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Background: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma., Methods: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098., Findings: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab., Interpretation: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully., Funding: F Hoffmann-La Roche/Genentech., Competing Interests: Declaration of interests A-LC reports honoraria from BMS, Eisai, Ipsen, and Ono Pharmaceutical; consulting or advisory roles with Bayer Schering Pharma, BMS, Eisai, Exelixis, Ipsen, IQVIA, Merck Serono, Novartis, Nucleix, Omega Therapeutics, Ono Pharmaceutical, and Roche/Genentech; and participation on data monitoring or advisory boards for Abbisko Therapeutics. AOK reports honoraria from AstraZeneca, Bayer, BMS, Eisai, Exelixis, Merck, and Roche/Genentech; and travel expenses from Roche/Genentech. MK reports honoraria from Bayer, Chugai, Eisai, Eli Lilly, and Takeda; and grants or contracts from AbbVie, Chugai, EA Pharma, Eisai, GE Healthcare, Otsuka, and Taiho. HCL reports grants or contracts from AstraZeneca, MSD, and Roche. JH reports a leadership role in AstraZeneca; honoraria from Oncolys; consulting or advisory roles with AbbVie Korea; grants or contracts from Roche; and speaker's bureau from AstraZeneca, Gilead, Roche, and Yuhan Korea. WYT reports consulting or advisory roles with Eisai Korea, Roche Korea, and Sysmex Korea; and speaker's bureau from Bayer Korea, Gilead Korea, Samil Pharm, and Yuhan. TU reports grants or contracts from Roche and travel expenses from Gilead. EC, NM, JHS, YW, SPH, and QL report employment at Genentech and stock in Roche. CW reports employment at, and stock in, Roche. PKHC reports being Chief Medical Officer for AVATAMED; stock in AVATAMED; honoraria from AstraZeneca, Bayer, Perspectum, Roche, Sirtex, and Worrell; consulting fees from Asia-Pacific Association for the Study of the Liver, Asia-Pacific Primary Liver Cancer Expert Meeting, Bayer Liver Forum, Eastern and Western Association for Liver Tumors, Hong Kong Liver Cancer and Gastrointestinal Cancer Foundation, IQVIA, JSH International Liver Conference, Korean Radioembolization Association, Korean Radioembolization Association Webinar, Liver Cancer Collaborative Annual Scientific and Clinical Meeting, Malaysian Hepato-pancreato-biliary Congress, Malaysian Society of Interventional Radiology, Perspectum, Philippine Society of Nuclear Medicine, Roche, Singapore Hepatology Conference, State Key Laboratory of Liver Research, Taiwan Society of Interventional Radiology, and Tsinghua Medical Forum; consulting or advisory roles with AUM Biosciences, BeiGene, Omega Therapeutics, Roche, and Sirtex; grants or contracts from A*Star, AMiLi, MiRXES, National Medical Research Council, Perspectum, Roche, SingHealth Duke-NUS Programme Grant Award, SingHealth Duke-NUS Global Health Institute Pilot Research Grant, Stratificare and Sirtex; speaker's bureau from AstraZeneca, Bayer, Omega Therapeutics, Roche, and Worrell; support for attending meetings or travel expenses from Roche Diagnostics Asia Pacific and Roche Singapore; patent publication number 10202007868Q; participation in a Data Safety Monitoring Board or Advisory Board for AUM Biosciences, Genentech, IMCB, Perspectum, and Singapore-Samsung Medical Centre (SG-SMC) Joint Lab; and receipt of equipment, materials, drugs, assistance with medical writing, gifts, or other services from Roche and Sirtex. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background & Aims: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B 12 (B 12 ) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH., Methods: We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B 12 (B 12 ) and folate (Fol) to reverse NASH features in mice and cell culture., Results: Serum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B 12 /Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated β -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH., Conclusions: HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B 12 /folate also may represent a novel first-line therapy for NASH., Lay Summary: The incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B 12 and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Few studies have evaluated the outcomes of curative liver resection (LR) in octogenarian patients, analysed cancer-specific survival (CSS) with HCC-related death or explored the age-varying effect of HCC-related death in elderly patients undergoing LR. We aim to determine the effect of age on the short and long-term outcomes of LR for HCC., Methodology: Between 2000 and 2018, 1,092 patients with primary HCC who underwent LR with curative intent were retrospectively reviewed. The log-rank test and Gray's test were used to assess the equality of survivor functions and competing risk-adjusted cumulative incidence functions between patients in the three age categories respectively. Regression adjustment was used to control for confounding bias via a Principal Component Analysis. Quantile, Firth logistic, Cox, and Fine-Gray competing risk regression were used to analyse continuous, binary, time-to-event, and cause-specific survival respectively. Restricted cubic splines were used to illustrate the dose-effect relationship between age and patient outcomes., Results: The study comprised of 764 young patients (<70 years), 278 septuagenarians (70-79 years old) and 50 octogenarians (≥80 years). Compared to young patients, octogenarians had significantly lower 5-year OS(62.1% vs 37.7%, p < 0.001). However, there was no significant difference in 1-year RFS(73.1% vs 67.0%, p = 0.774) or 5-year CSS (5.4% vs 15.2%, p = 0.674). Every 10-year increase in age was significantly associated with an increase length of stay (p < 0.001), postoperative complications (p = 0.004) and poorer OS(p = 0.018) but not significantly associated with major complications (p = 0.279), CSS(p = 0.338) or RFS(p = 0.941)., Conclusion: Age by itself was associated with OS after LR for HCC but was not a significant risk factor for HCC-related death., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Introduction: Although hepatectomy is the mainstay of curative therapy for hepatocellular carcinoma (HCC), post-operative complications remain high. Presently there is conflicting data on the impact of morbidity on oncologic outcomes. We sought to identify predictors for the occurrence of post-hepatectomy complications, as well as to analyse the impact on overall survival (OS) and recurrence-free survival (RFS)., Materials and Methods: We performed a retrospective review of 888 patients who underwent resection for HCC from 2001 to 2016 in our institution., Results: A total of 237 patients (26.7%) developed 254 complications of Clavien-Dindo Grade ≥2. Hepatitis B (p = 0.0397), elevated ASA score (p = 0.0002), higher platelet counts (p = 0.0277), raised pre-operative APRI scores (p = 0.0105) and bloodloss (p < 0.0001) were independently associated with the development of complications. After propensity-score matching, 458 patients were compared in a 1:1 ratio (229 with complications versus 229 without). Patients with complications had significantly longer median length of stay (9 days [IQR 7-15] versus 6 days [IQR 5-8], p < 0.0001), higher 90-day mortality rates as well as inferior OS (p = 0.0139), but there was no difference in RFS (p = 0.4577). Age (p = 0.0006), elevated Child Pugh points (p < 0.0001), microvascular invasion (p = 0.0002), multifocal tumours (p = 0.0002), R1 resection (p = 0.0443) and development of complications (p = 0.0091) were independent predictors of inferior OS., Conclusion: Post-operative morbidity affected both short-term and OS outcomes after hepatectomy for HCC. Hepatitis B, higher ASA scores, elevated preoperative APRI and increased blood loss were found to predict a higher likelihood of developing complications. This may potentially be mitigated by careful patient selection and adopting strict measures to minimise intraoperative bleeding., Competing Interests: Declaration of competing interest The authors confirm that this manuscript has not been published elsewhere previously, and has not been submitted for publication elsewhere.Dr Goh BK has received travel grants and honorarium from Transmedic the local distributor of the Da Vinci robotic platform, Johnson and Johnson, Medtronic and Baxter. The authors have no other conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)