BACKGROUND AIMSNab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) had promising efficacy in phase II trials for advanced biliary tract cancer (BTC) but failed to demonstrate superiority in phase III. We investigated Gem/Cis/nab-P efficacy and identified molecular subgroups with clinical benefit.APPROACH RESULTSThis prospective observational cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received Gem/Cis/nab-P from July 2021 to December 2022. Of these, 108 were included in genomic and transcriptomic analyses of pretreatment tumor samples that met quality control criteria. Among 119 patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% extrahepatic cholangiocarcinoma, and 23.5% gallbladder cancer. Most patients had metastatic disease (68.9%). At a median follow-up of 23.7 months, the median progression-free survival was 8.3 months and median overall survival 19.8 months. Grade ≥3 treatment-related adverse events occurred in 70 patients (58.8%), and dose reduction was required in 99.2%. Frequent genetic alterations were TP53 (53.7%), KRAS (29.6%), and CDKN2A (20.4%), with TP53 mutations being significantly associated with worse outcomes. Transcriptomic analysis identified four molecular subtypes: cholangiocyte-like, stromal, metabolic, and inflammatory-proliferative. The cholangiocyte-like subtype, marked by increased cholangiocyte markers, had the most favorable prognosis. Stromal and metabolic subtypes showed moderate outcomes, characterized by a fibroblast-rich stroma with activated angiogenesis and enriched metabolic pathways, respectively. The inflammatory-proliferative subtype had the worst prognosis, with cell cycle and inflammatory activation, and an exhausted immune microenvironment.CONCLUSIONSThis study demonstrated the clinical activity of Gem/Cis/nab-P in advanced BTC and highlighted that biology-driven patient stratification based on genomic and transcriptomic features may provide important prognostic information.
{"title":"Biology-driven stratification of advanced biliary tract cancer treated with nab-paclitaxel plus gemcitabine-cisplatin: A prospective observational cohort study.","authors":"Seonjeong Woo,Beodeul Kang,Sung Hwan Lee,Jung Sun Kim,Haeyoun Kang,Seok Jeong Yang,Chansik An,Gwangil Kim,Gae Hoon Jo,Chang-Il Kwon,Min Je Sung,Suk Pyo Shin,Sanghoon Jung,Sohyun Hwang,Chan Kim,Hong Jae Chon","doi":"10.1097/hep.0000000000001650","DOIUrl":"https://doi.org/10.1097/hep.0000000000001650","url":null,"abstract":"BACKGROUND AIMSNab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) had promising efficacy in phase II trials for advanced biliary tract cancer (BTC) but failed to demonstrate superiority in phase III. We investigated Gem/Cis/nab-P efficacy and identified molecular subgroups with clinical benefit.APPROACH RESULTSThis prospective observational cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received Gem/Cis/nab-P from July 2021 to December 2022. Of these, 108 were included in genomic and transcriptomic analyses of pretreatment tumor samples that met quality control criteria. Among 119 patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% extrahepatic cholangiocarcinoma, and 23.5% gallbladder cancer. Most patients had metastatic disease (68.9%). At a median follow-up of 23.7 months, the median progression-free survival was 8.3 months and median overall survival 19.8 months. Grade ≥3 treatment-related adverse events occurred in 70 patients (58.8%), and dose reduction was required in 99.2%. Frequent genetic alterations were TP53 (53.7%), KRAS (29.6%), and CDKN2A (20.4%), with TP53 mutations being significantly associated with worse outcomes. Transcriptomic analysis identified four molecular subtypes: cholangiocyte-like, stromal, metabolic, and inflammatory-proliferative. The cholangiocyte-like subtype, marked by increased cholangiocyte markers, had the most favorable prognosis. Stromal and metabolic subtypes showed moderate outcomes, characterized by a fibroblast-rich stroma with activated angiogenesis and enriched metabolic pathways, respectively. The inflammatory-proliferative subtype had the worst prognosis, with cell cycle and inflammatory activation, and an exhausted immune microenvironment.CONCLUSIONSThis study demonstrated the clinical activity of Gem/Cis/nab-P in advanced BTC and highlighted that biology-driven patient stratification based on genomic and transcriptomic features may provide important prognostic information.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"361 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785843","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}
Pub Date : 2025-12-19DOI: 10.1097/hep.0000000000001654
Harmeet Malhi,Gregory J Gores
{"title":"Discontinuing Letters to the Editor: Loss of utility and pertinence.","authors":"Harmeet Malhi,Gregory J Gores","doi":"10.1097/hep.0000000000001654","DOIUrl":"https://doi.org/10.1097/hep.0000000000001654","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"13 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786204","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}
Pub Date : 2025-12-17DOI: 10.1097/hep.0000000000001653
Madhumita Premkumar, Kamal Kajal
{"title":"Reply to ‘Nuances in POCUS-guided hemodynamic assessment in cirrhosis’","authors":"Madhumita Premkumar, Kamal Kajal","doi":"10.1097/hep.0000000000001653","DOIUrl":"https://doi.org/10.1097/hep.0000000000001653","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"152 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765246","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}
Pub Date : 2025-12-17DOI: 10.1097/hep.0000000000001652
Madalina-Gabriela Indre, Federico Ravaioli
{"title":"Response to: Beyond semantics—acknowledging diagnostic differences between NAFLD and MASLD","authors":"Madalina-Gabriela Indre, Federico Ravaioli","doi":"10.1097/hep.0000000000001652","DOIUrl":"https://doi.org/10.1097/hep.0000000000001652","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"17 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765242","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}
Pub Date : 2025-12-17DOI: 10.1097/hep.0000000000001651
Magnus Holmer, Michael Ingre, Martti Färkkilä, Cyriel Ponsioen, Bregje Mol, Christoph Schramm, Trine Folseraas, Kristine Wiencke, Nora Cazzagon, Elisa Catanzaro, Antonio Molinaro, Emma Nilsson, Johan Vessby, Stergios Kechagias, Nils Nyhlin, Mårten Werner, Annika Bergquist
{"title":"Reply: Competing risk and surveillance thresholds for HCC in Patients with PSC","authors":"Magnus Holmer, Michael Ingre, Martti Färkkilä, Cyriel Ponsioen, Bregje Mol, Christoph Schramm, Trine Folseraas, Kristine Wiencke, Nora Cazzagon, Elisa Catanzaro, Antonio Molinaro, Emma Nilsson, Johan Vessby, Stergios Kechagias, Nils Nyhlin, Mårten Werner, Annika Bergquist","doi":"10.1097/hep.0000000000001651","DOIUrl":"https://doi.org/10.1097/hep.0000000000001651","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"153 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765244","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}
Pub Date : 2025-12-17DOI: 10.1097/hep.0000000000001649
Giovani Schulte Farina, Jonathan Soldera
{"title":"Letter to the Editor: Beyond Semantics—Acknowledging diagnostic differences between NAFLD and MASLD","authors":"Giovani Schulte Farina, Jonathan Soldera","doi":"10.1097/hep.0000000000001649","DOIUrl":"https://doi.org/10.1097/hep.0000000000001649","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"5 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765245","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}
Pub Date : 2025-12-17DOI: 10.1097/hep.0000000000001648
Abhilash Koratala, Eduardo R. Argaiz
{"title":"Nuances in POCUS-guided hemodynamic assessment in cirrhosis","authors":"Abhilash Koratala, Eduardo R. Argaiz","doi":"10.1097/hep.0000000000001648","DOIUrl":"https://doi.org/10.1097/hep.0000000000001648","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"93 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765249","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}
Pub Date : 2025-12-17DOI: 10.1097/hep.0000000000001647
Weiwei Wang, Lingling Wu, Kun Zhao, Anquan Shang
{"title":"Letter to the Editor: Competing risk and surveillance thresholds for HCC in patients with PSC","authors":"Weiwei Wang, Lingling Wu, Kun Zhao, Anquan Shang","doi":"10.1097/hep.0000000000001647","DOIUrl":"https://doi.org/10.1097/hep.0000000000001647","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"1 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765247","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}
Pub Date : 2025-12-17DOI: 10.1097/hep.0000000000001644
Lorna Dove, Ryan M. Chadha, Jennifer C. Lai, Andrea DiMartini, Annmarie Liapakis, Neehar Parikh, Roberto Firpi-Morell, Lanla Conteh, Michael Fallon, James Trotter, Daniela Ladner, Gonzalo Sapisochin, Michael Lucey
Background and Aims: Liver transplant is a specialized treatment for a spectrum of indications that use a scarce resource. Transplant is guided by principles of justice, equity and benefit with a constant conflict between competing interests. Organs are a national resource with a goal of equitable distribution across sites. An AASLD guideline for the evaluation and selection of appropriate transplant candidates has been available since 2005. Methods: A multidisciplinary writing group of liver transplant experts and a librarian convened over 24 months. The writing group reviewed the literature, generated guideline recommendations and rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine. The group categorized the strength of recommendations based on the level of evidence, risk–benefit ratio, and patient preferences. Conclusions: Liver transplant is a lifesaving procedure that should be offered to selected patients with clear indications and a reasonable prospect of benefit. The evaluation is designed to identify those in need, to outline hurdles to a successful outcome, and to develop an effective transplant plan. The goal of this document is to provide a template for this process.
{"title":"AASLD AST Practice Guideline on adult liver transplantation: Candidate evaluation","authors":"Lorna Dove, Ryan M. Chadha, Jennifer C. Lai, Andrea DiMartini, Annmarie Liapakis, Neehar Parikh, Roberto Firpi-Morell, Lanla Conteh, Michael Fallon, James Trotter, Daniela Ladner, Gonzalo Sapisochin, Michael Lucey","doi":"10.1097/hep.0000000000001644","DOIUrl":"https://doi.org/10.1097/hep.0000000000001644","url":null,"abstract":"Background and Aims: Liver transplant is a specialized treatment for a spectrum of indications that use a scarce resource. Transplant is guided by principles of justice, equity and benefit with a constant conflict between competing interests. Organs are a national resource with a goal of equitable distribution across sites. An AASLD guideline for the evaluation and selection of appropriate transplant candidates has been available since 2005. Methods: A multidisciplinary writing group of liver transplant experts and a librarian convened over 24 months. The writing group reviewed the literature, generated guideline recommendations and rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine. The group categorized the strength of recommendations based on the level of evidence, risk–benefit ratio, and patient preferences. Conclusions: Liver transplant is a lifesaving procedure that should be offered to selected patients with clear indications and a reasonable prospect of benefit. The evaluation is designed to identify those in need, to outline hurdles to a successful outcome, and to develop an effective transplant plan. The goal of this document is to provide a template for this process.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"166 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765250","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}
BACKGROUND AIMSHepatic fibrosis presents a major global health challenge, yet effective preventive and therapeutic strategies remain limited. Hepatic macrophages, which play a dual role in fibrosis progression, are central to understanding its pathogenesis. This study aimed to elucidate how macrophage lipid metabolism mediated by CD36 regulates immune function and fibrosis development.APPROACH RESULTSWe demonstrated that macrophages engulf lipids secreted by hepatic stellate cells (HSCs) via the CD36 receptor, resulting in enhanced lipid peroxidation, ferroptosis, and diminished antigen-presenting capacity, thereby impairing CD8⁺ T cell function. Conversely, CD36 deficiency restored antigen presentation through activation of the cGAS-STING pathway. Single-cell RNA sequencing further revealed that loss of CD36 in myeloid cells upregulated MHC-I-related gene expression in macrophages and promoted CD8⁺ T cell activation within the fibrotic liver microenvironment. Macrophage-specific CD36 knockout protected mice from fibrosis progression. In patients with liver cirrhosis, histological and serological analyses showed elevated CD36 expression, underscoring its clinical relevance.CONCLUSIONSCD36-driven lipid uptake reprograms macrophage metabolism, leading to ferroptosis and impaired adaptive immunity. Targeting CD36 restores macrophage antigen-presenting function and enhances CD8⁺ T cell activation, identifying CD36 as a potential therapeutic target for hepatic fibrosis. The clinical trial was registered in the Research Registry (researchregistry10830).
{"title":"Myeloid CD36 deficiency alleviates hepatic fibrosis by promoting adaptive immunity of macrophage.","authors":"Liangyun Li,Yilong Fang,Jintong Zhang,Mengmeng Song,Sijin Sun,Xin Chen,Sai Zhu,Shaoxi Diao,Yuxin Zhao,Haidi Li,Zixiang Chen,Xiaofeng Li,Zhenlong Liu,Xiaoming Meng,Tao Xu,Yong He,Hua Wang,Cheng Huang,Jun Li","doi":"10.1097/hep.0000000000001646","DOIUrl":"https://doi.org/10.1097/hep.0000000000001646","url":null,"abstract":"BACKGROUND AIMSHepatic fibrosis presents a major global health challenge, yet effective preventive and therapeutic strategies remain limited. Hepatic macrophages, which play a dual role in fibrosis progression, are central to understanding its pathogenesis. This study aimed to elucidate how macrophage lipid metabolism mediated by CD36 regulates immune function and fibrosis development.APPROACH RESULTSWe demonstrated that macrophages engulf lipids secreted by hepatic stellate cells (HSCs) via the CD36 receptor, resulting in enhanced lipid peroxidation, ferroptosis, and diminished antigen-presenting capacity, thereby impairing CD8⁺ T cell function. Conversely, CD36 deficiency restored antigen presentation through activation of the cGAS-STING pathway. Single-cell RNA sequencing further revealed that loss of CD36 in myeloid cells upregulated MHC-I-related gene expression in macrophages and promoted CD8⁺ T cell activation within the fibrotic liver microenvironment. Macrophage-specific CD36 knockout protected mice from fibrosis progression. In patients with liver cirrhosis, histological and serological analyses showed elevated CD36 expression, underscoring its clinical relevance.CONCLUSIONSCD36-driven lipid uptake reprograms macrophage metabolism, leading to ferroptosis and impaired adaptive immunity. Targeting CD36 restores macrophage antigen-presenting function and enhances CD8⁺ T cell activation, identifying CD36 as a potential therapeutic target for hepatic fibrosis. The clinical trial was registered in the Research Registry (researchregistry10830).","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"246 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760036","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}
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