Pub Date : 2026-03-01Epub Date: 2025-12-22DOI: 10.1016/j.jhepr.2025.101700
Bregje Mol , Moyrha van Nieuwamerongen , Kim N. van Munster , Martti Färkkilä , Trine Folseraas , Sara K.V. Tjønnfjord , Johannes R. Hov , Kirsten Boberg , Mette Vesterhus , Kristin K. Jørgensen , Annika Bergquist , Jorn C. Goet , Annemarie C. de Vries , Adriaan J.P. van der Meer , Rinse K. Weersma , Akin Inderson , Johannes A. Bogaards , Cyriel Y. Ponsioen , IPSCR study group
Background & Aims
The gut–liver axis is believed to be crucial in the pathogenesis of primary sclerosing cholangitis (PSC). However, the impact of colectomy on liver disease progression is unclear. Our study estimated the effect of colectomy on PSC progression with correction for time dependency and established risk factors by pooling data from several cohorts across different countries.
Methods
We analysed data from the International PSC Registry (IPSCR), comprising patients from Finland, The Netherlands, Norway, and Sweden. Primary endpoint was defined as liver transplantation (LT) or PSC-related death. Cox proportional hazards regression onto time-dependent colectomy status, with specification for extent, was performed with adjustment for sex, age at diagnosis, large or small duct PSC, features of autoimmune hepatitis, time-dependent inflammatory bowel disease (IBD) status, centre of inclusion, and country of residence.
Results
A total of 3,110 participants were included, of whom 470 (15%) had undergone colectomy. During a total follow-up of 32,236 patient-years, 395 deaths and 653 LTs were observed. Compared with patients with PSC with intact colon, the hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy with permanent ileostomy (HR 0.41; 95% CI 0.24–0.71). This effect was less pronounced in case of hemi- or subtotal colectomy (HR 0.81; 95% CI: 0.58–1.12) and not observed for proctocolectomy with pouch (HR 1.00; 95% CI: 0.73–1.38). The reduced risk was mainly associated with a lower rate of LT or death resulting from liver failure (HR 0.24; 0.10–0.53).
Conclusions
Proctocolectomy with permanent ileostomy was associated with decreased risk for LT and PSC-related death. These findings support the role of the gut–liver axis in the pathophysiology of PSC and call for consideration in counselling patients who face impending colorectal surgery.
Impact and implications
The impact of the gut-liver axis in the pathophysiology of primary sclerosing cholangitis (PSC) has remained uncertain. In this study, proctocolectomy with ileostomy was associated with improved transplant-free survival, defined as a reduced risk of liver transplantation or PSC-related death, indicating that intestinal factors may influence disease progression. These findings are important for clinicians, researchers, and patients as they suggest that surgical management of colonic disease may have prognostic implications in PSC, and for further studies to clarify mechanisms and guide clinical decision-making.
{"title":"Proctocolectomy with permanent ileostomy is associated with improved transplant-free survival in patients with PSC","authors":"Bregje Mol , Moyrha van Nieuwamerongen , Kim N. van Munster , Martti Färkkilä , Trine Folseraas , Sara K.V. Tjønnfjord , Johannes R. Hov , Kirsten Boberg , Mette Vesterhus , Kristin K. Jørgensen , Annika Bergquist , Jorn C. Goet , Annemarie C. de Vries , Adriaan J.P. van der Meer , Rinse K. Weersma , Akin Inderson , Johannes A. Bogaards , Cyriel Y. Ponsioen , IPSCR study group","doi":"10.1016/j.jhepr.2025.101700","DOIUrl":"10.1016/j.jhepr.2025.101700","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The gut–liver axis is believed to be crucial in the pathogenesis of primary sclerosing cholangitis (PSC). However, the impact of colectomy on liver disease progression is unclear. Our study estimated the effect of colectomy on PSC progression with correction for time dependency and established risk factors by pooling data from several cohorts across different countries.</div></div><div><h3>Methods</h3><div>We analysed data from the International PSC Registry (IPSCR), comprising patients from Finland, The Netherlands, Norway, and Sweden. Primary endpoint was defined as liver transplantation (LT) or PSC-related death. Cox proportional hazards regression onto time-dependent colectomy status, with specification for extent, was performed with adjustment for sex, age at diagnosis, large or small duct PSC, features of autoimmune hepatitis, time-dependent inflammatory bowel disease (IBD) status, centre of inclusion, and country of residence.</div></div><div><h3>Results</h3><div>A total of 3,110 participants were included, of whom 470 (15%) had undergone colectomy. During a total follow-up of 32,236 patient-years, 395 deaths and 653 LTs were observed. Compared with patients with PSC with intact colon, the hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy with permanent ileostomy (HR 0.41; 95% CI 0.24–0.71). This effect was less pronounced in case of hemi- or subtotal colectomy (HR 0.81; 95% CI: 0.58–1.12) and not observed for proctocolectomy with pouch (HR 1.00; 95% CI: 0.73–1.38). The reduced risk was mainly associated with a lower rate of LT or death resulting from liver failure (HR 0.24; 0.10–0.53).</div></div><div><h3>Conclusions</h3><div>Proctocolectomy with permanent ileostomy was associated with decreased risk for LT and PSC-related death. These findings support the role of the gut–liver axis in the pathophysiology of PSC and call for consideration in counselling patients who face impending colorectal surgery.</div></div><div><h3>Impact and implications</h3><div>The impact of the gut-liver axis in the pathophysiology of primary sclerosing cholangitis (PSC) has remained uncertain. In this study, proctocolectomy with ileostomy was associated with improved transplant-free survival, defined as a reduced risk of liver transplantation or PSC-related death, indicating that intestinal factors may influence disease progression. These findings are important for clinicians, researchers, and patients as they suggest that surgical management of colonic disease may have prognostic implications in PSC, and for further studies to clarify mechanisms and guide clinical decision-making.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101700"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147306246","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 : 2026-03-01Epub Date: 2025-12-13DOI: 10.1016/j.jhepr.2025.101712
Daniel Segna , Benjamin Messerli , Ulrich Baumann , Jaume Bosch , Annalisa Berzigotti
Background & Aims
Patients with decompensated cirrhosis are susceptible to iatrogenic hypervolemia. A pilot study using point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) found severe hypervolemia in 20% of patients after intravenous (IV) albumin, despite adherence to current guidelines. CPMX2 is a novel non-invasive device that uses external jugular vein (EJV) compression to assess central venous pressure, but its ability to predict post-albumin hypervolemia has not been studied. We aimed to track changes in intravascular volume status during passive leg raise (PLR) and IV albumin using both methods.
Methods
IVC diameters (IVCmin, IVCmax) and IVC collapsibility index (IVCCI) were measured by POCUS, and EJV compression pressures (EJVmin, EJVmax, EJVmean) were measured by CPMX2, in parallel before and during PLR, as well as before and after IV albumin. Potential intravascular overload was defined as IVCmax >2.1 cm and IVCCI <50%, or EJVmean ≥9 mmHg.
Results
In this prospective cohort of 20 patients (35% women; median age 62 years; mean BMI 25.7 kg/m2; 55% Child-Pugh B; 80% receiving paracentesis), all IVC diameters and EJV compression pressures increased during PLR and after IV albumin. Percentage changes in EJV compression pressures were greater than changes in IVC diameters during PLR (mean EJVmax +88%, EJVmean +65% vs. IVCmax +16%, IVCmin +26%; all p <0.01). After IV albumin, changes were comparable between the methods (mean EJVmax +68%, EJVmin +80%, EJVmean +75% vs IVCmax +58%, IVCmin +79%). Potential post-albumin volume overload occurred in most cases (POCUS 65%, CPMX2 95%).
Conclusions
Both POCUS and CPMX2 detected substantial volume changes during PLR and following IV albumin. CPMX2 appeared more sensitive to dynamic changes during PLR and identified more patients with potential post-albumin volume overload, suggesting it may help individualize fluid management in decompensated cirrhosis.
Impact and implications
Intravascular volume overload after albumin infusion is a major concern in patients with decompensated cirrhosis and was observed in its most severe form in 20% of patients using POCUS-IVC (point-of-care ultrasound of the inferior vena cava). In this pilot study, we detected substantial volume shifts during passive leg raise and after albumin infusion using both POCUS-IVC and a novel external jugular vein compression technique (CPMX2) in parallel. CPMX2 appeared more sensitive to dynamic changes during passive leg raise and identified a larger proportion of patients with intravascular volume overload following intravenous albumin. These findings suggest that CPMX2 could serve as a promising non-invasive tool for early assessment and individualized monitoring of volume status in decompensated cirrhosis.
{"title":"Compression pressure of the external jugular vein for the assessment of intravascular volume status in decompensated cirrhosis: A pilot study","authors":"Daniel Segna , Benjamin Messerli , Ulrich Baumann , Jaume Bosch , Annalisa Berzigotti","doi":"10.1016/j.jhepr.2025.101712","DOIUrl":"10.1016/j.jhepr.2025.101712","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Patients with decompensated cirrhosis are susceptible to iatrogenic hypervolemia. A pilot study using point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) found severe hypervolemia in 20% of patients after intravenous (IV) albumin, despite adherence to current guidelines. CPMX2 is a novel non-invasive device that uses external jugular vein (EJV) compression to assess central venous pressure, but its ability to predict post-albumin hypervolemia has not been studied. We aimed to track changes in intravascular volume status during passive leg raise (PLR) and IV albumin using both methods.</div></div><div><h3>Methods</h3><div>IVC diameters (IVCmin, IVCmax) and IVC collapsibility index (IVCCI) were measured by POCUS, and EJV compression pressures (EJVmin, EJVmax, EJVmean) were measured by CPMX2, in parallel before and during PLR, as well as before and after IV albumin. Potential intravascular overload was defined as IVCmax >2.1 cm and IVCCI <50%, or EJVmean ≥9 mmHg.</div></div><div><h3>Results</h3><div>In this prospective cohort of 20 patients (35% women; median age 62 years; mean BMI 25.7 kg/m<sup>2</sup>; 55% Child-Pugh B; 80% receiving paracentesis), all IVC diameters and EJV compression pressures increased during PLR and after IV albumin. Percentage changes in EJV compression pressures were greater than changes in IVC diameters during PLR (mean EJVmax +88%, EJVmean +65% <em>vs.</em> IVCmax +16%, IVCmin +26%; all <em>p</em> <0.01). After IV albumin, changes were comparable between the methods (mean EJVmax +68%, EJVmin +80%, EJVmean +75% vs IVCmax +58%, IVCmin +79%). Potential post-albumin volume overload occurred in most cases (POCUS 65%, CPMX2 95%).</div></div><div><h3>Conclusions</h3><div>Both POCUS and CPMX2 detected substantial volume changes during PLR and following IV albumin. CPMX2 appeared more sensitive to dynamic changes during PLR and identified more patients with potential post-albumin volume overload, suggesting it may help individualize fluid management in decompensated cirrhosis.</div></div><div><h3>Impact and implications</h3><div>Intravascular volume overload after albumin infusion is a major concern in patients with decompensated cirrhosis and was observed in its most severe form in 20% of patients using POCUS-IVC (point-of-care ultrasound of the inferior vena cava). In this pilot study, we detected substantial volume shifts during passive leg raise and after albumin infusion using both POCUS-IVC and a novel external jugular vein compression technique (CPMX2) in parallel. CPMX2 appeared more sensitive to dynamic changes during passive leg raise and identified a larger proportion of patients with intravascular volume overload following intravenous albumin. These findings suggest that CPMX2 could serve as a promising non-invasive tool for early assessment and individualized monitoring of volume status in decompensated cirrhosis.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101712"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213147","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 : 2026-03-01Epub Date: 2025-12-04DOI: 10.1016/j.jhepr.2025.101705
Marzia Rossi , Andrea Vecchi , Camilla Tiezzi , Francesca Guerrieri , Marie Laure Plissonnier , Elisabetta Degasperi , Dana Sambarino , Diletta Laccabue , Arianna Alfieri , Elena Adelina Gabor , Amalia Penna , Valentina Reverberi , Anna Montali , Alessio Pelagatti , Sara Doselli , Benedetta Farina , Giuseppe Pedrazzi , Paola Fisicaro , Gabriele Missale , Pietro Lampertico , Carolina Boni
<div><h3>Background & Aims</h3><div>In chronic HBV infection, HBV-specific CD8 T cells are dysfunctional and comprise distinct subsets defined by phenotype and antigen specificity. We aimed to characterize the transcriptional and functional features of HBV-specific CD8 T-cell subsets in patients with HBeAg-negative chronic HBV infection who were either viremic (CHB) or had achieved spontaneous or nucleos(t)ide analogue (NUC)–induced HBsAg loss (RES), to better elucidate HBV-specific CD8 T-cell dysfunction and identify potential molecular targets for functional cure.</div></div><div><h3>Methods</h3><div>Gene expression profiles of PD1<sup>hi</sup>CD127<sup>low/-</sup> and PD1+CD127+ memory-like (<em>ML</em>) core<sub>18-27</sub>-specific CD8 T-cell subsets were analyzed by Nanostring, adapted for low-input samples in 5 patients with HBeAg-negative CHB and 6 with RES. An expanded cohort of 23 patients with CHB and 22 with RES was evaluated for phenotypic and functional profiling. Selected deregulated genes were functionally validated in an additional cohort of 14 patients with HLA-A2-negative CHB.</div></div><div><h3>Results</h3><div>Analysis of 84 genes concurrently expressed across all CD8 T-cell subsets identified an 11-gene signature describing a progressive transition from exhaustion-oriented PD1<sup>hi</sup>CD127<sup>low/-</sup> CD8 T cells in patients with CHB to memory-oriented <em>ML</em> CD8 cells in patients with RES, representing the two extremes of differentiation. Intermediate stages of memory differentiation were identified among <em>ML</em> CD8 T cells from patients with CHB, with high or low TOX expression (<em>p</em> <0.05 by Spearman's rank correlation). Higher frequencies of TOX<sup>low</sup> <em>ML</em> CD8 cells in patients with CHB were associated with a greater serum HBsAg decline during NUC treatment compared to TOX<sup>high</sup> <em>ML</em>CHB (Δ slope <em>p</em> value = 0.003). Targeting selected deregulated genes with specific immune modulators significantly enhanced cytokine production by CD8 T cells, with response rates ranging from 30% to 86% of patients.</div></div><div><h3>Conclusions</h3><div>Distinct exhaustion signatures characterize HBV-specific CD8 T-cell subsets and vary across disease phases. These findings support the development of individualized transcriptional and functional correction strategies and identify novel immune modulators with potential for immune-based anti-HBV therapies.</div></div><div><h3>Impact and implications</h3><div>Exhausted HBV-specific CD8 T cells in chronic HBV infection are not a homogeneous population but comprise distinct subsets with differing capacities to control infection. This study identifies: (i) a transcriptional continuum of HBV-specific CD8 T-cell subsets spanning exhaustion to memory differentiation, reflecting disease progression and recovery in HBeAg-negative CHB; (ii) a core CD8 T-cell exhaustion gene signature characterized by progressively increased expre
{"title":"Transcriptional and functional HBV-specific CD8 T cell changes from disease to functional cure in HBeAg-negative chronic hepatitis B","authors":"Marzia Rossi , Andrea Vecchi , Camilla Tiezzi , Francesca Guerrieri , Marie Laure Plissonnier , Elisabetta Degasperi , Dana Sambarino , Diletta Laccabue , Arianna Alfieri , Elena Adelina Gabor , Amalia Penna , Valentina Reverberi , Anna Montali , Alessio Pelagatti , Sara Doselli , Benedetta Farina , Giuseppe Pedrazzi , Paola Fisicaro , Gabriele Missale , Pietro Lampertico , Carolina Boni","doi":"10.1016/j.jhepr.2025.101705","DOIUrl":"10.1016/j.jhepr.2025.101705","url":null,"abstract":"<div><h3>Background & Aims</h3><div>In chronic HBV infection, HBV-specific CD8 T cells are dysfunctional and comprise distinct subsets defined by phenotype and antigen specificity. We aimed to characterize the transcriptional and functional features of HBV-specific CD8 T-cell subsets in patients with HBeAg-negative chronic HBV infection who were either viremic (CHB) or had achieved spontaneous or nucleos(t)ide analogue (NUC)–induced HBsAg loss (RES), to better elucidate HBV-specific CD8 T-cell dysfunction and identify potential molecular targets for functional cure.</div></div><div><h3>Methods</h3><div>Gene expression profiles of PD1<sup>hi</sup>CD127<sup>low/-</sup> and PD1+CD127+ memory-like (<em>ML</em>) core<sub>18-27</sub>-specific CD8 T-cell subsets were analyzed by Nanostring, adapted for low-input samples in 5 patients with HBeAg-negative CHB and 6 with RES. An expanded cohort of 23 patients with CHB and 22 with RES was evaluated for phenotypic and functional profiling. Selected deregulated genes were functionally validated in an additional cohort of 14 patients with HLA-A2-negative CHB.</div></div><div><h3>Results</h3><div>Analysis of 84 genes concurrently expressed across all CD8 T-cell subsets identified an 11-gene signature describing a progressive transition from exhaustion-oriented PD1<sup>hi</sup>CD127<sup>low/-</sup> CD8 T cells in patients with CHB to memory-oriented <em>ML</em> CD8 cells in patients with RES, representing the two extremes of differentiation. Intermediate stages of memory differentiation were identified among <em>ML</em> CD8 T cells from patients with CHB, with high or low TOX expression (<em>p</em> <0.05 by Spearman's rank correlation). Higher frequencies of TOX<sup>low</sup> <em>ML</em> CD8 cells in patients with CHB were associated with a greater serum HBsAg decline during NUC treatment compared to TOX<sup>high</sup> <em>ML</em>CHB (Δ slope <em>p</em> value = 0.003). Targeting selected deregulated genes with specific immune modulators significantly enhanced cytokine production by CD8 T cells, with response rates ranging from 30% to 86% of patients.</div></div><div><h3>Conclusions</h3><div>Distinct exhaustion signatures characterize HBV-specific CD8 T-cell subsets and vary across disease phases. These findings support the development of individualized transcriptional and functional correction strategies and identify novel immune modulators with potential for immune-based anti-HBV therapies.</div></div><div><h3>Impact and implications</h3><div>Exhausted HBV-specific CD8 T cells in chronic HBV infection are not a homogeneous population but comprise distinct subsets with differing capacities to control infection. This study identifies: (i) a transcriptional continuum of HBV-specific CD8 T-cell subsets spanning exhaustion to memory differentiation, reflecting disease progression and recovery in HBeAg-negative CHB; (ii) a core CD8 T-cell exhaustion gene signature characterized by progressively increased expre","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101705"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213132","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 : 2026-03-01Epub Date: 2026-01-18DOI: 10.1016/j.jhepr.2026.101738
Dong Jun Shin , Sohyun Hwang , Beodeul Kang , Won Suk Lee , So Jung Kong , Hannah Yang , Haeyoun Kang , Sung Hwan Lee , Jung Sun Kim , Jinhyung Heo , Ho Yeong Lim , Jingwen Shi , Yongchun Tong , Gwangil Kim , Chan Kim , Hong Jae Chon
Background & Aims
The membrane proteoglycan glypican-3 (GPC3) is expressed in ∼70%–80% of hepatocellular carcinomas (HCCs), and its soluble fragment is released into the circulation by protease cleavage. We investigated correlations between tumor and plasma GPC3 levels and their associations with clinical outcomes in advanced HCC.
Methods
We analyzed 186 patients with advanced HCC treated between 2017 and 2023. Tumor GPC3 expression was assessed using immunohistochemistry and RNA sequencing, and plasma GPC3 by ELISA. Clinical outcomes were investigated in 106 patients receiving first-line atezolizumab plus bevacizumab.
Results
Plasma GPC3 was detectable in 59.3% of patients (median 11.4 pg/ml), and correlated with tumor expression (H-score: R = 0.40, p <0.001). Plasma GPC3 positivity (>0 pg/ml) increased across H-score strata (p <0.001) but remained undetectable in 25.9% with H-scores >200. High plasma GPC3 (>10 pg/ml) was associated with shorter progression-free survival (3.4 vs. 9.4 months, p = 0.003), overall survival (12.3 vs. 30.6 months, p <0.001) and lower objective response rates (17.9% vs. 47.9%, p = 0.001). Compared to tumor values, plasma GPC3 better predicted 6- and 12- month outcomes, and was independently associated with worse progression-free survival (hazard ratio 1.70, 95% CI 1.07–2.69, p = 0.02) and overall survival (1.96, 1.12–3.40, p = 0.02) on multivariable analyses.
Conclusions
While plasma GPC3 levels showed moderate concordance with tumor expression, meaningful discrepancies were also noted in a significant fraction of patients. High plasma GPC3 independently predicted worse survival outcomes in patients treated with atezolizumab plus bevacizumab, showing superior prognostic performance over tumor-based measures.
Impact and implications
Glypican-3 (GPC3) is a promising biomarker and therapeutic target in hepatocellular carcinoma (HCC), yet the relationship between plasma and tumor GPC3 levels remains unclear, and their clinical relevance has not been well defined, particularly in patients receiving atezolizumab plus bevacizumab. Our study provides clinical evidence supporting plasma GPC3 as a non-invasive biomarker in HCC, showing that circulating GPC3 levels are associated with tumor expression but more closely linked to clinical outcomes, serving as an independent predictor of survival and treatment response in patients treated with atezolizumab plus bevacizumab. These findings suggest that plasma-based assessment may complement tissue-based evaluation and support real-time risk stratification in advanced HCC, although further validation in diverse, prospective cohorts is warranted.
背景与目的：膜蛋白多糖甘聚糖-3 （GPC3）在约70%-80%的肝细胞癌（HCCs）中表达，其可溶性片段通过蛋白酶裂解释放到循环中。我们研究了晚期HCC患者肿瘤和血浆GPC3水平的相关性及其与临床结局的关系。方法：我们分析了2017年至2023年期间接受治疗的186例晚期HCC患者。采用免疫组化和RNA测序检测肿瘤GPC3表达，ELISA检测血浆GPC3表达。106例接受阿特唑单抗加贝伐单抗一线治疗的患者的临床结果进行了研究。结果：59.3%的患者血浆中检测到GPC3（中位11.4 pg/ml），并且与肿瘤表达相关（h -评分：R = 0.40, p 0 pg/ml）在h -评分层中升高(p 200。高血浆GPC3 （10 pg/ml）与较短的无进展生存期（3.4 vs. 9.4个月，p = 0.003）和总生存期（12.3 vs. 30.6个月，p vs. 47.9%, p = 0.001）相关。与肿瘤值相比，血浆GPC3更好地预测6个月和12个月的预后，并且在多变量分析中与较差的无进展生存（风险比1.70,95% CI 1.07-2.69, p = 0.02）和总生存（1.96,1.12-3.40,p = 0.02）独立相关。结论：血浆GPC3水平与肿瘤表达中度一致，但在相当一部分患者中也存在显著差异。高血浆GPC3独立预测atezolizumab + bevacizumab治疗的患者更差的生存结果，比基于肿瘤的指标显示出更好的预后表现。影响和意义：Glypican-3 （GPC3）是肝细胞癌（HCC）中很有前景的生物标志物和治疗靶点，但血浆和肿瘤GPC3水平之间的关系尚不清楚，其临床相关性尚未明确，特别是在接受阿特唑单抗和贝伐单抗联合治疗的患者中。我们的研究提供了临床证据，支持血浆GPC3作为HCC的非侵入性生物标志物，表明循环GPC3水平与肿瘤表达相关，但与临床结果更密切相关，可作为atezolizumab联合贝伐单抗治疗的患者生存和治疗反应的独立预测因子。这些发现表明，基于血浆的评估可以补充基于组织的评估，并支持晚期HCC的实时风险分层，尽管需要在不同的前瞻性队列中进一步验证。
{"title":"Plasma GPC3 reflects tumor GPC3 expression and predicts clinical outcomes in advanced HCC treated with atezolizumab + bevacizumab","authors":"Dong Jun Shin , Sohyun Hwang , Beodeul Kang , Won Suk Lee , So Jung Kong , Hannah Yang , Haeyoun Kang , Sung Hwan Lee , Jung Sun Kim , Jinhyung Heo , Ho Yeong Lim , Jingwen Shi , Yongchun Tong , Gwangil Kim , Chan Kim , Hong Jae Chon","doi":"10.1016/j.jhepr.2026.101738","DOIUrl":"10.1016/j.jhepr.2026.101738","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The membrane proteoglycan glypican-3 (GPC3) is expressed in ∼70%–80% of hepatocellular carcinomas (HCCs), and its soluble fragment is released into the circulation by protease cleavage. We investigated correlations between tumor and plasma GPC3 levels and their associations with clinical outcomes in advanced HCC.</div></div><div><h3>Methods</h3><div>We analyzed 186 patients with advanced HCC treated between 2017 and 2023. Tumor GPC3 expression was assessed using immunohistochemistry and RNA sequencing, and plasma GPC3 by ELISA. Clinical outcomes were investigated in 106 patients receiving first-line atezolizumab plus bevacizumab.</div></div><div><h3>Results</h3><div>Plasma GPC3 was detectable in 59.3% of patients (median 11.4 pg/ml), and correlated with tumor expression (H-score: R = 0.40, <em>p</em> <0.001). Plasma GPC3 positivity (>0 pg/ml) increased across H-score strata (<em>p</em> <0.001) but remained undetectable in 25.9% with H-scores >200. High plasma GPC3 (>10 pg/ml) was associated with shorter progression-free survival (3.4 <em>vs.</em> 9.4 months, <em>p</em> = 0.003), overall survival (12.3 <em>vs.</em> 30.6 months, <em>p</em> <0.001) and lower objective response rates (17.9% <em>vs.</em> 47.9%, <em>p</em> = 0.001). Compared to tumor values, plasma GPC3 better predicted 6- and 12- month outcomes, and was independently associated with worse progression-free survival (hazard ratio 1.70, 95% CI 1.07–2.69, <em>p</em> = 0.02) and overall survival (1.96, 1.12–3.40, <em>p</em> = 0.02) on multivariable analyses.</div></div><div><h3>Conclusions</h3><div>While plasma GPC3 levels showed moderate concordance with tumor expression, meaningful discrepancies were also noted in a significant fraction of patients. High plasma GPC3 independently predicted worse survival outcomes in patients treated with atezolizumab plus bevacizumab, showing superior prognostic performance over tumor-based measures.</div></div><div><h3>Impact and implications</h3><div>Glypican-3 (GPC3) is a promising biomarker and therapeutic target in hepatocellular carcinoma (HCC), yet the relationship between plasma and tumor GPC3 levels remains unclear, and their clinical relevance has not been well defined, particularly in patients receiving atezolizumab plus bevacizumab. Our study provides clinical evidence supporting plasma GPC3 as a non-invasive biomarker in HCC, showing that circulating GPC3 levels are associated with tumor expression but more closely linked to clinical outcomes, serving as an independent predictor of survival and treatment response in patients treated with atezolizumab plus bevacizumab. These findings suggest that plasma-based assessment may complement tissue-based evaluation and support real-time risk stratification in advanced HCC, although further validation in diverse, prospective cohorts is warranted.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101738"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326114","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 : 2026-03-01Epub Date: 2025-11-20DOI: 10.1016/j.jhepr.2025.101684
Lucy Meunier , Clement Monet , Antonio Saviano , Marwin Farrugia , François Villeret , Fanny Lebossé , Marion Khaldi , Olivier Moranne , Christine Chambon , Philippe Ichai , Astrid Laurent-Bellue , Ariane Laparra , Rodolphe Anty , Simona Tripon , Mialy Randrianarisoa , Alexandre Maria , Lina Hountondji , Eleonora De Martin
Background & Aims
Immune checkpoint inhibitors (ICIs) improve cancer survival but can cause severe immune-related hepatitis. Standard therapy with corticosteroids and second-line agents such as mycophenolate mofetil fails in some cases. Therapeutic plasma exchange (TPE) has been suggested as rescue therapy, but supporting evidence is limited.
Methods
We retrospectively analyzed French multicenter data (March 2021–April 2025) on patients with grade 4 ICI-induced hepatitis refractory to corticosteroids ± other immunosuppressants who underwent TPE.
Results
Thirteen patients (median age 63 years; 54% male) were included. Eleven had acute hepatitis, including seven with acute liver injury, and two had steroid-refractory cholestatic hepatitis. TPE was initiated a median of 28 days after hepatitis onset (median MELD score 21) and administered in 2–8 sessions. Liver function improved in eight patients (61.5%), allowing resumption of anticancer therapy without ICI rechallenge in five. Three patients with cirrhosis and hepatocellular carcinoma died of liver failure, and three died from other causes. TPE-related adverse events were mild to moderate.
Conclusion
TPE is feasible, safe, and may be effective for severe steroid- and immunosuppressant-refractory ICI-induced hepatitis. Early initiation could improve outcomes; prospective studies are needed to clarify optimal timing and patient selection.
Impact and implications
Severe immune checkpoint inhibitor-induced hepatitis represents a rare but life-threatening complication for which therapeutic options are limited once corticosteroids and immunosuppressants fail. Our study provides the first multicenter evidence suggesting that therapeutic plasma exchange (TPE) is a feasible and safe approach that may improve hepatic outcomes in this setting. These findings are particularly relevant for oncologists, hepatologists, and intensivists facing refractory immune checkpoint inhibitor-induced liver injury, as TPE could offer a bridge to recovery when liver transplantation is not feasible. Early consideration of TPE, alongside careful patient selection, could optimize outcomes, although larger prospective studies are required to confirm efficacy and define the best timing and indications.
{"title":"Plasma exchange as potential treatment of severe immune checkpoint inhibitor-induced hepatitis","authors":"Lucy Meunier , Clement Monet , Antonio Saviano , Marwin Farrugia , François Villeret , Fanny Lebossé , Marion Khaldi , Olivier Moranne , Christine Chambon , Philippe Ichai , Astrid Laurent-Bellue , Ariane Laparra , Rodolphe Anty , Simona Tripon , Mialy Randrianarisoa , Alexandre Maria , Lina Hountondji , Eleonora De Martin","doi":"10.1016/j.jhepr.2025.101684","DOIUrl":"10.1016/j.jhepr.2025.101684","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Immune checkpoint inhibitors (ICIs) improve cancer survival but can cause severe immune-related hepatitis. Standard therapy with corticosteroids and second-line agents such as mycophenolate mofetil fails in some cases. Therapeutic plasma exchange (TPE) has been suggested as rescue therapy, but supporting evidence is limited.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed French multicenter data (March 2021–April 2025) on patients with grade 4 ICI-induced hepatitis refractory to corticosteroids ± other immunosuppressants who underwent TPE.</div></div><div><h3>Results</h3><div>Thirteen patients (median age 63 years; 54% male) were included. Eleven had acute hepatitis, including seven with acute liver injury, and two had steroid-refractory cholestatic hepatitis. TPE was initiated a median of 28 days after hepatitis onset (median MELD score 21) and administered in 2–8 sessions. Liver function improved in eight patients (61.5%), allowing resumption of anticancer therapy without ICI rechallenge in five. Three patients with cirrhosis and hepatocellular carcinoma died of liver failure, and three died from other causes. TPE-related adverse events were mild to moderate.</div></div><div><h3>Conclusion</h3><div>TPE is feasible, safe, and may be effective for severe steroid- and immunosuppressant-refractory ICI-induced hepatitis. Early initiation could improve outcomes; prospective studies are needed to clarify optimal timing and patient selection.</div></div><div><h3>Impact and implications</h3><div>Severe immune checkpoint inhibitor-induced hepatitis represents a rare but life-threatening complication for which therapeutic options are limited once corticosteroids and immunosuppressants fail. Our study provides the first multicenter evidence suggesting that therapeutic plasma exchange (TPE) is a feasible and safe approach that may improve hepatic outcomes in this setting. These findings are particularly relevant for oncologists, hepatologists, and intensivists facing refractory immune checkpoint inhibitor-induced liver injury, as TPE could offer a bridge to recovery when liver transplantation is not feasible. Early consideration of TPE, alongside careful patient selection, could optimize outcomes, although larger prospective studies are required to confirm efficacy and define the best timing and indications.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101684"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057557","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 : 2026-03-01Epub Date: 2025-12-02DOI: 10.1016/j.jhepr.2025.101703
Sandeep Das , Sumit Kumar Anand , M Peyton McKinney , Koral S.E. Richard , Iqbal Mahmud , Sumati Rohilla , Fabio Arias , Alia Ghrayeb , Bo Wei , Lin Tan , Zhipeng Liu , Dhananjay Kumar , Alexandra C. Finney , Nilesh Pandey , Harpreet Kaur , Rajan Pandit , Xiaolu Zhang , Cyrine Ben Dhaou , Sarah P. Thayer , Babak Razani , Oren Rom
<div><h3>Background & Aims</h3><div>Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with metabolic dysfunction-associated steatohepatitis (MASH). No therapy targets both diseases simultaneously, and a roadblock for discovering new treatments is the lack of animal models that recapitulate both diseases, especially in females.</div></div><div><h3>Methods</h3><div>Male and female <em>Ldlr</em><sup>-/-</sup> mice (n = 8-13) were fed a western diet (WD), modified choline-deficient high-fat diet (mCDHFD), or modified MASH-inducing diet (mMASHD) containing equivalent physiological levels of cholesterol. Comprehensive multiomics including metabolomics, lipidomics, and transcriptomics, alongside histopathological and biochemical analyses, were integrated to characterize concurrent MASH and atherosclerosis. Transcriptomics was validated in other mouse models and integrated with human data (n = 79).</div></div><div><h3>Results</h3><div>While mCDHFD induced MASH-fibrosis in both sexes, WD was effective only in males, whereas mMASHD primarily affected females. mCDHFD induced concurrent MASH and atherosclerosis in both sexes, while WD effectively recapitulated disease co-occurrence only in males. Correlation analyses highlighted links between MASH and atherosclerosis, identifying circulating cholesterol and C–C motif chemokine ligand 2 (CCL2) as potential predictors of coexisting disease (<em>p <</em>0.04). Integrated metabolomic and transcriptomic analyses identified arginine–proline, glycine–serine, glutathione, and sphingolipid metabolism (<em>p</em> <0.03) as key dysregulated pathways, with sphinganine emerging as a predictor of disease severity. Hepatic itaconate and lactate levels were positively correlated with disease severity, whereas glycine, carnitine, 2-aminomuconic acid, and thiamine pyrophosphate were negatively associated (<em>p <</em>0.04). Lipidomic analyses revealed dysregulated polyunsaturated fatty acid, steryl ester, and dihexosylceramide metabolism. Integration of mouse and human transcriptomes revealed similarities in metabolic and proinflammatory/proatherogenic pathways.</div></div><div><h3>Conclusion</h3><div>This sex-based multiomics analysis establishes a murine model of concurrent MASH and atherosclerosis, reveals sex-specific dietary responses, and identifies metabolic and transcriptional pathways with potential utility as biomarkers and therapeutic targets.</div></div><div><h3>Impact and implications</h3><div>This study addresses the critical need for an animal model that replicates both metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerotic cardiovascular disease, particularly in females, to facilitate therapeutic development. Using male and female <em>Ldlr</em><sup>-/-</sup> mice, we found that different diets containing equivalent physiological levels of cholesterol induce sex-specific responses, with a modified choline-deficient high-fat diet effectivel
{"title":"Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis","authors":"Sandeep Das , Sumit Kumar Anand , M Peyton McKinney , Koral S.E. Richard , Iqbal Mahmud , Sumati Rohilla , Fabio Arias , Alia Ghrayeb , Bo Wei , Lin Tan , Zhipeng Liu , Dhananjay Kumar , Alexandra C. Finney , Nilesh Pandey , Harpreet Kaur , Rajan Pandit , Xiaolu Zhang , Cyrine Ben Dhaou , Sarah P. Thayer , Babak Razani , Oren Rom","doi":"10.1016/j.jhepr.2025.101703","DOIUrl":"10.1016/j.jhepr.2025.101703","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with metabolic dysfunction-associated steatohepatitis (MASH). No therapy targets both diseases simultaneously, and a roadblock for discovering new treatments is the lack of animal models that recapitulate both diseases, especially in females.</div></div><div><h3>Methods</h3><div>Male and female <em>Ldlr</em><sup>-/-</sup> mice (n = 8-13) were fed a western diet (WD), modified choline-deficient high-fat diet (mCDHFD), or modified MASH-inducing diet (mMASHD) containing equivalent physiological levels of cholesterol. Comprehensive multiomics including metabolomics, lipidomics, and transcriptomics, alongside histopathological and biochemical analyses, were integrated to characterize concurrent MASH and atherosclerosis. Transcriptomics was validated in other mouse models and integrated with human data (n = 79).</div></div><div><h3>Results</h3><div>While mCDHFD induced MASH-fibrosis in both sexes, WD was effective only in males, whereas mMASHD primarily affected females. mCDHFD induced concurrent MASH and atherosclerosis in both sexes, while WD effectively recapitulated disease co-occurrence only in males. Correlation analyses highlighted links between MASH and atherosclerosis, identifying circulating cholesterol and C–C motif chemokine ligand 2 (CCL2) as potential predictors of coexisting disease (<em>p <</em>0.04). Integrated metabolomic and transcriptomic analyses identified arginine–proline, glycine–serine, glutathione, and sphingolipid metabolism (<em>p</em> <0.03) as key dysregulated pathways, with sphinganine emerging as a predictor of disease severity. Hepatic itaconate and lactate levels were positively correlated with disease severity, whereas glycine, carnitine, 2-aminomuconic acid, and thiamine pyrophosphate were negatively associated (<em>p <</em>0.04). Lipidomic analyses revealed dysregulated polyunsaturated fatty acid, steryl ester, and dihexosylceramide metabolism. Integration of mouse and human transcriptomes revealed similarities in metabolic and proinflammatory/proatherogenic pathways.</div></div><div><h3>Conclusion</h3><div>This sex-based multiomics analysis establishes a murine model of concurrent MASH and atherosclerosis, reveals sex-specific dietary responses, and identifies metabolic and transcriptional pathways with potential utility as biomarkers and therapeutic targets.</div></div><div><h3>Impact and implications</h3><div>This study addresses the critical need for an animal model that replicates both metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerotic cardiovascular disease, particularly in females, to facilitate therapeutic development. Using male and female <em>Ldlr</em><sup>-/-</sup> mice, we found that different diets containing equivalent physiological levels of cholesterol induce sex-specific responses, with a modified choline-deficient high-fat diet effectivel","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101703"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347699","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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