Search

Objective The long-term impact of personalized diet and exercise programs for steatotic liver disease (SLD) remains unclear. Materials The subjects of this retrospective cohort study included 104 consecutive Japanese patients with SLD. The long-term treatment efficacy of personalized diet and exercise treatment was evaluated two years after the start of observation. Regular and repeated hospitalizations every 6 months (RRH group, n=23) indicated the 4 times of the number of hospitalizations, and irregular hospitalizations (IH group, n=56) showed the 1 to three times. The group without hospitalization was defined as the no hospitalization group (NH group, n=25). To balance confounding biases, the difference in treatment efficacy between the RRH and IH groups was evaluated using propensity score (PS)-matched analysis. A diet of 25 to 30 kcal/kg multiplied by ideal body weight (BW) daily, and aerobic and resistance exercise (exercise intensity of 4 to 5 metabolic equivalents daily, respectively) was performed for 6 days. Results At 2 years compared to baseline, the decrease rates of liver function tests, HbA1c, and physical findings in the RRH group were significantly higher than those in the NH or IH groups by multiple comparisons. According to the liver function tests and physical findings, the rate of decrease in the RRH group (17 cases) was significantly higher than that in the IH group (17 cases) using a PS-matched analysis. Conclusion The present study indicated the long-term favorable efficacy of personalized diet and exercise programs for SLD. In particular, this RRH program was effective in improving the findings of liver function tests and might help to sustain diet and exercise.

Aim: The aim of this study was to evaluate the use of a new classification for safer transradial access hepatic interventional radiology, based on preoperative evaluation of the location of the left subclavian artery bifurcation in the aortic arch., Methods: A total of 38 consecutive patients with hepatocellular carcinoma and 74 sessions of radial access for visceral intervention (R.A.V.I.) were reviewed. We classified the location of the left subclavian artery bifurcation in the aortic arch in three areas using an oblique view computed tomography image matched with the curve of the aortic arches according to a new criteria Three Areas Criteria For R.A.V.I. (named "TAC-F-R"), and measured the required time from initial left radial artery arteriography to celiac artery or superior mesenteric artery arteriography., Results: The median time required for left radial artery arteriography to the celiac artery or superior mesenteric artery arteriography in each of the three areas were: area A, 0:11:10 (h, min, s); area B, 0:14:44; and area C, 0:31:51. There were significant differences between each area after Bonferroni correction (p < 0.01; A vs. B, p = 0.086; A vs. C, p = 0.001; and B vs. C, p = 0.045), with areas A and B requiring a significantly shorter time. Finally, no patients showed neurogenic disfunction within 1 week after the R.A.V.I., Conclusions: The new classification, "TAC-F-R," for safer transradial access hepatic interventional radiology is effective for avoiding difficult cases, and selects more suitable patients with hepatocellular carcinoma for the R.A.V.I., (© 2023 Japan Society of Hepatology.)

Aims: The effects of genetic polymorphism on a personalized diet and exercise program for steatotic liver disease (SLD) are still unclear., Methods: Participants of this retrospective cohort study were 203 Japanese patients with SLD diagnosed by abdominal ultrasonography. All of them were introduced the personalized diet and exercise treatment. A diet of 25-30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4-5 metabolic equivalents daily, respectively) were performed for 6 days. Treatment efficacy was evaluated in terms of the rate of decrease of liver function tests, glycolipid metabolism markers, physical findings, image findings, and cardiovascular disease (CVD) risk score at 6 months compared with baseline. Furthermore, the impact of genetic polymorphism was also investigated., Results: At 6 months compared with baseline, liver function tests (AST, ALT, γGTP), glycolipid metabolism markers (hemoglobin A1c, triglycerides [TG], low-density lipoprotein cholesterol), physical findings (BW, body mass index), image finding (liver stiffness measurement), and CVD risk score (Suita score) improved significantly. There was no significant difference in treatment efficacy, except for the rates of decrease of TG, according to genotype PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314. The rates of decrease of TG with TM6SF2 CT were significantly higher than those with CC or TT, and the rates of TG with HSD17B13 AA were significantly higher than those with AG by multiple comparisons., Conclusion: Personalized diet and exercise program for SLD improved liver function tests, physical findings, glycolipid metabolism markers, and CVD risk score. Genetic polymorphism might partially affect treatment efficacy. Further studies should be performed to develop an individualized program for SLD, considering genetic polymorphism., (© 2023 Japan Society of Hepatology.)

Background: We determined the long-term clinical outcome and the durability of treatment cessation after HBsAg seroclearance following nucleos(t)ide analog (NA) therapy in patients with chronic hepatitis B (CHB)., Methods: We analyzed virological relapse (VR), HBsAg reversion, clinical relapse, and changes in HBsAg and HBcrAg levels by iTACT assay after treatment cessation of 90 CHB patients who achieved HBsAg seroclearance by NA treatment., Results: Median age of patients at treatment cessation was 57 years. Median duration of NA treatment and follow-up from cessation of NA were 9.25 and 5.2 years, respectively. Although VR occurred in 19 of 90 (21.1%) patients, HBV DNA levels of 18 patients had temporal elevations and sustained levels under the detection level thereafter. HBsAg reversion using Architect HBsAg QT assay occurred in six patients (6.7%) after cessation of NA. Five patients had temporal HBsAg level elevations and sustained levels under the detection level thereafter. One patient had virological and clinical relapse at 6 months after cessation of NA, and received NA re-treatment. HBsAg levels by iTACT assay from end of treatment (EOT) gradually decreased and in 18 of 28 (64%) patients reached an undetectable level at 5 years after EOT. In contrast, HBcrAg levels by iTACT assay slowly decreased, and in 8 of 29 patients (28%) reached an undetectable level at 5 years after EOT., Conclusions: Patients receiving NA treatment who achieved HBsAg seroclearance as determined by HBsAg QT assay rarely experienced virological or clinical relapse after the cessation of treatment., (© 2023. Japanese Society of Gastroenterology.)

Aim: There are few reports on the prognosis of liver-related events in Japanese patients with nonalcoholic fatty liver disease (NAFLD). We undertook an observational study to compare the prognosis between fibrotic and nonfibrotic groups in Japanese NAFLD patients., Methods: Prognosis in 393 NAFLD patients who underwent liver biopsy between April 2013 and April 2015 at multiple centers were investigated. The time to onset of liver-related events, cardiovascular events, development of extrahepatic cancers, and death were compared between the pathologically fibrotic nonalcoholic steatohepatitis (NASH) group and nonalcoholic fatty liver (NAFL) + nonfibrotic NASH group. A similar analysis was carried out based on the fibrotic classification diagnosed using four noninvasive fibrosis prediction models., Results: The mean age and body mass index at the time of liver biopsy was 55.7 years old and 28.04 kg/m 2 , respectively The cumulative incidence of liver-related events at 1080 days after liver biopsy was 5.79% in the pathologically fibrotic NASH group and 0% in the NAFL + nonfibrotic NASH group, with a significant difference (p = 0.0334). The cumulative incidence of liver-related events was significantly higher in the positive group for the prediction model than in the negative group in all four models (all p values were <0.0001). There was no significant difference between the pathologically fibrotic NASH group and NAFL + nonfibrotic NASH group in terms of cumulative incidence of cardiovascular events, development of extrahepatic cancers, and death., Conclusions: The incidence of liver-related events was significantly higher in the fibrotic NASH group than that of the NAFL + nonfibrotic NASH group in Japanese NAFLD patients., (© 2023 Japan Society of Hepatology.)

Background: Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma., Methods: In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting., Findings: Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each])., Interpretation: In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice., Funding: Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck., Competing Interests: Declaration of interests JML reports serving in a consulting or advisory role for AstraZeneca, Bayer HealthCare Pharmaceuticals, Bluejay, Boston Scientific, Bristol Myers Squibb, Captor Therapeutics, Eisai, Exelixis, Genentech, Glycotest, Ipsen, Eli Lilly, Merck, MiNA Alpha, Omega Therapeutics, and Roche; and receiving research funding paid to his institution from Bayer Pharmaceuticals, Bristol Myers Squibb, Eisai, and Ipsen. MKu reports receiving honoraria from Bayer, Chugai–Roche, Eisai, Lilly Japan, and Takeda and receiving research funding paid to his institution from AbbVie, Chugai–Roche, EA Pharma, Eisai, GE Healthcare, Otsuka, and Taiho Pharmaceutical. PM reports serving in a consulting or advisory role for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, and Roche and receiving research funding from Ipsen. TM reports serving in a consulting or advisory role for Bayer, Beigene, BTG, Eisai, Ipsen, MSD, and Roche and receiving research funding from Bayer, BTG, and Ipsen. MI reports receiving honoraria from Abbott Laboratories, AbbVie, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharma, EA Pharma, Eisai, Fujifilm, Guardant Health Japan, Incyte, Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, SERVIER, Taiho Pharmaceutical, Taisho Pharmaceutical Holdings, Takeda, Teijin Pharma, and Yakult Pharmaceutical; reports serving in a consulting or advisory role for AbbVie, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Chugai Pharma, Eisai, Guardant Health Japan, Lilly Japan, MSD, Novartis, Ono Pharmaceutical, and SERVIER; and reports receiving research funding paid to his institution from AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharma, Delta-Fly Pharma, Eisai, InVitae, J-Pharma, Lilly Japan, Merck, Merus, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, and Pfizer. JE reports serving in a consulting or advisory role for AstraZeneca, Basilea, Bayer, BeiGene, Boston Scientific, Bristol Myers Squibb, BTG, Eisai, Ipsen, Merck Serono, MSD, Roche, SERVIER, and Taiho Oncology; receiving research funding paid to his institution from Beigene, Boston Scientific, and Bristol Myers Squibb; and receiving travel accommodations, and expenses from Amgen, Bristol Myers Squibb, and Roche. ZR reports serving in a consulting or advisory role for AstraZeneca, Merck Sharp & Dohme, and Roche. GM reports receiving support for the present manuscript from MSD and Eisai; consulting fees from MSD, Roche, Eisai, and Terumo; receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Eisai and AstraZeneca; receiving support for attending meetings or travel from MSD, Eisai, AstraZeneca, and Roche; and participation on a data safety monitoring board or advisory board for Roche, Eisai, MSD, and AstraZeneca. HYL reports receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche and participation on a data safety monitoring board or advisory board for Bayer, Eisai, Roche, and Ipsen. JHK reports receiving grants or contracts paid to his institution from Ono Pharmaceutical and Roche; receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, MSD, Roche, Roche Diagnostics, Pfizer, AstraZeneca, Eisai, Lilly, and Sanofi; receiving support for meetings or travel from Roche; participation in a data safety monitoring board or advisory board for Bixink, Eisai, Yuhan, Novartis, Daiichi Sankyo, Pfizer, Roche, and Everest Medicine; and receiving equipment, materials, drugs, medical writing, gifts or other services from Eisai, Ono Pharma, and Roche. VB reports receiving consulting fees from Eisai, Novartis, and Bayer, honoraria for lectures, presentations, and educational events from Bristol Myers Squibb, Roche, Eisai, Ipsen, and Bayer, and support for attending meetings or travel from Bristol Myers Squibb, Ipsen, and Roche. HK is an employee of Toranomon Hospital and reports other relationships with AbbVie, Eisai, Gilead Sciences, Sumitomo Chemical, and Sumitomo Dainippon Pharma. A-LC reports receiving honoraria from AstraZeneca, Bayer Yakuhin, Eisai, and Genentech/Roche and serving in a consulting or advisory role for AstraZeneca, Bayer Schering Pharma, BeiGene, Bristol Myers Squibb, Eisai, Genentech–Roche, Ipsen, IQVIA, MSD, Ono Pharmaceutical, and Roche. PRG reports receiving honoraria from Adaptimmune, AstraZeneca–MedImmune, Bayer Schering Pharma, Boston Scientific, Bristol Myers Squibb, Guerbet, Ipsen, Lilly, MSD, Roche–Genentech, and Sirtex Medical; serving in a consulting or advisory role for Adaptimmune, Bayer Schering Pharma, Boston Scientific, Bristol Myers Squibb, Lilly, MSD, Roche–Genentech, and Sirtex Medical; serving on a speaker's bureau for Bayer Schering Pharma, Ipsen, Lilly, and Roche; receiving research funding from Roche–Genentech; and receiving travel, accommodation, and expenses from Bayer Schering Pharma, Lilly, and Sirtex Medical. SK serves in a consulting or advisory role for Bayer, Eisai, and Lilly; reports receiving research funding from AVI Pharma, Bayer, Eisai, Lilly, Otsuka, Pfizer, Sumitomo Dainippon Pharma, and Takeda; and other relationships with AVI Pharma, Bayer, Eisai, Lilly, Sumitomo Dainippon Pharma, and Takeda. AW is an employee of Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA; has stock and other ownership interests in Merck, Rahway, NJ, USA. KM is an employee of Eisai and reports receiving travel, accommodations, and expenses from Eisai. CD is an employee of Eisai. LD is an employee of Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA; and has stock and other ownership interests in Merck, Rahway, NJ, USA. ABS is an employee of and has received travel, accommodations, and expenses from Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA and has stock and other ownership interests in Merck, Rahway, NJ, USA. RSF reports serving in a consulting or advisory role for AstraZeneca, Bayer, Bristol Myers Squibb, CStone Pharmaceuticals, Eisai, Exelixis, Genentech–Roche, Hengrui Therapeutics, Lilly, Merck, Novartis, and Pfizer; reports receiving research funding paid to his institution from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, and Roche–Genentech; and providing expert testimony for Bayer. SQ, RX, B-YR, MKw declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh <60 kg, the dose was 8 mg/day) plus pembrolizumab 200 mg once every 3 weeks demonstrated antitumor activity and a manageable safety profile in patients with first-line unresectable hepatocellular carcinoma (uHCC) in the open-label phase 1b Study 116/KEYNOTE-524 (primary analysis data cutoff date: October 31, 2019; median follow-up: 10.6 months). This analysis (updated data cutoff date: March 31, 2021) reports efficacy results from 17 months of additional follow-up time., Methods: 100 patients with uHCC were included in the primary analysis (median follow-up: 27.6 months). Endpoints included overall survival (OS), investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per modified RECIST. Landmark analyses of OS by the best response at 3 and 9 months were performed. Pembrolizumab antidrug antibodies (ADAs) and concentrations were also measured (cutoff date: August 7, 2020)., Results: ORR was 43.0% (95% CI 33.1-53.3%) and median DOR was 17.1 months (95% CI 6.9-19.3 months). Median PFS and OS were 9.3 months (95% CI 7.4-9.8 months) and 20.4 months (95% CI 14.4-25.9 months), respectively. No treatment-emergent ADAs were detected., Conclusion: Results show a sustained treatment effect with lenvatinib plus pembrolizumab in patients with uHCC in the first-line setting., Competing Interests: Masatoshi Kudo: honoraria – Eli Lilly, Bayer, Eisai, Chugai, Takeda, and AstraZeneca; grant – Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, and GE Healthcare; and advisory consulting – Chugai, Roche, Eisai, and AstraZeneca. Richard S. Finn: consulting or advisory role – Pfizer, Bayer, Novartis, Bristol Myers Squibb, Merck, Eisai, Lilly, Genentech/Roche, AstraZeneca, Exelixis, and C Stone Pharma; research funding – Pfizer (Inst), Bayer (Inst), Novartis (Inst), Eisai (Inst), Lilly (Inst), Merck (Inst), Bristol Myers Squibb (Inst), and Roche/Genentech (Inst); and expert testimony – Novartis. Masafumi Ikeda: honoraria – Abbott Japan, Bayer Yakuhin, Bristol Myers Squibb Japan, Chugai Pharma, Eisai, Lilly Japan, Novartis, Taiho Pharmaceutical, Teijin Pharma, Yakult, Nihon Servier, AstraZeneca, MSD, Takeda, Astellas Pharma, AbbVie, Fujifilm Toyama Chemical, EA Pharma, Ono Pharmaceutical, Incyte Biosciences Japan, and Taisho Pharmaceutical; consulting or advisory role – Eisai, Novartis, Lilly Japan, Chugai Pharma, Ono Pharmaceutical, AstraZeneca, Nihon Servier, Takeda, and GlaxoSmithKline; and research funding – AstraZeneca (Inst), Bayer Yakuhin (Inst), Bristol Myers Squibb (Inst), Chugai Pharma (Inst), Eisai, Lilly Japan (Inst), Merck Biopharma (Inst), Delta-Fly Pharma (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Yakult (Inst), MSD (Inst), J-Pharma (Inst), Takeda (Inst), Pfizer (Inst), Chiome Bioscience (Inst), Merus N.V. (Inst), Nihon Servier (Inst), and Syneos Health (Inst). Max W. Sung: honoraria – Genentech and Bayer. Ari D. Baron: speakers’ bureau – Bristol Myers Squibb, Merck, Lilly, Amgen, Eisai, Johnson & Johnson, and AbbVie. Takuji Okusaka: honoraria – Meiji Seika Kaisha, Merck Sharp & Dohme, Shire, AbbVie, Eisai, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceuticals, Teijin Pharma, Lilly, Nippon Shinyaku, Servier, Novartis, Bayer, Pfizer, and Mundipharma; consulting or advisory role – Taiho Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Bristol Myers Squibb, AstraZeneca, and Eisai; research funding – Novartis (Inst), Eisai (Inst), Dainippon Sumitomo Pharma (Inst), Baxter (Inst), Lilly (Inst), Taiho Pharmaceutical (Inst), AstraZeneca (Inst), Chugai Pharma (Inst), Bristol Myers Squibb, and Merck Sharp & Dohme (Inst); and travel, accommodations, and expenses – Takara Bio. Masahiro Kobayashi: honoraria – Eisai Japan. Hiromitsu Kumada: honoraria – Merck Sharp & Dohme, Dainippon Sumitomo Pharma, AbbVie, Gilead Sciences, and Eisai. Shuichi Kaneko: honoraria – Merck Sharp & Dohme, Eisai, Gilead Sciences, Dainippon Sumitomo Pharma, Bayer, Bristol Myers Squibb, and Lilly; consulting or advisory role – Bayer, Merck Sharp & Dohme, Lilly, and Eisai; research funding – Merck Sharp & Dohme (Inst), Bayer (Inst), Chugai Pharma (Inst), and Eisai (Inst). Marc Pracht: consulting – BMS and Ipsen. Tim Meyer: consulting – Eisai, BMS, Adaptimmune, Ipsen, Roche, and AstraZeneca; grant funding – MSD. Satoshi Nagao, Kalgi Mody, and Zahra Ramji: employment – Eisai. Kenichi Saito: employment – Eisai; and patents, royalties, and other intellectual property – applying for patent for pharmaceutical composition. Leonid Dubrovsky: employment – Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Josep M. Llovet: research support – Eisai, Bristol Myers Squibb, Bayer Pharmaceuticals, Boehringer-Ingelheim, and Ipsen; and consultancy – Eisai, Merck, Bayer Pharmaceuticals, Bristol Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Ipsen, Glycotest, Nucleix, Biopharma, Sirtex, and AstraZeneca., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background & Aims: Risk scores have been designed to predict the development of hepatocellular carcinoma (HCC) in treatment-naive patients with chronic hepatitis B (CHB). However, little is known about their predictive accuracy in HBeAg-negative patients in the grey zone (GZ). We aimed to develop a HBcrAg-based HCC risk score and explore whether it outperforms other risk scores in GZ patients., Methods: Two retrospective cohorts of HBeAg-negative patients with American Association for the Study of Liver Diseases-defined GZ were established for derivation and validation (Taiwanese, N = 911; Japanese, N = 806). All of them were non-cirrhotic at baseline and remained treatment-naive during the follow-up. The primary endpoint was HCC development., Results: In a median follow-up period of 15.5 years, 85 patients developed HCC in the derivation cohort. We found that age, sex, alanine aminotransferase, platelet count, and HBcrAg, but not HBV DNA levels, were independent predictors and a 20-point GZ-HCC score was developed accordingly. The 10-year and 15-year area under the ROC curve (AUROC) ranged from 0.83 to 0.86, which outperformed the HBV DNA-based HCC risk scores, including REACH-B and GAG-HCC scores (AUROC ranging from 0.66 to 0.74). The better performance was also validated in EASL- and Asian Pacific Association for the Study of the Liver-defined GZ patients. These findings remained consistent in the validation cohort. Finally, the low-risk and high-risk GZ patients (stratified by a score of 8) had an HCC risk close to inactive CHB and immune-active CHB patients, respectively, in both cohorts., Conclusions: The HBcrAg-based GZ-HCC score predicts HCC better than other HBV DNA-based risk scores in GZ patients who are HBeAg-negative patients, which may help optimise their clinical management., Impact and Implications: We have developed a risk score based on HBcrAg, which has shown better predictive ability for HCC compared with other risk scores based on HBV DNA. Using a score of 8, GZ patients can be classified into low- and high-risk groups, which can guide follow up and early treatment, respectively. This validated risk score is a valuable tool for optimising the management of GZ patients who are HBeAg-negative., Competing Interests: T-CT has served on speaker’s bureaus for Fujirebio, Bristol-Myers Squibb, and Gilead Sciences and received grant support from Gilead Sciences. TH served as a speaker for Gilead Sciences, Eisai Co., Ltd, and Fujirebio. FS served as a speaker for Gilead Sciences. HK served as a speaker for Gilead Sciences, AbbVie Inc., MSD K.K., Eisai Co., Ltd, and Sumitomo Pharma. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background: The aim of this study was to evaluate the clinical impact of a combination of systemic sequential therapy and locoregional therapy on the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC)., Methods: Sixty-four consecutive patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The clinical impact of the combined use of systemic sequential therapy and locoregional therapy was evaluated by determining overall survival (OS). The combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while only systemic sequential therapy and repeated locoregional-treatment was defined as a single treatment procedure (STP)., Results: R0 resection, MCT, and STP resulted in significantly better OS compared with no additional treatment (median OS, not reached vs. 18.2 months and 12.6 vs. 8.1 months, respectively; p = 0.002). Multivariate analysis confirmed that the use of R0 resection and MCT were associated with better OS (hazard ratio [HR]; 0.053, p = 0.006 and 0.189, p < 0.001, respectively) compared with that for STP (HR; 0.279, p = 0.003)., Conclusions: MCT is may effective in patients with BCLC stage C HCC and intrahepatic target nodules who have previously received systemic therapy-based treatment.

Aims: Both diet and exercise counseling are recommended for patients with fatty liver, including nonalcoholic fatty liver disease (NAFLD), to achieve weight loss goals. However, data evaluating treatment efficacy are limited., Methods: The subjects of this retrospective cohort study were 186 consecutive Japanese cases with fatty liver diagnosed by abdominal ultrasonography. Treatment efficacy and predictive factors of "Hospitalization Program for Improvement Purpose for Fatty Liver" as a combined diet and aerobic and resistance exercise program were evaluated according to the hospitalization group (153 cases) or the no hospitalization group (33 cases). To balance the confounding biases, treatment efficacy was evaluated using propensity score-matched analysis. In the hospitalization group, a diet of 25-30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4-5 metabolic equivalents daily, respectively) were performed for 6 days., Results: In liver function tests and BW at 6 months compared with baseline, the rates of decrease of the hospitalization group (24 cases) were significantly higher than those of the no hospitalization group (24 cases), using propensity score-matched analysis. In markers of glycolipid metabolism and ferritin levels, the rates of the hospitalization group were not different from those of the no hospitalization group. In the hospitalization group (153 cases), multivariate regression analysis identified the etiology of non-NAFLD, the presence of diabetes mellitus, and large waist circumference as independent predictors of decreased rates of hemoglobin A1c levels., Conclusion: The diet and exercise program for fatty liver improved liver function tests and BW. Further study should be performed to develop a feasible and suitable program., (© 2023 Japan Society of Hepatology.)

Background: The aims of this study were to evaluate the clinical impact of curative-intent subsequent treatment on overall prognosis in lenvatinib-treated hepatocellular carcinoma (HCC) patients., Methods: Eighty-three consecutive patients with intrahepatic target nodules who received lenvatinib were reviewed. The clinical impact of curative-intent subsequent treatments was investigated through analysis of overall survival (OS) according to pathological deterioration stratified by mALBI grade., Results: In patients with mALBI grade 1 and 2a liver function, R0 resection and lenvatinib-transarterial chemoembolization (lenvatinib-TACE) sequential therapy resulted in significantly better OS compared with other, non-curative-intent subsequent therapy and lack of additional treatment (median OS, 37.6 vs 29.0 months and 17.1 vs 8.9 months, respectively; P < 0.001). Multivariate analysis confirmed that use of R0 resection and lenvatinib-TACE sequential therapy were associated with better OS (hazard ratio [HR], 0.021; P < 0.001 and 0.108; P < 0.001) compared with other, non-curative-intent subsequent treatment (HR 0.256; P = 0.010). In contrast, in patients with mALBI grade 2b liver function, multivariate analysis confirmed higher treatment efficacy for non-curative-intent subsequent treatment with respect to OS (HR 0.041; P < 0.001) compared with R0 resection and lenvatinib-TACE sequential therapy (HR 0.057; P = 0.027 and 0.063; P = 0.001)., Conclusion: Curative-intent subsequent treatment is more useful for HCC patients with better liver function (mALBI grade 1 and 2a) and intrahepatic target nodules who have received lenvatini b-based treatment., (© 2022. Japanese Society of Gastroenterology.)

Introduction: Simple predictive markers enabling even nonspecialized medical doctors and clinicopathological features of primary liver cancer (PLC) following HCV clearance with direct-acting antivirals (DAAs) are unclear., Methods: The subjects of this retrospective study were 2,476 patients following HCV clearance with DAAs. All patients were confirmed to be PLC-free before and during DAAs., Results: PLC was diagnosed in 73 patients during the follow-up, with an incidence rate per 1 000 person-years of 5.9. The annual rate of PLC during the first 6 years was 0.6%. Multivariate analysis identified gender, GGT, and FIB-4 index as the significant determinants of PLC. According to a combination of these risk factors, the cumulative PLC incidence rates were significantly different among the five subgroups based on the number of PLC risk scores. In 73 patients with PLC, the rates of abnormal AFP, PIVKAII, and serum TERT C228T positive were 37.0, 32.4, and 22.2%. PIVKAII levels in BCLC stage A and B were significantly higher than those in stage 0. In 41 patients, who underwent surgical resection for PLC, maximum tumor diameters of abnormal PIVKAII were significantly larger than those of normal PIVKAII. PLC of abnormal PIVKAII significantly indicated presence of vp more than that of normal PIVKAII, and did not contain well-differentiated HCC., Conclusions: Combination of simple markers, enabling even nonspecialized medical doctors, is useful for the evaluation of PLC risk following HCV clearance with DAAs. However, imaging studies are regularly recommended for the early detection of PLC., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: When lenvatinib is administered to people with hepatocellular carcinoma (HCC), tumor blood flow is reduced due to the inhibition of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR). Few studies have examined the decrease in tumor blood flow with respect to changes in tumor blood vessels (TBVs) in clinical practice. We investigated the mechanism of tumor blood flow control by investigating changes in the diameter of relatively large TBVs in large-sized lesions with high blood flow., Methods: From January 2011 to October 2021, patients receiving lenvatinib for unresectable intrahepatic HCC at Toranomon Hospital, Tokyo, Japan, were considered for inclusion. We investigated the TBV diameter in the arterial phase of dynamic computed tomography before treatment and its change over time (2-12 weeks after lenvatinib initiation). The relationship between changes in TBV diameter and prognosis was also examined., Results: Of 114 patients treated with lenvatinib for HCC, 26 patients who had intrahepatic lesions with a tumor diameter of 30 mm or more enrolled in the study. The median tumor and TBV diameters before treatment were 58 mm and 2.55 mm, respectively. Twenty-five patients (96%) had a shrinkage in TBV diameter 2-12 weeks after lenvatinib administration. The maximum TBV diameter shrinkage of 20% or more was observed in 19 patients (73%), and progression-free survival was prolonged in these patients compared to the group with less than 20% TBV diameter shrinkage (p = 0.039)., Discussion/conclusion: Due to the antiangiogenic effect of lenvatinib, a shrinkage in the TBV diameter of HCC was observed. The shrinkage of TBV may be regarded as a process of normalization of TBVs. The shrinkage of TBVs in imaging analysis may be associated with improved prognosis; however, additional studies are still required., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Personalized medicine and molecular therapies with the diagnosis of somatic genetic alterations are expected to be developed for liver cancer. Nevertheless, it is unknown whether a mutation in the telomere reverse transcriptase promoter (TERT C228T) in serum cfDNA might be useful for making prognostic predictions after surgical resection for primary liver cancer., Methods: This cohort study retrospectively investigated 111 patients who had undergone surgical resection of liver cancer for the first time. We investigated the differences between clinicopathological features and prognosis according to classification of three tumor markers, including AFP, PIVKAII, and TERT C228T., Results: Multivariate analysis identified etiology (fatty liver disease vs. HBV odds ratio [OR] 6.853) and fibrosis stage (2-4, OR: 0.137) as determinants of TERT C228T-positive liver cancer with normal levels of AFP and PIVKAII (TERT single positive liver cancer). TERT single positive (Yes, OR: 0.301), fibrosis (FIB)-4 index (≥3.25, OR: 2.038), Child-Pugh classification (B, OR: 4.975), and number of tumors (≥2, OR: 4.098) were identified as determinants of the recurrence of liver cancer. TERT single positive (Yes, OR: 3.311), FIB-4 index (≥3.25, OR: 0.433), and number of tumors (≥2, OR: 0.262) were identified as determinants of disease-free survival., Conclusions: Our results highlight the impact of classification of prognostic tumor markers. TERT single positive is one predictor of favorable prognosis after surgical resection for liver cancer., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Chronic hepatitis C virus (HCV) infection has the greatest health impact in patients with advanced liver disease. The direct-acting antiviral (DAA) regimen glecaprevir/pibrentasvir (G/P) is approved for treatment of HCV-infected patients without cirrhosis and with compensated cirrhosis. However, events of liver decompensation/failure have been reported in patients treated with protease-inhibitor-containing DAA regimens, often in patients with advanced liver disease. This study examines the safety of on-label G/P treatment in patients with compensated cirrhosis (F4 at baseline) with markers of advanced liver disease. Patients with cirrhosis were categorized into 4 subgroups, based on different noninvasive markers of advanced liver disease identified using laboratory measures: platelet count < or ≥ 100 × 10 9 /L, and Child-Pugh score 5 or 6. Separate analyses were performed using pooled data from clinical trials and from real-world post-marketing observational studies. G/P was well tolerated in patients with platelet count ≥100 × 10 9 /L (n = 800), platelet count <100 × 10 9 /L (n = 215), a Child-Pugh score of 5 (n = 915) and a Child-Pugh score of 6 (n = 95). In the clinical trial and real-world cohorts two patients and no patients experienced a serious adverse event (AE) possibly related to study drug, respectively; three patients and no patients experienced an AE of special interest for hepatic decompensation and hepatic failure. This analysis reaffirms G/P's safety profile in indicated patients with compensated cirrhosis, including those with markers of more advanced liver disease. Increasing the number of patients treated with short-duration G/P therapy may contribute to meeting HCV elimination targets., (© 2022 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Aim: To compare the clinicopathological features of typical steatohepatitic HCC (SH-HCC) with other HCCs., Methods: Subjects were 486 patients with untreated HCC who underwent hepatectomy at our hospital from January 2015 to December 2020. We compared patient backgrounds, preoperative laboratory data, imaging findings (ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI]), and postoperative pathological findings (tumor and background of liver). The Liver Imaging Reporting And Data System (LI-RADS) was used to examine CT and MRI findings., Results: Typical SH-HCCs were significantly different from other HCCs with respect to age, hepatitis B virus (HBV) infection, and nonalcoholic steatohepatitis (NASH). Diabetes and hyperlipidemia were also significantly more common. Regarding histopathology, tumor size and background steatosis were significantly different between groups. Although ultrasonography, CT, and MRI could each alone diagnose SH-HCCs with a diameter < 20 mm in ≥ 50% of patients, the combined use of these tests improved diagnostic accuracy. By LI-RADS, 87% of SH-HCC cases were classified as LR-5, which are considered to be malignant tumors., Conclusions: It seems possible to diagnose SH-HCC by combining ultrasonography, CT, and MRI., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that might influence the research reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background & Aims: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection., Methods: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log 10 IU/ml reduction from baseline) rate, safety and pharmacokinetics., Results: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log 10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours., Conclusions: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified., Clinical Trial Number: NCT03020745., Lay Summary: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections., Competing Interests: Conflict of interest MFY has been an advisor for and received consulting fees from AbbVie, Arbutus, Bristol-Myers Squibb (BMS), Dicerna, GSK, Gilead, Janssen, Merck Sharp & Dohme (MSD), Clear B Therapeutics, Springbank and Roche; and received grants from Assembly biosciences, Arrowhead, BMS, Fujirebio, Gilead, MSD, Springbank and Sysmex. JHeo, YS, QX, JJ, YK, JLT, WX, ZD, S-JP, RK, Y-OK and HJY report no conflicts of interest. HK has received teaching fees from MSD, Gilead, AbbVie, Eisei and Dainippon Sumitomo. FS has received teaching fees from AbbVie and Gilead. JLHou has received consulting fees from Aligos, Assembly, Gilead Sciences, Johnson & Johnson, Roche; lecturer fees from Gilead, Johnson & Johnson, Roche and grants from BMS. KC has received grants from AbbVie and Dainippon Sumitomo; and has received teaching fees from MSD, BMS and Gilead. MI received grants and teaching fees from BMS. S-GL has been an advisor for and received grants from Abbott Diagnostics, Gilead, Roche and MSD; and has been an advisor for Kaleido Bioscience, Arbutus, Assembly Grifols, Janssen, Fibronostics and GSK. YTanaka received grants from Gilead, Janssen and Chugai; and teaching fees from Gilead and Fujirebio, Inc. J-HY received grants from GSK, Dicerna Pharmaceuticals, Roche, AstraZeneca, Daewoong and Hanmi. MK was an advisor for Gilead and GSK; and received speaking fees from Gilead, AbbVie, MSD, Eisai, Chugai and Bayer. MEL has been an advisor for and received speaking fees for Abbott Diagnostics, Hi-Eisai, Menarini, Mylan and Roche. YTao, JC, RE, MD, SB-B, KH, FMC, MP and DT are employees of GSK and hold GSK stocks/options. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Purpose: Protease-free regimens for chronic hepatitis C virus (HCV) infection are safe and effective for persons with either compensated or decompensated cirrhosis. We examined the efficacy and safety of sofosbuvir-velpatasvir in participants with HCV and compensated cirrhosis in Japan., Methods: This was a Phase 3, multi-center, open-label study. At 20 sites, 37 individuals with chronic HCV infection of any genotype and compensated cirrhosis received sofosbuvir-velpatasvir (400 mg/100 mg) daily for 12 weeks. Participants were treatment-naïve or treatment-experienced with interferon-based treatments with or without HCV NS3/4A protease inhibitors. Prior exposure with HCV NS5A or NS5B inhibitors was prohibited. The primary study endpoint was sustained virologic response 12 weeks after treatment (SVR12)., Results: Among participants, 62% had HCV genotype 1 infection, and 38% had HCV genotype 2. More than three quarters (29/37, 78%) were HCV treatment naïve. All participants (37/37, 100%) achieved SVR12. Seventeen participants (46%) and three participants (8%) had pretreatment resistance-associated substitutions to HCV NS5A and NS5B nucleoside inhibitors respectively, yet no on-treatment breakthrough or relapse occurred. Sofosbuvir-velpatasvir for 12 weeks treatment was safe and well tolerated. The most commonly reported adverse events were headache (8%, 3/37) and diarrhea (5%, 2/37). One serious adverse event, patella fracture, occurred and was considered not treatment related. No participants discontinued study treatment due to an adverse event. Three participants (8%) had a Grade 3 laboratory abnormality; all were hyperglycemia., Conclusion: Sofosbuvir-velpatasvir resulted in high SVR rates and was well tolerated among Japanese patients with HCV and compensated cirrhosis. This single-tablet regimen offers a highly effective, protease-inhibitor free regimen for treating HCV., Clinicaltrials: gov Identifier: NCT04112303., (© 2022 Gilead Sciences and The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

We report a 61-year-old man treated with betamethasone for sudden-onset deafness. Several days later, he had a temperature > 38 °C. He sought care at another hospital and was admitted based on abnormal liver function tests (aspartate aminotransferase [AST], 866 IU/L [normal < 31 IU/L] and alanine aminotransferase [ALT] 1524 IU/L [normal < 31 IU/L]). Liver function improved daily and the patient was discharged from the hospital after 5 days. Two days after discharge, he had a recurrent fever and liver dysfunction. After admission to our hospital, liver function improved spontaneously. A liver biopsy was performed, but a diagnosis was not established; however, a tentative diagnosis of antinuclear antibody-negative autoimmune hepatitis was made and the patient was started on prednisolone (30 mg). Two days later, he developed a fever and persistent liver dysfunction, thus the prednisolone was discontinued. The next day, the AST and ALT increased significantly (18,000 and 12,000 U/L, respectively). Because the level of consciousness was altered, plasma exchange was started for acute liver failure. After discontinuing the prednisolone, the hospital course was uneventful. Drug-induced liver injury due to corticosteroids is rare. Herein, we report a patient with acute liver failure who survived with timely treatment., (© 2022. Japanese Society of Gastroenterology.)

Aim: The phase III REFLECT study utilized bodyweight-based lenvatinib dosing in patients with unresectable hepatocellular carcinoma, based on results of the phase II Study 202. This post hoc analysis compared efficacy and safety in patients with lower and higher bodyweights., Methods: This comparison included patients from Study 202 (Japanese, n = 43; Korean, n = 3) and Japanese patients from REFLECT (n = 81) who received lenvatinib. In Study 202, all patients received a starting dose of lenvatinib 12 mg/day; in REFLECT, patients received starting doses based on bodyweight (patients <60 kg, 8 mg/day; ≥60 kg, 12 mg/day). Safety and efficacy were assessed in both studies according to bodyweight., Results: In Study 202, treatment-related, treatment-emergent adverse events (TEAEs) led to dose reductions in 80.8% and 55.0% of patients in the lower and higher bodyweight groups, respectively. In REFLECT, treatment-related TEAEs led to dose reductions in 52.5% and 70.7% of patients in the 8 and 12 mg groups, respectively. In Study 202, median overall survival (OS) was 16.2 months (95% confidence interval [CI], 9.8-25.1) and 21.3 months (95% CI, 10.1-not estimable) in the lower and higher bodyweight groups, respectively. In REFLECT, median OS was 15.8 months (95% CI, 10.4-27.6) and 18.2 months (95% CI, 11.3-26.9) in the 8 and 12 mg groups, respectively., Conclusions: Comparison between patients in Study 202 and REFLECT demonstrates efficacy was maintained with improved safety in patients with lower bodyweights who received lenvatinib 8 mg/day in REFLECT versus patients who received lenvatinib 12 mg/day in Study 202., (© 2022 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

The aim of this study was to determine the impact at 5 years of sodium-glucose cotransporter 2 inhibitor (SGLT2i) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM) on liver histopathology and clinical features. In this retrospective study, the histological impacts at 5 years after the start of SGLT2i in NAFLD with T2DM were investigated. Six patients with NAFLD and T2DM were treated for the long term with canagliflozin of SGLT2i, and liver biopsies were obtained at the points of the pretreatment, 24 weeks, 3 years, and 5 years after the start of treatment. The primary outcome was liver histopathological changes at 5 years (defined as decrease in NAFLD activity score of one point or more without worsening in fibrosis stage, compared with the pretreatment). The additional treatment of glucagon-like peptide 1 receptor agonist (GLP-1RA) was performed in 2 patients after the point of 3 years, and evaluated as histological worsening. As the primary outcome, histological improvement, no change, and worsening were 50%, 17%, and 33% at 5 years, respectively. Overall, the scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased at 5 years in 67%, 33%, 0%, and 33%, respectively. As the secondary outcomes, homeostasis model assessment of insulin resistance and serum ferritin decreased significantly at 5 years. None developed 3-point major adverse cardiovascular events. Two patients with the addition of GLP-1RA on SGLT2i did not show the worsening of steatosis, ballooning, and fibrosis stage at 5 years compared with 3 years. Conclusion: A 5-year follow-up study with SGLT2i indicated the favorable histological impact on NAFLD with T2DM., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1 + dendritic cells and dysfunctional CD8 + T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

Introduction: Many patients with chronic hepatitis B (CHB) are classified as indeterminate patients because they fall outside the defined CHB phases. We aimed to explore hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-negative patients with indeterminate phase and investigated whether the risk could be stratified by serum levels of hepatitis B core-related antigen (HBcrAg)., Methods: Two retrospective cohorts enrolling HBeAg-negative, treatment-naïve CHB patients without cirrhosis were constructed (N = 2,150 in Taiwanese discovery cohort and N = 1,312 in Japanese validation cohort with a mean follow-up period of 15.88 and 12.07 years, respectively). The primary end point was HCC development., Results: According to the American Association for the Study of Liver Disease guidelines, 990 (46%) HBeAg-negative patients had indeterminate CHB phase at baseline in the Taiwanese cohort. Compared with the patients with inactive CHB and those with immune-active CHB, the indeterminate patients exhibited intermediate but diverse risk of HCC. When HCC risk was stratified by a HBcrAg level of 10,000 U/mL, 10-year HCC cumulative incidence was 0.51% and 5.33% for low HBcrAg and high HBcrAg groups, respectively, with a hazard ratio of 4.47 (95% confidence interval: 2.62-7.63). This cutoff was validated to stratify HCC risk not only in different subgroup analyses but also in an independent Japanese cohort. Finally, the overall HBeAg-negative CHB patients could be simply reclassified into high-risk and low-risk groups by combining ALT, hepatitis B virus DNA, and HBcrAg levels in both cohorts., Discussion: Serum HBcrAg level of 10,000 U/mL stratifies HCC risk in HBeAg-negative patients with indeterminate phase, which is useful for optimizing their clinical management., (Copyright © 2022 by The American College of Gastroenterology.)

Objective The relationship between the prognosis and magnitude of a decrease in tumor blood flow according to estimated tumor differentiation remains unclear. This study investigated the relationship between reductions in the rate of mean computed tomography (CT) attenuation values and the clinical prognosis. Methods We evaluated 63 consecutive patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC). The oncological aggressiveness of the tumors was estimated using classification by dynamic CT enhancement patterns. The utility of changes in mean CT attenuation values of intra-hepatic targets during treatment to estimate the prognosis was investigated by calculating the progression-free survival (PFS) and post-progression survival (PPS). A multivariate analysis was used to identify potential confounders for the survival after progression during lenvatinib therapy. Results The rate of decrease in the mean CT attenuation value gradually increased according to the degree of deterioration in estimated tumor differentiation, and the rate of a decrease in attenuation ≥40% showed a tendency to increase (p=0.064). This trend was reflected by a better objective response in oncological aggressiveness heterogeneous enhancement patterns (Type-3 and Type-4) than a homogeneous enhancement pattern (Type-2) (83% vs. 56% of modified Response Evaluation Criteria in Solid Tumors). This resulted in a similar PFS between the groups (p=0.773), whereas the PPS was significantly worse when the rate of decrease in the attenuation value was ≥40% (p=0.012). A multivariate analysis confirmed that a rate of decease in attenuation value ≥40% was a poor prognostic factor for the PPS (hazard ratio, 2.993; 95% confidence interval, 1.196-7.490; p=0.019). Conclusion A rate of decrease in attenuation ≥40% may reflect a good response of a highly malignant tumor to lenvatinib. Therefore, this value may have utility as a surrogate marker for estimating the oncological aggressiveness of tumors and their associated prognosis.

Background & Aims: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression., Methods: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122)., Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients., Conclusion: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Molecular therapies and precision medicine are expected to be developed for liver cancer based on the diagnosis of DNA somatic alterations. However, it remains unclear whether TERT promoter mutation (TERT C228T) in serum cfDNA is useful for the diagnosis of liver cancer with non-viral fatty liver disease (FLD)., Methods: This retrospective cohort study examined 258 Japanese patients who had a confirmed diagnosis of primary liver cancer. We investigated the factors associated with TERT C228T and abnormal levels of liver cancer-specific tumor markers (AFP and PIVKAII) in serum samples., Results: Multivariate analysis identified the etiology of FLD, vascular invasion, and non-cirrhosis as determinants of TERT C228T-positive liver cancer. Rates of positive TERT C228T in FLD were significantly higher than those of HBV and HCV. Conversely, rates of abnormal AFP in FLD were significantly lower than those of HBV and HCV. Viral suppression of HBV/HCV and alcohol intake did not affect TERT C228T, but AFP was significantly reduced by viral suppression. The rates of positive TERT C228T were significantly lower in HCV patients with viral clearance than those of FLD patients., Conclusion: Our results highlight the importance of serum TERT C228T for the detection of non-viral FLD-related liver cancer. TERT C228T is a tumor marker that might not be influenced by inflammation., (© 2022. The Author(s).)

Background: Zinc deficiency is likely to occur in chronic liver disease. The aim of this study was to determine the prevalence of zinc deficiency in different types of chronic liver disease and to identify the factors that predicted low serum zinc levels., Methods: The study was an observational single-center design. We obtained the medical records of 666 patients with chronic liver disease whose serum zinc levels had been measured. The cutoff value for zinc deficiency was a serum level < 70 µg/dL., Results: Serum zinc levels in the alcoholic liver disease (ALD) group were significantly lower than in the other groups (hepatitis C virus [HCV], hepatitis B virus [HBV], and other cause) (P < 0.01). The CONUT and ALBI score (r = 0.527, P < 0.01), serum zinc level and ALBI score (r = - 0.607, P < 0.01), and serum zinc level and CONUT score (r = - 0.465, P < 0.01) correlated with each other. The prevalence of zinc deficiency were 44.8%, 63.2%, 86.7%, 97.1%, and 100% in the mALBI grade 1-CONUT normal, CONUT undernutrition, and mALBI grade 2a, 2b, and 3 groups, respectively. Multivariate analysis identified ALD, CONUT score, aspartate aminotransferase, and hemoglobin as significant, independent predictors of zinc deficiency (P < 0.05)., Conclusions: This study identified ALD, CONUT score, aspartate aminotransferase, and hemoglobin as predictors of zinc deficiency in chronic liver disease. The rate of zinc deficiency is high even in patients classified as mALBI grade 1, especially in ALD, while caution may be required in those classified as mALBI grade 1-CONUT undernutrition., (© 2022. Japanese Society of Gastroenterology.)

Background: Long-term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long-term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B., Methods: The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long-term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF., Results: Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1-2 and 3a-4 at baseline. In patients with CKD stages 3a-4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m 2 /year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1-2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1., Conclusions: Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a-4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized., (© 2021 Japan Society of Hepatology.)

Background and Aims: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of early progressive disease (e-PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev)., Methods: Twenty consecutive patients with measurable intrahepatic target nodules who received Atezo/Bev treatment were reviewed. The oncological aggressiveness of tumors estimated by 18F-FDG-PET/CT was analyzed using the rate of e-PD within 12 weeks and early progression-free survival (e-PFS) and overall survival (OS). Multivariate analysis was used to identify potential confounders for PD during Atezo/Bev therapy., Results: Using the Response Evaluation Criteria in Solid Tumors version 1.1, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with lower objective response rates compared with TLR values <2 (18% vs. 33%, respectively). Moreover, TLR values ≥2 were significantly associated with higher e-PD rates compared with TLR values <2 (64% vs. 11%, respectively) and worse e-PFS (p = 0.021). In multivariate analysis, TLR ≥2 showed marginal significance as a predictor of e-PD (p = 0.053), and utility as a predictor for worse e-PFS (hazard ratio, 7.153; 95% confidence interval, 1.258-40.689; p = 0.027). In contrast, no significant differences in OS with/without e-PD were observed during the treatment course. In this study, 8 patients experienced e-PD and almost 40% of patients experienced acceptable disease control following subsequent lenvatinib treatment., Conclusion: Pretreatment 18F-FDG-PET/CT may be a useful new predictor of e-PD and may enable early decision-making based on early treatment changes following Atezo/Bev treatment of HCC., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Serum hepatitis B core-related antigen (HBcrAg) and surface antigen (HBsAg) are surrogate markers of intrahepatic covalently closed circular DNA. The measurement range of the current HBcrAg assay is relatively narrow. Thus, we examined the potential of HBcrAg and HBsAg measured by ultrasensitive assays for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B treated with entecavir (ETV). We conducted a retrospective cohort study of 180 patients who received ETV for >1 year. All patients had hepatitis B e-antigen negativity at baseline. Serum HBcrAg and HBsAg levels at baseline and year 1 were measured in all patients by ultrasensitive assays using immunoassay for total antigen including complex by pretreatment (iTACT) technology. During the median follow-up of 11.0 years, 22 patients developed HCC (11.8/1,000 person-years). Baseline HBsAg levels were not associated with HCC development during ETV treatment. However, high HBcrAg levels at baseline and at year 1 were significantly associated with HCC development (log-rank test; P < 0.001). In 110 patients (61.1%) with ≥4.0 log U/mL at baseline (high HBcrAg cohort), HBcrAg declined to ≤2.9 log U/mL at year 1 in 25 patients (22.7%). The adjusted hazard ratio for HCC incidence was significantly lower in patients with HBcrAg ≤2.9 log U/mL at year 1 than in those in the high HBcrAg cohort. Conclusion: Measurement of HBcrAg by ultrasensitive assay has better potential for predicting HCC during antiviral treatment than the current HBcrAg assay., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Introduction: It is unclear whether the relationships between changes in fibrosis and circulating microRNA-122 (miR-122) dynamics might influence the prognosis of nonalcoholic fatty liver disease (NAFLD)., Methods: This study investigates the impact of serum miR-122 dynamics and histological changes on the incidence of liver cancer and mortality in 81 Japanese NAFLD patients who underwent serial liver biopsies. The median interval between the first and second liver biopsies was 2.9 years., Results: The fibrosis stage scores indicated progression, no change, and improvement (a decrease of one point or more) in 21.0%, 56.8%, and 22.2% of the patients, respectively. There were 64 patients in the high-risk group who had no improvement in stage scores. Among these, the miR-122 levels were significantly lower in 7 patients with liver cancer than those of the 54 patients who had no liver cancer at the second liver biopsy. The cumulative rates of liver cancer were significantly higher in cases with miR-122 ratios <0.5 (serum miR-122 level at second biopsy to that at first biopsy) than those with ratios ≥0.5. The cumulative survival rates in cases with miR-122 ratios <0.5 tended to be lower than those with ratios ≥0.5. Of the 64 high-risk patients, 39 indicated stage 2 or greater (severe fibrosis stage) at the first liver biopsy and also showed similar results of cumulative liver cancer and survival rates., Conclusions: Longitudinal examination of serial liver biopsies indicated that the circulating miR-122 dynamics might be useful in predicting the prognosis for NAFLD patients with severe fibrosis stage and no improvement of the stage scores., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: Tenofovir disoproxil fumarate (TDF) is widely used and recommended as first-line treatment for patients infected with the hepatitis B virus (HBV). However, current data are limited regarding the efficacy and safety of switching to TDF for the treatment of chronic hepatitis B in hepatitis B e-antigen (HBeAg)-positive patients who are virologically suppressed with another nucleos(t)ide analogue. The primary objective of this study was to evaluate the hepatitis B surface antigen (HBsAg) reduction potential of switching from entecavir (ETV) to TDF at week 48 in HBeAg-positive chronic hepatitis B patients with undetectable serum HBV-DNA., Methods: In this multicenter, single-arm, open-label, phase 4 clinical study, 75 participants currently treated with ETV 0.5 mg once daily were switched to TDF 300 mg once daily for 96 weeks., Results: At week 48, 3/74 participants (4%) achieved 0.25 log 10 reduction of HBsAg levels from baseline (the primary endpoint). Mean HBsAg reduction was -0.14 log 10 IU/mL and 12% (9/74) achieved 0.25 log 10 reduction by 96 weeks. No participants achieved HBsAg seroclearance. HBsAg reduction at weeks 48 and 96 was numerically greater in participants with higher alanine aminotransferase levels (≥ 60 U/L). Seventeen participants (25%) achieved HBeAg seroclearance up to week 96. No participants experienced viral breakthrough. All drug-related adverse events (18 participants [24%]) were mild in intensity, including an increase in urine beta-2-microglobulin (15 participants [20%])., Conclusions: In conclusion, HBsAg reduction was limited after switching from ETV to TDF in this study population. Further investigation is warranted to better understand the clinical impact of switching from ETV to TDF. ClinicalTrials.gov: NCT03258710 registered August 21, 2017. https://clinicaltrials.gov/ct2/show/NCT03258710?term=NCT03258710&draw=2&rank=1., (© 2021. The Author(s).)

Background: Reliable noninvasive predictors of the top three causes of death [cardiovascular diseases (CVDs), malignancies, and liver-related events in patients with non-alcoholic fatty liver disease (NAFLD)] have not yet been determined., Methods: We retrospectively investigated the incidence of three complications [CVDs, malignancy (except for liver cancer), and liver-related events] in 477 Japanese patients with histo-pathologically confirmed NAFLD for a median follow-up of 5.9 years. In addition to histological findings, we also investigated noninvasive predictors., Results: A score of ≥ 2.67 for the noninvasive diagnosis of stage 4 fibrosis based on the Fibrosis-4 (FIB-4) index indicated a high level area under the receiver operating characteristic (AUROC) curve (0.90), sensitivity (82.9%), specificity (86.4%), and negative predictive value [(NPV) of 98.5%]. The yearly incidence rates of CVDs, malignancies, and liver-related events were found to be 1.04%, 0.83%, and 0.30%, respectively. Multivariate analysis identified a FIB-4 index ≥ 2.67 score as a significant and independent, noninvasive predictor of these three complications. Furthermore, the cumulative incidence rates of CVDs were significantly different among the three genotypes of PNPLA3. PNPLA3 genotype CC, chronic kidney disease (CKD), and FIB-4 index ≥ 2.67 was could be attributed to these three significant CVD risk factors. The rates of CVDs were significantly different among the three subgroups based on the combination of risk factors. In malignancy (except for liver cancer), the incidence rate of colon cancer was 25.0%; in particular, the rate in females was 53.8%., Conclusions: Our results highlighted the importance of the PNPLA3 genotype and FIB-4 index ≥ 2.67 on the incidence of complications in Japanese patients with NAFLD, especially the incidence of CVDs. Early diagnosis, based on the presence of one or more risk factors, and early treatment might improve the prognosis for NAFLD patients., (© 2021. The Author(s).)

Background: Few studies have demonstrated the potency of tenofovir alafenamide (TAF) in patients with poor response to other nucleos(t)ide analogs (NAs)., Methods: We conducted a retrospective study comprising consecutive 40 patients exhibiting a poor response to other NAs, who subsequently received TAF-containing regimens. The primary outcome was the prevalence of virological response (VR) at each time and maintained virological response (MVR) under TAF-containing regimens until week 96., Results: In the entire cohort, the prevalence of MVR was 71.1% (27/38). Further, poor tenofovir disoproxil fumarate (TDF) response was significantly associated with a lower prevalence of MVR (p = 0.014). In TDF-naïve patients, the prevalence of MVR was 92.3% (12/13) and 62.5% (5/8) in patients with lamivudine resistance (LAM-r) and entecavir resistance (ETV-r), respectively. Further, viral load and HBeAg status at baseline were associated with a lower prevalence of MVR (p = 0.013). Among the seven patients with prior TDF exposure, 2 patients achieved MVR. Among them, one patient with development of viral breakthrough during TDF/LAM achieved MVR after switching to TAF/ETV. In contrast, one of the five patients with non-MVR had three substitutions (rtS106C, rtD134N/S, and rtL269I) of quadruple mutations in addition to ETV-r. Other patients with rtA181T + rtN236T also could not achieve MVR., Conclusion: TAF exhibited high antiviral potency in patients with LAM-r and ETV-r. However, TAF potency was associated with previous TDF response, viral load, and HBeAg status at baseline. Additionally, a quadruple mutation may impact tenofovir resistance; however, further studies are needed to verify this., (© 2021. Japanese Society of Gastroenterology.)

Aim: To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH)., Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end-point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end-points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated., Results: Forty-eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was -3.0% and -13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen-3 N-terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis-4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment., Conclusions: In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti-inflammatory and antifibrotic effects of apararenone., (© 2021 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need., Methods: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection., Findings: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively)., Conclusions: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening., Competing Interests: DECLARATION OF INTERESTS Y.H. serves as an advisory board member for Helio Health and founding shareholder for Alentis Therapeutics, and received a research funding from Morphic Therapeutics. T.F.B. serves as advisor and is a founding shareholder or Alentis Therapeutics. R.T received a lecture fee from Bayer, Chugai, Eisai, Takeda and Wako/Fujifilm. N.P. has served as a consultant for Bristol Myers-Squibb, Exact Sciences, Eli Lilly, and Freenome. A.G.S. has served on advisory boards of Genentech, Eisai, Bayer, Exelixis, Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest.

Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group., Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed., Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5-15.7] compared to 13.7 months (95% CI 12.0-15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4-9.2; ≥ 60 kg group: 95% CI 6.9-9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group., Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups., Clinincal Trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.

Background: Hepatitis C virus is the leading cause of liver cirrhosis and hepatocellular carcinoma in Japan. We aimed to examine the long-term (> 20 years) mortality and hepatocellular carcinoma rates and associated risk factors in 1412 Japanese patients with decompensated hepatitis C virus-related cirrhosis (Child-Pugh B or C)., Methods: Cumulative survival and hepatocellular carcinoma rates were determined using Kaplan-Meier analysis. Independent risk factors were identified by multivariate analysis. A two-tailed P-value of < 0.05 was considered significant., Results: The patients were followed up for a median of 2 years (range 0.5-24.2 years). In total, 62.3%, 41.7%, 4.7%, and 68.3% of the patients had a history of hepatocellular carcinoma, ascites, hepatic encephalopathy, and esophageal varices, respectively. The 1-, 5-, 10-, and 20-year cumulative overall survival rates in the total cohort was 74.9%, 29.0%, 9.1%, and 1.4%, respectively. The 1-, 3-, 5-, and 10-year cumulative survival rates for patients without hepatocellular carcinoma were 93.1%, 54.4%, 18.2%, and 4.0%, respectively, and the corresponding cumulative post-decompensation hepatocellular carcinoma rates were 14.0%, 31.6%, 46.1%, and 66.2%, respectively. The independent risk factors for mortality were older age, Child-Pugh C cirrhosis, the presence of hepatocellular carcinoma, low estimated glomerular filtration rate, low serum sodium level, low platelet count, and high γ-glutamyl transferase and α-fetoprotein levels for all patients and older age, Child-Pugh C cirrhosis, and low estimated glomerular filtration rate for patients without hepatocellular carcinoma. Overall, 1035 patients (73.3%) died; the causes of death were liver failure with/without hepatocellular carcinoma, pneumonia, sepsis, cardiovascular disease, and non-hepatocellular carcinoma malignancies. The corresponding morality rates per person-year were 133.4, 59.9, 10.9, 10.6, 9.0, and 5.2, respectively., Conclusions: Among Japanese patients with decompensated hepatitis C virus-related cirrhosis, hepatocellular carcinoma is associated with poor prognosis. Our results highlight the importance of managing liver-related events, including hepatocellular carcinoma, in these patients.

We report a rare case of amebiasis associated with an intraabdominal abscess without colitis, an intestinal perforation, or other extraintestinal amebiasis. A patient was admitted with cirrhosis and a history of spontaneous bacterial peritonitis (SBP) and was found to have a high C-reactive protein (CRP) level. Dynamic CT and ultrasound echo findings showed an intraabdominal abscess. No intestinal lesions or extraintestinal lesions other than the intraabdominal abscess were observed. Blood cultures and puncture fluid cultures were negative for bacteria. However, microscopic examination of the puncture fluid showed a cystic form of amoeba, leading to a diagnosis of an amoeba abscess. The abscess disappeared after 10 days of oral treatment with metronidazole. When an abdominal abscess is seen in an immunocompromised patient such as a cirrhotic patient, amoeba infection should be considered as a possible diagnosis.

Aims: Hepatitis B surface antigen (HBsAg) seroclearance indicates a "functional cure" in chronic hepatitis B (CHB) virus infection. However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core-related antigen (HBcrAg), measured by the ultra-highly sensitive assays, in cases with HCC development after HBsAg seroclearance., Methods: We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (five HCC patients and 12 non-HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra-highly sensitive assays featuring "immunoassay for total antigen including complex via pretreatment (iTACT)" technology., Results: All five patients who developed HCC were positive for HBsAg or HBcrAg by iTACT-HBsAg or iTACT-HBcrAg at all follow-up points. HBcrAg levels in the HCC group, using iTACT-HBcrAg, were significantly higher than those in the non-HCC group at HBsAg seroclearance (3.6 LogU/ml (2.8-4.2) versus 2.6 (<2.1-3.8), p = 0.020). The best cutoff value of iTACT-HBcrAg for predicting HCC development was 2.7 LogU/ml by receiver operating characteristic curve analysis. The prevalence of HBcrAg ≥2.7 in the HCC group was significantly higher than that in non-HCC group (100% [5/5] versus 33% [4/12], p = 0.029)., Conclusions: Residual low viral antigen might predict HCC development even if HBsAg seroclearance was achieved according to a conventional assay. The results suggest that iTACT assays of HBsAg and HBcrAg would be useful for monitoring CHB patients., (© 2020 The Japan Society of Hepatology.)

Objective A survival benefit was demonstrated for ramucirumab (RAM) in patients with unresectable hepatocellular carcinoma (uHCC) and α-fetoprotein (AFP) concentrations ≥400 ng/mL who had previously received sorafenib (SOR). However, it is unclear whether RAM has a similar efficacy in patients with uHCC that progresses after lenvatinib (LEN) treatment. This study aimed to evaluate the early anti-tumor response to RAM as a second-line treatment for advanced uHCC after LEN treatment. Methods We retrospectively assessed the efficacy and safety of RAM at 6 weeks after initiation. The therapeutic effects were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients We evaluated 7 patients with uHCC who received RAM as a second- or third-line treatment after LEN failure. Results The disease control rate (DCR) was 28.6% (2 of 7 patients). After the initiation of RAM, a rapid disease progression resulted in 1 patient death after 19 days. The median progression-free survival (PFS) was 41 days. There were no grade 3 or 4 treatment-related adverse events. At 6 weeks, there was no deterioration in the modified albumin-bilirubin (mALBI) grade. In patients with an imaging response of stable disease (SD), the rate of AFP production decreased from the baseline. Conclusion RAM may have a therapeutic potential for the suppression of uHCC progression in patients previously treated with LEN, as well as for maintaining the liver function during treatment. Evaluating the AFP trends may therefore be useful for predicting RAM effectiveness.

Aim: The number of patients with fatty liver disease (FLD) is increasing globally. Ethanol consumption in FLD is known to be associated with an increased risk of hepatocellular carcinoma (HCC), but the effects of alcohol consumption on the occurrence of multiple HCCs remain unclear. We explored the relationship between the daily ethanol intake and the HCC number., Methods: This single-center retrospective study enrolled 114 patients without viral or immune hepatitis undergoing first-line HCC treatment who had been diagnosed with FLD by abdominal ultrasonography or a liver biopsy at the same time as or before HCC detection. We categorized patients into four groups according to the daily alcohol consumption (<20 g: non-alcoholic fatty liver disease, n = 45; 20-39 g: low-intermediate ethanol intake with FLD, n = 13; 40-69 g: high-intermediate ethanol intake with FLD, n = 31; ≥70 g: alcoholic fatty liver disease, n = 25). The relationship between the daily ethanol consumption and the number of HCCs (single or multiple) was examined., Results: The risk of multiple HCCs was significantly higher in the high-intermediate ethanol intake with FLD (HR 2.89, 95% CI 1.04-8.02, P = 0.042) and alcoholic fatty liver disease (HR 3.14, 95% CI 1.07-9.22, P = 0.037) groups than in the others. A multivariate analysis showed that a daily ethanol intake ≥40 g was associated with a significantly increased risk of multiple HCCs (HR 2.82, 95% CI 1.16-6.88, P = 0.023)., Conclusions: Our findings suggest that a high daily ethanol intake might lead to multiple hepatocarcinogenesis in patients with FLD., (© 2020 The Japan Society of Hepatology.)

Introduction: It remains unclear whether TERT promoter mutation (TERT C228T) in serum cell-free DNA (cfDNA) is useful for the diagnosis of hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD)., Methods: In this retrospective study, we analyzed the relationships between TERT C228T in serum cfDNA and levels of AFP and PIVKAII in 57 Japanese patients with histopathologically confirmed NAFLD background, consisting of 36 patients with HCC and 21 without HCC. We also examined the liver-related survival rate and HCC recurrence rate after the initial treatment for HCC. TERT C228T was detected using a highly sensitive method based on wild-type blocking PCR (detection limit in excess of 0.7% mutant-type DNA)., Results: In all of the 57 patients, multivariate analysis identified TERT C228T positive as significant determinant of primary HCC. In the 36 patients with HCC, the percentage of patients positive for TERT C228T was 63.9%. The percentage of patients positive for TERT C228T with normal AFP and PIVKAII was 35.3%. The positive predictive value and specificity for prediction of BCLC stage 0 or A were both high. In 6 patients, TERT C228T was repeatedly negative during follow-up but became positive at the time of HCC diagnosis. Four patients who underwent HCC surgical resection had well-differentiated solitary HCC measuring <30 mm, and all were TERT C228T positive with normal AFP and PIVKAII. TERT C228T status had no influence on the cumulative liver-related survival rate and HCC recurrence rate., Conclusions: Our results highlight the superiority of TERT C228T in serum cfDNA compared with AFP and PIVKAII in the early diagnosis of primary HCC in NAFLD patients., (© 2020 S. Karger AG, Basel.)

Background: The sensitivity of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in hepatocellular carcinoma (HCC) is low; however, clinical evidence demonstrating its prognostic value in patients with HCC has recently been reported. This study aimed to assess the value of 18F-FDG-PET/CT as a tool for evaluating the response of HCC to lenvatinib treatment., Methods: We evaluated 11 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with 18F-FDG-PET/CT from April 2018 to December 2019. The tumor-to-normal liver ratio (TLR) of the target tumor was measured before and during the course of lenvatinib treatment with 18F-FDG-PET/CT (pre and post analysis, respectively), with a TLR ≥2 classified as PET-positive HCC. At the time of each evaluation, we also used the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the modified RECIST (mRECIST), and the tumor marker alfa-fetoprotein (AFP)., Results: Of 11 patients, 3 (27%) and 8 (73%) had an objective response to lenvatinib treatment at the time of post-analysis by RECIST 1.1 and mRECIST, respectively. There were 3 (27%) and 7 (64%) patients with PET-positive HCC at the time of pre- and post-analysis, respectively. There was a significant correlation between the rates of change in AFP and TLR during lenvatinib treatment (r = 0.69, p = 0.019). Based on these results, we were able to perform liver resection on 4 patients with PET-positive HCC as conversion therapy. Three samples from these patients showed poorly differentiated tumors., Conclusion: 18F-FDG-PET/CT has potential as an evaluation tool for describing biological tumor behavior and reflecting disease progression, location, and treatment response. This modality may provide useful information for considering prognosis and subsequent therapy., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

Background and Aim: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of overall prognosis in patients with hepatocellular carcinoma treated with lenvatinib., Methods: Forty-eight consecutive patients who received lenvatinib treatment were reviewed. The oncological aggressiveness of tumors estimated using 18F-FDG-PET/CT was investigated by the analysis of progression-free survival (PFS), post-progression survival (PPS), and overall survival (OS). Multivariate analysis was used to identify potential confounders for OS during lenvatinib therapy., Results: Using the Modified Response Evaluation Criteria in Solid Tumors, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with a better objective response to lenvatinib than a TLR <2 (78 vs. 62%), resulting in a similar PFS (p = 0.751). Because of a significantly worse PPS, OS with a TLR ≥2 was poor compared to a TLR < 2 (p = 0.012). Multivariate analysis confirmed that a TLR ≥ 2 was associated with poor OS (hazard ratio, 2.709; 95% CI, 1.140-6.436; p = 0.024). Analysis of 24 patients who received a repeat 18F-FDG-PET/CT showed that daily changes expressed as ΔTLR × 103/day over the treatment course tended to be different among the types of subsequent treatment. A R0 resection and lenvatinib-TACE sequential therapy provided good disease control (median, -4.593 and -0.024, respectively) compared with other treatments (median, 5.278) (p = 0.075)., Conclusion: Lenvatinib has acceptable disease control regardless of estimated tumor differentiation. A high TLR (≥2) is a poor prognostic factor of OS following lenvatinib treatment, while ΔTLR × 103/day provides useful information of disease control status., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Even though both interferon (IFN)-based and direct-acting antiviral (DAA) therapies against hepatitis C virus (HCV) reduce the risk of hepatocellular carcinoma (HCC), post-sustained virological response (SVR) patients remain at elevated risk of HCC., Methods: A total of 4620 patients who achieved SVR were enrolled in this retrospective cohort study. After excluding patients who had a history of HCC or developed HCC within 1 year and whose follow-up period was less than 1 year and who were positive for HBsAg, we investigated the association between clinical characteristics and HCC development after SVR in the remaining 3771 patients., Results: Median observation period was 41 months. We confirmed known risk factors. In addition, we found that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. Finally, we propose an estimation model for the incidence of HCC after SVR. Based on gender, FIB-4 index, AFP, and PNPLA3 polymorphism, about 18% of all patients were classified as having high risk, with a cumulative incidence rate (CIR) at 5 years of 16.5%. Another 17% were classified as having moderate risk with a CIR of 7.6%. The remaining 65% showed a CIR of 0.5%. The effect of PNPLA3 polymorphism might be more pronounced in patients with lower body mass index (BMI) and without diabetes mellitus compared to those with higher BMI and diabetes mellitus., Conclusions: We demonstrated that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. These findings might be useful to inform risk stratification for HCC surveillance after SVR.

Background: The aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC)., Methods: Consecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy., Results: Heterogeneous enhancement patterns ( Type-3 and -4 ), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern ( Type-2 ) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS ( p = 0.313). Because of significantly worse PPS, overall survival of Type-4 tumor was poor compared to Type-2 or -3 tumors ( p = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01-0.71; p = 0.023), while Type-4 enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06-8.05; p = 0.039)., Conclusion: Oncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC., Competing Interests: Yusuke Kawamura, MD, PhD reports receiving a honoraria from Eisai. Masahiro Kobayashi, MD. reports receiving a honoraria from Eisai. Junichi Shindoh, MD, PhD reports receiving a honoraria from Eisai. Hiromitsu Kumada, MD, PhD reports receiving a honoraria from Eisai. The other authors declare no conflicts of interest., (Copyright © 2020 by S. Karger AG, Basel.)