JHEP Reports最新文献

{"title":"Reply to: “Comment on “Lower incidence of hepatocellular carcinoma with tenofovir alafenamide in chronic hepatitis B: Evidence from a large-scale cohort””","authors":"Jisoo Lee , Jae-Young Kim , Jeong-Ju Yoo , Hye Won Lee , Sang Gyune Kim , Young Seok Kim","doi":"10.1016/j.jhepr.2025.101371","DOIUrl":"10.1016/j.jhepr.2025.101371","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101371"},"PeriodicalIF":9.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum FGF21 as a predictor of response to atezolizumab and bevacizumab in HCC","authors":"Risako Kohya , Goki Suda , Masatsugu Ohara , Shunichi Hosoda , Takuya Sho , Makoto Chuma , Atsumasa Komori , Yuki Kugiyama , Yutaka Yasui , Kaoru Tsuchiya , Masayuki Kurosaki , Joji Tani , Shun Kaneko , Mina Nakagawa , Yasuhiro Asahina , Shinya Maekawa , Nobuyuki Enomoto , Yoshiya Yamamoto , Masaru Baba , Ren Yamada , Naoya Sakamoto","doi":"10.1016/j.jhepr.2025.101364","DOIUrl":"10.1016/j.jhepr.2025.101364","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Fibroblast growth factor 21 (FGF21) is a crucial regulator of cell metabolism. Tumour-secreted FGF21 has shown immune-checkpoint factor functions, and high FGF21 levels are associated with a poor prognosis for patients. However, its prognostic value and impact on treatment response in patients with hepatocellular carcinoma (HCC) treated with immune-checkpoint inhibitors (ICIs) remain unclear. Thus, this study investigated the potential of high FGF21 levels as a prognostic marker and whether traditional ICI-based therapy can improve the prognosis of patients with high FGF21 levels.</div></div><div><h3>Methods</h3><div>In this retrospective multicentre study, patients with unresectable HCC who received atezolizumab/bevacizumab in the NORTE study group (n = 117) were classified into high (≥915 pg/ml; n = 29) and non-high (n = 88) FGF21 groups. For validation, we investigated patients treated with atezolizumab/bevacizumab in an independent cohort (n = 285). Overall survival, progression-free survival, and treatment response were compared between patients with and without high baseline FGF21 levels.</div></div><div><h3>Results</h3><div>The median overall survival (<em>p</em> <0.001) and progression-free survival (<em>p</em> = 0.045) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. Independent cohort analysis validated these results. In the overall cohort, the median progression-free survival (5.75 <em>vs.</em> 8.84 months; <em>p</em> = 0.027) and median overall survival (14.13 <em>vs.</em> 22.08 months; <em>p</em> <0.001) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. The durable response (≥6 months) + complete response rate was significantly decreased in the high FGF21 group (<em>p</em> = 0.045). No patient with a high FGF21 level achieved a complete response, whereas this was achieved in 4.1% (13/319) of patients with non-high FGF21 levels. Multivariate Cox regression analysis identified high baseline serum FGF21 as an independent poor prognostic factor for overall survival (hazard ratio 2.20, <em>p</em> <0.001).</div></div><div><h3>Conclusions</h3><div>Serum FGF21 may be a robust, non-invasive prognostic and treatment response marker for unresectable HCC treated with atezolizumab/bevacizumab.</div></div><div><h3>Impact and implications</h3><div>FGF21 has been reported to act as a secreted immune-checkpoint factor, and elevated levels of FGF21 are associated with a poor prognosis in patients with HCC. It is not fully understood whether ICIs can overcome the impact of high FGF21 levels on the shortened prognosis of patients with HCC. In this multicentre retrospective study, patients with HCC and high baseline levels of serum FGF21 who received atezolizumab/bevacizumab treatment exhibited a significantly shorter overall survival and shorter progression-free survival. These findings suggest serum FGF21 as a robust prognostic marker","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101364"},"PeriodicalIF":9.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-Cirrhosis-ECG (ACE) score for predicting decompensation and liver outcomes","authors":"Joseph C. Ahn ,&nbsp;Puru Rattan ,&nbsp;Patrick Starlinger ,&nbsp;Adrià Juanola ,&nbsp;Maria José Moreta ,&nbsp;Jordi Colmenero ,&nbsp;Bashar Aqel ,&nbsp;Andrew P. Keaveny ,&nbsp;Aidan F. Mullan ,&nbsp;Kan Liu ,&nbsp;Zachi I. Attia ,&nbsp;Alina M. Allen ,&nbsp;Paul A. Friedman ,&nbsp;Vijay H. Shah ,&nbsp;Peter A. Noseworthy ,&nbsp;Julie K. Heimbach ,&nbsp;Patrick S. Kamath ,&nbsp;Pere Gines ,&nbsp;Douglas A. Simonetto","doi":"10.1016/j.jhepr.2025.101356","DOIUrl":"10.1016/j.jhepr.2025.101356","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Accurate prediction of disease severity and prognosis are challenging in patients with cirrhosis. We evaluated whether the deep learning-based AI-Cirrhosis-ECG (ACE) score could detect hepatic decompensation and predict clinical outcomes in cirrhosis.</div></div><div><h3>Methods</h3><div>We analyzed 2,166 ECGs from 472 patients in a retrospective Mayo Clinic cohort, 420 patients in a prospective Mayo transplant cohort, and 341 patients in an external validation cohort from Hospital Clínic de Barcelona. The ACE score's performance was assessed using receiver-operating characteristic analysis for decompensation detection and competing risks Cox regression for outcome prediction.</div></div><div><h3>Results</h3><div>The ACE score showed high accuracy in detecting hepatic decompensation (area under the curve 0.933, 95% CI: 0.923–0.942) with 88.0% sensitivity and 84.3% specificity at an optimal threshold of 0.25. In multivariable analysis, each 0.1-point increase in ACE score was independently associated with increased risk of liver-related death (hazard ratio [HR] 1.44, 95% CI 1.32–1.58, <em>p</em> &lt;0.001). Adding ACE to model for end-stage liver disease-sodium significantly improved prediction of adverse outcomes across all cohorts (c-statistics: retrospective cohort 0.903 <em>vs.</em> 0.844; prospective cohort 0.779 <em>vs.</em> 0.735; external validation 0.744 <em>vs.</em> 0.732; all <em>p</em> &lt;0.001).</div></div><div><h3>Conclusions</h3><div>The ACE score accurately identifies hepatic decompensation and independently predicts liver-related outcomes in cirrhosis. This non-invasive tool enhances current prognostic models and may improve risk stratification in cirrhosis management.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates the potential of artificial intelligence to enhance prognostication in liver disease, addressing the critical need for improved risk stratification in cirrhosis management. The AI-Cirrhosis-ECG (ACE) score, derived from widely available ECGs, shows promise as a non-invasive tool for detecting hepatic decompensation and predicting liver-related outcomes, which could significantly impact clinical decision-making and resource allocation in hepatology. These findings are particularly important for hepatologists, transplant surgeons, and patients with cirrhosis, as they offer a novel approach to complement existing prognostic models such as model for end-stage liver disease-sodium. In practical terms, the ACE score could be integrated into routine clinical assessments to provide more accurate risk predictions, potentially improving the timing of interventions, optimizing transplant listing decisions, and ultimately enhancing patient outcomes. However, further validation in diverse populations and integration with other established predictors is necessary before widespread clinical implementation.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101356"},"PeriodicalIF":9.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815576","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":"Salsalate improves the anti-tumor efficacy of Lenvatinib in MASH-driven hepatocellular carcinoma.","authors":"Evangelia E. Tsakiridis ,&nbsp;Elham Ahmadi ,&nbsp;Jaya Gautam ,&nbsp;Yi Ran Hannah She ,&nbsp;Russta Fayyazi ,&nbsp;James S.V. Lally ,&nbsp;Simon Wang ,&nbsp;Fiorella Di Pastena ,&nbsp;Celina M. Valvano ,&nbsp;Daniel Del Rosso ,&nbsp;Olga-Demetra Biziotis ,&nbsp;Brandon Meyers ,&nbsp;Paola Muti ,&nbsp;Theodoros Tsakiridis ,&nbsp;Gregory Steinberg","doi":"10.1016/j.jhepr.2025.101354","DOIUrl":"10.1016/j.jhepr.2025.101354","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Metabolic dysfunction associated steatohepatitis (MASH) is a growing contributor of hepatocellular carcinoma (HCC) worldwide. The complex microenvironment of these tumors, characterized by metabolic dysfunction, hypoxia, steatosis, and fibrosis limits, the effectiveness of standard of care therapies such as the multi-tyrosine kinase inhibitor Lenvatinib. Salsalate, a rheumatoid arthritis therapy that stimulates AMP-activated protein kinase (AMPK) enhances fatty acid oxidation and reduces de-novo lipogenesis, fibrosis and cell proliferation pathways. We hypothesise that addition of Salsalate could improve the efficacy of Lenvatinib in MASH-HCC.</div></div><div><h3>Methods</h3><div>We assessed the efficacy of combination therapy using clinically relevant concentrations of Lenvatinib and Salsalate in human HCC cell models, orthotopic xenograft and MASH-HCC mouse models. Additionally, in vitro assays assessing fat oxidation and lipogenesis, protein immunoblotting and RNA-sequencing were employed to understand mechanisms at play.</div></div><div><h3>Results</h3><div>Combined Lenvatinib plus Salsalate synergistically suppressed proliferation and clonogenic survival in cells (p≤0.0001), prolonged survival in an orthotopic xenograft model (p=0.02) and reduced angiogenesis, fibrosis and steatosis (p≤0.05) in a MASH-HCC model. These effects were associated with activation of AMPK and inhibition of the mTOR-HIF1α and Erk1/2 signaling pathways. RNA-sequencing analysis in both Hep3B cells and livers of the MASH-HCC mouse model revealed that Salsalate enhanced mitochondria fatty acid oxidation and suppressed fibrosis and cell cycle progression while Lenvatinib reduced angiogenesis with regulatory network analysis suggesting a potential role for Activating Transcription Factor 3 and ETS-proto-oncogene-1.</div></div><div><h3>Conclusions</h3><div>These data indicate that combining Lenvatinib and Salsalate which exert distinct effects leading to improvements in the liver microenvironment (steatosis, angiogenesis and fibrosis) and inhibition of tumor proliferation, may have therapeutic potential for MASH driven HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101354"},"PeriodicalIF":9.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815574","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":"Associations between fruit and vegetable consumption and HCC occurrence in patients with liver cirrhosis","authors":"Florian Manneville ,&nbsp;Zineb Zouakia ,&nbsp;Séverine Donneger ,&nbsp;Leopold K. Fezeu ,&nbsp;Alice Bellicha ,&nbsp;Pierre Nahon ,&nbsp;Mathilde Touvier ,&nbsp;Nathalie Ganne-Carrié ,&nbsp;Chantal Julia","doi":"10.1016/j.jhepr.2025.101355","DOIUrl":"10.1016/j.jhepr.2025.101355","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Prospective studies are needed to increase knowledge of fruit and vegetable consumption effects on hepatocellular carcinoma (HCC) risk. This study aimed to investigate the association between fruit and vegetable consumption and incident HCC in French patients with liver cirrhosis.</div></div><div><h3>Methods</h3><div>This study used data from a French prospective observational cohort nested in two national prospective cohorts of patients with histologically proven compensated alcohol-related or viral liver cirrhosis. Fruit and vegetable consumption was assessed by a trained dietitian using semi-quantitative food-frequency questionnaire validated in French and analyzed as binary exposure according to predefined thresholds (≥ 240 g/day for fruit or vegetables and ≥ 400 g/day for fruit and vegetables combined). Incident HCC was primary outcome. Propensity scores were used in Poisson regression models.</div></div><div><h3>Results</h3><div>Among 179 patients analyzed, 20 HCC were diagnosed during follow-up (median 7.3 [Q1-Q3: 4.1-8.0] years). A significant association was observed between HCC incidence and vegetable consumption ≥ 240 g/day (adjusted RR 0.35, 95%CI [0.13; 0.98], p = 0,04), but not with consumption of fruit and vegetable ≥ 400 g/day (RR 0.49, 95%CI [0.18; 1.32], p =0,16), nor with fruit consumption ≥ 240 g/day (RR= 0.80, 95% CI [0.28; 2.31], p=0.68).</div></div><div><h3>Conclusions</h3><div>This longitudinal study documented insufficient fruit and/or vegetable consumption in 42.5% of patients with liver cirrhosis and a 65% reduction of HCC incidence in those with vegetable consumption ≥ 240 g/day. Reproduction of results in a larger sample are necessary to explore the potential of fruit and vegetables as protective factors in HCC.</div></div><div><h3>Impact and implications</h3><div>The association between fruit and vegetable consumption and the risk of hepatocellular carcinoma (HCC) is poorly documented in the population of cirrhotic patients, while such knowledge is crucial for adapting HCC prevention messages. Our study shows 57.5% of patients with liver cirrhosis reported consuming fruit and/or vegetables at or above the French and WHO threshold of 400g/day, with a higher proportion of patients consuming at least 240g/day of vegetable compared with those consuming at least 240g/day of fruit (47.5% versus 38.6%). The results suggest that consuming at least 240g/day of vegetables reduces the risk of HCC by 65% in patients with liver cirrhosis.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101355"},"PeriodicalIF":9.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cirrhosis epidemiology in Denmark 1998–2022, and 2030 forecast","authors":"Linda Skibsted Kornerup ,&nbsp;Frederik Kraglund ,&nbsp;Gro Askgaard ,&nbsp;Hendrik Vilstrup ,&nbsp;Peter Jepsen","doi":"10.1016/j.jhepr.2025.101353","DOIUrl":"10.1016/j.jhepr.2025.101353","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The incidence of cirrhosis resulting from alcohol-related liver disease (ALD) is decreasing in Denmark, whereas the incidence of obesity is increasing, driving an increase in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to perform an up-to-date study of the epidemiology of cirrhosis in Denmark, including etiologies, and a forecast through to 2030.</div></div><div><h3>Methods</h3><div>We identified all patients diagnosed with cirrhosis between 1998 and 2022, categorized into ALD and non-ALD cirrhosis, in nationwide Danish healthcare registries. Cirrhosis prevalence and incidence were computed. We used an age–period–cohort model to visualize impacts of age, calendar year, and birthyear on etiology-specific cirrhosis incidence rates (alcohol or non-alcohol, interpreted as mainly the result of MASLD), with predicted incidence rates for 2023–2030. The Kaplan-Meier function was used for survival probabilities.</div></div><div><h3>Results</h3><div>We included 30,747 (76%) patients with ALD cirrhosis and 9,548 (24%) with non-ALD cirrhosis. Patients with non-ALD cirrhosis were older and had more comorbidities compared with patients with ALD cirrhosis; median age at diagnosis was 66 <em>vs.</em> 59 years, increasing in both groups overall, from 56 years in 1998 to 66 years in 2022. The ALD cirrhosis proportion was stable at around 80% from 1998 to the end of 2014, and gradually declined to 58% in 2022. Overall cirrhosis prevalence will have peaked in 2024, and non-ALD cirrhosis will outnumber ALD cirrhosis from 2027. Thus, mortality among patients with cirrhosis is declining owing to fewer deaths the first year after cirrhosis diagnosis.</div></div><div><h3>Conclusions</h3><div>We forecast a change in cirrhosis epidemiology affecting hepatology practice in Denmark: patients will be older, fewer will have ALD, more will have MASLD, and their longer life expectancy and comorbidities will be more burdensome for healthcare systems.</div></div><div><h3>Impact and implications</h3><div>Alcohol-related liver (ALD) cirrhosis poses a substantial and growing burden on hospitals worldwide. Information about the current and imminent epidemiology of cirrhosis is important for our understanding of the public health, for researchers designing trials of interventions, and for planning of future assignments of healthcare systems. In the current study, we used Danish nationwide healthcare registries to study past, current, and future trends in the epidemiology of cirrhosis. Our results forecast a change in cirrhosis epidemiology and thereby a change in hepatology practice in Denmark. We expect that patients with ALD cirrhosis will be outnumbered by increasingly older patients who present in the outpatient clinic with cirrhosis from MASLD and a higher burden of comorbidities.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101353"},"PeriodicalIF":9.5,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pravastatin reduces all-cause mortality in elderly individuals at risk of liver fibrosis: Post hoc analysis of the PROSPER trial","authors":"Vivian de Jong ,&nbsp;Willy Theel ,&nbsp;Manuel Castro Cabezas ,&nbsp;Diederick E. Grobbee ,&nbsp;Wouter Jukema ,&nbsp;Stella Trompet","doi":"10.1016/j.jhepr.2025.101337","DOIUrl":"10.1016/j.jhepr.2025.101337","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD), especially the progressive stages accompanied by liver fibrosis, are associated with liver-related and cardiovascular (CV) complications in middle-aged cohorts. We evaluated whether liver fibrosis is associated with increased mortality and cause-specific endpoints in an elderly population, and whether statin treatment could reduce these risks.</div></div><div><h3>Methods</h3><div>PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a double-blind randomized clinical trial comparing pravastatin to placebo in an elderly Caucasian population of 5,804 patients (&gt;70 years of age) at increased risk of CV disease. Endpoints were composite and single (CV) endpoints and all-cause mortality. The Fibrosis-4 index (FIB-4) score was classified as: low risk of liver fibrosis (FIB-4 &lt;2.0), indeterminate risk (2.0≤ FIB-4 ≤2.66), and high risk (FIB-4 ≥2.67). Time-to-event data were analyzed using the Cox proportional hazards model.</div></div><div><h3>Results</h3><div>Most participants were classified in the low FIB-4 class (n = 3,919), followed by the indeterminate (n = 1,269) and high classes (n = 561). In the placebo group, the risk of all-cause mortality increased with a high FIB-4 classification: high-class hazard ratio (HR) = 1.54 (95% CI, 1.10–2.17), compared with the low class (reference group). In the pravastatin group, the HR for all-cause mortality was not associated with FIB-4 classification: high-class HR = 1.01 (95% CI, 0.69–1.49). The interaction between FIB-4 class and treatment was significant (<em>p</em> = 0.049). High FIB-4 classifications were not significantly associated with major adverse cardiovascular events (MACE) or other endpoints in either arms.</div></div><div><h3>Conclusions</h3><div>A high FIB-4 classification is associated with increased all-cause mortality in the elderly, although pravastatin appears to mitigate this increased risk.</div></div><div><h3>Clinical Trials registration</h3><div>The study is registered at <span><span>www.isrctn.com/</span><svg><path></path></svg></span>(ISRCTN40976937).</div></div><div><h3>Impact and implications</h3><div>The progressive stages of MASLD (liver fibrosis) are associated with liver-related and CV complications in middle-aged cohorts (∼55 years of age). The impact of liver fibrosis in elderly populations is less well studied. In addition, the use of statins has long been debated, but evidence appears to point to a beneficial effect in populations with MASLD. However, data from prospective trials remain limited. Our findings indicate a potential survival benefit associated with pravastatin use in the elderly (&gt;70 years of age) with an indication of liver fibrosis.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 4","pages":"Article 101337"},"PeriodicalIF":9.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive tests for fibrotic MASH for reducing screen failure in therapeutic trials","authors":"Jeanne Fichez ,&nbsp;Thomas Mouillot ,&nbsp;Luisa Vonghia ,&nbsp;Charlotte Costentin ,&nbsp;Clémence Moreau ,&nbsp;Marine Roux ,&nbsp;Adèle Delamarre ,&nbsp;Sven Francque ,&nbsp;Ming-Hua Zheng ,&nbsp;Jérôme Boursier","doi":"10.1016/j.jhepr.2025.101351","DOIUrl":"10.1016/j.jhepr.2025.101351","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Therapeutic trials in metabolic dysfunction-associated steatohepatitis (MASH) are hampered by a high 70–80% screen failure rate mostly because of the absence of fibrotic MASH on baseline liver biopsies, underscoring the need for better selection of candidates. We compared the performance of eight non-invasive tests, designed or not for the diagnosis of fibrotic MASH.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A total of 1,005 patients with histologically proven MASLD were included in five tertiary care centers. Three non-invasive tests developed for fibrotic MASH were evaluated: the simple blood test Fibrotic NASH Index (FNI), the specialized blood test MACK-3, and the elastography-based test FAST. Five non-invasive tests recommended for advanced fibrosis were evaluated as well: the simple blood test FIB-4, the specialized blood tests FibroTest and Enhanced Liver Fibrosis test (ELF™), and the elastography-based tests FibroScan and Agile3+. Fibrotic MASH was defined as MASH with MASLD activity score ≥4 and fibrosis score F ≥2.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Among simple blood tests (n = 1,005), FNI had a significantly higher area under the receiver operating characteristic (AUROC) for fibrotic MASH than FIB-4 (0.709 [0.677–0.741] &lt;em&gt;vs.&lt;/em&gt; 0.662 [0.628–0.695], &lt;em&gt;p&lt;/em&gt; = 0.019). Among elastography-based tests (n = 817), FAST had a significantly higher AUROC (0.774 [0.743–0.806]) than FibroScan (0.728 [0.694–0.763], &lt;em&gt;p&lt;/em&gt; = 0.013) and Agile3+ (0.708 [0.672–0.744], &lt;em&gt;p&lt;/em&gt; = 0.004). Among specialized blood tests (n = 545), MACK-3 had a significantly higher AUROC (0.772 [0.734–0.811]) than FibroTest (0.615 [0.568–0.663], &lt;em&gt;p&lt;/em&gt; &lt;0.001) and ELF (0.700 [0.656–0.744], &lt;em&gt;p&lt;/em&gt; = 0.028). Sequential combination (FAST then Agile3+; MACK-3 then ELF) identified a subset including one-third of patients in whom the false-positive rate was only 30%.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Sequential combinations using first-line tests designed for fibrotic MASH improves the identification of candidates for MASH therapeutic trials.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Drug development in metabolic dysfunction-associated steatohepatitis (MASH) is hampered by a high screen failure rate, one of the main reasons being the absence of MASH and significant fibrosis (fibrotic MASH) on the baseline liver biopsy, a key inclusion criterion in MASH therapeutic trials. Non-invasive tests represent an attractive opportunity to better select candidates for these trials, but most of them have been developed for advanced fibrosis and the new tests designed for the diagnosis of fibrotic MASH remain poorly validated. In this work, we demonstrate that the tests specifically designed for fibrotic MASH are more accurate for this diagnostic target than the tests currently recommended and initially developed for advanced fibrosis. We propose sequential combinations that will facilitate the identification of ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 4","pages":"Article 101351"},"PeriodicalIF":9.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copyright and information","authors":"","doi":"10.1016/S2589-5559(25)00023-0","DOIUrl":"10.1016/S2589-5559(25)00023-0","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 2","pages":"Article 101347"},"PeriodicalIF":9.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143296917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Second-line treatment patterns and outcomes in advanced HCC after progression on atezolizumab/bevacizumab","authors":"Meng Wu ,&nbsp;Claudia A.M. Fulgenzi ,&nbsp;Antonio D’Alessio ,&nbsp;Alessio Cortellini ,&nbsp;Ciro Celsa ,&nbsp;Giulia F. Manfredi ,&nbsp;Bernardo Stefanini ,&nbsp;Y. Linda Wu ,&nbsp;Yi-Hsiang Huang ,&nbsp;Anwaar Saeed ,&nbsp;Angelo Pirozzi ,&nbsp;Tiziana Pressiani ,&nbsp;Lorenza Rimassa ,&nbsp;Martin Schoenlein ,&nbsp;Kornelius Schulze ,&nbsp;Johann von Felden ,&nbsp;Yehia Mohamed ,&nbsp;Ahmed O. Kaseb ,&nbsp;Arndt Vogel ,&nbsp;Natascha Roehlen ,&nbsp;Celina Ang","doi":"10.1016/j.jhepr.2024.101232","DOIUrl":"10.1016/j.jhepr.2024.101232","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Atezolizumab/bevacizumab (A/B) is now a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but the optimal second-line regimen is not known. We evaluated real-world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS).</div></div><div><h3>Methods</h3><div>In this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with advanced HCC who progressed on first-line A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death.</div></div><div><h3>Results</h3><div>A total of 406 patients alive after progression on first-line A/B were included in the final analysis, of whom 45.3% (n = 184) received best supportive treatment (BST) and 54.7% (n = 222) continued active systemic treatment. In the second line, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG &lt;2, and continued active treatment were predictors of better PPS. mPPS was significantly longer for patients who continued active treatment <em>vs.</em> BST (9.7 <em>vs.</em> 2.6 months; HR 0.41, <em>p &lt;</em>0.001). In the second-line setting, patients treated with TKIs had a numerically shorter mPPS compared to those treated with IO (8.4 <em>vs.</em> 14.9 months; HR 1.37, <em>p =</em> 0.256).</div></div><div><h3>Conclusions</h3><div>Continuation of active therapy after A/B progression was independently associated with better survival even after adjusting for baseline disease characteristics. mPPS with IO-based therapy exceeded a year, suggesting that IO continuation post-progression may retain benefit. The precise sequencing of TKI and IO regimens warrants further investigation.</div></div><div><h3>Impact and implications:</h3><div>There is currently a lack of level 1 data on second-line treatment options for patients with advanced hepatocellular carcinoma who progress after frontline atezolizumab plus bevacizumab, as all second-line approvals were established during the frontline sorafenib era. Our study aims to fill in some of the knowledge gap by investigating real-world patient outcomes in the second-line treatment setting. Findings from this study show that patients who continued active treatment had improved post-progression survival compared to those who received best supportive care, and medication regimens incorporating tyrosine kinase inhibitors as well as immunotherapy agents were active. These results can help inform clinicians of possible treatment options for patients who progress after frontline atezolizumab plus bevacizumab while we await maturing data from randomized-controlled trials.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 2","pages":"Article 101232"},"PeriodicalIF":9.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}