a severe course with a fatal outcome in comparison to AP of other causes. However, in our case, ischemic AP with infected WON was successfully treated by EUS-D despite the presence of a WON with a colonic fistula.

In November 2020, atezolizumab plus bevacizumab became available for the treatment of hepatocellular carcinoma (HCC), and its efficacy is expected as a new treatment option for HCC. However, the occurrence of immune-related adverse events (irAEs) associated with the administration of immune checkpoint inhibitors is a major concern in clinical practice. We reported a case of irAE-induced myocarditis after the treatment for HCC. Based on the symptoms and echocardiographic findings, we suspected irAE-induced myocarditis and acute heart failure, and the patient was admitted to the hospital for further investigation and treatment. From starting the patient on therapy with methylprednisolone succinate sodium, the laboratory data and symptoms tended to improve. The patient was discharged to home on the 25th day of treatment. Because the number of patients with irAE myocarditis is expected to increase in clinical practice in the near future, further accumulation and investigation of cases are necessary.

The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1. The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics. Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment. The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.

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.

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).

The introduction of direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection in patients undergoing hemodialysis (HD) has improved sustained virological response (SVR) rates. Our aim was to assess the characteristics of the virological response to daclatasvir (DCV) and asunaprevir (ASV) combination therapy for HCV in HD patients. A multicenter prospective study was conducted at eight centers in Japan. Patients on HD with chronic genotype 1b HCV infections were orally administered DCV and ASV for 24 weeks at doses of a 60-mg capsule once daily and a 100-mg tablet twice daily, respectively. The primary endpoint of this trial was the proportion of patients with a sustained virological response at 24 weeks after the treatment ended (SVR24). We also investigated the characteristics associated with the virological response to combination therapy. Thirty patients were enrolled in this study, and the proportion that achieved an SVR24 after treatment was 83.3% (25/30). Virological failure was observed in 4 patients (13.3%). Two exhibited virological breakthrough at weeks 16 and 20 of drug administration, and viral relapse occurred in 2 patients at weeks 4 and 8 after the end of treatment. Virological failure was defined as HCV-RNA levels exceeding 5.5 log10 IU/mL, and resistance-associated variants (RAVs) NS5A-L31M/V and Y93H were not exhibited at baseline. DCV and ASV therapy for chronic HCV on HD was significantly effective. Most importantly, patients with the low viral loads undergoing HD demonstrated a higher response to combination therapy regardless of RAV. UMIN Clinical Trials Registry UMIN000016181