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Background & Aims: Radiofrequency ablation (RFA) and ablative external beam radiotherapy (ablative RT) are commonly used to treat small intrahepatic malignancies. We meta-analysed oncologic outcomes and systematically reviewed the clinical consideration of tumour location and size., Methods: PubMed, Medline, Embase, and Cochrane Library databases were searched on February 24, 2022. Studies comparing RFA and ablative RT, providing one of the endpoints (local control or survival), and encompassing ≥5 patients in each arm were included., Results: Twenty-one studies involving 4,638 patients were included. Regarding survival, the odds ratio (OR) was 1.204 ( p  = 0.194, favouring RFA, not statistically significant) among all studies, 1.253 ( p  = 0.153) among hepatocellular carcinoma (HCC) studies, and 1.002 ( p  = 0.996) among colorectal cancer metastasis studies. Regarding local control, the OR was 0.458 ( p <0.001, favouring ablative RT) among all studies, 0.452 ( p <0.001) among HCC studies, favouring the ablative RT arm, and 0.649 ( p  = 0.484) among colorectal cancer metastasis studies. Pooled 1- and 2-year survival rates for HCC studies were 91.8% and 77.7% after RFA, and 89.0% and 76.0% after ablative RT, respectively; and for metastasis studies were 88.2% and 66.4% after RFA and 82.7% and 60.6% after RT, respectively. Literature analysis suggests that ablative RT can be more effective than RFA for tumours larger than 2-3 cm or for specific sublocations in the liver ( e.g. subphrenic or perivascular sites), with moderate quality of evidence (reference to the grading system of the American Society for Radiation Oncology Primary Liver Cancer Clinical Guidelines). The pooled grade ≥3 complication rates were 2.9% and 2.8% in the RFA and ablative RT arms, respectively ( p  = 0.952)., Conclusions: Our study shows that ablative RT can yield oncologic outcomes similar to RFA, and suggests that it can be more effective for the treatment of tumours in locations where RFA is difficult to perform or for large-sized tumours., Systematic Review Registration: This study was registered with PROSPERO (Protocol No: CRD42022332997)., Impact and Implications: Radiofrequency ablation (RFA) and ablative radiotherapy (RT) are non-surgical modalities for the treatment of small intrahepatic malignancies. Ablative RT showed oncologic outcomes at least similar to those of RFA, and was more effective at specific locations ( e.g. perivascular or subphrenic locations)., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)

Hepatocellular carcinoma (HCC) is a major public health problem worldwide for which the incidence and mortality are similar, pointing to the lack of effective treatment options. Knowing the different issues involved in the management of HCC, from risk factors to screening and management, is essential to improve the prognosis and quality of life of affected individuals. This document summarises the current state of knowledge and the unmet needs for all the different stakeholders in the care of liver cancer, meaning patients, relatives, physicians, regulatory agencies and health authorities so that optimal care can be delivered to patients. The document was commissioned by the International Liver Cancer Association and was reviewed by senior members, including two ex-presidents of the Association. This document lays out the recommended approaches to the societal management of HCC based on the economic status of a given region., Competing Interests: Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Hepatocellular carcinoma (HCC) accounts for 90% of liver tumours and is one of the leading causes of mortality. Cirrhosis due to viral hepatitis, alcohol or steatohepatitis is the major risk factor, while liver dysfunction due to cirrhosis is a deciding factor in its treatment. The treatment modalities for HCC include liver transplant, hepatectomy, radiofrequency ablation, transarterial chemoembolisation, transarterial radioembolisation, targeted therapy, immunotherapy, and radiation therapy. The role of radiation therapy has been refined with the increasing use of stereotactic body radiation therapy (SBRT). Trials over the past two decades have shown the efficacy and safety of SBRT in recurrent and definitive HCC, leading to its acceptance and adoption in some more recent guidelines. However, high quality level I evidence supporting its use is currently lacking. Smaller randomised trials of external beam radiation therapy suggest high efficacy of radiation therapy compared to other treatments for patients with unresectable HCC, and phase III trials comparing SBRT with other modalities are ongoing. In this review, we discuss the rationale for SBRT in HCC and present evidence on its efficacy, associated toxicity, and technological advances., Competing Interests: Shirley Lewis, Laura Dawson, Aisling Barry, Issa Mohamad- None. Teodor Stanescu- Research funding from Elekta for the development and implementation of novel imaging and treatment techniques for liver and pancreas on the Unity MR-Linac system. Ali Hosni- Nonfinancial leadership of liver TSG at Elekta MRL consortium. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Objective: Advanced-stage hepatocellular carcinoma is a heterogeneous group with limited treatment options. TACE has been advocated recently by various study groups. The purpose of this study was to evaluate if TACE in combination with sorafenib, as well as TACE alone, was safe and efficacious in treating BCLC stage C HCC., Methods: A retrospective evaluation of the clinical data of 78 patients with BCLC stage C HCC who received either TACE-sorafenib (TS) combination therapy or TACE monotherapy as their first treatment was done. The two groups were compared in terms of radiological tumor response 1 month after the intervention. The two groups were also compared in terms of time to progression (TTP), overall survival (OS), and adverse events., Results: The disease control rate (44.9% and 25.8%, respectively, P  = 0.09) was higher in the TS combination group than in the TACE monotherapy group after 1 month of treatment. The TS combination group had significantly superior TTP and OS than the TACE group (TTP was 4.6 and 3.1 months, respectively, P  = 0.001), and OS was 10.1 and 7.8 months, respectively, P < 0.001). The TACE-S group had a greater cumulative survival time at 6 months, 9 months, and 1 year than the TACE group (97.9%, 51.1%, 25.7% vs. 90.4%, 51.6%, and 0%, respectively)., Conclusion: TS combination therapy in advanced-stage (BCLC-C) HCC significantly improved disease control rate, TTP, and OS compared with TACE alone, without any significant increase in adverse reactions., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Clinical routine in hepatology involves the diagnosis and treatment of a wide spectrum of metabolic, infectious, autoimmune and neoplastic diseases. Clinicians integrate qualitative and quantitative information from multiple data sources to make a diagnosis, prognosticate the disease course, and recommend a treatment. In the last 5 years, advances in artificial intelligence (AI), particularly in deep learning, have made it possible to extract clinically relevant information from complex and diverse clinical datasets. In particular, histopathology and radiology image data contain diagnostic, prognostic and predictive information which AI can extract. Ultimately, such AI systems could be implemented in clinical routine as decision support tools. However, in the context of hepatology, this requires further large-scale clinical validation and regulatory approval. Herein, we summarise the state of the art in AI in hepatology with a particular focus on histopathology and radiology data. We present a roadmap for the further development of novel biomarkers in hepatology and outline critical obstacles which need to be overcome., Competing Interests: JNK declares consulting services for Owkin (France) and Panakeia (UK) and has received honoraria for scientific talks and participation in advisory boards by MSD, Eisai and Bayer. JC is a consultant for Guerbet, Bayer and Philips. VP is involved in a collaborative study with Owkin, France. DN and TPS declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Hepatocellular carcinoma (HCC) usually arises in the context of a chronically damaged liver. Liver functional estimation is of paramount importance in clinical decision making. The Child-Pugh score (CPS) can be used to categorise patients into 3 classes (A to C) based on the severity of liver functional impairment according to 5 parameters (albumin, bilirubin, prothrombin time, presence of ascites and hepatic encephalopathy). The albumin-bilirubin (ALBI) grade has emerged as an alternative, reproducible and objective measure of liver functional reserve in patients with HCC, defining worsening liver impairment across 3 grades (I to III). The ALBI score can identify different subgroups of patients with different prognoses across the diverse Barcelona Clinic Liver Cancer stages and CP classes, making it an appealing clinical predictor. In patients treated with potentially curative approaches (resection, transplantation, radiofrequency ablation, microwave ablation), ALBI grade has been shown to correlate with survival, tumour relapse, and post-hepatectomy liver failure. ALBI grade also predicts survival, toxicity and post-procedural liver failure in patients treated with transarterial chemoembolisation, radioembolisation, external beam radiotherapy as well as multi-kinase inhibitors (sorafenib, lenvatinib, cabozantinib, regorafenib) and immune checkpoint inhibitor therapy. In this review, we summarise the body of evidence surrounding the role of ALBI grade as a biomarker capable of optimising patient selection and therapeutic sequencing in HCC., Competing Interests: DJP received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and Astra Zeneca; received research funding (to institution) from MSD and BMS. RS received consulting fees for EISAI, Roche, Bayer, SIRTEX, Novartis; research funding (to institution) from Incyte, Novartis, Astex Pharmaceuticals, Bayer and Boston Scientific. LR received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. All remaining authors have declared no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilised in the production of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background & Aims: Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and 'all-comers'., Methods: This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000-2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs., Results: From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8-55.8) and 38.2% (CI 25.4-52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [ p <0.0001]) and not significantly higher for the UCSF-DS group (SHR 1.60 [ p  = 0.32]), compared with patients remaining within Milan. The all-comers presented more frequent features of aggressive HCC and higher tumour burden at explant. Among the UCSF-DS group, an AFP value of ≤20 ng/ml at listing was associated with lower recurrence (SHR 2.01 [ p  = 0.006]) and better survival. However, recurrence was still significantly high irrespective of AFP ≤20 ng/ml in all-comers., Conclusions: Patients within the UCSF-DS protocol at listing have similar post-transplant outcomes compared with those within Milan when successfully downstaged. Meanwhile, all-comers have a higher recurrence and inferior survival irrespective of response to LRT. Additionally, in the UCSF-DS group, an ALP of ≤20 ng/ml might be a novel tool to optimise selection of candidates for LT., Clinical Trial Number: This study was registered as part of an open public registry (NCT03775863)., Lay Summary: Patients with more extended HCC (within the UCSF-DS protocol) successfully downstaged to the conventional Milan criteria do not have a higher recurrence rate after LT compared with the group remaining in the Milan criteria from listing to transplantation. Moreover, in the UCSF-DS patient group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimise selection of candidates for LT., Competing Interests: There are no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background & Aims: Patients affected by hepatocellular carcinoma (HCC) represent a vulnerable population during the COVID-19 pandemic and may suffer from altered allocation of healthcare resources. The aim of this study was to determine the impact of the COVID-19 pandemic on the management of patients with HCC within 6 referral centres in the metropolitan area of Paris, France., Methods: We performed a multicentre, retrospective, cross-sectional study on the management of patients with HCC during the first 6 weeks of the COVID-19 pandemic (exposed group), compared with the same period in 2019 (unexposed group). We included all patients discussed in multidisciplinary tumour board (MTB) meetings and/or patients undergoing a radiological or surgical programmed procedure during the study period, with curative or palliative intent. Endpoints were the number of patients with a modification in the treatment strategy, or a delay in decision-to-treat., Results: After screening, n = 670 patients were included (n = 293 exposed to COVID, n = 377 unexposed to COVID). Fewer patients with HCC presented to the MTB in 2020 ( p  = 0.034) and fewer had a first diagnosis of HCC (n = 104 exposed to COVID, n = 143 unexposed to COVID, p  = 0.083). Treatment strategy was modified in 13.1% of patients, with no differences between the 2 periods. Nevertheless, 21.5% vs. 9.5% of patients experienced a treatment delay longer than 1 month in 2020 compared with 2019 ( p <0.001). In 2020, 7.1% (21/293) of patients had a diagnosis of an active COVID-19 infection: 11 (52.4%) patients were hospitalised and 4 (19.1%) patients died., Conclusions: In a metropolitan area highly impacted by the COVID-19 pandemic, we observed fewer patients with HCC, and similar rates of treatment modification, but with a significantly longer treatment delay in 2020 vs.  2019., Lay Summary: During the coronavirus disease 2019 (COVID-19) pandemic era, fewer patients with hepatocellular carcinoma (HCC) presented to the multidisciplinary tumour board, especially with a first diagnosis of HCC. Patients with HCC had a treatment delay that was longer in the COVID-19 period than in 2019., Competing Interests: JCN received a research grant from Bayer for INSERM UMR1138. The other authors declare no conflicts of interest that pertain to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background & Aims: There are conflicting data regarding the epidemiology of hepatocellular carcinoma (HCC) arising in the context of non-alcoholic and metabolic-associated fatty liver disease (NAFLD and MAFLD). We aimed to examine the changing contribution of NAFLD and MAFLD, stratified by sex, in a well-defined geographical area and highly characterised HCC population between 1990 and 2014., Methods: We identified all patients with HCC resident in the canton of Geneva, Switzerland, diagnosed between 1990 and 2014 from the prospective Geneva Cancer Registry and assessed aetiology-specific age-standardised incidence. NAFLD-HCC was diagnosed when other causes of liver disease were excluded in cases with type 2 diabetes, metabolic syndrome, or obesity. Criteria for MAFLD included one or more of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation., Results: A total of 76/920 (8.3%) of patients were diagnosed with NAFLD-HCC in the canton of Geneva between 1990 and 2014. Between the time periods 1990-1994 and 2010-2014, there was a significant increase in HCC incidence in women (standardised incidence ratio [SIR] 1.83, 95% CI 1.08-3.13, p  = 0.026) but not in men (SIR 1.10, 95% CI 0.85-1.43, p  = 0.468). In the same timeframe, the proportion of NAFLD-HCC increased more in women (0-29%, p  = 0.037) than in men (2-12%, p  = 0.010) while the proportion of MAFLD increased from 21% to 68% in both sexes and from 7% to 67% in women ( p <0.001). From 2000-2004 to 2010-2014, the SIR of NAFLD-HCC increased to 1.92 (95% CI 0.77-5.08) for men and 12.7 (95% CI 1.63-545) in women, whereas it decreased or remained stable for other major aetiologies of HCC., Conclusions: In a populational cohort spanning 25 years, the burden of NAFLD and MAFLD associated HCCs increased significantly, driving an increase in HCC incidence, particularly in women., Lay Summary: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, increasingly arising in patients with liver disease caused by metabolic syndrome, termed non-alcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). We assessed all patients with HCC between 1990 and 2014 in the canton of Geneva (western Switzerland) and found an increase in all HCC cases in this timeframe, particularly in women. In addition, we found that HCC caused by NAFLD or MAFLD significantly increased over the years, particularly in women, possibly driving the increase in overall HCC cases., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC., Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle., Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051])., Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade., Lay Summary: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo., Competing Interests: M.K.: conflict with Daiichi Sankyo, Otsuka, Taiho, Astellas Pharma, Chugai, AbbVie, BMS, EA Pharma, Takeda, Gilead, Eisai, Ono, Bayer, MSD, BMS, and Eli Lilly and Company. P.G.: conflict with Bayer, BMS, MSD, Merck, SIRTEX, AstraZeneca, Sillajen, Eli Lilly and Company, Ipsen, Roche, and Eisai. G.B.: declares no conflicts of interest that pertain to this work. Y-K.K.: conflict with ONO, BMS, Eli Lilly and Company, Roche, Daehwa, and Taiho. C-J. Yen: declares no conflicts of interest that pertain to this work. R.S.F.: conflict with Astra Zeneca, Bayer, BMS, Eli Lilly and Company, Pfizer, Merck, Novartis, Roche/Genentech, and Eisai. J.M.L.: conflict with Bayer, Eisai Inc, BMS, IPSEN, Eli Lilly and Company, Celsion Corp, Elelixis, Merck, Glycotest, Can-Fite, Blueprint, Incyte, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech Inc, and Spring Bank Pharmaceuticals. E.A.: received honoraria from IPSEN, Bayer, Terasphere, Sirtex, Sanofi, Novartis, and Servier; served as an advisor and consultant for IPSEN, Bayer, Terasphere, Sirtex, Sanofi, Novartis, and Servier; and reports receipt of research grant and funding from Eli Lilly and Company. P.M.: conflict with Bayer, Ipsen/Exelixis, BMS, Onxeo, MSD, AstraZeneca, Eisai, and Roche. S.L.C.: conflict with Eisai, Merck, and AstraZeneca. D.H.P.: conflict with Bayer, Eisai, BMS, and Sirtex. M.I.: conflict with Bayer, Bristol-Myers Squibb, Eisai, Sumitomo Dainippon, EA Pharma, Takeda Pharmaceutical, AstraZeneca, Chugai, Merck Serono, Gilead, ASLAN, Daiichi Sankyo, Novartis, Teijin Pharma, Kyowa Hakko Kirin, NanoCarrier, Shire, Yakult, Taiho, Baxalta, Nobelpharma, Otsuka, Ono, MSD, J-Pharma, Mylan, NIHON SERVIER, and Eli Lilly and Company. T.Y.: received personal fees from Eli Lilly and Eisai. A.V.: conflict with Eli Lilly and Company, EISAI, Roche, BMS, MSD, Bayer, BTG, AstraZeneca, Ipsen, Novartis; Y-H. Huang: Eisai, BMS, Merck, AstraZeneca, Bayer, Gilead, Abbvie, Roche, Eli Lilly, and IPSEN. P.B.A.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. R.Y.: Eli Lilly Japan KK, stocks held in Eli Lilly and Company. K.S.: Eli Lilly Japan KK. C.W.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. R.C.W.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. A.X.Z.: conflict with Eisai, BMS, Merck, Novartis, Sanofi, AstraZeneca, Bayer, Roche, Eli Lilly and Company, and Exelixis. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Authors.)

Primary bile acids were reported to augment secretion of chemokine (C‒X‒C motif) ligand 16 (CXCL16) from liver sinusoidal endothelial cells (LSECs) and trigger natural killer T (NKT) cell-based immunotherapy for liver cancer. However, abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control. Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation, we proposed a strategy using nanoemulsion-loaded obeticholic acid (OCA), a clinically approved selective farnesoid X receptor (FXR) agonist, for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy. The OCA-nanoemulsion (OCA-NE) was prepared via ultrasonic emulsification method, with a diameter of 184 nm and good stability. In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells. As a result, OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model, which performed much better than oral medication of free OCA. Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN- γ , as well as increased NKT cell populations inside the tumor. Overall, our research provides a new evidence for the antitumor effect of receptors for primary bile acids, and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Background & Aims: In 2005, the registration of all randomised controlled trials (RCTs) before enrolment of participants became a condition for publication by the International Committee of Medical Journal Editors to increase transparency in trial reporting. Among RCTs on transarterial chemoembolisation (TACE) for the treatment of hepatocellular carcinoma (HCC) published after 2007, we assess the proportion that were registered and compare registered primary outcomes (PO) with those reported in publications to determine whether primary outcome reporting bias favoured significant outcomes., Methods: We searched MEDLINE and EMBASE for reports of RCTs evaluating TACE for HCC treatment between 1 September 2007 and 31 March 2018. Registration and publication information for each included RCT was compared using a standardised data extraction form., Results: Thirteen out of 53 (25%) included RCTs were correctly registered ( i.e. before the starting date of the RCT), 14 (26%) were registered after the RCT starting date, and 26 (49%) were not registered. Six out of 14 of the retrospectively registered RCTs (43%) were registered after their completion date. The PO was clearly reported in the published article of all registered RCTs, whereas the report was not clear in 8/26 (31%) of the non-registered RCTs ( p  = 0.01). Among registered RCTs, 8/27 (30%) had major discrepancies between registered and published PO. The influence of these discrepancies could be assessed in 6 of them and was shown to statistically favour significant results in 2., Conclusions: Registration and outcome reporting in RCTs on TACE for HCC are often inadequate. Registration should be reinforced because it is a key to transparency., Lay Summary: Trial registration is fundamental to our understanding and interpretation of results, as it provides information on all relevant clinical trials (to place the results in a broader context), and on the details of their associated protocols (to ensure that the scientific plan is followed). Once a randomised controlled trial (RCT) is completed, the trial results are usually publicly shared via scientific articles that are expected to thoroughly and objectively report them. This study shows that half of the RCTs evaluating transarterial chemoembolisation for hepatocellular carcinoma were not registered, and identified major discrepancies between registered and published primary outcome favouring significant results., Competing Interests: The authors declare no conflict of interest than pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background & Aims: Liver resection (LR) in patients with hepatocellular carcinoma (HCC) and clinically significant portal hypertension (CSPH) defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg is not encouraged. Here, we reappraised the outcomes of patients with cirrhosis and CSPH who underwent LR for HCC in highly specialised liver centres., Methods: This was a retrospective multicentre study from 1999 to 2019. Predictors for postoperative liver decompensation and textbook outcomes were identified., Results: In total, 79 patients with a median age of 65 years were included. The Child-Pugh grade was A in 99% of patients, and the median model for end-stage liver disease (MELD) score was 8. The median HVPG was 12 mmHg. Major hepatectomies and laparoscopies were performed in 28% and 34% of patients, respectively. Ninety-day mortality and severe morbidity rates were 6% and 27%, respectively. Postoperative and persistent liver decompensation occurred in 35% and 10% of patients at 3 months. Predictors of liver decompensation included increased preoperative HVPG ( p  = 0.004), increased serum total bilirubin ( p  = 0.02), and open approach ( p  = 0.03). Of the patients, 34% achieved a textbook outcome, of which the laparoscopic approach was the sole predictor ( p  = 0.004). The 5-year overall survival and recurrence-free survival rates were 55% and 43%, respectively., Conclusions: Patients with cirrhosis, HCC and HVPG ≥10 mmHg can undergo LR with acceptable mortality, morbidity, and liver decompensation rates. The laparoscopic approach was the sole predictor of a textbook outcome., Lay Summary: Patients with cirrhosis, hepatocellular carcinoma, and clinically significant portal hypertension (defined as a hepatic venous pressure gradient ≥10 mmHg) can undergo resection with acceptable mortality, morbidity, liver decompensation rates, and a textbook outcome. These results can be achieved in selected patients with preserved liver function, good general status, and sufficient remnant liver volume., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Hepatocholangiocarcinoma, fibrolamellar carcinoma, hepatic haemangioendothelioma and hepatic angiosarcoma represent less than 5% of primary liver cancers. Fibrolamellar carcinoma and hepatic haemangioendothelioma are driven by unique somatic genetic alterations ( DNAJB1-PRKCA and CAMTA1-WWTR1 fusions, respectively), while the pathogenesis of hepatocholangiocarcinoma remains more complex, as suggested by its histological diversity. Histology is the gold standard for diagnosis, which remains challenging even in an expert centre because of the low incidences of these liver cancers. Resection, when feasible, is the cornerstone of treatment, together with liver transplantation for hepatic haemangioendothelioma. The role of locoregional therapies and systemic treatments remains poorly studied. In this review, we aim to describe the recent advances in terms of diagnosis and clinical management of these rare primary liver cancers., Competing Interests: Jean-Charles Nault received research grant from 10.13039/100004326Bayer for 10.13039/501100001677Inserm UMR1148, Nathalie Ganne-Carrié received personal fees from Bayer, Gilead, Ipsen and Shionogi. Elia Gigante, François Cauchy, Maxime Ronot, Valérie Paradis, Olivier soubrane: none to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background & Aims: Antiviral treatment is known to improve survival in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Yet, the treatment uptake in CHB patients remains low. We aimed to report the secular trend in antiviral treatment uptake from 2007-2017, and to compare the effect of different nucleos(t)ide analogue (NA) initiation times (before vs. after HCC diagnosis) on survival., Methods: A 3-month landmark analysis was used to compare overall survival in patients not receiving NA treatment ( i.e. no NA), patients receiving NAs after their first HCC treatment ( i.e. post-HCC NA), and patients receiving NAs ≤3 months before their first HCC treatment ( i.e. pre-HCC NA). A propensity score-weighted Cox proportional hazards model was used to balance clinical characteristics between the 3 groups and to estimate hazard ratios (HRs)., Results: The uptake of antiviral treatment in HCC patients increased from 47.3% in 2007 to 98.3% in 2017. The pre-HCC NA group contributed mostly to the uptake rate, which increased from 72.7% to 96.0% in the past decade. In addition, 3,843 CHB patients (407 no NA; 2,932 pre-HCC NA; 504 post-HCC NA) with HCC, receiving at least 1 type of HCC treatment, were included in the analysis. Lack of NA treatment at the time of HCC diagnosis increased the risk of death (weighted HR 3.05; 95% CI 2.70-3.44; p <0.001). The impact of the timing of NA treatment was insignificant (weighted HR 0.90; 95% CI 0.78-1.04; p  = 0.161)., Conclusions: The uptake of antiviral treatment in HCC patients increased over the past decade. NA treatment, regardless of whether it was initiated before or after HCC diagnosis, improved survival. It is never too late to initiate NA treatment, even after HCC diagnosis., Lay Summary: More and more patients who have hepatitis B-related liver cancer received antiviral treatment over the past decade. The timing of starting antiviral treatment, regardless of whether it was before or after liver cancer happens, does not really matter in terms of survival benefits., Competing Interests: VWS Wong has served as an advisory committee member for 3vbio, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, and Terns, and a speaker for Bristol Myers Squibb, Echosens, Gilead Sciences, and Merck. He has also received an unrestricted grant from Gilead Sciences. TCFY has served as an advisory committee member and a speaker for Gilead Sciences. HLYC has served as an advisory committee member for AbbVie, APTORUM, Aligos, Arbutus, Hepion, Intellia, Janssen, Gilead, MedImmune, Merck, Roche, Vir Biotechnology, GRAIL, Vaccitech, and VenatoRx, and as a speaker for Mylan, Gilead, and Roche. GLHW has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, AbbVie, Bristol Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen, and Roche. She received a research grant from Gilead. The other authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Liver resection is one of the main curative options for early hepatocellular carcinoma (HCC) in patients with cirrhosis and is the treatment of choice in non-cirrhotic patients. However, careful patient selection is required to balance the risk of postoperative liver failure and the potential benefit on long-term outcomes. In the last decades, improved surgical techniques and perioperative management, as well as better patient selection, have enabled the indications for liver resection to be expanded. In this review, we aim to describe the main indications for liver resection in the management of HCC, its role compared to percutaneous ablation and liver transplantation in the therapeutic algorithm, as well as the recent advances in liver surgery that could be used to improve the prognosis of patients with HCC., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Authors.)