Background & AimsAdvanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) carries an extremely poor prognosis, necessitating novel therapeutic strategies. This phase Ib trial evaluated the safety and preliminary efficacy of combining carbon-ion radiotherapy (C-ion RT) with immune checkpoint inhibitors (ICIs) in patients with advanced HCC with MVI.MethodsFifteen patients with MVI-positive advanced HCC were enrolled (Cohort A: durvalumab monotherapy, n = 3; Cohort B: durvalumab plus tremelimumab, n = 12). C-ion RT (60 Gy, four fractions) was delivered to the MVI-containing primary tumor, while systemic therapy with durvalumab (+tremelimumab) was administered concurrently. The primary endpoints included dose-limiting toxicities and adverse events. Secondary endpoints included progression-free survival and overall survival.ResultsNo dose-limiting toxicities were observed, and the combination exhibited a manageable safety profile. The most common adverse events were pyrexia, rash, and elevated lipase levels. Grade 3–4 adverse events occurred in 53.3%, including cytokine release syndrome and meningitis. Median progression-free survival and overall survival were 4.7 and 10.4 months, respectively. Although C-ion RT achieved effective local control of irradiated lesions, non-irradiated lesions showed limited systemic immune responses.ConclusionsThe combination of MVI-targeted C-ion RT and immune checkpoint inhibitors demonstrated safe and effective local tumor control in advanced HCC. This novel approach of selective irradiation to MVI-containing tumors, combined with systemic immunotherapy, warrants further investigation to optimize the synergistic effects and enhance systemic efficacy in this poor-prognosis group.Impact and implicationsAdvanced hepatocellular carcinoma with macrovascular invasion (MVI) has a poor prognosis, highlighting the need for new therapeutic strategies. Our phase Ib study suggests that carbon-ion radiotherapy targeting MVI combined with immune checkpoint inhibitors is feasible and achieves sustained local tumor control. RNA-sequencing revealed that immune activation pathways were enriched in responders, while resistance was associated with mesenchymal and angiogenesis signatures. These results reinforce the potential of MVI-targeted irradiation combined with immune checkpoint inhibitors as a promising treatment strategy for these high-risk patients, warranting further investigation to improve systemic tumor control.Clinical Trials RegistrationjRCT2031210046.

<h2>Abstract</h2> Steatotic liver disease (SLD) is a spectrum of highly prevalent liver disease that is encountered at many different healthcare levels. Awareness about metabolic dysfunction-associated SLD (MASLD), MetALD (MASLD and increased alcohol intake) and ALD (alcohol-related liver disease) is increasing beyond hepatology, as highlighted by the various SLD guidelines that have been issued by scientific societies from different disciplines, such as endocrinology. The guidance presented here aims to improve cross-disciplinary knowledge and know-how by providing guidance to healthcare professionals from a global, holistic, multi-society and -stakeholder perspective. The patient trajectory was used as an overarching anchor point to ensure uniform guidance at all points along the SLD spectrum, with the ultimate goal of improving patient identification and optimising their care. This consensus guidance covers patient identification and risk stratification, relevant cross-disciplinary primary and secondary care approaches, referral to and from tertiary care and strategies for disease management and monitoring. Strategies at each point of the patient trajectory are recommended and stratified as optimal (i.e., "nice-to-have") or minimal (i.e., "must-have"), per expert-opinion, making them adaptable to differences in healthcare settings, levels of resource availability and policies.

Background & AimsMetabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by profound remodeling of hepatic macrophages, including the emergence of lipid-associated macrophages (LAMs). However, the mechanisms through which LAMs promote fibrosis and their key molecular drivers remain elusive.MethodsMacrophage-specific CD36 knockdown was achieved using AAV8-delivered short hairpin (sh)RNA. A suite of experimental systems, including co-culture models, lipid trafficking assays, chromatin immunoprecipitation sequencing (ChIP)-qPCR, and lipidomics, was used to dissect the cluster of differentiation (CD)36–peroxisome proliferator-activated receptor (PPAR)γ–SPP1 axis. Genetic and pharmacological tools were used for mechanistic and therapeutic studies. Clinical relevance was assessed in well-characterized patient cohorts.ResultsWe identified a unique CD36+ macrophage subpopulation that aligns with LAMs and expands markedly in human and murine MASLD livers, strongly correlating with fibrosis severity. Macrophage-specific CD36 deletion attenuated steatosis, transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] reduced by >30%, p <0.01) and fibrosis (reduction in fibrosis area by 30–45%, p <0.01) in two MASH mouse models. Mechanistically, CD36 mediated lipid transfer from steatotic hepatocytes to LAMs. Lipid loading activated PPARγ, triggering its nuclear translocation and direct binding to the SPP1 promoter, stimulating SPP1 secretion. In turn, SPP1 activated hepatic stellate cells. Clinically, the CD36–PPARγ–SPP1 gene signature was independently associated with both fibrosis stage (p = 0.009) and steatosis grade (p = 0.03) in patients (N = 48). Importantly, pharmacological inhibition of CD36 suppressed lipid uptake and SPP1 release, attenuating fibrogenesis, whereas combination therapy with a PPARγ agonist yielded synergistic antisteatotic and antifibrotic effects.ConclusionsOur study identifies the CD36–PPARγ–SPP1 axis as a core mechanism whereby lipid-loaded macrophages drive liver fibrosis in MASLD. Thus, therapeutic cotargeting of CD36 and PPARγ presents a novel and promising strategy to counteract fibrosis progression in advanced disease.Impact and implicationsOur study provides an investigation of the features and signals of lipid-associated macrophages (LAMs) that are present in MASLD liver and express a specific protein called CD36. We found that these cells internalize hepatocyte-derived lipids via CD36 and activate the PPARγ–SPP1 axis, contributing to liver fibrosis. More importantly, targeting CD36 effectively improves serum aminotransferases, liver steatosis, and liver fibrosis. Understanding the novel signal in LAMs and discovering the diverse roles of PPARγ in different cell populations could be therapeutically targeted to treat MASLD-related liver fibrosis.

[This corrects the article DOI: 10.1016/j.jhepr.2025.101516.].

Background & AimsThe transcriptomic classification of intrahepatic cholangiocarcinoma (iCCA) has recently been refined from two to five classes, each associated with pathological features, targetable genetic alterations, and survival outcomes. Despite its potential prognostic and therapeutic value, the transcriptomic classification is not routinely used in practice because of technical limitations, including insufficient tissue material and the high cost of molecular analyses. Here, we assessed a self-supervised learning (SSL) model for predicting iCCA transcriptomic classes on digitised whole-slide images (WSIs)MethodsTranscriptomic classes defined from RNA sequencing data were available for all samples. The SSL method (Giga-SSL) was used to train our model on a discovery set of 766 WSIs from 137 biopsies and 109 surgical specimens obtained from 246 patients, using a five-fold cross-validation scheme. The model was validated in The Cancer Genome Atlas (TCGA) cohort (n = 29) and a French external validation set (n = 32), both using WSIs from surgical samples.ResultsThe most frequent transcriptomic class was the hepatic stem-like class (37% [90/246] in the discovery set). Our model showed good to very good performance in predicting the four most frequent transcriptomic classes in the discovery set (AUC 0.63-0.84), especially for the hepatic stem-like class (AUC 0.84). The model performed equally well in predicting these transcriptomic classes in the two validation sets, with AUCs ranging from 0.76 to 0.80 in the TCGA set and 0.62 to 0.92 in the French external set.ConclusionsWe developed and validated an SSL-based model capable of predicting iCCA transcriptomic classes from routine histological slides of both biopsy and surgical samples. This approach may facilitate the clinical implementation of transcriptomic classification, improve prognostic assessment, and guide therapeutic decision-making in iCCA.Impact and implicationsPredicting transcriptomic classes directly from routine histological slides has the potential to enhance the clinical management of intrahepatic cholangiocarcinoma, enabling more accurate prognostication and supporting therapeutic decision-making. By eliminating the need for manual slide annotation, large tissue samples, or resource-intensive molecular analyses, our self-supervised learning-based model offers a practical and scalable solution that can be applied to both biopsy and surgical specimens. This approach could accelerate the adoption of transcriptomic classification in everyday practice and help guide more personalized treatment strategies for patients with intrahepatic cholangiocarcinoma.

Background & AimsHBsAg loss improves clinical outcomes in persons with HIV and HBV coinfection. We aimed to evaluate if hepatitis B core-related antigen and circulating HBV RNA levels were associated with HBsAg loss in Euro-B, a multi-cohort collaboration including data from the Swiss HIV Cohort Study, EuroSIDA, and the French HIV/HBV cohort.MethodsWe included persons with HIV, a positive HBsAg, and ≥6 months of follow-up on tenofovir-containing antiretroviral therapy. We evaluated quantitative HBsAg, HBV DNA, hepatitis B core-related antigen, and HBV RNA levels over time and assessed HBsAg loss (i.e. quantitative HBsAg <0.05 IU/ml) during tenofovir therapy.ResultsAmong 599 participants median age was 41 years (IQR 35–47), 18.4% were female and 47.3% HBeAg-positive. We observed HBsAg loss in 12.9% of participants after 2 years and in 18.2% during a median follow-up of 8.2 years (IQR 3.6–13.1). Individuals who were HBeAg-negative were more likely to have a negative hepatitis B core-related antigen and HBV RNA below the detection limit than participants who were HBeAg-positive. Quantitative HBsAg ≤1,000 IU/ml at baseline was the strongest predictor of HBsAg loss regardless of HBeAg status. Additionally, HBsAg loss was associated with lower baseline HBV RNA levels (odds ratio 0.66, 95% CI 0.49–0.88) and higher baseline HBV DNA levels in participants who were HBeAg-positive.ConclusionsIn this European cohort of persons with HIV/HBV, 18% experienced HBsAg loss during tenofovir-containing antiretroviral therapy. In addition to low baseline quantitative HBsAg levels, HBV RNA may predict HBsAg loss in individuals who are HBeAg-positive.Impact and implicationsThe present study builds on a multi-cohort collaboration including persons with HIV/HBV from Europe. It provides estimates on the probability of HBsAg loss during long-term tenofovir-containing antiretroviral therapy and describes the potential of the novel biomarkers HBV RNA and hepatitis B core-related antigen as its predictors. The discrepancies regarding HBV RNA and HBcrAg levels before and during therapy observed between persons who were HBeAg-negative and HBeAg-positive with HIV/HBV may influence treatment decisions and the development of new treatment strategies.Clinical Trials RegistrationThe study is registered at ClinicalTrials.gov (NCT04984772).

Backgrounds & AimsOvert hepatic encephalopathy (OHE) is the most feared complication after transjugular intrahepatic portosystemic shunt (TIPS) placement. We aimed to evaluate the usefulness of the animal naming test (ANT) in predicting the occurrence of OHE after elective TIPS placement.MethodsThe ANT (1 min) was evaluated before TIPS, at discharge, and at 1, 3, and 6 months in all patients treated with elective TIPS between September 2019 and November 2024.ResultsWe included 100 consecutive patients (80% men; median age 59 years; median MELD score 11). Indications for TIPS were ascites, secondary prophylaxis, hydrothorax, and pre-surgery in 63%, 19%, 5%, 13%, respectively; 24% had a history of OHE. The median ANT before TIPS was 21 (IQR 17–27). The cumulative incidence of OHE was 30%, considering death and liver transplantation as competing events. In multivariate analysis, independent predictors of OHE development were age (hazard ratio [HR] 1.04; 95% CI 1.00-1.09; p = 0.02), pre-TIPS ammonia level (HR 1.01; 95% CI 1.00-1.03; p = 0.02), ammonia level at discharge (HR 1.01; 95% CI 1.01-1.03; p = 0.04), and ANT at discharge (HR 0.89; 95% CI 0.81-0.97; p = 0.005), but not ANT before TIPS. After discharge, the predictive value of ANT was stable for the diagnosis of subsequent OHE.ConclusionANT at discharge may be useful in identifying patients at higher risk of OHE after TIPS.Impact and implicationsOvert hepatic encephalopathy (OHE) remains a major limitation of transjugular intrahepatic portosystemic shunt (TIPS) placement. While the animal naming test (ANT) before TIPS could not accurately predict the development of OHE, both ANT and ammonia after TIPS were predictive of OHE. Each decrease of ANT of 1 point was associated with an increased risk of OHE of 8%. Incorporating this test into routine post-procedural assessment could improve early identification of high-risk patients, guide preventive strategies, and optimize follow-up.