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Background/aim Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u-HCC) classified as beyond the up-to-7 criteria (UT-7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u-HCC patients classified as UT-7 out/multiple. Material/methods From September 2020 to September 2021, 95 u-HCC Japanese patients classified as UT-7 out/multiple/Child-Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child-Pugh 5:6=68:27, TNM stage II:III=17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). Results Atez/Bev was given as first-line treatment to 52 (54.7%). Objective response rate (ORR) and disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/42.5% and 84.7%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0months). Child-Pugh A/modified Albumin-bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any-grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). Conclusion Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition. This article is protected by copyright. All rights reserved.

We investigated the impact on survival of modified albumin–bilirubin (mALBI) grade versus Child–Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child–Pugh class B/C were significantly associated with survival [hazard ratio (HR), 2.471; 95% confidence interval (CI), 1.944–3.141 and HR, 2.178; 95%CI, 1.591–2.982]. In patients with a Child–Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083–3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child–Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child–Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child–Pugh classification in patients with unresectable HCC who received lenvatinib therapy.

Hepatitis B virus (HBV) infection is a major public health problem worldwide. The study aimed to evaluate the efficacy of pegylated interferon (Peg-IFN) alfa-2a treatment for seroclearance of HBs antigen (HBsAg) in HBe antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. This retrospective study investigated 16 HBeAg-negative CHB patients who received Peg-IFN alfa-2a weekly for 48 weeks. Thereafter, the patients were followed-up for 48 weeks after the end of therapy. The following criteria were also used for inclusion: HBV-DNA

Introduction The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2. Methods A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment. Results The overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2–92.6) (110/126) and 97.3% (95% CI 92.4–99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5–96.9) (105/113), 99.1% (95% CI 95.2–100.0) (112/113), and 100.0% (95% CI 97.4–100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment. Conclusion The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection. Trial Registration UMIN registration no. 000038604.

Background and Aim Although tenofovir alafenamide (TAF), as well as entecavir (ETV), is widely used as first‐line treatment for patients with chronic hepatitis B, there are only a few studies comparing sequential therapy from ETV to TAF and continuous ETV monotherapy in patients with maintained virologic response to ETV. Methods In a retrospective multicenter study, we investigated the efficacy and safety of sequential therapy from ETV to TAF (ETV‐TAF group) and compared them with continuous ETV monotherapy (ETV group), using propensity score matching, in chronic hepatitis B patients. Results From 442 patients, we analyzed 142 patients from each group comprising 71 patients matched for several data, including age, HBV genotype, hepatitis B envelope antigen, cirrhosis, alanine aminotransferase, platelet count, prior ETV monotherapy period, and hepatitis B surface antigen (HBsAg) change during prior ETV monotherapy. In the ETV‐TAF group, HBsAg levels significantly decreased from baseline to 48 weeks after switching to TAF (−0.02 log IU/mL, P = 0.038). HBcrAg levels also significantly decreased after switching to TAF (−0.1 log IU/mL, P = 0.004). However, there were no significant differences in the reduction of HBsAg and HBcrAg levels between the ETV‐TAF and ETV groups. There was no significant difference in the change of estimated glomerular filtration rate levels from baseline to 48 weeks between the two groups. Conclusions The present study indicated that the efficacy, especially of the HBsAg‐reducing action, and safety of sequential therapy from ETV to TAF were similar to those of continuous ETV monotherapy among chronic hepatitis B patients with maintained virologic response to ETV., In a retrospective, multicenter study involving 17 institutions, we investigated the efficacy and safety of sequential therapy from entecavir (ETV) to tenofovir alafenamide (TAF) (ETV‐TAF group). The present study indicated that the efficacy, especially of the hepatitis B surface antigen‐reducing action, and safety of sequential therapy from ETV to TAF were similar to those of continuous ETV monotherapy.

Background and Aim This study aimed to elucidate the clinical importance of muscle volume loss (pre‐sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u‐HCC). Methods Of 437 u‐HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre‐sarcopenia was diagnosed based on a previously reported cut‐off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm2)/height (m)2]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre‐sarcopenia. Results Cox hazard multivariate analysis showed alpha‐fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P

Background Lenvatinib is used for unresectable hepatocellular carcinoma (u-HCC) as first-line, as well as second- and third-line therapy in Japan. We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment. Methods Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020, 28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner. Results The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was −2.19. Of the 28 patients, 23 were male, 21 were classified as Child–Pugh A and 7 as Child–Pugh B, and 25 were Barcelona Clinic Liver Cancer Stage C. Ramucirumab was given as second-line therapy in 14, third-line in 9, and fourth-line in 5. Therapeutic response was obtained in only 26 patients; the objective response rate was 3.8% (1/26) and the disease-control rate was 42.3% (11/26), with a median period to progression of 2.0 months. The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events (gastrointestinal bleeding, ascites) in 2. Conclusions The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.

AIM The aim of this study was to determine whether oral L-carnitine administration reduces the blood ammonia concentration and number of hospital admissions for hepatic encephalopathy in patients with advanced cirrhosis. METHODS Of 68 patients with hepatic encephalopathy treated with oral L-carnitine supplementation from April 2013 to March 2016, we enrolled 19 patients who had received full standard treatment. We analyzed blood ammonia concentration, number of hospital admissions, and prognosis to determine how effective L-carnitine was in achieving mid-term to long-term suppression of recurrent hepatic encephalopathy. RESULTS Median blood ammonia concentrations at the start, 1 week, 12 weeks, 24 weeks, and 48 weeks were 159, 79, 75, and 82 μg/dL, respectively. Blood ammonia concentrations 12 week, 24 weeks, and 48 weeks after L-carnitine administration were significantly lower than those at the start (P

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.

Background and Aims: Endoscopic submucosal dissection (ESD) seems to be a reasonable option for gastrointestinal subepithelial lesions (SELs) localized within the submucosa. Indications for ESD include small neuroendocrine tumors (NETs) and indeterminate SELs. However, the prospective data regarding ESD and surveillance remain unclear. This study was performed to prospectively investigate the outcomes of ESD, including organ-specific outcomes and the mid-term prognosis. Methods: This prospective multicenter study included 57 patients who underwent ESD for SELs localized within the submucosa [definite NETs (n = 42) and indeterminate SELs (n = 15)]. The efficacy and safety of ESD were evaluated in the whole cohort and in subgroups (NETs and indeterminate SELs). All patients were followed up. Results: The rates of en bloc resection, curative resection, and complications were 98.2%, 66.7%, and 7.7% for the overall population (n=57); 100%, 61.9%, and 2.4% for NETs (n=42); and 93.3%, 80.0%, and 20.0% for indeterminate SELs (n=15), respectively. The rates of curative resection for NETs were poorer in the stomach (20%, n=5) and duodenum (33%, n=3) than in the rectum (71%, n=34). Including 11 of 16 patients with NETs who underwent a conservative approach resulting in non-curative resection, no patients developed tumor recurrence during the follow-up period (median, 24.5 months; range, 1–60 months). ESD followed by surveillance demonstrated acceptable mid-term outcomes for non-curative NETs. Conclusions: ESD can be an efficient therapy for SELs localized within the submucosa. However, gastric and duodenal ESD for NETs may be limited in terms of its curative and technical aspects. Clinicians should be aware of the potential complications of ESD for indeterminate SELs.

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.

Introduction: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is considered a safe and minimally invasive procedure. We previously reported that the mortality and complication rates for RFA were 0.038% (5/13,283 patients) and 3.54% (579 complications/16,346 procedures), respectively, from 1999 to 2010 (previous period). In this study, we investigated the clinical criteria for RFA and the mortality and complication rates from 2011 to 2015 (recent period). Methods: Data were collected from 25 centers by using a questionnaire developed by the Chugoku-Shikoku Society for Local Ablation Therapy of HCC. The criteria for RFA, RFA modification, use of image-guidance modalities, mortality, and complications during the previous and recent periods were compared. Results: We evaluated 11,298 procedures for 9,411 patients, including those that involved new devices (bipolar RFA and internally adjustable electrode system). The criterion of hepatic function for RFA increased from a Child-Pugh score ≤8 during the previous period to ≤9 during the recent period. The criteria regarding the tumor location and other risk factors have been expanded recently because of the increased use of several modifications of the RFA procedure and image-guidance modalities. The mortality rate was 0.064% (6/9,411 patients), and the complication rate was 2.92% (330 complications/11,298 procedures). There was no difference in mortality rates between the 2 periods (p = 0.38), but the complication rates was significantly lower during the recent period (p = 0.038). Discussion and Conclusions: Our findings confirmed that RFA, including the use of new devices, is a low-risk procedure for HCC, despite the expansion of the criteria for RFA during the recent period.

We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2–22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495–2.452), Eastern Cooperative Oncology Group performance status ≥1 (HR, 1.429), and α-fetoprotein ≥400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p

AIM Direct-acting antivirals (DAAs) are currently available even for patients with decompensated cirrhosis. Reportedly, hepatic functional reserve improved in the short term after achievement of sustained virologic response (SVR). We aimed to clarify the outcomes after achievement of SVR in patients with decompensated cirrhosis who were treated by DAAs in real-world clinical practice. METHODS A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted in 86 patients with decompensated cirrhosis, who were evaluated for 48 weeks post-treatment. RESULTS The cohort included 8 patients with Child-Pugh class A, 56 with B, and 22 with C. The proportion of Child-Pugh class A patients increased from 9.1% at baseline to 44.1% at 48 weeks post-treatment, while that of class B and C patients decreased from 66.2% to 35.1% and from 24.7% to 14.3%, respectively. Among the patients with Child-Pugh class B and C, univariate analysis identified low total bilirubin, Child-Pugh score, Child-Pugh class B, ALBI score, and high serum albumin as factors associated with improvement to Child-Pugh class A. The optimal cut-off value of the factors for predicting improvement to Child-Pugh class A were 1.4 mg/dL for total bilirubin, 2.9 g/dL for serum albumin, 8 points for Child-Pugh score, and -1.88 for ALBI score. CONCLUSION Achievement of SVR with sofosbuvir/velpatasvir improved the liver functional reserve at 12 weeks post-treatment and maintained the stable effects until 48 weeks post-treatment in patients with decompensated cirrhosis. Specifically, the patients with less advanced conditions had the likelihood of improving to Child-Pugh class A at 48 weeks post-treatment. This article is protected by copyright. All rights reserved.

Simple Summary Drug-eluting beads-transcatheter chemoembolization (DEB-TACE) has recently been performed. However, local recurrence of HCC at the tumor margins is often observed. Conventional transcatheter chemoembolization (cTACE) comprises accumulating lipiodol-containing anticancer drugs into the drainage area, which is the first invasive site of hepatocellular carcinoma (HCC). We evaluate the therapeutic effect of DEB-TACE followed by cTACE in patients with intermediate stage HCC. HCC patients were divided into two groups: one group received DEB-TACE followed by cTACE (cTACE group) and the other group received only DEB-TACE (non-cTACE group). The complete response (CR) rate was significantly higher in the cTACE group than in the non-TACE group. The only factor that increased the complete response rate in the cTACE group was the number of tumors. The overall survival (OS) rate of CR patients was higher than that of non-CR patients in the cTACE group. cTACE group adverse events included severe thrombocytopenia but only in one patient. The combined therapy with DEB-TACE followed by cTACE may be useful for HCC patients. Abstract EB-TACE has recently been performed because of its lower hepatotoxicity compared to cTACE in less advanced HCC. However, local recurrence at the tumor margins is often observed after DEB-TACE. cTACE involves filling the intratumoral sinusoids with lipiodol-containing anticancer drugs and accumulating in the drainage area, which is the first site of HCC recurrence. The aim of this study is to evaluate the therapeutic effect of DEB-TACE followed by cTACE in HCC patients. Between 2014 and 2020, 65 patients with Barcelona clinic liver cancer (BCLC) stage B (intermediate stage) of HCC were enrolled and divided into two groups: one group received DEB-TACE followed by cTACE (cTACE group) and the other group received only DEB-TACE (non-cTACE group). Sixty-five patients were medically followed. The median observation time was 14 ± 13.1 months after the first DEB-TACE and outcomes were analyzed for multiple factors. Results: The complete response rate was significantly higher in the cTACE group than in the non-TACE group. The analysis showed that the only factor that increased the CR rate in the cTACE group was the total tumor number (less than four). The OS rate of CR patients was higher than that of non-CR patients in the cTACE group. Adverse events in the cTACE group included severe thrombocytopenia but only in one of twenty-seven patients. Conclusions: The combined therapy with DEB-TACE followed by cTACE may be a new effective therapeutic strategy for the intermediate stage of HCC patients.

Aim Regorafenib is a second-line treatment for unresectable hepatocellular carcinoma (u-HCC) after sorafenib-refractory treatment. This study examined the effects of regorafenib administration on hepatic functional reserve and the treatment course after regorafenib discontinuation. Methods This retrospective, multicenter study involved 51 patients treated with regorafenib after sorafenib-refractory treatment for u-HCC at seven institutions before March 2021. Results Fourteen, 13, and 24 patients were classified based on modified albumin-bilirubin (mALBI) grade 1, 2a, and 2b, respectively. The median survival time (MST) and progression-free survival were 16.7 and 3.3 months, respectively. Only mALBI grade 2b or 3 was significantly associated with survival rate (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.01-4.49; p=0.047). A comparison of median ALBI scores at the initiation of regorafenib (-2.35) with those at 4 weeks (-1.93) revealed a significant relative change (p=0.0001). After 4 weeks, grade 1 or 2a persisted in 15 patients (Group 1); grade 1 or 2a deteriorated to 2b in 12 patients (Group 2); grade 2b or 3 before regorafenib administration was present in 22 patients (Group 3); and MST was 33.3, 12.8, and 11.3 months in the three groups, respectively (p=0.05). Patients treated with lenvatinib (LEN) (n=27, MST=23.4 months) after regorafenib had a significantly longer survival time from regorafenib initiation than those not treated with LEN (n=24, 11.8 months; p=0.043). Conclusions Hepatic functional reserve significantly declined after regorafenib administration. During regorafenib treatment, favorable hepatic functional reserve before administration and maintenance of favorable hepatic reserve after administration lead to prolonged prognosis. This article is protected by copyright. All rights reserved.

Pooled gastric residues involving blood clots and food interrupt appropriate endoscopic intervention, leading to poor outcomes in endoscopic hemostasis and lifesaving. However, procedures and devices that enable the effective removal of gastrointestinal residues remain unsatisfactory. This study aimed to evaluate the efficacy and safety of our developed suction method in ex vivo and in vivo studies. We created a hand-made device with a large suction diameter, consisting of a balloon overtube and an ultrathin endoscope for navigation. In the ex vivo study, we compared the success rate and the suctioning time for four types of simulated residue between a standard endoscope and our device. Our device had s significantly higher suction ability and a shorter procedure time than the standard endoscope. The subsequent in vivo animal study involved five beagle dogs that were administered with food jelly to mimic gastric residue. Suction was performed twice for five dogs (ten attempts). The outcome measure was the successful procedure rate, secondary outcomes were procedure-associated complications and procedure time. The procedure was successful in all attempts, without any complications. The mean procedure time was 5 min. This novel method enabled the efficient and safe removal of gastric residue, and our findings will likely lead to the development of the instrument.

BACKGROUND In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan. METHODS In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen. RESULTS Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. CONCLUSION The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naive, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan.

Background Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u‐HCC), changes in hepatic function during therapy have yet to be reported. Aim This retrospective clinical study aimed to elucidate early responses to Atez/Bev. Methods From September 2020 to April 2021, 171 u‐HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin‐bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively. Results In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR‐6W/DCR‐6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR‐6W/DCR‐6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post‐progression treatment following lenvatinib (ORR‐6W/DCR‐6W = 7.7%/79.5%), for which no known effective post‐progression treatment has been established. In 111 patients who underwent a 6‐week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (−2.525 ± 0.419 vs −2.323 ± 0.445, p

We investigated the impact on survival of modified albumin–bilirubin (mALBI) grade vs. Child–Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child–Pugh class B/C were significantly associated with survival (hazard ratio [HR], 2.471; 95% confidence interval [CI], 1.944–3.141 and HR, 2.178; 95%CI, 1.591–2.982). In patients with a Child–Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083–3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child–Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child–Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child–Pugh classification in patients with unresectable HCC who received lenvatinib therapy.

Formulating sequential therapeutic strategies based on the pathological conditions of patients and by using molecular targeted agents (MTAs) and transcatheter arterial chemoembolization (TACE) is crucial for the treatment of unresectable advanced hepatocellular carcinoma (HCC). The current report presents the case of a patient with HCC involving a large intrahepatic primary tumor and lung metastases, and discusses treatment strategies for advanced HCC based on the current literature. Sequential therapy with MTAs was effective after TACE. Lenvatinib was effective for treating the metastases in the lungs and spleen. Only the progressing intrahepatic tumor was additionally treated with TACE. The patient has been alive for 3 years and continued lenvatinib treatment without HCC progression or decline in liver function. In conclusion, although multiple MTAs introduced into the clinic have been gradually replacing TACE, on-demand TACE in the multidisciplinary treatment of advanced HCC may be effective for intrahepatic hypervascular tumors resistant to MTAs, including lenvatinib. It may be possible to re-initiate lenvatinib treatment with good efficacy against distant metastatic lesions, thereby contributing to long-term survival.

White globe appearance (WGA) is defined as a microendoscopic white lesion with a globular shape underlying the gastric epithelium and is considered a marker of gastric cancer. We recently reported that endoscopically visualized white spot (WS) corresponding to WGA appeared on the nonatrophic mucosa of patients with acid-suppressing agents (A-SA) use. We evaluated patients undergoing routine esophagogastroduodenoscopy and divided the patients into an A-SA group (n = 112) and a control group (n = 158). We compared the presence of WS in both groups. We also compared WS-positive- (n = 31) and -negative (n = 43) groups within the A-SA group regarding these patients’ backgrounds and serum gastrin concentrations. Comparing the A-SA group with controls, the prevalence of WS was significantly higher (31/112 vs. 2/158, p &lt, 0.001). The number of patients with high serum gastrin concentrations was significantly higher in the WS-positive group (18/31) vs. the WS-negative group (5/43) (p &lt, 0.001). Within the A-SA group, the prevalence of WS was also significantly higher in patients taking potassium-competitive acid blockers vs. proton-pump inhibitors (21/31 vs. 10/31, p &lt, 0.001). The WS-positive group had a significantly greater percentage of patients, with a high serum gastrin level (p &lt, 0.001). WS may be associated with hypergastrinemia and potassium-competitive acid blockers.

Background/Aim: Hepatocellular carcinoma patients (HCC) related with non-alcoholic steatohepatitis (NASH) has been recently reported to be not responsive to immune-checkpoint inhibitor treatment (ICI). This study aimed to evaluate therapeutic efficacy in non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC) treated with lenvatinib.Material/Methods: Five-hundred-thirty u-HCC with Child-Pugh A were enrolled, and divided into the NAFLD/NASH (n=103) and Viral/Alcohol (n=427) groups. Clinical features were compared in a retrospective manner.Results: Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P=0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P=0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated AFP (≥400ng/mL) (HR1.294, P=0.014), elevated ALT (≥30 U/L) (HR1.247, P=0.029), modified ALBI grade 2b (HR1.236, P=0.047), and NAFLD/NASH etiology (HR0.763, P=0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.750, P=0.076), whereas AFP (≥400ng/mL) (HR1.402, P=0.009), later line use (HR0.737, P=0.0137), BCLC C stage (HR1.297, P=0.035), and modified ALBI grade 2b (HR1.875, P

Simple Summary In this study, the rate of hepatocellular carcinoma (HCC) recurrence (HCC-R) after hepatitis C virus eradication by direct-acting antiviral (DAA) treatment was relatively high, corresponding to 63.8% (83/130) of the studied cases. The patients who electively received palliative treatment before DAA treatment and showed a shorter interval period between the last treatment for HCC and DAA initiation, also displayed a significant increase in alpha-fetoprotein during follow-up after therapy, relative to cases without HCC-R. Overall, the survival was comparable in both groups because of the improvement in liver function tests after the DAA therapy, and thus no differences in survival rates were observed between patients with or without HCC-R. The results of this study indicate that interferon (IFN)-free DAA treatment after treatment for HCC could be recommended to improve prognosis in this subset of cases. However, it remains imperative to observe the timing, i.e., at least 9–12 months after the last treatment for HCC, before proposing DAA therapy. Abstract There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924–8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016–1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered.

Background/Aim: An effective postprogression treatment of lenvatinib (LEN) against unresectable hepatocellular carcinoma (u-HCC) has not been established. We aimed to elucidate the clinical role of continuing LEN beyond progression of disease (PD). Methods: From March 2018 to October 2020, 99 u-HCC patients, in whom PD was confirmed (male:female = 78:21, median age 72 years, Child-Pugh A = 99, Barcelona Clinic Liver Cancer stage A:B:C = 2:43:54, LEN as first-line = 55), were enrolled (stopped LEN at PD [A group], n = 26; continued LEN beyond PD [B group], n = 73). Radiological response was evaluated with RECIST 1.1. Clinical features and prognostic factors for overall survival (OS) were retrospectively investigated using inverse probability weighting (IPW) calculated by propensity score. Results: Median time to progression, best response, and modified albumin-bilirubin grade (mALBI) at both baseline and PD did not show significant difference between the groups. Postprogression treatment in the A group was best supportive care in 17, sorafenib in 4, regorafenib in 3, ramucirumab in 1, and hepatic arterial infusion chemotherapy in 1. After adjusting with IPW, the B group showed better prognosis in regard to OS after PD and OS after introducing LEN than the A group (10.8/19.6 vs. 5.8/11.2 months, p < 0.001, respectively). In IPW-adjusted Cox hazard multivariate analysis, significant prognostic factors for OS after PD were mALBI 2b/3 at PD (HR 1.983, p = 0.021), decline of Eastern Cooperative Oncology Group performance status (ECOG PS) from baseline at PD (HR 3.180, p < 0.001), elevated alpha-fetoprotein (≥100 ng/mL) at introducing LEN (HR 2.511, p = 0.004), appearance of new extrahepatic metastasis (HR 2.396, p = 0.006), positive for hand-foot skin reaction (HFSR) before PD (any grade) (HR 0.292, p < 0.001), and continuing LEN beyond PD (HR 0.297, p < 0.001). Conclusion: When ECOG PS and hepatic reserve function permit, continuing LEN treatment beyond PD, especially in u-HCC patients showed HFSR during LEN treatment, might be a good therapeutic option, at least until a more effective drug as a postprogression treatment after LEN failure is developed.

Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure.From June 2017 to October 2020, 63 patients with Child-Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R-L group, n = 47) and those who did not receive lenvatinib after regorafenib (non-R-L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting.Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R-L and non-R-L groups, whereas the albumin-bilirubin score, Child-Pugh class, and tumor burden were not. Progression-free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R-L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p 0.001 and p = 0.022, respectively). Modified albumin-bilirubin grade 2b (score-2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment.These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.

The Over-The-Scope Clip (OTSC) can effectively treat refractory gastrointestinal diseases. However, most reports have focused on short-term effectiveness. We examined clinical outcomes of the deployed clips and long-term characteristics.Of 47 patients with OTSC treatment, 35 with follow-up periods of ≥3 months were retrospectively examined. The indications were 11 bleedings, 17 perforations, and seven fistulas. The observation period was defined as medium-term (3 to12 months) or long-term (≥12 months). The primary outcome was the clinical success rate without disease recurrence. The secondary outcomes were the complication rate, survival duration, and clip retention rate.The medium- and long-term clinical success rates were 100% during the observation period (median, 44 months; range, 3-78 months). The complication rate was 2.9% (Regardless of clip detachment, the OTSC can be effective in long-term.

Background Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. Patients and methods We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. Results Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin–bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). Conclusion NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients., Highlights • Evidence supported the idea that etiology could sustain a crucial role in biological behavior. • NASH constitutes one of the more important risk factors for hepatocarcinoma, and its incidence is increasing very fast. • We performed an analysis in patients treated with lenvatinib as the first-line therapy. • NASH was found to be an independent prognostic factor.

Background and Aim: Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome. Methods: We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS). Results: The appearance of arterial hypertension G≥2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46–0.93, P=.0188], whereas decreased appetite G≥2 independently predicted decreased OS (HR 1.70, 95% CI 1.25–2.32, P=.0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56–0.93, P=.0149), whereas decreased appetite G≥2 predicted decreased PFS (HR 1.36, 95% CI 1.04–1.77, P=.0277). Conclusions: Our main findings are that the occurrence of arterial hypertension G≥2 is a predictor of longer survival, whereas decreased appetite G≥2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients’ quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.

Diaphragmatic hernia (DH) is a defect, which can be congenital or can develop later in life. Moreover, chromosomal and genetic abnormalities, environmental exposures, and nutritional deficiencies may be related to the development of congenital DH. In contrast, the risk factors of acquired DH include traumas, such as blunt injuries due to traffic accidents and surgical procedures. We report the case of a 71-year-old man admitted to our gastroenterology department for the treatment of esophageal varices. Four days after the endoscopic treatment, the patient vomited severely and reported severe right upper abdominal pain. He was diagnosed with DH, and surgical fixation was performed. The diaphragmatic injury lesion was located on the estimated needle track of percutaneous radiofrequency ablation, which was performed through the thoracic diaphragm with artificial pleural effusion for hepatocellular carcinoma.

AIM The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. METHODS This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). RESULTS The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p

Aims To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). Methods A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. Results The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462). Conclusions Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.

The Over-the-scope clip (OTSC) has been recently introduced for multiple purposes, including refractory bleeding, perforation, fistula, and anastomotic dehiscence of the gastrointestinal tract. However, no easy access techniques for delivering OTSCs to distant sites have been described. Therefore, we have developed a simple and safe guidewire-assisted OTSC delivery (GOD) method for use on the distal intestine. This study aimed to investigate the technical feasibility and safety of the method.Between June 2018 and April 2019, all eight patients who underwent the GOD method were retrospectively examined. The primary outcome was the successful rate of OTSC delivery to the lesion without complications. The secondary outcomes were GOD procedure time, total procedure time, technical and clinical OTSC success rates, and GOD- and OTSC-associated complications.The rate of successful OTSC delivery was 100%. The median procedure time of GOD was 21 min (range 8-29). The median total procedure time was 38.5 min (range 26-41). The technical and clinical success rates of OTSC were 100% and 75% (6/8), respectively. No GOD- or OTSC-associated complications occurred.The GOD method is a feasible and safe technique for delivering OTSC toward the small and proximal large intestine.

The granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates cell proliferation and differentiation of precursor cells in the bone marrow. Several cases of G-CSF-producing malignant tumors in various organs have been reported, but there are only nine cases of G-CSF-producing hepatocellular carcinoma (HCC) reported in the English literature. G-CSF-producing tumors grow rapidly and have a high probability of distant metastases; thus, they generally have a poor prognosis. Given that the mechanism of the carcinogenesis of G-CSF-producing HCC remains unclear, an efficient treatment strategy also remains to be elucidated. We report herein a case of G-CSF-producing HCC accompanied by leukocytosis and high serum G-CSF concentrations in the disease progression stage after long-term complete response. We also reviewed previous reports to investigate the clinical behaviors of G-CSF-producing HCC, including our case. Clinicians should consider G-CSF-producing HCC in patients with a hepatic mass and drastic leukocytosis, without any evidence of infection and blood disorders. Early diagnosis and prompt therapy, including radical resection, may provide a more favorable prognosis.

Background Endoscopic submucosal tunnel dissection (ESTD) has recently been an effective procedure for resecting large early esophageal neoplasm. However, excessive dissection beyond the distal limit may occur because the prepared distal end often cannot be distinguished through the tunnel. This study aimed to assess the efficacy and safety of a novel crystal violet navigation (CVN) for identifying the distal end. Material and methods In the observational case series study, all 22 patients who underwent esophageal ESTD using the CVN were included. When setting the distal end, the distal incision line was dyed purple using a crystal violet solution. The rates of purple color identified via the tunnel, successful tunnel penetration without extra dissection, en bloc and curative resection, procedure time for ESTD and CVN, and procedure-associated complications were evaluated. Results The rates of purple color and successful tunnel penetration were both 100%. En bloc and curative resection were 100%, and 86%, respectively. The mean total procedure time was 103.9 ± 46.2 (mean ± SD) minutes, while the mean time for the CVN was 14.1 ± 3.44 s. No complications were observed. Conclusions The simple CVN method can be a navigation tool for identifying the distal end during the ESTD procedure.

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.

Background and Aim Chronic liver diseases (CLDs) progress from chronic inflammation to fibrosis to tumorigenesis. Galectin-9, a β-galactoside-specific animal lectin, is indicated to contribute to all three steps of progression. The aim of this study was to determine which of the three steps was most dominant in elevating the serum galectin-9 concentration and to test the possibility of galectin-9 as a serum biomarker. Methods Japanese patients with chronic hepatitis (CH), liver cirrhosis (LC), hepatocellular carcinoma (HCC), nonalcoholic fatty liver disease or alcoholic liver disease who provided informed consent were enrolled in this study. Serum galectin-9 levels were measured using a sandwich ELISA. Multiple regression analyses were performed using EZR to identify factors which determined serum galectin-9 concentration. Results One hundred one patients with 50 of CH and 51 of LC were enrolled; the cohort included 45 cases of HCV infection, 13 cases of HBV infection, 46 cases with HCC-related complications. The median serum galectin-9 concentration was 77.54pg/ml (inter quartile range: 18.89-241.9pg/ml). Multiple linear regression analyses proved Fib-4 index and APRI, indexes of liver fibrosis, were able to predict the serum galectin-9 levels with statistical significance. A multiple logistic regression analysis determined 10pg/ml increase of the serum galectin-9 concentration presented an odds ratio of 3.90 for liver fibrosis progression. Conclusions The serum galectin-9 concentration represents a potential biomarker of liver fibrosis in patients with CLDs, regardless of chronic inflammation or the presence of HCC complications. Furthermore, higher serum galectin-9 levels are a predictor for liver fibrosis progression.

Patients with end-stage renal disease who are undergoing dialysis may be at high risk of developing hepatocellular carcinoma (HCC). We investigated the characteristics and prognosis of HCC in patients undergoing dialysis in Japan. Patients characteristics, progression of HCC at diagnosis, and survival rates after diagnosis were compared between 108 HCC patients undergoing dialysis and 526 non-dialysis patients followed up at liver center. The comparisons were also performed after adjusting for patient age, gender, platelet count, and etiology using propensity-score matching. HCC was more advanced in patients undergoing dialysis than in non-dialysis controls. The 3- and 5-year survival rates of patients undergoing dialysis were 56.3% and 38.3%, respectively, which were lower than those of non-dialysis controls (66.5% and 52.7%, respectively, P = 0.0026). The results were the same after propensity score matching (P = 0.0014). In Japan, HCC was more advanced at diagnosis in patients undergoing dialysis in comparison to HCC in patients at liver centers, resulting in a lower survival rate after diagnosis.

Liver metastasis from gastrointestinal cancer defines a patient's prognosis. Despite medical developments, pancreatic cancer with liver metastasis confers a very poor prognosis. Galectin-9 (Gal‑9) is a tandem-repeat-type galectin that has recently been demonstrated to exert antitumor effects on various types of cancer cells by inducing apoptosis. However, the apoptotic pathway of Gal‑9 in solid tumors is unclear. The aim of the present study was to evaluate the effects of Gal‑9 on human liver metastasis from pancreatic cancer. Gal‑9 suppressed cell proliferation in metastatic liver cancer cell lines derived from pancreatic cancer (KMP2, KMP7, and KMP8) and increased the levels of caspase-cleaved keratin 18 and fluorescein isothiocyanate (FITC)-conjugated Annexin V. Furthermore, expression of apoptosis-related molecules such as caspase-7, cleaved caspase-3, cleaved PARP, cytochrome c, Smac/Diablo and HtrA2/Omi was enhanced. However, Gal‑9 did not affect expression of various cell cycle-related proteins. The microRNA (miRNA) expression profile was markedly altered by Gal‑9, and various miRNAs might contribute to tumor growth suppression. Our data reveal that Gal‑9 suppresses the growth of liver metastasis, possibly by inducing apoptosis through a mechanism involving mitochondria and changes in miRNA expression. Thus, Gal‑9 might serve as a therapeutic agent for the treatment of liver metastasis from pancreatic cancer.

There is no consensus regarding which therapeutic option is better and/or safer for treating hemodialysis (HD) patients with hepatocellular carcinoma (HCC). The present study compared surgical resection (Hx) and radiofrequency ablation (RFA) with regard to therapeutic efficacy in HD patients with HCC. Of 108 HD patients with naïve HCC treated at 15 institutions between 1988 and 2014 enrolled in the present study, 58 fulfilled the up-to-7 criteria [7 as the sum of the size of the largest tumor (cm) and the number of tumors] and were treated with Hx (n=23) or RFA (n=35); their clinical features, complications and prognosis were assessed. The frequency of hepatitis C virus was higher in the RFA group compared with that in the Hx group (P=0.002), whereas there were no differences between the groups with regard to the average time from the first HD (P=0.953), tumor-nodes-metastasis (TNM) stage (Union for International Cancer Control 7th edition) (P=0.588), TNM stage (Liver Cancer Study Group of Japan 5th edition) (P=0.095), Child-Pugh classification (P=0.094), and Japan Integrated Scoring system (P=0.489). There were no significant differences in overall survival (OS) and disease-free survival (DFS) rates between the Hx and RFA groups [1-, 3- and 5-year OS rates: 81.7, 55.6 and 43.3% vs. 89.9, 67.1 and 56.3%, respectively (P=0.454); 1-, 3- and 5-year DFS rates: 71.1, 30.5 and 18.3% vs. 63.8, 31.6 and 21.1%, respectively (P=0.911)] Complications were observed in 4 patients (11.4%) in the RFA group (2 with subcapsular hemorrhage, 1 with intraperitoneal bleeding and 1 with tardive intrahepatic hematoma) and in 4 patients (17.4%) in the Hx group (2 with postoperative infection, 1 with liver failure and 1 with pleural effusion) (P=0.700). In conclusion, Hx and RFA have a similar therapeutic efficacy in HD patients with naïve HCC who fulfilled the up-to-7 criteria.

A 72-year-old female was referred for further evaluation of epigastralgia. Abdominal contrast computed tomography revealed numerous tumors in the two lobes of the liver. Liver biopsy and immunohistochemical staining revealed that the tumor cells were positive for factor VIII-associated antigen, platelet endothelial cell adhesion molecule 1 and human hematopoietic progenitor cell antigen, concordant with a diagnosis of hepatic epithelioid hemangioendothelioma (HEH). To elucidate the etiology of HEH, particularly the microRNA (miRNA) profiles, tissue samples obtained from normal and tumor tissues were analyzed using a miRNA array system. A total of 14 miRNAs were significantly upregulated and 93 miRNAs were downregulated in the tumor tissues (P

Objective: To determine the relationship between treatment outcomes and hand-foot syndrome (HFS), and the relationship between survival rate and post-progression treatment after sorafenib therapy. Methods: The study assessed 314 patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib at 5 general hospitals in Kagawa Prefecture, Japan. Results: At the start of sorafenib therapy, 23.6% of the patients had HCC of a Child-Pugh class other than A. The initial sorafenib dose was 800 mg in 9.2% of the patients and 400 mg in 64.3%. Time to progression was 129 days (95% CI: 87.3-170.7) and the median overall survival (OS) was 392 days (95% CI: 316.0-468.0). The OS of the patients with Child-Pugh class A HCC was significantly better than that of the patients with Child-Pugh class B HCC (p < 0.0001). The survival curves for Child-Pugh class A-5 points and class A-6 points were significantly different, with that for class A-5 points being better (p < 0.0001). A significant difference was observed between the patients who exhibited HFS and those who did not, with the former exhibiting a better survival rate (p < 0.001). In addition, the survival rate of the patients who received post-progression treatment after sorafenib therapy was significantly better than that of the patients who did not (p < 0.001). Conclusion: In sorafenib therapy, patients with HFS and those who received post-progression treatment exhibited good OS.

A 60-year-old woman was referred to our department for an incidental finding of gastric polypoid lesion on enhanced CT (E-CT) (figure 1A). She had a medical history of hepatocellular carcinoma (HCC) treated 3 years prior with transcatheter arterial chemoembolisation. E-CT is routinely performed once a year for the surveillance post HCC therapy. No obvious recurrence was detected in the liver. Upper gastrointestinal endoscopy revealed a 30 mm pedunculated gastric polypoid lesion on the greater curvature of the antrum (figure 1B). Figure 1 CT scan revealing a gastric hypervascular tumour in the stomach (A). Upper gastrointestinal endoscopy showing a 30 mm pedunculated gastric polypoid lesion on the greater curvature of the antrum (B). Endoscopic submucosal dissection was performed for pedunculated polypoid lesion …

The prognosis of hepatocellular carcinoma (HCC) patients exhibiting macroscopic vascular invasion (MVI) is poor, and the most appropriate treatment approach remains unclear. The current study aimed to investigate the efficacy and safety of sorafenib treatment following chemoradiotherapy for advanced HCC exhibiting MVI. A newly reported regimen, including 5-fluorouracil and cisplatin therapy (NewFP), plus three-dimensional conformal radiotherapy (3D-CRT) for MVI was used as the initial treatment. Additionally, sorafenib, as a secondary treatment, was administered after NewFP plus 3D-CRT for MVI. The present retrospective study enrolled patients with unresectable advanced HCC that was treated with NewFP plus 3D-CRT for MVI between January 2009 and December 2017. In total, 32 HCC patients with MVI were registered. Of these 32 patients, 18 were treated with NewFP plus 3D-CRT for MVI (NewFP + 3D-CRT group) and 14 were treated with sorafenib following NewFP plus 3D-CRT for MVI (sorafenib after NewFP + 3D-CRT group). The study endpoints were overall survival, overall response rate and disease control rate. Clinical factors influencing overall survival were identified using univariate and multivariate analyses. The median survival time in the NewFP + 3D-CRT group and sorafenib following NewFP + 3D-CRT group was 6.7 and 49.2 months, respectively (P=0.0003). For patients with advanced HCC exhibiting MVI, the initial treatment with NewFP plus 3D-CRT for MVI was well tolerated. The administration of sorafenib as the secondary treatment following NewFP plus 3D-CRT for MVI was associated with a significantly higher overall response rate, disease control rate and increased overall survival as compared with the NewFP plus 3D-CRT treatment.

Aim The incidence of hepatitis C virus (HCV) infection is much higher in hemodialysis patients than that in healthy individuals. The prognosis of hemodialysis patients with HCV infection is poorer than that without HCV infection. Therefore, antiviral intervention is pivotal for HCV infection in hemodialysis patients. Recent evaluations of the pangenotypic regimen of glecaprevir/pibrentasvir show that it is highly effective and safe for HCV-infected hemodialysis patients. However, a few reports showed that the effect of HCV elimination by glecaprevir/pibrentasvir improved liver dysfunction or anemia. The aim of the present study was to determine clinical outcomes after HCV elimination using the glecaprevir/pibrentasvir regimen in HCV-infected hemodialysis patients. Methods This study was a retrospective, six-center study conducted in Japan, in which 24 hemodialysis patients with HCV genotype 1-2 treated with glecaprevir/pibrentasvir were recruited. Blood examinations were performed at end of treatment (EOT), and at 3, 6, and 12 months post-treatment during the 12-month follow-up period. Results The overall sustained virologic response rate was 100% (24/24). During the DAA treatment period, adverse events were observed in 20.8% of patients (5/24), and pruritus was the most frequently observed in 12.5% (3/24). Interestingly, we observed an improved control of anemia after EOT with a significant increase in hemoglobin levels. In addition, total bilirubin was diminished, and platelet counts and albumin, total cholesterol, and alpha-fetoprotein levels remained unchanged after EOT in hemodialysis patients. Furthermore, erythropoietin concentration was not increased after EOT. Conclusions HCV elimination using glecaprevir/pibrentasvir treatment might be a major breakthrough for the control of anemia in hemodialysis patients.

Direct acting antivirals (DAA) have recently been developed to treat patients with hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved the cure rate of patients. However, the occurrence rate of hepatocellular carcinoma (HCC) following HCV eradication remains unknown. Therefore, the present study aimed to identify predictors of HCC occurrence following DAA treatment. Among 1,454 patients infected with HCV, 1,088 patients who achieved sustained virologic response and who had no history of HCC treatment were recruited between September 2014 and November 2018. The incidence of HCC in patients infected with HCV following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinicopathological characteristics and blood test results. During the present study, 26 patients developed HCC. The incidence of HCC was 0.61, 1.88, 2.82 and 3.71% at 6, 12, 18 and 24 months after treatment with DAA, respectively. The results of multivariate analysis identified age [hazard ratio (HR), 1.0729; P=0.0044] and α-fetoprotein (AFP) level after DAA treatment (HR, 1.0486; P=0.0486) as independent factors that may contribute to HCC occurrence following DAA treatment. By using these two factors, a novel scoring system (0-2 points) was established to predict HCC occurrence following HCV eradication by DAA treatment. The incidence of HCC at 2 years was 0.3% in the 0 points group, 6.27% in the 1 point group and 18.37% in the 2 points group. In conclusion, AFP level after DAA treatment and age at DAA administration were identified as independent predictors of HCC occurrence in patients that were treated with DAA. The scoring system that was established in the present study is simple and easy, and using pre-treatment factors may be a convenient tool to predict the risk of HCC occurrence in HCV-free patients following DAA treatment.

Visceral adipose tissue contributes to the pathophysiology of metabolic syndrome. Metformin has been reported to suppress lipogenesis in a murine preadipocyte cell line. However, the effect of metformin on the differentiation of human visceral adipose tissue remains unknown. MicroRNAs (miRNAs or miRs) have been suggested as therapeutic targets because of their involvement in the differentiation and maturation of fatty cells. The aim of this study was to determine whether metformin suppresses the differentiation of human preadipocytes and to identify miRNAs associated with the regulation of lipid metabolism. Human visceral preadipocytes (HPrAD-vis) were preincubated in growth media and then cultured with differentiation media containing metformin for 1 or 2 weeks. Adipogenic differentiation of the cells was assessed by Oil Red O staining, and soluble adiponectin in the culture media was measured using an enzyme-linked immunosorbent assay. Cell proliferation was assessed using a WST-8 assay, and the gene and protein expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT‑enhancer-binding protein α (C/EBPα) was determined by RT-qPCR and western blot analysis, respectively. miRNAs were profiled using human miRNA Oligo chips after total RNA was extracted and labeled. Oil Red O staining showed that metformin suppressed the accumulation of lipid droplets in HPrAD-vis cells. The adiponectin concentration in the culture media was also decreased in metformin-treated cells. The WST-8 assay revealed no effect on proliferation or growth inhibition following metformin treatment, although metformin suppressed the expression of PPARγ and C/EBPα. miRNA profiling further revealed differences between the metformin-treated group and control HPrAD-vis cells. Thus, the findings of the present study demonstrated that metformin suppressed the differentiation of human preadipocytes in vitro and altered the miRNA profile of these cells. Thus, the miRNAs whose expression levels were altered by metformin may contribute to the observed suppression of HPrAD-vis cell differentiation.