Pub Date : 2025-11-06DOI: 10.1016/j.jhepr.2025.101666
George N. Ioannou , Tamar H. Taddei , Beata M. Planeta , Grant D. Huang , Noel S. Weiss , Timothy R. Morgan , Jason A. Dominitz , Ghassan K. Abou-Alfa , Mustafa R. Bashir , Michael V. Beheshti , Amit G. Singal , Cynthia A. Moylan , Robin J. Boland , Lynn F. Buchwalder , Rajni L. Mehta , Kimberly S. Hoisington , Nhan V. Do , Shari S. Rogal , David E. Kaplan , Jihane N. Benhammou , Ifeyinwa Onyiuke
Abdominal ultrasound every 6 months with or without serum alpha-fetoprotein (AFP) is recommended for hepatocellular carcinoma (HCC) screening in patients with cirrhosis. However, high-quality evidence demonstrating that this screening strategy reduces HCC-related mortality in cirrhosis is lacking. Dynamic contrast-enhanced abbreviated MRI (DCE aMRI) protocols for HCC screening have nearly identical performance to full multiphasic MRI (the gold standard for HCC diagnosis) and can be completed in under 15 min. PREMIUM is a multicentre randomised controlled trial comparing HCC screening by ultrasound+AFP every 6 months vs. DCE aMRI+AFP every 6 months for up to 8 years among patients with cirrhosis. Sponsored by and executed within the Department of Veterans Affairs (VA), participant recruitment began in November 2023. Eligible participants are Veterans aged 18-75 years with cirrhosis, high HCC risk, Child-Turcotte-Pugh (CTP) score ≤9, model for end-stage liver disease (MELD) score ≤20, and no MRI contraindications or life-threatening comorbidities. The DCE aMRI protocol consists of T1-weighted axial pre-contrast and DCE sequences (arterial, portal, and 5-minute delayed) following administration of extracellular gadolinium-based contrast agent, plus a T2-weighted sequence between portal and delayed phases. PREMIUM aims to randomise 4,700 participants (2,350 in each arm), who will undergo per-protocol imaging and follow-up for up to 8 years. The primary outcome is HCC-related mortality. Secondary outcomes include HCC stage at diagnosis, receipt of potentially curative HCC treatment, and all-cause mortality. The study is powered to detect at least a 35% relative reduction in HCC-related mortality in the aMRI+AFP arm vs. the ultrasound+AFP arm. If PREMIUM demonstrates reduced HCC-related mortality in the aMRI+AFP arm, it could provide the necessary evidence to recommend aMRI+AFP for HCC screening in patients with cirrhosis (ClinicalTrials.gov identifier: NCT05486572).
The PREMIUM Study is a registered clinical trial: NCT05486572.
{"title":"Practice changing RCT design and rationale: Abbreviated MRI plus AFP vs. ultrasound plus AFP for HCC surveillance in cirrhosis (PREMIUM study)","authors":"George N. Ioannou , Tamar H. Taddei , Beata M. Planeta , Grant D. Huang , Noel S. Weiss , Timothy R. Morgan , Jason A. Dominitz , Ghassan K. Abou-Alfa , Mustafa R. Bashir , Michael V. Beheshti , Amit G. Singal , Cynthia A. Moylan , Robin J. Boland , Lynn F. Buchwalder , Rajni L. Mehta , Kimberly S. Hoisington , Nhan V. Do , Shari S. Rogal , David E. Kaplan , Jihane N. Benhammou , Ifeyinwa Onyiuke","doi":"10.1016/j.jhepr.2025.101666","DOIUrl":"10.1016/j.jhepr.2025.101666","url":null,"abstract":"<div><div>Abdominal ultrasound every 6 months with or without serum alpha-fetoprotein (AFP) is recommended for hepatocellular carcinoma (HCC) screening in patients with cirrhosis. However, high-quality evidence demonstrating that this screening strategy reduces HCC-related mortality in cirrhosis is lacking. Dynamic contrast-enhanced abbreviated MRI (DCE aMRI) protocols for HCC screening have nearly identical performance to full multiphasic MRI (the gold standard for HCC diagnosis) and can be completed in under 15 min. PREMIUM is a multicentre randomised controlled trial comparing HCC screening by ultrasound+AFP every 6 months <em>vs.</em> DCE aMRI+AFP every 6 months for up to 8 years among patients with cirrhosis. Sponsored by and executed within the Department of Veterans Affairs (VA), participant recruitment began in November 2023. Eligible participants are Veterans aged 18-75 years with cirrhosis, high HCC risk, Child-Turcotte-Pugh (CTP) score ≤9, model for end-stage liver disease (MELD) score ≤20, and no MRI contraindications or life-threatening comorbidities. The DCE aMRI protocol consists of T1-weighted axial pre-contrast and DCE sequences (arterial, portal, and 5-minute delayed) following administration of extracellular gadolinium-based contrast agent, plus a T2-weighted sequence between portal and delayed phases. PREMIUM aims to randomise 4,700 participants (2,350 in each arm), who will undergo per-protocol imaging and follow-up for up to 8 years. The primary outcome is HCC-related mortality. Secondary outcomes include HCC stage at diagnosis, receipt of potentially curative HCC treatment, and all-cause mortality. The study is powered to detect at least a 35% relative reduction in HCC-related mortality in the aMRI+AFP arm <em>vs</em>. the ultrasound+AFP arm. If PREMIUM demonstrates reduced HCC-related mortality in the aMRI+AFP arm, it could provide the necessary evidence to recommend aMRI+AFP for HCC screening in patients with cirrhosis (<span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> identifier: NCT05486572).</div><div>The PREMIUM Study is a registered clinical trial: NCT05486572.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101666"},"PeriodicalIF":7.5,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034431","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 : 2025-11-04DOI: 10.1016/j.jhepr.2025.101635
Sabrina Welland , Ann-Kristin Zöller , Ilektra A. Mavroeidi , Aurelie Tomczak , Christian Müller , Dong Yawen , Danmei Zhang , Felix Keil , Maria Pangerl , Taotao Zhou , Hossein Taghizadeh , Sebastian Lange , Maximilian N. Kinzler , Kataryna Shmanko , Maryam Barsch , Carolin Zimpel , Angela Djanani , Henning Schulze-Bergkamen , Julius Keyl , Florian Lüke , Arndt Vogel
<div><h3>Background & Aims</h3><div>Biliary tract cancers (BTC) are aggressive malignancies with limited treatment options. Owing to the high frequency of actionable genomic alterations (GA) and the availability of targeted therapies, molecular testing has become increasingly important; however, its clinical implementation remains inconsistent. This study aimed to evaluate real-world molecular testing practices, characterize the BTC molecular landscape, and assess the prognostic and predictive relevance of selected GA.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed genomic and clinical data from 1,521 patients treated at 18 centers in Germany and Austria. A side-by-side comparison of clinical grade reports generated on two different sequencing platforms was performed for 90 patients.</div></div><div><h3>Results</h3><div>Twenty-four different NGS panels were used across 18 centers. A comparative analysis highlighted the significant variability in reports used to inform therapeutic decisions in clinical practice. Although there were substantial differences in the number of GA covered, the broader panels identified a similar number of actionable GA, indicating that key therapeutic targets are sufficiently represented. Integration with clinical data suggested that certain GA, such as <em>HER2</em> amplifications (3%)<em>, BRAF</em><sup><em>V600E</em></sup> mutations (2%), and <em>FGFR2</em> alterations (14%), may have prognostic significance beyond their predictive value. Patients with actionable alterations (610, 40%) that were treated accordingly (n = 204, 13%) had prolonged overall survival (31.8 months <em>vs.</em> 22.8 months, <em>p</em> <0.01).</div></div><div><h3>Conclusion</h3><div>Standardized biomarker testing is crucial for effective integration of targeted therapies in the management of BTC. Our findings reinforce the value of targeted treatments and underscore the predictive and prognostic significance of selected GA.</div></div><div><h3>Impact and implications</h3><div>Genomic profiling is recommended in patients with biliary tract cancers (BTC) but lacks harmonization across platforms and centers. By retrospectively analyzing genomic and clinical information from 1,521 patients with BTC diagnosed and treated at 18 centers in Germany and Austria, we provide real-world insights into the implementation of molecular profiling in BTC, highlighting variability in next generation sequencing-based testing and its impact on the detection of genomic alterations. Standardized molecular testing strategies will be key to enable the integration of more consistent and comparable genomic datasets across studies. Further, by elucidating the prognostic relevance of individual genomic alterations, our insights carry significant implications for interpreting single-arm clinical trials within genomically stratified patient cohorts and underscore the importance of randomized studies to delineate the benefit of targeted therapies.</d
{"title":"Clinical practice and implications of biomarker testing in biliary tract cancer: An observational study","authors":"Sabrina Welland , Ann-Kristin Zöller , Ilektra A. Mavroeidi , Aurelie Tomczak , Christian Müller , Dong Yawen , Danmei Zhang , Felix Keil , Maria Pangerl , Taotao Zhou , Hossein Taghizadeh , Sebastian Lange , Maximilian N. Kinzler , Kataryna Shmanko , Maryam Barsch , Carolin Zimpel , Angela Djanani , Henning Schulze-Bergkamen , Julius Keyl , Florian Lüke , Arndt Vogel","doi":"10.1016/j.jhepr.2025.101635","DOIUrl":"10.1016/j.jhepr.2025.101635","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Biliary tract cancers (BTC) are aggressive malignancies with limited treatment options. Owing to the high frequency of actionable genomic alterations (GA) and the availability of targeted therapies, molecular testing has become increasingly important; however, its clinical implementation remains inconsistent. This study aimed to evaluate real-world molecular testing practices, characterize the BTC molecular landscape, and assess the prognostic and predictive relevance of selected GA.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed genomic and clinical data from 1,521 patients treated at 18 centers in Germany and Austria. A side-by-side comparison of clinical grade reports generated on two different sequencing platforms was performed for 90 patients.</div></div><div><h3>Results</h3><div>Twenty-four different NGS panels were used across 18 centers. A comparative analysis highlighted the significant variability in reports used to inform therapeutic decisions in clinical practice. Although there were substantial differences in the number of GA covered, the broader panels identified a similar number of actionable GA, indicating that key therapeutic targets are sufficiently represented. Integration with clinical data suggested that certain GA, such as <em>HER2</em> amplifications (3%)<em>, BRAF</em><sup><em>V600E</em></sup> mutations (2%), and <em>FGFR2</em> alterations (14%), may have prognostic significance beyond their predictive value. Patients with actionable alterations (610, 40%) that were treated accordingly (n = 204, 13%) had prolonged overall survival (31.8 months <em>vs.</em> 22.8 months, <em>p</em> <0.01).</div></div><div><h3>Conclusion</h3><div>Standardized biomarker testing is crucial for effective integration of targeted therapies in the management of BTC. Our findings reinforce the value of targeted treatments and underscore the predictive and prognostic significance of selected GA.</div></div><div><h3>Impact and implications</h3><div>Genomic profiling is recommended in patients with biliary tract cancers (BTC) but lacks harmonization across platforms and centers. By retrospectively analyzing genomic and clinical information from 1,521 patients with BTC diagnosed and treated at 18 centers in Germany and Austria, we provide real-world insights into the implementation of molecular profiling in BTC, highlighting variability in next generation sequencing-based testing and its impact on the detection of genomic alterations. Standardized molecular testing strategies will be key to enable the integration of more consistent and comparable genomic datasets across studies. Further, by elucidating the prognostic relevance of individual genomic alterations, our insights carry significant implications for interpreting single-arm clinical trials within genomically stratified patient cohorts and underscore the importance of randomized studies to delineate the benefit of targeted therapies.</d","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101635"},"PeriodicalIF":7.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682308","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 : 2025-11-04DOI: 10.1016/j.jhepr.2025.101657
Hani Vu , Yuliangzi Sun , Zherui Xiong , Xiao Tan , Daniel Radford-Smith , Andrew Causer , Alex M. Dickens , Tuulia Hyötyläinen , Ilia Evstafev , Matej Oresic , Christian Nefzger , Eoin D. O’Sullivan , Matthew J. Watt , Grant A. Ramm , Andrew Clouston , Katharine M. Irvine , Quan H. Nguyen , Elizabeth E. Powell
Background & Aims
Granular detail about the location and nature of liver cell interactions and the metabolic, inflammatory and fibrogenic pathways driving progressive fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) is needed to identify novel therapeutic targets.
Methods
We generated Visium spatial transcriptomic data from 33 human liver biopsies across the spectrum of MASLD. Gene expression data were overlaid with histological annotations to integrate spatial molecular and histopathological information, enabling interrogation of disease progression. Differential gene expression, pathway, cellular deconvolution and ligand-receptor interaction analyses were conducted for each annotated anatomical category, with specific protein expression validated using immunohistochemistry staining.
Results
Unsupervised clustering based on gene expression data classified the annotated spots into two main clusters enriched for fibro-inflammatory vs. parenchymal regions. Transcriptomic cellular deconvolution aligned well with manually annotated histopathological features. Fibrotic regions were enriched for genes involved in extracellular matrix/receptor interactions and inflammatory pathways (Benjamini-Hochberg adjusted p values <0.05), underscoring known pathological mechanisms. We also identified immunoglobulin gene induction in late-stage fibrosis, which was spatially associated with a senescence signature, as has previously been reported in aging tissues. Dynamic changes in metabolic gene expression from early to late fibrosis were observed, suggesting MASLD progression is accompanied by a decline in normal liver metabolic function and reprogramming of metabolic fuel utilisation from oxidative to glycolytic metabolism, which may be both a cause and a consequence of senescence.
Conclusions
Taken together, our valuable discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD.
Impact and implications
Metabolic dysfunction-associated steatotic liver disease (MASLD) has a complex pathogenesis driven by cell and matrix interactions in inflammatory niches. In this study, we identify a senescence signature in fibroinflammatory regions, characterised by high immunoglobulin expression and associated with a shift from oxidative to glycolytic metabolism. We identify spatially co-expressed ligand-receptor pairs, including senescence-associated factors, correlated with progressive fibrosis. This discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD and lays the groundwork for future research into the role of senescence in MASLD.
{"title":"Progressive fibrosis in human MASLD is associated with spatially linked transcriptomic signatures of metabolic reprogramming and senescence","authors":"Hani Vu , Yuliangzi Sun , Zherui Xiong , Xiao Tan , Daniel Radford-Smith , Andrew Causer , Alex M. Dickens , Tuulia Hyötyläinen , Ilia Evstafev , Matej Oresic , Christian Nefzger , Eoin D. O’Sullivan , Matthew J. Watt , Grant A. Ramm , Andrew Clouston , Katharine M. Irvine , Quan H. Nguyen , Elizabeth E. Powell","doi":"10.1016/j.jhepr.2025.101657","DOIUrl":"10.1016/j.jhepr.2025.101657","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Granular detail about the location and nature of liver cell interactions and the metabolic, inflammatory and fibrogenic pathways driving progressive fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) is needed to identify novel therapeutic targets.</div></div><div><h3>Methods</h3><div>We generated Visium spatial transcriptomic data from 33 human liver biopsies across the spectrum of MASLD. Gene expression data were overlaid with histological annotations to integrate spatial molecular and histopathological information, enabling interrogation of disease progression. Differential gene expression, pathway, cellular deconvolution and ligand-receptor interaction analyses were conducted for each annotated anatomical category, with specific protein expression validated using immunohistochemistry staining.</div></div><div><h3>Results</h3><div>Unsupervised clustering based on gene expression data classified the annotated spots into two main clusters enriched for fibro-inflammatory <em>vs</em>. parenchymal regions. Transcriptomic cellular deconvolution aligned well with manually annotated histopathological features. Fibrotic regions were enriched for genes involved in extracellular matrix/receptor interactions and inflammatory pathways (Benjamini-Hochberg adjusted <em>p</em> values <0.05), underscoring known pathological mechanisms. We also identified immunoglobulin gene induction in late-stage fibrosis, which was spatially associated with a senescence signature, as has previously been reported in aging tissues. Dynamic changes in metabolic gene expression from early to late fibrosis were observed, suggesting MASLD progression is accompanied by a decline in normal liver metabolic function and reprogramming of metabolic fuel utilisation from oxidative to glycolytic metabolism, which may be both a cause and a consequence of senescence.</div></div><div><h3>Conclusions</h3><div>Taken together, our valuable discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD.</div></div><div><h3>Impact and implications</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has a complex pathogenesis driven by cell and matrix interactions in inflammatory niches. In this study, we identify a senescence signature in fibroinflammatory regions, characterised by high immunoglobulin expression and associated with a shift from oxidative to glycolytic metabolism. We identify spatially co-expressed ligand-receptor pairs, including senescence-associated factors, correlated with progressive fibrosis. This discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD and lays the groundwork for future research into the role of senescence in MASLD.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101657"},"PeriodicalIF":7.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814289","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 : 2025-11-04DOI: 10.1016/j.jhepr.2025.101667
Benedikt S. Hofer , Lukas Burghart , Thomas Reiberger , Albert F. Stättermayer
{"title":"Extending the Baveno VII definition of recompensation to autoimmune hepatitis: Considerations regarding treatment timing and response criteria","authors":"Benedikt S. Hofer , Lukas Burghart , Thomas Reiberger , Albert F. Stättermayer","doi":"10.1016/j.jhepr.2025.101667","DOIUrl":"10.1016/j.jhepr.2025.101667","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101667"},"PeriodicalIF":7.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034366","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 : 2025-11-03DOI: 10.1016/j.jhepr.2025.101661
Lu Li , Xianhua Mao , Chi Ho Lee , David Tak Wai Lui , Rex Wan-Hin Hui , Lung-Yi Mak , Man-Fung Yuen , Ka Shing Cheung , Wai-Kay Seto
<div><h3>Background & Aims</h3><div>Glucose-lowering drugs (GLDs) including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2is) have been broadly evaluated in patients with coexisting metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). However, their comparative efficacy in reducing the risk of liver-related events remains unclear. Thus, we aim to simultaneously compare the efficacy of different GLDs for patients with MASLD and T2D.</div></div><div><h3>Methods</h3><div>We searched PubMed, EMBASE, Cochrane Library and Web of Science for observational studies from inception to April 2025. We evaluated the comparative efficacy of six GLDs, including GLP-1RAs, SGLT2is, dipeptidyl peptidase-4 inhibitors, metformin, sulfonylureas, and thiazolidinediones using pairwise meta-analysis and Bayesian network meta-analysis. We assessed overall and individual liver-related events, including the development of cirrhosis, decompensation and hepatocellular carcinoma (HCC), with treatments ranked via SUCRA (surface under the cumulative ranking) scores.</div></div><div><h3>Results</h3><div>Twelve studies involving 737,408 patients with MASLD and diabetes were analyzed. Both GLP-1RAs and SGLT2is, when compared to non-GLP-1RA and non-SGLT2i controls, were significantly associated with reduced risk for overall liver-related events (hazard ratio [HR] 0.79, 95% CI 0.70-0.90, and HR 0.75, 95% CI 0.63-0.88, respectively). Similar results were also observed for HCC and liver decompensation (HRs 0.74-0.81). In individuals with obesity, a greater risk reduction was observed for GLP-1RAs (HR 0.74, 95% CI 0.56-0.99) but not for SGLT2is. GLP-1RAs also outperformed SGLT2is in non-Asian populations (HR 0.91, 95% CI 0.83-0.99). Network meta-analysis identified GLP-1RAs and SGLT2is (SUCRA 90%/80%, respectively) as the most effective for risk reduction, with significantly greater efficacy than other GLDs (HRs 0.75-0.79).</div></div><div><h3>Conclusions</h3><div>GLP-1RAs and SGLT2is were associated with reduced risks of liver-related events in patients with MASLD and T2D. GLP-1RAs showed superior benefit in individuals with obesity and in non-Asian populations, supporting a personalized approach to treatment selection.</div></div><div><h3>Impact and implications</h3><div>The long-term liver-related efficacy of different glucose-lowering drugs (GLDs) in patients with coexisting metabolic dysfunction-associated steatotic liver disease and type 2 diabetes remains unclear, despite a higher lifetime risk of advanced liver disease in this population. We evaluated the comparative efficacy of six GLDs by pairwise meta-analysis and Bayesian network meta-analysis, demonstrating GLP-1RAs and SGLT2is may be among the most effective GLDs for reducing liver-related events, with GLP-1RAs appearing particularly beneficial for patients with obesity. These findings support a personalized approach to tr
背景和目的降糖药物（GLDs），包括胰高血糖素样肽-1受体激动剂（GLP-1RAs）和钠-葡萄糖共转运蛋白2抑制剂（SGLT2is），在同时存在代谢功能障碍相关脂肪变性肝病（MASLD）和2型糖尿病（T2D）的患者中得到了广泛的评估。然而，它们在降低肝脏相关事件风险方面的相对疗效尚不清楚。因此，我们的目的是同时比较不同GLDs对MASLD和T2D患者的疗效。方法检索PubMed、EMBASE、Cochrane Library和Web of Science，检索从成立到2025年4月的观察性研究。我们使用两两荟萃分析和贝叶斯网络荟萃分析评估了六种GLDs的比较疗效，包括GLP-1RAs、SGLT2is、二肽基肽酶-4抑制剂、二甲双胍、磺脲类药物和噻唑烷二酮类药物。我们评估了总体和个体肝脏相关事件，包括肝硬化、失代偿和肝细胞癌（HCC）的发展，并通过SUCRA（累积排名下的表面）评分对治疗进行排名。结果12项研究共纳入737,408例MASLD合并糖尿病患者。与非glp - 1ra和非sglt2i对照相比，GLP-1RAs和sglt2i与总体肝脏相关事件风险降低显著相关（风险比[HR] 0.79, 95% CI 0.70-0.90；风险比[HR] 0.75, 95% CI 0.63-0.88）。类似的结果也被观察到HCC和肝脏失代偿（hr 0.74-0.81）。在肥胖个体中，GLP-1RAs的风险降低更大（HR 0.74, 95% CI 0.56-0.99），但SGLT2is的风险降低更大。GLP-1RAs在非亚洲人群中的表现也优于SGLT2is （HR 0.91, 95% CI 0.83-0.99）。网络荟萃分析确定GLP-1RAs和SGLT2is （SUCRA分别为90%/80%）是降低风险最有效的，其疗效显著高于其他GLDs （hr为0.75-0.79）。结论：glp - 1ras和SGLT2is与MASLD和T2D患者肝脏相关事件的风险降低相关。GLP-1RAs在肥胖个体和非亚洲人群中显示出优越的益处，支持个性化的治疗选择方法。影响和意义不同降糖药物（GLDs）对同时存在代谢功能障碍相关脂肪变性肝病和2型糖尿病患者的长期肝脏相关疗效尚不清楚，尽管这类人群终生发生晚期肝病的风险较高。我们通过两两meta分析和贝叶斯网络meta分析评估了六种GLDs的比较疗效，证明GLP-1RAs和SGLT2is可能是减少肝脏相关事件最有效的GLDs之一，GLP-1RAs对肥胖患者尤其有益。这些发现支持个性化的治疗选择方法，并强调需要未来的临床试验来确认GLDs的疗效。INPLASY注册号inplasy202530085。
{"title":"Impact of SGLT2i and GLP-1RA on liver-related events in patients with MASLD and type 2 diabetes: A network meta-analysis","authors":"Lu Li , Xianhua Mao , Chi Ho Lee , David Tak Wai Lui , Rex Wan-Hin Hui , Lung-Yi Mak , Man-Fung Yuen , Ka Shing Cheung , Wai-Kay Seto","doi":"10.1016/j.jhepr.2025.101661","DOIUrl":"10.1016/j.jhepr.2025.101661","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Glucose-lowering drugs (GLDs) including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2is) have been broadly evaluated in patients with coexisting metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). However, their comparative efficacy in reducing the risk of liver-related events remains unclear. Thus, we aim to simultaneously compare the efficacy of different GLDs for patients with MASLD and T2D.</div></div><div><h3>Methods</h3><div>We searched PubMed, EMBASE, Cochrane Library and Web of Science for observational studies from inception to April 2025. We evaluated the comparative efficacy of six GLDs, including GLP-1RAs, SGLT2is, dipeptidyl peptidase-4 inhibitors, metformin, sulfonylureas, and thiazolidinediones using pairwise meta-analysis and Bayesian network meta-analysis. We assessed overall and individual liver-related events, including the development of cirrhosis, decompensation and hepatocellular carcinoma (HCC), with treatments ranked via SUCRA (surface under the cumulative ranking) scores.</div></div><div><h3>Results</h3><div>Twelve studies involving 737,408 patients with MASLD and diabetes were analyzed. Both GLP-1RAs and SGLT2is, when compared to non-GLP-1RA and non-SGLT2i controls, were significantly associated with reduced risk for overall liver-related events (hazard ratio [HR] 0.79, 95% CI 0.70-0.90, and HR 0.75, 95% CI 0.63-0.88, respectively). Similar results were also observed for HCC and liver decompensation (HRs 0.74-0.81). In individuals with obesity, a greater risk reduction was observed for GLP-1RAs (HR 0.74, 95% CI 0.56-0.99) but not for SGLT2is. GLP-1RAs also outperformed SGLT2is in non-Asian populations (HR 0.91, 95% CI 0.83-0.99). Network meta-analysis identified GLP-1RAs and SGLT2is (SUCRA 90%/80%, respectively) as the most effective for risk reduction, with significantly greater efficacy than other GLDs (HRs 0.75-0.79).</div></div><div><h3>Conclusions</h3><div>GLP-1RAs and SGLT2is were associated with reduced risks of liver-related events in patients with MASLD and T2D. GLP-1RAs showed superior benefit in individuals with obesity and in non-Asian populations, supporting a personalized approach to treatment selection.</div></div><div><h3>Impact and implications</h3><div>The long-term liver-related efficacy of different glucose-lowering drugs (GLDs) in patients with coexisting metabolic dysfunction-associated steatotic liver disease and type 2 diabetes remains unclear, despite a higher lifetime risk of advanced liver disease in this population. We evaluated the comparative efficacy of six GLDs by pairwise meta-analysis and Bayesian network meta-analysis, demonstrating GLP-1RAs and SGLT2is may be among the most effective GLDs for reducing liver-related events, with GLP-1RAs appearing particularly beneficial for patients with obesity. These findings support a personalized approach to tr","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101661"},"PeriodicalIF":7.5,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786929","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 : 2025-11-01DOI: 10.1016/j.jhepr.2025.101583
Lorenz Balcar , Marta Tonon , Joan Valls , Thomas Reiberger , Juan Carlos García-Pagán , Georg Semmler , Salvatore Piano
{"title":"Reply to: “Predicting the need for early TIPS in patients with cirrhosis and ascites: More art than science”","authors":"Lorenz Balcar , Marta Tonon , Joan Valls , Thomas Reiberger , Juan Carlos García-Pagán , Georg Semmler , Salvatore Piano","doi":"10.1016/j.jhepr.2025.101583","DOIUrl":"10.1016/j.jhepr.2025.101583","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101583"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462781","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 : 2025-11-01DOI: 10.1016/j.jhepr.2025.101552
Anthony C. Bejjani , Sasan Roayaie , Richard S. Finn
{"title":"Targeting TIGIT to improve outcomes in advanced HCC","authors":"Anthony C. Bejjani , Sasan Roayaie , Richard S. Finn","doi":"10.1016/j.jhepr.2025.101552","DOIUrl":"10.1016/j.jhepr.2025.101552","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101552"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462775","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 : 2025-11-01DOI: 10.1016/j.jhepr.2025.101513
Ignazio Piseddu , Leonie S. Jochheim , Katrin Boettcher , Bernhard Scheiner , Friedrich Sinner , Simon Johannes Gairing , Matthias Thaler , Stefan Enssle , Monika Karin , Valentina Zarka , Alexander Philipp , Andreas Thalmeier , Jan Gaertig , Lorenz Balcar , Julia Martina Schütte , Julia S. Schneider , Katarina Ondrejkova , Monika Rau , Alexander Weich , David Anz , Najib Ben Khaled
<div><h3>Background & Aims</h3><div>Atezolizumab/bevacizumab (atezo/bev) has revolutionized the standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, only a subgroup of patients responds to atezo/bev and derives durable clinical benefit. This study aims to analyze the frequency and risk factors of early mortality (EM) in patients with HCC treated with atezo/bev.</div></div><div><h3>Methods</h3><div>This study uses data from a large, European real-world cohort and flow cytometry-based immunophenotyping of patient’s baseline PBMC. EM was defined as death from any cause within 90 days of treatment initiation. Logistic regression analysis was used to identify parameters associated with EM.</div></div><div><h3>Results</h3><div>A total of 317 patients with unresectable HCC treated with first-line atezo/bev were included. EM rate in the cohort was 15.8%, with a median survival of 12.6 months. The proportion of patients with preserved liver function and BCLC stage B was significantly lower in the EM cohort. The strongest predictor of EM was advanced liver disease in univariate analysis, as reflected by surrogates of impaired liver function such as Child–Pugh score (CPS) B (<em>p</em> <0.0001), albumin–bilirubin grade 2/3 (<em>p</em> = 0.026, <em>p</em> <0.0001) or high model for end-stage liver disease score (<em>p</em> <0.0001). CPS B remained a significant risk factor after adjusting for other variables. Biomarker analysis and immunophenotyping revealed high C-reactive protein, reduced lymphocyte frequencies, increased CD44 expression on regulatory T cells and elevated PD-L1 levels on CD8<sup>+</sup> T cells to be associated with EM.</div></div><div><h3>Conclusions</h3><div>EM rate was 15.8% in patients with HCC treated with atezo/bev. Significant risk factors for early death involved impaired liver function, elevated biomarkers of inflammation and alterations of systemic immunity.</div></div><div><h3>Impact and implications</h3><div>Although rare in clinical trial populations, early mortality (EM) is a significant concern following the initiation of immune checkpoint inhibitors in patients with hepatocellular carcinoma (HCC) in real-world cohorts, highlighting the need for adequate risk stratification and patient selection. Using data of a large, European real-world cohort as well as FACS-based immunophenotyping of baseline peripheral blood mononuclear cells, we comprehensively characterized the frequency, risk factors, and biomarkers associated with EM in atezo/bev-treated patients with HCC. We identified EM to represent a common event in patients with HCC after treatment initiation and demonstrated impaired liver function, elevated biomarkers of inflammation, and reduced lymphocyte frequencies and increased regulatory T cell activity to be associated with increased EM risk. These findings can help clinicians identify patients with HCC at high risk of EM, enabling adequate and informed decision-making r
AimsAtezolizumab/bevacizumab （atezo/bev）彻底改变了不可切除肝细胞癌（HCC）患者的护理标准。然而，只有一个亚组患者对atezo/bev有反应并获得持久的临床益处。本研究旨在分析atezo/bev治疗HCC患者早期死亡（EM）的频率和危险因素。方法：本研究使用来自欧洲真实世界的大型队列数据和基于流式细胞术的患者基线PBMC免疫表型分析。EM定义为治疗开始90天内任何原因导致的死亡。结果共纳入317例接受一线atezo/bev治疗的不可切除HCC患者。该队列的EM率为15.8%，中位生存期为12.6个月。EM队列中保留肝功能和BCLC B期的患者比例明显较低。单变量分析中，EM的最强预测因子是晚期肝病，这反映在肝功能受损的替代指标上，如Child-Pugh评分（CPS） B （p <0.0001）、白蛋白-胆红素等级2/3 （p = 0.026, p <0.0001）或终末期肝病评分的高模型（p <0.0001）。在调整其他变量后，CPS B仍然是显著的危险因素。生物标志物分析和免疫表型分析显示，高c反应蛋白、淋巴细胞频率降低、调节性T细胞CD44表达升高、CD8+ T细胞PD-L1水平升高与肝癌相关。结论atezo/bev治疗HCC患者的sem率为15.8%。早期死亡的重要危险因素包括肝功能受损、炎症生物标志物升高和全身免疫改变。影响和意义尽管在临床试验人群中罕见，但在现实世界队列中，肝细胞癌（HCC）患者开始使用免疫检查点抑制剂后，早期死亡率（EM）是一个值得关注的问题，这突出了充分的风险分层和患者选择的必要性。使用欧洲真实世界的大型队列数据以及基于facs的基线外周血单个核细胞免疫表型，我们全面表征了atezo/bev治疗的HCC患者中与EM相关的频率、危险因素和生物标志物。我们确定EM代表HCC患者在治疗开始后的常见事件，并证明肝功能受损，炎症生物标志物升高，淋巴细胞频率降低和调节性T细胞活性增加与EM风险增加相关。这些发现可以帮助临床医生识别具有EM高风险的HCC患者，从而在临终关怀和姑息治疗方面做出充分和明智的决策。
{"title":"Early mortality in atezolizumab/bevacizumab for HCC is associated with impaired liver function and alterations of systemic immunity","authors":"Ignazio Piseddu , Leonie S. Jochheim , Katrin Boettcher , Bernhard Scheiner , Friedrich Sinner , Simon Johannes Gairing , Matthias Thaler , Stefan Enssle , Monika Karin , Valentina Zarka , Alexander Philipp , Andreas Thalmeier , Jan Gaertig , Lorenz Balcar , Julia Martina Schütte , Julia S. Schneider , Katarina Ondrejkova , Monika Rau , Alexander Weich , David Anz , Najib Ben Khaled","doi":"10.1016/j.jhepr.2025.101513","DOIUrl":"10.1016/j.jhepr.2025.101513","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Atezolizumab/bevacizumab (atezo/bev) has revolutionized the standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, only a subgroup of patients responds to atezo/bev and derives durable clinical benefit. This study aims to analyze the frequency and risk factors of early mortality (EM) in patients with HCC treated with atezo/bev.</div></div><div><h3>Methods</h3><div>This study uses data from a large, European real-world cohort and flow cytometry-based immunophenotyping of patient’s baseline PBMC. EM was defined as death from any cause within 90 days of treatment initiation. Logistic regression analysis was used to identify parameters associated with EM.</div></div><div><h3>Results</h3><div>A total of 317 patients with unresectable HCC treated with first-line atezo/bev were included. EM rate in the cohort was 15.8%, with a median survival of 12.6 months. The proportion of patients with preserved liver function and BCLC stage B was significantly lower in the EM cohort. The strongest predictor of EM was advanced liver disease in univariate analysis, as reflected by surrogates of impaired liver function such as Child–Pugh score (CPS) B (<em>p</em> <0.0001), albumin–bilirubin grade 2/3 (<em>p</em> = 0.026, <em>p</em> <0.0001) or high model for end-stage liver disease score (<em>p</em> <0.0001). CPS B remained a significant risk factor after adjusting for other variables. Biomarker analysis and immunophenotyping revealed high C-reactive protein, reduced lymphocyte frequencies, increased CD44 expression on regulatory T cells and elevated PD-L1 levels on CD8<sup>+</sup> T cells to be associated with EM.</div></div><div><h3>Conclusions</h3><div>EM rate was 15.8% in patients with HCC treated with atezo/bev. Significant risk factors for early death involved impaired liver function, elevated biomarkers of inflammation and alterations of systemic immunity.</div></div><div><h3>Impact and implications</h3><div>Although rare in clinical trial populations, early mortality (EM) is a significant concern following the initiation of immune checkpoint inhibitors in patients with hepatocellular carcinoma (HCC) in real-world cohorts, highlighting the need for adequate risk stratification and patient selection. Using data of a large, European real-world cohort as well as FACS-based immunophenotyping of baseline peripheral blood mononuclear cells, we comprehensively characterized the frequency, risk factors, and biomarkers associated with EM in atezo/bev-treated patients with HCC. We identified EM to represent a common event in patients with HCC after treatment initiation and demonstrated impaired liver function, elevated biomarkers of inflammation, and reduced lymphocyte frequencies and increased regulatory T cell activity to be associated with increased EM risk. These findings can help clinicians identify patients with HCC at high risk of EM, enabling adequate and informed decision-making r","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101513"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462782","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号