Burcin Özdirik, Hilmar Berger, Fernanda Raya Tonetti, Noemí Cabré, Nicole Treichel, Thomas Clavel, Frank Tacke, Michael Sigal, Bernd Schnabl
Background and Aims
Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy without treatment options beyond liver transplantation. The gut–liver axis, especially the role of gut microbes, has emerged as a crucial pathway contributing to PSC pathogenesis. Recent research has revealed Enterococcus (E.) faecalis and its virulence factor cytolysin to increase mortality risk in patients with alcohol-associated hepatitis. Thus, we studied the role of enterococci, particularly E. faecalis and its virulence factor genes cytolysin and gelatinase, in faecal samples from patients with PSC.
Methods
To assess the relevance of Enterococcus species, we performed 16S rRNA gene amplicon analysis in faecal samples from 60 patients with PSC. We validated our findings by qPCR of faecal microbial DNA in an extended cohort of 105 patients with PSC, 104 patients with inflammatory bowel disease (IBD) and 68 healthy subjects.
Results
High-throughput 16S rRNA amplicon analysis revealed an increased relative abundance of enterococci in PSC patients compared with healthy controls and IBD patients, respectively, (p < 0.0001). PSC patients with high enterococci abundance had a decreased probability of transplant-free survival (p = 0.028). E. faecalis and its virulence factors cytolysin and gelatinase were more abundant in patients with PSC. Higher faecal cytolysin was associated with lower overall survival (p = 0.04), while survival was independent of gelatinase levels.
Conclusion
Our data highlight the association of E. faecalis and faecal cytolysin with lower survival in patients with PSC. These data should prompt further research into the pathogenic role of cytolysin-positive E. faecalis, and to explore its role as a potential therapeutic target.
{"title":"Faecal Cytolysin is Associated With Worse Survival in Patients With Primary Sclerosing Cholangitis","authors":"Burcin Özdirik, Hilmar Berger, Fernanda Raya Tonetti, Noemí Cabré, Nicole Treichel, Thomas Clavel, Frank Tacke, Michael Sigal, Bernd Schnabl","doi":"10.1111/liv.16181","DOIUrl":"https://doi.org/10.1111/liv.16181","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy without treatment options beyond liver transplantation. The gut–liver axis, especially the role of gut microbes, has emerged as a crucial pathway contributing to PSC pathogenesis. Recent research has revealed <i>Enterococcus (E.) faecalis</i> and its virulence factor cytolysin to increase mortality risk in patients with alcohol-associated hepatitis. Thus, we studied the role of enterococci, particularly <i>E. faecalis</i> and its virulence factor genes cytolysin and gelatinase, in faecal samples from patients with PSC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To assess the relevance of <i>Enterococcus</i> species, we performed 16S rRNA gene amplicon analysis in faecal samples from 60 patients with PSC. We validated our findings by qPCR of faecal microbial DNA in an extended cohort of 105 patients with PSC, 104 patients with inflammatory bowel disease (IBD) and 68 healthy subjects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>High-throughput 16S rRNA amplicon analysis revealed an increased relative abundance of enterococci in PSC patients compared with healthy controls and IBD patients, respectively, (<i>p</i> < 0.0001). PSC patients with high enterococci abundance had a decreased probability of transplant-free survival (<i>p</i> = 0.028). <i>E. faecalis</i> and its virulence factors cytolysin and gelatinase were more abundant in patients with PSC. Higher faecal cytolysin was associated with lower overall survival (<i>p</i> = 0.04), while survival was independent of gelatinase levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data highlight the association of <i>E. faecalis</i> and faecal cytolysin with lower survival in patients with PSC. These data should prompt further research into the pathogenic role of cytolysin-positive <i>E. faecalis,</i> and to explore its role as a potential therapeutic target.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Surveillance corresponds to the systematic and repeated action of a screening test during the time with the goal of improving survival [<span>1</span>]. In the hepatocellular carcinoma (HCC) realm, surveillance aims to reduce the risk of cancer-related death through the detection and treatment of HCC at an early stage. However, to recommend or not recommend surveillance in a specific population, it is crucial to integrate the incidence of a specific cancer together with the careful consideration of the competing risks for death and cost-efficacy analysis. As an example, for patients with decompensated liver cirrhosis not candidates for liver transplantation and untreatable for HCC due to liver function or comorbidities, the benefit of detecting an HCC vanishes since survival is dismal due to non-HCC-liver-related events (overdiagnosis) [<span>2</span>]. While the future of HCC surveillance probably leans toward personalised approaches (i.e., with the integration of new biomarkers, and with more sensitive techniques such as magnetic resonance [MR]), bi-annual abdominal ultrasound (US) with or without alpha-fetoprotein (AFP) [<span>3</span>] remains the cornerstone of current practice. Despite the strong recommendation of international guidelines [<span>4-6</span>], surveillance is underused, and this may depend on both physicians (i.e., lower rates for primary care doctors) and patients (low adherence) issues [<span>7, 8</span>]. Therefore, improving the training of both doctors and patients is a key objective in strategies aimed at enhancing surveillance adherence. A variety of approaches have been explored, such as the education of primary care physicians, nurse-led programmes, mailed outreach strategy, and EMR-led best practice alerts [<span>9-12</span>]. The results are heterogeneous but can achieve interesting results in nurse-led programmes, with 53% up to 80%–90% of adherence. However, these results should be confirmed in large-scale populations, and the availability of expert and dedicated nurses should be encouraged. Finally, it is to be noted that a widely expert opinion suggests that US surveillance should be performed by physicians with extensive expertise in liver US.</p><p>In the study by Brahmania et al. [<span>13</span>] in <i>Liver International</i>, the authors performed a retrospective study aiming to evaluate the impact of a region-wide automated recall program on adherence to HCC surveillance Specifically, in 2013 in Calgary (Canada) a diagnostic-image (DI) provider created an automated protocol-based surveillance strategy based on the software used for a breast cancer surveillance program using mammography for patients eligible for HCC screening.</p><p>A healthcare provider (gastroenterologist, hepatologist or primary care) was allowed to enrol patients in the program by submitting a completed one-page requisition with demographic characteristics, reason for screening, and the presence or absence of liver cirrhosis. Patien
{"title":"Surveillance in HCC: Making the Most of What We Have Today","authors":"Marco Sanduzzi-Zamparelli, Giuseppe Cabibbo","doi":"10.1111/liv.70057","DOIUrl":"https://doi.org/10.1111/liv.70057","url":null,"abstract":"<p>Surveillance corresponds to the systematic and repeated action of a screening test during the time with the goal of improving survival [<span>1</span>]. In the hepatocellular carcinoma (HCC) realm, surveillance aims to reduce the risk of cancer-related death through the detection and treatment of HCC at an early stage. However, to recommend or not recommend surveillance in a specific population, it is crucial to integrate the incidence of a specific cancer together with the careful consideration of the competing risks for death and cost-efficacy analysis. As an example, for patients with decompensated liver cirrhosis not candidates for liver transplantation and untreatable for HCC due to liver function or comorbidities, the benefit of detecting an HCC vanishes since survival is dismal due to non-HCC-liver-related events (overdiagnosis) [<span>2</span>]. While the future of HCC surveillance probably leans toward personalised approaches (i.e., with the integration of new biomarkers, and with more sensitive techniques such as magnetic resonance [MR]), bi-annual abdominal ultrasound (US) with or without alpha-fetoprotein (AFP) [<span>3</span>] remains the cornerstone of current practice. Despite the strong recommendation of international guidelines [<span>4-6</span>], surveillance is underused, and this may depend on both physicians (i.e., lower rates for primary care doctors) and patients (low adherence) issues [<span>7, 8</span>]. Therefore, improving the training of both doctors and patients is a key objective in strategies aimed at enhancing surveillance adherence. A variety of approaches have been explored, such as the education of primary care physicians, nurse-led programmes, mailed outreach strategy, and EMR-led best practice alerts [<span>9-12</span>]. The results are heterogeneous but can achieve interesting results in nurse-led programmes, with 53% up to 80%–90% of adherence. However, these results should be confirmed in large-scale populations, and the availability of expert and dedicated nurses should be encouraged. Finally, it is to be noted that a widely expert opinion suggests that US surveillance should be performed by physicians with extensive expertise in liver US.</p><p>In the study by Brahmania et al. [<span>13</span>] in <i>Liver International</i>, the authors performed a retrospective study aiming to evaluate the impact of a region-wide automated recall program on adherence to HCC surveillance Specifically, in 2013 in Calgary (Canada) a diagnostic-image (DI) provider created an automated protocol-based surveillance strategy based on the software used for a breast cancer surveillance program using mammography for patients eligible for HCC screening.</p><p>A healthcare provider (gastroenterologist, hepatologist or primary care) was allowed to enrol patients in the program by submitting a completed one-page requisition with demographic characteristics, reason for screening, and the presence or absence of liver cirrhosis. Patien","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Risk of Acute Liver Injury Following the Nirmatrelvir/Ritonavir Use","authors":"Jiliang Ning","doi":"10.1111/liv.16206","DOIUrl":"https://doi.org/10.1111/liv.16206","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xinrui Jin, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip
<p>In 2022, 865 300 people were diagnosed with liver cancer, and 757 900 people died of liver cancer, making it the sixth most common cancer and the third leading cause of cancer death globally [<span>1</span>]. Although high-quality randomised controlled trials are lacking, observational studies have consistently shown that hepatocellular carcinoma (HCC) surveillance by means of biannual abdominal ultrasonography with or without serum alpha-fetoprotein testing in high-risk groups can detect early cancer, increase the chance of instituting curative-intent treatments and reduce cancer deaths [<span>2</span>]. Therefore, current guidelines support HCC surveillance in patients with cirrhosis or patients with chronic hepatitis B (CHB) beyond a certain age [<span>3</span>].</p><p>However, such recommendations do not capture numerous modifiable and non-modifiable risk factors of HCC and the fact that HCC can develop in the absence of cirrhosis. Take CHB as an example, demographics (age and sex), family history of HCC, host genetics, virologic factors (viral load, genotypes and variants), environmental exposure (e.g., alcohol and aflatoxin) and comorbidities (e.g., diabetes) are well-established risk factors of HCC. Conversely, contemporary antiviral therapies with entecavir or tenofovir can reverse cirrhosis and reduce the risk of HCC. With this background, researchers have derived and validated a number of HCC risk scores, largely for CHB but also some for different chronic liver diseases [<span>4</span>]. When the incidence of HCC exceeds certain thresholds (often taken as 1% per year), HCC surveillance is deemed cost-effective and should be offered. Our group previously demonstrated that patients receiving antiviral therapies for CHB might have HCC incidence reduced to a level that is below guideline recommendations for surveillance and this can be effectively predicted by the PAGE-B and modified PAGE-B scores [<span>5</span>].</p><p>Most existing HCC risk scores were derived using traditional regression formulas with baseline variables. They are thus limited by superficial handling of complex interactions across parameters. Besides, a one-off assessment at baseline deviates from routine clinical practice, where healthcare providers see patients repeatedly over time and adjust their evaluation on HCC risk. This is an area where artificial intelligence (AI) holds promise. In this issue, Ha, Lee and colleagues present a new AI model for HCC prediction in patients on antiviral therapy for CHB [<span>6</span>].</p><p>Ha and Lee et al. conducted a retrospective, multicentre study, which included patients with CHB who continuously received 5 years of entecavir (ETV) or tenofovir (TFV) therapy. The derivation cohort, consisting of 5908 patients from one medical centre, was used for model training and internal validation, while an independent cohort comprising 562 patients from a different medical centre was utilised to externally validate the model's perfo
{"title":"Is AI-Based Hepatocellular Carcinoma Prediction Ready for Prime Time?","authors":"Xinrui Jin, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip","doi":"10.1111/liv.16165","DOIUrl":"https://doi.org/10.1111/liv.16165","url":null,"abstract":"<p>In 2022, 865 300 people were diagnosed with liver cancer, and 757 900 people died of liver cancer, making it the sixth most common cancer and the third leading cause of cancer death globally [<span>1</span>]. Although high-quality randomised controlled trials are lacking, observational studies have consistently shown that hepatocellular carcinoma (HCC) surveillance by means of biannual abdominal ultrasonography with or without serum alpha-fetoprotein testing in high-risk groups can detect early cancer, increase the chance of instituting curative-intent treatments and reduce cancer deaths [<span>2</span>]. Therefore, current guidelines support HCC surveillance in patients with cirrhosis or patients with chronic hepatitis B (CHB) beyond a certain age [<span>3</span>].</p><p>However, such recommendations do not capture numerous modifiable and non-modifiable risk factors of HCC and the fact that HCC can develop in the absence of cirrhosis. Take CHB as an example, demographics (age and sex), family history of HCC, host genetics, virologic factors (viral load, genotypes and variants), environmental exposure (e.g., alcohol and aflatoxin) and comorbidities (e.g., diabetes) are well-established risk factors of HCC. Conversely, contemporary antiviral therapies with entecavir or tenofovir can reverse cirrhosis and reduce the risk of HCC. With this background, researchers have derived and validated a number of HCC risk scores, largely for CHB but also some for different chronic liver diseases [<span>4</span>]. When the incidence of HCC exceeds certain thresholds (often taken as 1% per year), HCC surveillance is deemed cost-effective and should be offered. Our group previously demonstrated that patients receiving antiviral therapies for CHB might have HCC incidence reduced to a level that is below guideline recommendations for surveillance and this can be effectively predicted by the PAGE-B and modified PAGE-B scores [<span>5</span>].</p><p>Most existing HCC risk scores were derived using traditional regression formulas with baseline variables. They are thus limited by superficial handling of complex interactions across parameters. Besides, a one-off assessment at baseline deviates from routine clinical practice, where healthcare providers see patients repeatedly over time and adjust their evaluation on HCC risk. This is an area where artificial intelligence (AI) holds promise. In this issue, Ha, Lee and colleagues present a new AI model for HCC prediction in patients on antiviral therapy for CHB [<span>6</span>].</p><p>Ha and Lee et al. conducted a retrospective, multicentre study, which included patients with CHB who continuously received 5 years of entecavir (ETV) or tenofovir (TFV) therapy. The derivation cohort, consisting of 5908 patients from one medical centre, was used for model training and internal validation, while an independent cohort comprising 562 patients from a different medical centre was utilised to externally validate the model's perfo","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>We read with interest the recent study by Zheng et al. [<span>1</span>] that introduces an innovative MRI-based topology deep learning (DL) model achieving high diagnostic accuracy in the prediction microvascular invasion (MVI), highlighting a key development in the integration of artificial intelligence (AI) into oncologic imaging. Microvascular invasion is among the critical determinants of prognosis in HCC and is typically associated with early recurrence and poor survival outcomes. Accurate prediction of MVI is therefore paramount, not only to guide therapeutic decisions [<span>2</span>] but also to stratify patients for clinical trials. HCC begins often as a tumour with less-invasiveness in the early stages of its development. In the stage, it grows not invasively, forming a non-cancerous tissue capsule of compressed surrounding tissue. In liver resection for HCC, resection at the capsule level is sometimes considered R0 resection. However, during the developmental process, cancer cells invade outside the capsule and into vessels, such as the portal vein. After going through this step, the aggressiveness of HCC increases rapidly, and surgical intervention based on the aforementioned recognition cannot obtain a sufficient therapeutic effect. Therefore, the macroscopic type is strongly related to its prognosis after intervention [<span>3, 4</span>]. It has long been pointed out the difficulty connecting these findings to surgical outcomes. Present research by Zheng et al. suggests that new insights may be obtained by connecting detailed findings (not limited to morphological changes) of MRI to topology and putting them in AI analysis. Although minute extracapsular and/or vascular invasions can be confirmed in postoperative pathology, reliable preoperative imaging modality for their early detection has not yet been established.</p><p>Although the study represents a remarkable technical achievement, it also invites broader reflection on the role and responsibilities of AI in clinical decision-making: first, the development of interpretable AI models that clinicians can trust and understand; and second, the democratisation of these tools through open-source frameworks to ensure their widespread validation and application.</p><p>The growing field of AI in medicine has transformed how we approach complex problems, particularly in diagnostic imaging. Advances in convolutional neural networks (CNNs) and, more recently, topological data analysis (TDA), have enabled models to extract nuanced patterns from imaging data, surpassing the diagnostic capabilities of traditional radiological methods [<span>5</span>]. In the context of HCC, the concept of a ‘virtual biopsy’ is particularly compelling. By inferring histopathological features, such as MVI from imaging data alone, these models could obviate the need for invasive procedures, reduce patient morbidity and accelerate clinical decision-making. This field is rapidly developing, and the use of a comb
{"title":"Interpretable and Open AI Models: A Mandate for the Future of HCC Diagnostics","authors":"Simone Famularo, Luca Boldrini, Matteo Donadon, Zenichi Morise","doi":"10.1111/liv.16229","DOIUrl":"https://doi.org/10.1111/liv.16229","url":null,"abstract":"<p>We read with interest the recent study by Zheng et al. [<span>1</span>] that introduces an innovative MRI-based topology deep learning (DL) model achieving high diagnostic accuracy in the prediction microvascular invasion (MVI), highlighting a key development in the integration of artificial intelligence (AI) into oncologic imaging. Microvascular invasion is among the critical determinants of prognosis in HCC and is typically associated with early recurrence and poor survival outcomes. Accurate prediction of MVI is therefore paramount, not only to guide therapeutic decisions [<span>2</span>] but also to stratify patients for clinical trials. HCC begins often as a tumour with less-invasiveness in the early stages of its development. In the stage, it grows not invasively, forming a non-cancerous tissue capsule of compressed surrounding tissue. In liver resection for HCC, resection at the capsule level is sometimes considered R0 resection. However, during the developmental process, cancer cells invade outside the capsule and into vessels, such as the portal vein. After going through this step, the aggressiveness of HCC increases rapidly, and surgical intervention based on the aforementioned recognition cannot obtain a sufficient therapeutic effect. Therefore, the macroscopic type is strongly related to its prognosis after intervention [<span>3, 4</span>]. It has long been pointed out the difficulty connecting these findings to surgical outcomes. Present research by Zheng et al. suggests that new insights may be obtained by connecting detailed findings (not limited to morphological changes) of MRI to topology and putting them in AI analysis. Although minute extracapsular and/or vascular invasions can be confirmed in postoperative pathology, reliable preoperative imaging modality for their early detection has not yet been established.</p><p>Although the study represents a remarkable technical achievement, it also invites broader reflection on the role and responsibilities of AI in clinical decision-making: first, the development of interpretable AI models that clinicians can trust and understand; and second, the democratisation of these tools through open-source frameworks to ensure their widespread validation and application.</p><p>The growing field of AI in medicine has transformed how we approach complex problems, particularly in diagnostic imaging. Advances in convolutional neural networks (CNNs) and, more recently, topological data analysis (TDA), have enabled models to extract nuanced patterns from imaging data, surpassing the diagnostic capabilities of traditional radiological methods [<span>5</span>]. In the context of HCC, the concept of a ‘virtual biopsy’ is particularly compelling. By inferring histopathological features, such as MVI from imaging data alone, these models could obviate the need for invasive procedures, reduce patient morbidity and accelerate clinical decision-making. This field is rapidly developing, and the use of a comb","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>The landscape of hepatocellular carcinoma (HCC) treatment has constantly evolved, striving for personalised, precise and more effective therapeutic options. The utilisation of radioembolisation with yttrium-90 (90Y) has been growing over the past decade despite several initial negative phase 3 randomised trials conducted in patients with advanced HCC where Y90-radioembolisation was tested against sorafenib [<span>1, 2</span>]. This paradox can be explained by positive signals extracted from these trials regarding toxicity and quality of life, a refinement in patient selection criteria and, more importantly, a deeper understanding of the utmost importance of dosimetric parameters. The pivotal DOSISPHERE-01 trial first demonstrated the importance of an optimised and personalised dosimetric approach, aiming to maximise tumour control while minimising the risk to non-tumoral liver tissue [<span>3, 4</span>]. In this context, the study by Bucalau et al. published in this issue marks a significant advancement, introducing Holmium-166 (166Ho) radioembolisation coupled with personalised predictive dosimetry as a treatment modality for patients with HCC [<span>5</span>].</p><p>The study by Bucalau et al. followed a rigorous methodology, employing a personalised predictive dosimetry approach to optimise treatment efficacy [<span>5</span>]. By administering a 166Ho-radioembolisation to a targeted population of 15 patients with early to intermediate-stage HCC mostly, the research illustrates the path towards a more individualised treatment paradigm. The investigation reveals a significant achievement as all patients showed an objective response on the targeted tumours at 3 months and a very high complete response rate (78.6%), even in patients with large tumours. This study also highlighted the potential of 166Ho in enhancing the safety of radioembolisation, with no ≥ grade 3 short treatment-related adverse event, in line with previous studies [<span>6</span>]. Furthermore, the study contributes valuable dosimetric data on 166Ho, offering a foundation for future research and clinical application in liver cancer therapy both on the efficacy side (dose to the tumour) and on a safety perspective (dose to the non-tumoral liver). The dual PET imaging (FDG/choline) incorporated in the study further underscores the sophistication of 166Ho-SIRT in assessing tumour metabolism and response, paving the way for its integration into comprehensive cancer management protocols.</p><p>The use of Holmium-166 has several theoretical advantages over Yttrium-90 for radioembolisation. First, Holmium-166 emits both beta particles (used for therapeutic effect) and gamma radiation, which can be detected by gamma cameras. This allows for post-procedural imaging to assess the distribution of the radioembolisation particles. Yttrium-90, in contrast, primarily emits beta particles, making imaging more challenging and typically requiring the use of Bremsstrahlung SPECT or PET scans to
{"title":"Trans-Arterial Radioembolisation for HCC: Personalised Dosimetry Beyond Yttrium 90","authors":"Lambros Tselikas, Maxime Ronot","doi":"10.1111/liv.16184","DOIUrl":"https://doi.org/10.1111/liv.16184","url":null,"abstract":"<p>The landscape of hepatocellular carcinoma (HCC) treatment has constantly evolved, striving for personalised, precise and more effective therapeutic options. The utilisation of radioembolisation with yttrium-90 (90Y) has been growing over the past decade despite several initial negative phase 3 randomised trials conducted in patients with advanced HCC where Y90-radioembolisation was tested against sorafenib [<span>1, 2</span>]. This paradox can be explained by positive signals extracted from these trials regarding toxicity and quality of life, a refinement in patient selection criteria and, more importantly, a deeper understanding of the utmost importance of dosimetric parameters. The pivotal DOSISPHERE-01 trial first demonstrated the importance of an optimised and personalised dosimetric approach, aiming to maximise tumour control while minimising the risk to non-tumoral liver tissue [<span>3, 4</span>]. In this context, the study by Bucalau et al. published in this issue marks a significant advancement, introducing Holmium-166 (166Ho) radioembolisation coupled with personalised predictive dosimetry as a treatment modality for patients with HCC [<span>5</span>].</p><p>The study by Bucalau et al. followed a rigorous methodology, employing a personalised predictive dosimetry approach to optimise treatment efficacy [<span>5</span>]. By administering a 166Ho-radioembolisation to a targeted population of 15 patients with early to intermediate-stage HCC mostly, the research illustrates the path towards a more individualised treatment paradigm. The investigation reveals a significant achievement as all patients showed an objective response on the targeted tumours at 3 months and a very high complete response rate (78.6%), even in patients with large tumours. This study also highlighted the potential of 166Ho in enhancing the safety of radioembolisation, with no ≥ grade 3 short treatment-related adverse event, in line with previous studies [<span>6</span>]. Furthermore, the study contributes valuable dosimetric data on 166Ho, offering a foundation for future research and clinical application in liver cancer therapy both on the efficacy side (dose to the tumour) and on a safety perspective (dose to the non-tumoral liver). The dual PET imaging (FDG/choline) incorporated in the study further underscores the sophistication of 166Ho-SIRT in assessing tumour metabolism and response, paving the way for its integration into comprehensive cancer management protocols.</p><p>The use of Holmium-166 has several theoretical advantages over Yttrium-90 for radioembolisation. First, Holmium-166 emits both beta particles (used for therapeutic effect) and gamma radiation, which can be detected by gamma cameras. This allows for post-procedural imaging to assess the distribution of the radioembolisation particles. Yttrium-90, in contrast, primarily emits beta particles, making imaging more challenging and typically requiring the use of Bremsstrahlung SPECT or PET scans to","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The impact of low-level viremia(LLV) on the efficacy of immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma(uHCC) patients remains unclear. This study aims to investigate the effect of LLV on the outcomes of ICIs-based therapy in patients with uHCC.
Methods
In this multicenter retrospective study, we included patients with uHCC who received ICIs-based therapy at four centres between January 2019 and December 2022. All patients were positive for HBsAg and were on nucleos(t)ide analogues (NAs) antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance baseline characteristics between the LLV and maintained virological response (MVR) groups. Proteomic analysis was performed on a subset of patients to identify differential protein expression.
Results
A total of 329 patients (mean age 56 years; 92.4% male; 70.8% BCLC stage C) were included, with 170 patients in the LLV group and 159 in the MVR group. The objective response rate (ORR) was significantly lower in the LLV group compared to the MVR group (21.2% vs. 36.5%, p = 0.002), as was the disease control rate (DCR) (78.8% vs. 92.5%, p < 0.001). Median progression-free survival (mPFS) was shorter in the LLV group (7.6 vs. 12.6 months, p < 0.001), as was median overall survival (mOS) (22.8 vs. 40.0 months, p < 0.001). These differences remained consistent after PSM and IPTW adjustments. Multivariate analysis identified LLV as the only independent risk factor for overall survival (hazard ratio [HR] 0.522, 95% CI 0.348–0.781; p = 0.002). Proteomic analysis revealed significant differences in the expression of Flt3L, SLAMF1 and FGF-5 proteins between the LLV and MVR groups.
Conclusion
LLV is associated with poorer responses to ICIs-based therapy and reduced survival in patients with HBV-related uHCC.
{"title":"Low-Level Viremia Impairs Efficacy of Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma","authors":"Rong Li, Wenli Li, Qing Yang, Yujuan Guan, Yongru Chen, Peilin Zhu, Kaiyan Su, Qi Li, Xiaoyun Hu, Mengya Zang, Miaoxian Zhao, Manhua Zhong, Jingquan Yan, Keli Yang, Wei Zhu, Zhanzhou Lin, Guosheng Yuan, Jinzhang Chen","doi":"10.1111/liv.70066","DOIUrl":"https://doi.org/10.1111/liv.70066","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The impact of low-level viremia(LLV) on the efficacy of immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma(uHCC) patients remains unclear. This study aims to investigate the effect of LLV on the outcomes of ICIs-based therapy in patients with uHCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this multicenter retrospective study, we included patients with uHCC who received ICIs-based therapy at four centres between January 2019 and December 2022. All patients were positive for HBsAg and were on nucleos(t)ide analogues (NAs) antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance baseline characteristics between the LLV and maintained virological response (MVR) groups. Proteomic analysis was performed on a subset of patients to identify differential protein expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 329 patients (mean age 56 years; 92.4% male; 70.8% BCLC stage C) were included, with 170 patients in the LLV group and 159 in the MVR group. The objective response rate (ORR) was significantly lower in the LLV group compared to the MVR group (21.2% vs. 36.5%, <i>p</i> = 0.002), as was the disease control rate (DCR) (78.8% vs. 92.5%, <i>p</i> < 0.001). Median progression-free survival (mPFS) was shorter in the LLV group (7.6 vs. 12.6 months, <i>p</i> < 0.001), as was median overall survival (mOS) (22.8 vs. 40.0 months, <i>p</i> < 0.001). These differences remained consistent after PSM and IPTW adjustments. Multivariate analysis identified LLV as the only independent risk factor for overall survival (hazard ratio [HR] 0.522, 95% CI 0.348–0.781; <i>p</i> = 0.002). Proteomic analysis revealed significant differences in the expression of Flt3L, SLAMF1 and FGF-5 proteins between the LLV and MVR groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>LLV is associated with poorer responses to ICIs-based therapy and reduced survival in patients with HBV-related uHCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rafael Calais Gaspar, Ana Paula Azevêdo Macêdo, Susana Castelo Branco Ramos Nakandakari, Vitor Rosetto Muñoz, Gabriela Ferreira Abud, Renan Fudoli Lins Vieira, Ivo Vieira de Sousa Neto, Isadora Carolina Betim Pavan, Luiz Guilherme Salvino da Silva, Fernando Moreira Simabuco, Adelino S. R. da Silva, Wilson Salgado Junior, Julio Sergio Marchini, Carla Barbosa Nonino, Dennys Esper Cintra, Eduardo Rochete Ropelle, Utpal B. Pajvani, Ellen Cristini de Freitas, José Rodrigo Pauli
Background and Aims
Notch1 protein plays a significant role in hepatic metabolism, as evidenced by its correlation with insulin resistance in the livers of obese individuals, making it an intriguing research target. Therefore, this study aims to investigate the impact of aerobic exercise on Notch1 pathways in the hepatic tissue of obese mice and its role in controlling hepatic metabolism.
Methods
Therefore, we conducted a cross-sectional study utilising liver biopsies from lean and obese humans, as well as an intervention study involving mice subjected to a high-fat diet. The obese-trained mice group underwent a treadmill-running protocol for 4 weeks.
Results
Our findings revealed that obese individuals exhibited increased NOTCH1 mRNA levels compared to lean subjects. The detrimental effects of Notch1 signalling were confirmed by Notch1-overexpressed HepG2 cell lines. Obese mice with higher hepatic Notch1 signalling demonstrated a reduction in this pathway when subjected to a 4-week treadmill running. Another benefit noticed in this trained group was the amelioration of insulin resistance, as well as a reduction in pyruvate intolerance and gluconeogenic enzymes. Additionally, we observed that these protective findings were accompanied by a decrease in mTORC1 pathway activity and lipid accumulation in the liver. Pharmacological inhibition of Notch1 in obese mice led to an increase in mitochondrial respiration in the liver.
Conclusions
We conclude that Notch1 signalling may be a potentially useful therapeutic target in obesity, while aerobic exercise training suppresses the Notch1 pathway in the liver, contributing to the regulation of hepatic glucose and lipid metabolism in obese mice.
{"title":"Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice","authors":"Rafael Calais Gaspar, Ana Paula Azevêdo Macêdo, Susana Castelo Branco Ramos Nakandakari, Vitor Rosetto Muñoz, Gabriela Ferreira Abud, Renan Fudoli Lins Vieira, Ivo Vieira de Sousa Neto, Isadora Carolina Betim Pavan, Luiz Guilherme Salvino da Silva, Fernando Moreira Simabuco, Adelino S. R. da Silva, Wilson Salgado Junior, Julio Sergio Marchini, Carla Barbosa Nonino, Dennys Esper Cintra, Eduardo Rochete Ropelle, Utpal B. Pajvani, Ellen Cristini de Freitas, José Rodrigo Pauli","doi":"10.1111/liv.70068","DOIUrl":"https://doi.org/10.1111/liv.70068","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Notch1 protein plays a significant role in hepatic metabolism, as evidenced by its correlation with insulin resistance in the livers of obese individuals, making it an intriguing research target. Therefore, this study aims to investigate the impact of aerobic exercise on Notch1 pathways in the hepatic tissue of obese mice and its role in controlling hepatic metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Therefore, we conducted a cross-sectional study utilising liver biopsies from lean and obese humans, as well as an intervention study involving mice subjected to a high-fat diet. The obese-trained mice group underwent a treadmill-running protocol for 4 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed that obese individuals exhibited increased NOTCH1 mRNA levels compared to lean subjects. The detrimental effects of Notch1 signalling were confirmed by Notch1-overexpressed HepG2 cell lines. Obese mice with higher hepatic Notch1 signalling demonstrated a reduction in this pathway when subjected to a 4-week treadmill running. Another benefit noticed in this trained group was the amelioration of insulin resistance, as well as a reduction in pyruvate intolerance and gluconeogenic enzymes. Additionally, we observed that these protective findings were accompanied by a decrease in mTORC1 pathway activity and lipid accumulation in the liver. Pharmacological inhibition of Notch1 in obese mice led to an increase in mitochondrial respiration in the liver.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We conclude that Notch1 signalling may be a potentially useful therapeutic target in obesity, while aerobic exercise training suppresses the Notch1 pathway in the liver, contributing to the regulation of hepatic glucose and lipid metabolism in obese mice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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