JHEP Reports最新文献

{"title":"Defining clinically relevant myosteatosis in patients with liver cirrhosis.","authors":"Simone Di Cola, Gennaro D'Amico, Maryam Motamedrad, Aldo J Montano-Loza, Manuela Merli","doi":"10.1016/j.jhepr.2026.102045","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102045","url":null,"abstract":"<p><strong>Background: </strong>Myosteatosis is increasingly recognized as an indicator of high mortality risk in cirrhosis. However, no validated criteria to define this skeletal muscle alteration are currently available for clinical practice. We aimed to validate the recently proposed University of Alberta criteria and to assess their association with mortality.</p><p><strong>Methods: </strong>Individual patient data analysis combining two cirrhosis cohorts from Italy and Canada. Muscle attenuation and skeletal muscle index were assessed on CT scans at the L3 or L3-L4 level using a standardized protocol. Interobserver agreement was evaluated using intraclass correlation coefficients. Since the performance of the University of Alberta criteria in the Italian cohort was unsatisfactory, we used ROC analysis to derive a new attenuation threshold in the Italian cohort and validated it in the Canadian cohort. The association of the new cutoff for myosteatosis and its combination with sarcopenia and 1-year mortality was assessed by a proportional hazards model for competing risks, with liver transplantation as a competing event.</p><p><strong>Results: </strong>A total of 1,296 patients were included, with substantial differences in disease severity and baseline mortality rates between the cohorts. Interobserver agreement for muscle attenuation and skeletal muscle index was excellent (ICC >0.97). ROC analysis in the Italian cohort identified a muscle attenuation threshold of 26 Hounsfield units (HU) as the most discriminant cut-off for mortality risk, independent of sex and BMI. Patients' reclassification according to this threshold showed a sHR of 1.83 (95% CI 1.03-3.24; p=0.038) in the Italian and 1.63 (95%CI 1.25-2.11; p<0.001) in the Canadian cohort. Corresponding figures for myosteatosis combined with sarcopenia were 1.35 (95% CI, 1.07-1.71; p=0.01) and 1.32 (95% CI, 1.20-1.47; p<0.001), respectively.</p><p><strong>Conclusions: </strong>A muscle attenuation cut-off of HU ≤26 allows reproducible detection of myosteatosis in cirrhosis, across populations with different baseline disease severity.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102045"},"PeriodicalIF":8.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149061451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Before We Redraw the Line: Caution on Steatosis-Adjusted cT1 Cut-offs for Predicting Mortality.","authors":"Naim Alkhouri","doi":"10.1016/j.jhepr.2026.102044","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102044","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102044"},"PeriodicalIF":8.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149037773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling Liver Cancer Molecular and Histological Features by CRISPR Editing of Porcine Hepatocytes.","authors":"Lobna Elkhadragy, Olayinka G David, Caitlyn C Castillo, Luke N Redlon, Luke R Jordan, Nusrat I Khan, Hannah Liu, Isadora Andre Rosa Lopes, Yanqiong Zhou, Hiroaki Kanzaki, Yujin Hoshida, Jonathan P Samuelson, Amaia Lujambio, Lawrence B Schook, Grace Guzman, Kyle M Schachtschneider, Ron C Gaba","doi":"10.1016/j.jhepr.2026.102042","DOIUrl":"10.1016/j.jhepr.2026.102042","url":null,"abstract":"<p><strong>Background: </strong>/Aims: Hepatocellular carcinoma (HCC) is an aggressive disease with limited response to available therapies. Progress in therapeutic development has been hampered by the lack of preclinical models that recapitulate human HCC and support evaluation of multimodal therapies. Here, we employ CRISPR editing to identify alterations that drive hepatocyte transformation and to establish genetically defined HCC models.</p><p><strong>Methods: </strong>Hepatocytes were isolated from pigs (n=7) and subjected to combinations of 2-4 gene alterations, including CRISPR-mediated knockout of tumor suppressor genes (TP53, PTEN, CDKN2A, AXIN1), with or without c-Myc overexpression. Resulting cells were injected subcutaneously into immunodeficient mice to assess their tumorigenicity and histological features. To establish a large-animal model, autologous transformed hepatocytes were implanted into four intrahepatic sites (n=5 pigs). Transcriptomic profiling of cells, xenografts, and porcine tumors was conducted by RNA sequencing, using FDR<0.05 for DEG analysis.</p><p><strong>Results: </strong>Eight combinations of gene alterations yielded cells expandable in culture, in contrast to unmodified primary hepatocytes. Cells harboring at least three gene alterations (n=5 lines) formed xenograft tumors (n=22 mice), whereas cells with only two gene knockouts did not (n=5 mice). Xenografts with sgTP53; c-Myc^OE; sgPTEN and/or sgCDKN2A recapitulated histological features of human liver cancer, including clear cell, trabecular, and pseudoglandular HCC and cholangiocarcinoma. Transcriptomic analysis of transformed cells and xenograft tumors revealed activation of cell-cycle pathways and similarity to human HCC profiles. Autologous implantation of transformed hepatocytes generated intrahepatic tumors at 7/8 injection sites (87.5%) in two pigs, providing proof-of-concept for an immune-competent HCC model in wild-type pigs.</p><p><strong>Conclusions: </strong>This study delineates cooperative oncogenic alterations that drive hepatocyte transformation ex vivo and provides cell and animal models that recapitulate key histological and molecular features of human HCC.</p><p><strong>Impact and implications: </strong>HCC has poor response rates to available treatments, underscoring the urgent need for translational preclinical models. Through ex vivo CRISPR editing of clinically relevant genes in porcine hepatocytes, we established cell and animal models that recapitulate key molecular and histological features of human HCC. This platform provides a foundation for future mechanistic studies, genotype-phenotype mapping, and preclinical testing of precision therapies. Moreover, the porcine model's size and physiological similarity to humans make it a promising model for evaluating locoregional therapies and device-based therapies in an immune-competent setting.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102042"},"PeriodicalIF":8.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnitude of Portal Pressure Reduction and Clinical Outcomes in Randomized Trials.","authors":"Matthew Tam, Irene Pascual, Jarell Jie-Rae Tan, Daniel Veldhuijzen van Zanten, Beverley Kok, Shuen Sung, Janice Y Kung, Yu Jun Wong, Juan G Abraldes","doi":"10.1016/j.jhepr.2026.102028","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102028","url":null,"abstract":"<p><strong>Background & aims: </strong>Portal hypertension is a major driver of complications of cirrhosis. Observational studies suggest that reductions in hepatic venous pressure gradient (HVPG) improve prognosis, but the magnitude of risk reduction per unit HVPG decrease has not been quantified across randomized controlled trials (RCTs). We performed a meta-regression of RCTs to quantify this relationship.</p><p><strong>Methods: </strong>We systematically searched for RCTs testing pharmacological interventions against placebo or no treatment in portal hypertension that reported both HVPG measurements and clinical outcomes. The predictor was the between-group difference in HVPG change (treatment minus control, in mmHg). Primary endpoints were all-cause mortality and variceal events, defined hierarchically as variceal progression (when reported) or variceal bleeding. We used random-effects meta-regression, weighted by the inverse variance of the log odds ratio. Sensitivity analyses tested alternative weighting schemes accounting for HVPG measurement error.</p><p><strong>Results: </strong>Twenty-two RCTs (2,871 patients; 1,991 with HVPG measurements) were included. Each 1 mmHg greater HVPG reduction in the treatment versus control group was associated with significantly lower all-cause mortality (OR 0.850, 95% CI 0.771-0.937; p=0.004; I²=0%) and fewer variceal events (OR 0.852, 95% CI 0.744-0.976; p=0.032; I²=18.8%). Results were consistent across outcome-based, joint, and iteratively reweighted meta-regression models. Exploratory non-linear analyses showed no evidence against a linear relationship within the observed range.</p><p><strong>Conclusions: </strong>Each mmHg of HVPG reduction achieved by pharmacological therapy is associated with, at the trial level, approximately 15% lower odds of mortality and variceal events. These findings provide a quantitative framework for interpreting HVPG changes in Phase II trials and informing the design of Phase III studies.</p><p><strong>Impact and implications: </strong>Lowering portal pressure is central to preventing complications of cirrhosis, but the clinical benefit associated with a given treatment-related reduction in hepatic venous pressure gradient has not been quantified across randomized trials. In 22 trials, each additional 1 mmHg reduction was associated at the trial level with approximately 15% lower odds of death and variceal events. This quantitative relationship may help researchers and drug developers interpret phase II hemodynamic results and inform go/no-go decisions and phase III trial design. Because the analysis uses aggregate trial-level data, it does not establish causality or predict benefit for individual patients.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102028"},"PeriodicalIF":8.7,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intradermal hepatitis B vaccination with or without Imiquimod in cirrhosis after prior vaccine nonresponse: A Randomised Trial.","authors":"Vincent Haghnejad, Mélissa Lucas, Nicolas Jacquinot, Hélène Jeulin, Sebastien Daude, Mouni Bensenane-Oussalah, Evelyne Schvoerer, Yohann Bernard, Amandine Luc, Jean-Pierre Bronowicki","doi":"10.1016/j.jhepr.2026.102039","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102039","url":null,"abstract":"<p><strong>Background and aims: </strong>Patients with cirrhosis show impaired immune responses to standard intramuscular (IM) hepatitis B virus (HBV) vaccination, resulting in low seroconversion rates. Intradermal (ID) vaccination and topical imiquimod have been proposed as strategies to enhance vaccine immunogenicity. We conducted a randomized controlled pilot trial to compare three HBV revaccination strategies in patients with advanced chronic liver disease (ACLD) who previously failed standard IM vaccination: IM revaccination, ID revaccination, and ID revaccination combined with imiquimod (ID+IMQ). The primary endpoint was seroconversion at Month 7, defined as anti-HBs titres ≥10 mIU/mL.</p><p><strong>Methods: </strong>This monocentric, prospective study included 59 patients with ACLD and anti-HBs titres <10 mIU/mL after prior HBV vaccination. Patients were randomized (1:1:1) to receive either IM vaccination (n=19; Engerix-B® 20 μg IM at Months 0, 1 and 6), ID vaccination (n=19; two 10 μg ID injections at the same time points), or ID vaccination preceded by topical imiquimod 5% application (n=21).</p><p><strong>Results: </strong>In the intention-to-treat analysis, seroprotection rates at month 7 were 36.8% in the IM group, 84.2% in the ID group, and 66.7% in the ID+IMQ group (p<0.01). After Bonferroni correction, only the ID versus IM comparison remained statistically significant (p=0.003). Geometric mean anti-HBs titres were significantly higher in the ID (116 mIU/mL) and ID+IMQ (107 mIU/mL) groups compared with the IM group (12 mIU/mL) (p=0.004). No severe vaccine-related adverse reactions were observed.</p><p><strong>Conclusions: </strong>Intradermal HBV revaccination significantly improves seroconversion in non-responder patients with ACLD compared with IM vaccination, without additional benefit from imiquimod. These results support further evaluation of intradermal vaccination without imiquimod in a phase 3 trial.</p><p><strong>Clinical trial number: </strong>The study protocol has been registered before the patients' recruitment, in the European Clinical Trials Database (EudraCT) of the European Medicine Agency (2021-000644-22), as well as on ClinicalTrials. gov (NCT05028322).</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102039"},"PeriodicalIF":8.7,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers associated with efficacy of first-line nivolumab vs. sorafenib in advanced hepatocellular carcinoma: results from the CheckMate 459 phase III trial.","authors":"Jaclyn Neely, Jin Yao, Masatoshi Kudo, Richard S Finn, Bruno Sangro, Ignacio Melero, Anthony B El-Khoueiry, Thomas Yau, James J Harding, Olivier Rosmorduc, Marina Tschaika, Ruslan Novosiadly, Amanda Cruz, Robin Kate Kelley","doi":"10.1016/j.jhepr.2026.102038","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102038","url":null,"abstract":"<p><strong>Background & aims: </strong>First-line nivolumab demonstrated a higher objective response rate (ORR) and favorable safety profile vs. sorafenib in advanced HCC in the phase 3 CheckMate 459 trial; however, no significant improvement in overall survival (OS) was observed. Here, we report exploratory biomarker analyses from CheckMate 459.</p><p><strong>Methods: </strong>Archival or fresh tumor samples were collected before treatment and subjected to whole-exome sequencing, whole-transcriptome RNA sequencing, immunohistochemistry, and serological testing. Biomarkers were examined for association with clinical outcomes (ORR by blinded independent central review [BICR] per RECIST v1.1, progression-free survival [PFS] by BICR, and OS).</p><p><strong>Results: </strong>The minimum follow-up was 33.6 months. In the nivolumab arm, 201, 230, 343, and ≥ 293 patients were evaluable by whole-exome sequencing, RNA sequencing, immunohistochemistry, and serology; 199, 239, 334, and ≥ 279 patients were evaluable in the sorafenib arm, respectively. Baseline tumor mutational burden was not predictive of survival with nivolumab. OS outcomes with sorafenib were improved in patients with mutated vs. wild-type Wnt/β-catenin pathway; consequently, OS was improved with nivolumab vs. sorafenib in patients with unaltered Wnt/β-catenin pathway (HR 0.66; 95% CI 0.47-0.91). High T-cell inflammation gene signature score and tumors with high programmed death ligand 1 levels (combined positive score ≥10) had improved OS with nivolumab vs. sorafenib (HR 0.68; 95% CI 0.47-0.98 and HR 0.55; 95% CI 0.33-0.93, respectively); PFS and ORR were also improved. Among circulating blood biomarkers, high interferon-γ, low pro-collagen 11, and low frequency of granulocytic myeloid-derived suppressor cells were associated with improved nivolumab efficacy vs. sorafenib.</p><p><strong>Conclusions: </strong>These exploratory analyses from CheckMate 459 identified several candidate biomarkers that may be associated with efficacy of first-line nivolumab vs. sorafenib and support further studies to identify patients with advanced HCC who may benefit from programmed death-1 inhibition.</p><p><strong>Impact and implications: </strong>Nivolumab demonstrated a higher objective response rate and favorable safety profile as first-line treatment compared with sorafenib for patients with advanced HCC in the CheckMate 459 trial, yet did not show a significant improvement in overall survival. The exploratory analyses presented here have identified several candidate biomarkers that may be associated with efficacy of nivolumab in the first-line setting vs. sorafenib. These findings support additional studies to identify patients who may benefit from programmed death-1 inhibition treatment.</p><p><strong>Clinical trial number: </strong>NCT02576509.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102038"},"PeriodicalIF":8.7,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aligned ELF and VCTE cutoffs facilitate risk staging in patients with metabolic dysfunction-associated steatohepatitis.","authors":"Matthew F W Gee, Andrew N Billin, Donald B Chalfin, Rachel Fonstad, Edward B De Vol, Jordan J Feld, Keyur Patel, Arun J Sanyal","doi":"10.1016/j.jhepr.2026.102041","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102041","url":null,"abstract":"<p><strong>Background and aims: </strong>Clinical practice guidance for non-invasive test (NIT)-based management of metabolic dysfunction-associated steatohepatitis (MASH) includes the Enhanced Liver Fibrosis (ELF) Test and vibration-controlled transient elastography (VCTE). However, recommended thresholds were derived independently and not calibrated to yield equivalent liver-related event (LRE) risk across tests. We aimed to identify ELF and VCTE cutoffs that are aligned prognostically and to evaluate whether agreement-based combinations at aligned thresholds improve near-term risk stratification.</p><p><strong>Methods: </strong>Individual-level data were pooled from patients across placebo-controlled trials of MASH and advanced fibrosis. Baseline ELF and VCTE were evaluated in relation to subsequent LREs and histological change at 1 year. Prognostic alignment was performed by identifying VCTE thresholds with observed LRE risks corresponding to pre-specified ELF cutoffs. Prognostic performance of single tests and ELF/VCTE combinations was assessed using event risk, likelihood ratios, Kaplan-Meier analysis, and discrimination metrics (C-index and ROC/AUC).</p><p><strong>Results: </strong>Risk-aligned pairings supported ELF 9.80/VCTE 12.0 kPa, ELF 10.50/VCTE 20.0 kPa and ELF 11.30/VCTE 30.0 kPa. Agreement-based ELF/VCTE stratification improved discrimination versus VCTE alone (AUROC 0.779 vs 0.705; p=0.0129). At ELF 11.30/VCTE 30.0 kPa, LRE risk increased across negative concordance, discordance, and positive concordance strata (1.3%, 5.4%, and 21.6%, respectively). For prediction of histological change using ELF 9.80/VCTE 12.0 kPa, F3-to-F4 progression rates were 2.2%, 14.4%, and 25.5%, and F4 regression rates were 56.9%, 27.3%, and 12.2% across negative concordance, discordance, and positive concordance strata, respectively.</p><p><strong>Conclusions: </strong>ELF and VCTE thresholds can be aligned for comparable prognostic risk staging in advanced MASH. Agreement-based combinations of ELF and VCTE at aligned thresholds may help refine prediction of near-term liver-related events and histological change, supporting clinical risk assessment and informing MASH clinical trial enrichment strategies.</p><p><strong>Impact and implications: </strong>Current MASH care pathways increasingly rely on non-invasive tests, yet recommended ELF and VCTE thresholds have largely been established independently. We found that ELF and VCTE thresholds can be aligned according to comparable risk and that concordant and discordant test results provide clinically meaningful stratification of both liver-related outcomes and likelihood of histological progression and regression. These findings may help support more consistent risk assessment and patient stratification across clinical practice and research settings.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102041"},"PeriodicalIF":8.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body Roundness Index, MASLD risk and long-term follow-up outcomes among the general population.","authors":"Huai Zhang, Li-You Lian, Axing Lv, Tianyi Xia, Meili Jiang, Dianjianyi Sun, Canqing Yu, Ling Yang, Yiping Chen, Huaidong Du, Xiao-Dong Zhou, Giovanni Targher, Christopher D Byrne, Zhengming Chen, Jun Lv, Liming Li, Shenghong Ju, Yuanjie Pang, Ming-Hua Zheng","doi":"10.1016/j.jhepr.2026.102026","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102026","url":null,"abstract":"<p><strong>Background & aims: </strong>This study aimed to examine the associations of the body roundness index (BRI) with metabolic dysfunction-associated steatotic liver disease (MASLD), and long-term mortality outcomes, given that the body mass index (BMI) does not adequately reflect visceral adiposity.</p><p><strong>Methods: </strong>Three large-scale, population-based cohorts in China (CKB, n=24,910), the United States (NHANES, n=19,889), and Europe (UKB, n=383,504) were included in this study. The primary outcomes were MASLD prevalence and all-cause mortality. Logistic regression, restricted cubic spline (RCS), and Weibull regression models were used to quantify associations of BRI with MASLD and subsequent mortality over a 10-year follow-up, with BMI as the comparator.</p><p><strong>Results: </strong>There was an S-shaped association between BRI and MASLD prevalence (all P<0.001). An increased risk of MASLD was observed with higher BRI (for BRI Q5, adjusted odds ratio [OR] >5.68, P<0.001), even among individuals with normal BMI and moderate waist circumference. Low BRI with high BMI did not increase the risk of MASLD, whereas the combination of high BRI and high BMI substantially elevated the risk. There was a U-shaped association between BRI and all-cause mortality in MASLD. Weibull regression analysis further indicated that both excessively low and high BRI shortened survival time, with time ratios (TR) indicating reductions ranging from 14% to 58%.</p><p><strong>Conclusions: </strong>Higher body roundness index (BRI) was associated with increased MASLD risk, even in normal-weight individuals with moderate waist circumference; low BRI and high BMI did not increase MASLD risk, whereas high BRI and high BMI markedly increased it. Among individuals with MASLD, both excessively low and high BRI values were associated with increased all-cause mortality.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102026"},"PeriodicalIF":8.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal barrier dysfunction assessed by confocal laser endomicroscopy correlates with cirrhosis severity and clinical outcome^☆.","authors":"Benedikt Simbrunner, Marcel Sorribas, Jessica Schaerer, Marco Felber, Jordi Codinach, Susana Gomes Rodrigues, Mattias Mandorfer, Annalisa Berzigotti, Michael Trauner, Thomas Reiberger, Johann Hammer, Reiner Wiest","doi":"10.1016/j.jhepr.2026.102037","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102037","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Intestinal barrier dysfunction drives complications in advanced chronic liver disease (ACLD). Confocal laser endomicroscopy (CLE) enables direct visualization of transepithelial fluorescein leakage during endoscopy. This study evaluated the link between CLE-assessed intestinal permeability and disease severity in ACLD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;CLE was performed in two independent cohorts after intravenous fluorescein administration in the small intestine: (1) Bern cohort (n=4 healthy controls, n=16 ACLD) and (2) Vienna cohort (n=48 ACLD). Image analysis included established CLE scores, and novel quantitative assessments measuring fluorescence intensity in three compartments (\"3-compartment-method\"; lumen-epithelium-lamina propria) and along the epithelium (\"3-line-method\"; base-middle-apex). CLE-derived metrics were correlated with disease stage and biomarkers. In the Vienna cohort, correlation with portal hypertension (HVPG) and liver-related events (LRE: decompensation, ACLF, death) was assessed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Transepithelial fluorescein permeation into the gut lumen was absent in healthy controls but frequent in ACLD, and increased with disease severity (Vienna cohort: compensated vs. first decompensation vs. further decompensation: 24%, 57%, and 71%, p=0.019). The 3-line and 3-compartment methods robustly distinguished healthy controls from cirrhosis (3-line apex/base ratio: 0.42 ±0.12 vs. ACLD 0.83 ±0.18, p=0.001), and exhibited lowest inter-observer variability. In both cohorts, quantitative permeability measures - especially epithelial 3-line apex/base ratio and 3-line-slopes (all p&lt;0.05) - increased across Child-Turcotte-Pugh stages, and correlated with HVPG (apex/base-ratio: r=0.575, p&lt;0.001) and liver function parameters (e.g. albumin: r= -0.553, p&lt;0.001). CLE-based barrier dysfunction was linked to higher LRE incidence during follow-up (Cox regression; apex/base ratio: HR 10.6, 95% CI 1.71-66.0, p=0.011).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;CLE identifies high prevalence of intestinal permeability in ACLD, correlating with disease stage and adverse outcomes. The novel 3-line epithelial analysis demonstrated strong associations with portal hypertension and biomarkers reflecting ACLD severity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Intestinal barrier dysfunction is a key driver of complications in advanced chronic liver disease. Using confocal laser endomicroscopy (CLE) during endoscopy, the present study shows that transepithelial fluorescein leakage can be visualized and quantified, and aligns with cirrhosis stage, portal hypertension, and liver-related outcomes. These findings are relevant for hepatologists and translational researchers, as this technique might be used to identify patients with intestinal barrier dysfunction. Because the present analyses are exploratory and derive from two cohorts with limited sample size and requirement for manual image analysis,","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102037"},"PeriodicalIF":8.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel 3D models for β-catenin-driven liver cancers.","authors":"Vanessa Bou Malham, Fanny Léandre, Akila Hamimi, Isabelle Lagoutte, Sandrine Bouchet, Alexandre Archambault-Marsan, Jérémy Augustin, Angélique Gougelet, Sabine Colnot, Christèle Desbois-Mouthon","doi":"10.1016/j.jhepr.2026.102040","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102040","url":null,"abstract":"<p><strong>Background & aims: </strong>Constitutive activation of β-catenin is a key feature in the pathogenesis of HCC and hepatoblastoma (HB). Activating alterations in the CTNNB1 gene and, to a lesser extent, inactivating alterations in the APC gene are observed in 30-40% of HCC cases and 80-90% of HB cases. For both tumours, therapeutic management remains suboptimal. Therefore, relevant experimental models are needed to improve our understanding and to test new therapeutic approaches.</p><p><strong>Methods: </strong>Liver organoids (n=17 mice) and tumouroids (n=14 mice) were established from APC^Δhep and βcat^Δex3 mouse models, which are clinically relevant models for β-catenin-activated HCC and mesenchymal HB. We developed a new methodological approach based on dynamic suspension culture in a rotating bioreactor. Morphological and molecular characteristics, as well as drug responses were evaluated by histology, immunohistochemistry, immunofluorescence, transcriptomics and RT-qPCR.</p><p><strong>Results: </strong>This easy-to-implement methodology allows for the rapid production of large numbers of uniform organoids and tumouroids (30-75 per tumour) with no detectable cell death and hypoxia in their core. The robustness of the approach is also illustrated by the preservation of histological architecture, cell diversity (tumour cells, macrophages, endothelial cells) and gene expression in organoids and tumouroids compared with native liver tissue. Gene set enrichment analysis showed significant enrichment of 10 human HCC/HB tumour signatures in murine tumouroids. Organoids and tumouroids showed expected responsiveness to specific inhibitors, including the β-catenin antagonist WNTinib.</p><p><strong>Conclusions: </strong>These organoids and tumouroids represent robust in vitro models of β-catenin-driven HCC and mesenchymal HB. They provide a scalable platform for drug screening and may support the development of \"à la carte\" therapies urgently needed for these indications. Impact and implications; This study addresses the need for representative in vitro models to investigate β-catenin-driven liver cancers. The tumouroids developed here provide robust and reproducible 3D models that closely recapitulate the histological features, cellular diversity, and gene expression profiles of native liver tumours. These models offer a valuable platform for studying tumour biology, evaluating therapeutic candidates, and supporting the development of personalized treatment strategies. They may also contribute to reducing the use of animals in preclinical research.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102040"},"PeriodicalIF":8.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}