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Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics 胆道闭锁易感基因EFEMP1调控肝外胆管弹性纤维形成及力学。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101215
Kapish Gupta , Jessica Llewellyn , Emilia Roberts , Chengyang Liu , Ali Naji , Richard K. Assoian , Rebecca G. Wells

Background & Aims

EGF-containing fibulin extracellular matrix protein 1 (EFEMP1, also called fibulin-3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibrotic disease of the neonatal extrahepatic bile duct. Fibulin-3 is deposited in most tissues and Efemp1 null mice have decreased elastic fibers in visceral fascia; however, fibulin-3 does not have a role in the development of large elastic fibers and its overall function in the extrahepatic bile ducts remains unclear.

Methods

We used staining and histology to define the amount and organization of key extracellular matrix components in the extrahepatic bile ducts. We also repurposed pressure myography, a technique heretofore applied to the vasculature, to determine the contribution of elastin and fibulin-3 to extrahepatic bile duct mechanics. We examined extrahepatic bile duct structure and mechanics in three models: neonatal vs. adult rat ducts (n = 6 each), elastase-treated adult rat ducts (n = 6-7 each), and Efemp1+/- vs. wild-type mouse ducts (n = 6 each).

Results

We demonstrated that fibulin-3 is expressed in the submucosa of both neonatal and adult mouse, rat and human extrahepatic bile ducts and that, in adult Efemp1+/- mouse ducts, elastin organization into fibers is decreased by approximately half. Pressure myography showed that Efemp1+/- ducts have altered mechanics compared to control ducts, with Efemp1+/- ducts displaying significant stretch compared to controls (p = 0.0376); these changes in stretch are similar to those observed in elastase-treated vs. normal ducts (p <0.0001) and in neonatal ducts vs. adult ducts (p <0.0001).

Conclusion

Fibulin-3 has an important role in the formation of elastic fibers and the mechanical properties of the extrahepatic bile duct. This provides functional relevance for the biliary atresia susceptibility gene EFEMP1.

Impact and implications:

The gene EFEMP1 was found via a genome-wide association study to be a susceptibility gene for the neonatal disease biliary atresia. EFEMP1 encodes the protein fibulin-3, which regulates elastic fiber organization in the extrahepatic bile duct (EHBD), the major site of disease in biliary atresia. We showed that neonatal EHBDs as well as mice heterozygous for Efemp1 have decreased numbers of elastic fibers, and that this alters EHBD mechanics. This work is important for understanding the mechanism of biliary atresia, in particular susceptibility to obstruction.
背景与目的:egf -含纤维蛋白细胞外基质蛋白1 (EFEMP1,也称为纤维蛋白-3)是一种细胞外基质蛋白,在全基因组关联研究中与新生儿肝外胆管纤维化疾病胆道闭锁相关。纤维蛋白-3沉积在大多数组织中,Efemp1缺失小鼠内脏筋膜弹性纤维减少;然而,纤维蛋白-3在大弹性纤维的形成中没有作用,其在肝外胆管中的整体功能尚不清楚。方法:采用染色法和组织学方法确定肝外胆管中关键细胞外基质成分的数量和组织结构。我们还重新利用压力肌图,一种迄今为止应用于血管系统的技术,来确定弹性蛋白和纤维蛋白-3对肝外胆管力学的贡献。我们在三种模型中检测了肝外胆管的结构和力学:新生大鼠与成年大鼠胆管(n = 6),弹性酶处理的成年大鼠胆管(n = 6-7), Efemp1 +/-与野生型小鼠胆管(n = 6)。结果:我们发现,在新生和成年小鼠、大鼠和人肝外胆管的粘膜下层都有纤维蛋白-3的表达,而在成年Efemp1 +/-小鼠胆管中,弹性蛋白在纤维中的组织减少了大约一半。压力肌图显示,与对照组相比,Efemp1 +/-导管的力学改变,Efemp1 +/-导管与对照组相比显着拉伸(p = 0.0376);结论:纤维蛋白-3在肝外胆管弹性纤维的形成和力学性能方面起着重要作用。这为胆道闭锁易感基因EFEMP1提供了功能相关性。影响和启示:基因EFEMP1是通过全基因组关联研究发现的新生儿疾病胆道闭锁的易感基因。EFEMP1编码蛋白纤维蛋白-3,其调节肝外胆管(EHBD)的弹性纤维组织,而肝外胆管是胆道闭锁的主要疾病部位。我们发现新生儿EHBD以及Efemp1杂合小鼠的弹性纤维数量减少,这改变了EHBD的机制。这项工作对了解胆道闭锁的机制,特别是对梗阻的易感性具有重要意义。
{"title":"Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics","authors":"Kapish Gupta ,&nbsp;Jessica Llewellyn ,&nbsp;Emilia Roberts ,&nbsp;Chengyang Liu ,&nbsp;Ali Naji ,&nbsp;Richard K. Assoian ,&nbsp;Rebecca G. Wells","doi":"10.1016/j.jhepr.2024.101215","DOIUrl":"10.1016/j.jhepr.2024.101215","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>EGF-containing fibulin extracellular matrix protein 1 (EFEMP1, also called fibulin-3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibrotic disease of the neonatal extrahepatic bile duct. Fibulin-3 is deposited in most tissues and <em>Efemp1</em> null mice have decreased elastic fibers in visceral fascia; however, fibulin-3 does not have a role in the development of large elastic fibers and its overall function in the extrahepatic bile ducts remains unclear.</div></div><div><h3>Methods</h3><div>We used staining and histology to define the amount and organization of key extracellular matrix components in the extrahepatic bile ducts. We also repurposed pressure myography, a technique heretofore applied to the vasculature, to determine the contribution of elastin and fibulin-3 to extrahepatic bile duct mechanics. We examined extrahepatic bile duct structure and mechanics in three models: neonatal <em>vs.</em> adult rat ducts (n = 6 each), elastase-treated adult rat ducts (n = 6-7 each), and <em>Efemp1</em><sup>+/-</sup> <em>vs.</em> wild-type mouse ducts (n = 6 each).</div></div><div><h3>Results</h3><div>We demonstrated that fibulin-3 is expressed in the submucosa of both neonatal and adult mouse, rat and human extrahepatic bile ducts and that, in adult <em>Efemp1</em><sup>+/-</sup> mouse ducts, elastin organization into fibers is decreased by approximately half. Pressure myography showed that <em>Efemp1</em><sup>+/-</sup> ducts have altered mechanics compared to control ducts, with <em>Efemp1</em><sup>+/-</sup> ducts displaying significant stretch compared to controls (<em>p =</em> 0.0376); these changes in stretch are similar to those observed in elastase-treated <em>vs</em>. normal ducts (<em>p</em> &lt;0.0001) and in neonatal ducts <em>vs.</em> adult ducts (<em>p</em> &lt;0.0001).</div></div><div><h3>Conclusion</h3><div>Fibulin-3 has an important role in the formation of elastic fibers and the mechanical properties of the extrahepatic bile duct. This provides functional relevance for the biliary atresia susceptibility gene EFEMP1.</div></div><div><h3>Impact and implications:</h3><div>The gene EFEMP1 was found via a genome-wide association study to be a susceptibility gene for the neonatal disease biliary atresia. EFEMP1 encodes the protein fibulin-3, which regulates elastic fiber organization in the extrahepatic bile duct (EHBD), the major site of disease in biliary atresia. We showed that neonatal EHBDs as well as mice heterozygous for <em>Efemp1</em> have decreased numbers of elastic fibers, and that this alters EHBD mechanics. This work is important for understanding the mechanism of biliary atresia, in particular susceptibility to obstruction.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101215"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881894","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}
引用次数: 0
Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy 慢性乙型肝炎不同的病毒学轨迹确定了对核苷类似物治疗反应的异质性。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101229
Tingyan Wang , Cori Campbell , Alexander J. Stockdale , Stacy Todd , Karl McIntyre , Andrew Frankland , Jakub Jaworski , Ben Glampson , Dimitri Papadimitriou , Luca Mercuri , Erik Mayer , Christopher R. Jones , Hizni Salih , Gail Roadknight , Stephanie Little , Theresa Noble , Kinga A. Várnai , Cai Davis , Ashley I. Heinson , Michael George , Philippa C. Matthews

Background & Aims

The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos(t)ide analogue (NA) treatment and its relationship with liver disease are poorly understood. We aimed to study longitudinal VL patterns and their associations with CHB clinical outcomes.

Methods

Utilising large scale, routinely collected electronic health records from six centres in England, collated by the National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC), we applied latent class mixed models to investigate VL trajectory patterns in adults receiving NA treatment. We assessed associations of VL trajectory with alanine transaminase, and with liver fibrosis/cirrhosis.

Results

We retrieved data from 1,885 adults on NA treatment (median follow-up 6.2 years, IQR 3.7–9.3 years), with 21,691 VL measurements (median 10 per patient, IQR 5–17). Five VL classes were identified from the derivation cohort (n = 1,367, discrimination: 0.93, entropy: 0.90): class 1 ‘long term suppression’ (n = 827, 60.5%), class 2 ‘timely virological suppression’ (n = 254, 18.6%), class 3 ‘persistent moderate viraemia’ (n = 140, 10.2%), class 4 ‘persistent high-level viraemia’ (n = 44, 3.2%), and class 5 ‘slow virological suppression’ (n = 102, 7.5%). The model demonstrated a discrimination of 0.93 and entropy of 0.88 for the validation cohort (n = 518). Alanine transaminase decreased variably over time in VL-suppressed groups (classes 1, 2, 5; all p <0.001), but did not significantly improve in those with persistent viraemia (classes 3, 4). Patients in class 5 had twofold increased hazards of fibrosis/cirrhosis compared with class 1 (adjusted hazard ratio, 2.00; 95% CI, 1.33–3.02).

Conclusions

Heterogeneity exists in virological response to NA therapy in CHB patients, with over 20% showing potentially suboptimal responses. Slow virological suppression is associated with liver disease progression.

Impact and implications:

Treatment recommendations for people living with chronic hepatitis B virus (HBV) infection are becoming less stringent, meaning that more of the population will be eligible to receive therapy with nucleos(t)ide analogue agents. We explored outcomes of HBV treatment in a large UK dataset, describing different responses to treatment, and showing that the viral load is not completely suppressed after 1 year in about one in five cases, associated with an increased risk of liver complications. As treatment is rolled out more widely, patients and clinicians need to be aware of the potential for incomplete virologic responses. The findings can support the identification of high-risk individuals, improve early fibrosis and cirrhosis prediction, guide monitoring and preventive interventions, and support public health elimination goals.
背景与目的:慢性乙型肝炎(CHB)患者接受核苷类似物(NA)治疗后HBV病毒载量(VL)的动态变化及其与肝脏疾病的关系尚不清楚。我们的目的是研究纵向VL模式及其与慢性乙型肝炎临床结局的关系。方法:利用英国6个中心的大规模、常规收集的电子健康记录,由国家卫生与保健研究所健康信息学协作(NIHR HIC)整理,我们应用潜在类别混合模型来研究接受NA治疗的成人的VL轨迹模式。我们评估了VL轨迹与丙氨酸转氨酶和肝纤维化/肝硬化的关系。结果:我们检索了1885名接受NA治疗的成年人的数据(中位随访6.2年,IQR 3.7-9.3年),21,691个VL测量值(中位每位患者10个,IQR 5-17)。从衍生队列中鉴定出5类VL (n = 1367,鉴别率:0.93,熵:0.90):1类“长期抑制”(n = 827, 60.5%), 2类“及时病毒学抑制”(n = 254, 18.6%), 3类“持续中度病毒血症”(n = 140, 10.2%), 4类“持续高水平病毒血症”(n = 44, 3.2%), 5类“缓慢病毒学抑制”(n = 102, 7.5%)。该模型对验证队列(n = 518)的判别率为0.93,熵值为0.88。随着时间的推移,vl抑制组丙氨酸转氨酶有所下降(1、2、5类;结论:慢性乙型肝炎患者对NA治疗的病毒学反应存在异质性,超过20%的患者表现出潜在的次优反应。缓慢的病毒学抑制与肝脏疾病进展有关。影响和意义:对慢性乙型肝炎病毒(HBV)感染者的治疗建议正变得不那么严格,这意味着更多的人群将有资格接受核苷(t)类药物治疗。我们在一个大型的英国数据集中探讨了HBV治疗的结果,描述了对治疗的不同反应,并显示在大约五分之一的病例中,1年后病毒载量没有完全抑制,这与肝脏并发症的风险增加有关。随着治疗得到更广泛的推广,患者和临床医生需要意识到不完全病毒学反应的可能性。研究结果可以支持高危人群的识别,改善早期纤维化和肝硬化的预测,指导监测和预防干预,并支持公共卫生消除目标。
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引用次数: 0
EASL Schools of Hepatology: Pioneering the flipped classroom model and blended learning in medical education
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101266
Francesco Negro , Mounia Heddad Masson , Ulrich Beuers
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引用次数: 0
Editorial Board page
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/S2589-5559(24)00320-3
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引用次数: 0
Microwave ablation vs. single-needle radiofrequency ablation for the treatment of HCC up to 4 cm: A randomized-controlled trial 微波消融与单针射频消融治疗4厘米以内的HCC:一项随机对照试验。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101269
Katsutoshi Sugimoto , Kento Imajo , Hidekatsu Kuroda , Go Murohisa , Kazue Shiozawa , Kentaro Sakamaki , Takuya Wada , Hirohito Takeuchi , Kei Endo , Tamami Abe , Takashi Matsui , Takahiro Murakami , Masato Yoneda , Atsushi Nakajima , Shigehiro Kokubu , Takao Itoi

Background & Aims

Radiofrequency ablation (RFA) is the standard treatment for small hepatocellular carcinoma (HCC), specifically for tumors <3 cm in size and numbering fewer than three, excluding surgical candidates. Microwave ablation (MWA) is an innovative approach believed to have theoretical benefits over RFA; however, these advantages are yet to be empirically verified. Therefore, we evaluated and compared the effectiveness of MWA and RFA in managing HCC tumors up to 4 cm in size.

Methods

In this multicenter randomized controlled trial conducted across five centers in Japan, eligible participants had up to 4 tumors, each up to 4 cm in size, and were not considered for surgery. Patients were randomly assigned to undergo MWA or RFA. The primary outcome was the rate of local tumor progression (LTP), whereas secondary outcomes included overall survival (OS) and intra- and extrahepatic recurrence-free survival (RFS) at the end of the 2-year follow up.

Results

In total, 240 participants were screened from July 12, 2018, to December 7, 2021. Four participants were excluded: three did not meet inclusion criteria, and one died from an unknown cause during treatment. Consequently, 119 (130 lesions) and 117 (136 lesions) participants were treated with MWA and RFA, respectively. The proportion of lesions with LTP at the 2-year follow up was significantly lower in the MWA group (20 [16.4%] lesions) than in the RFA group (38 [30.4%] lesions) (risk ratio, 0.54; p = 0.007). OS and both intra- and extrahepatic RFS did not significantly differ between groups.

Conclusions

MWA is more effective than RFA in reducing local tumor progression for HCC tumors up to 4 cm. However, no differences were observed in OS and RFS.

Impact and implications:

While some randomized control trials (RCTs) have compared the efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC), the superiority of MWA over RFA remains unverified despite its theoretical benefit. This study is the first to demonstrate the utility of MWA over single-needle RFA for patients with HCC, with a significant difference between the two groups in the proportion of lesions with local tumor progression after a 2-year follow up. Moreover, the two techniques were safe, with only two severe complications reported in the entire study cohort. Given that an RCT differs slightly from daily clinical situations, practical and anatomical criteria for selecting the optimal technique on a lesion-by-lesion basis are required.
背景与目的:射频消融(RFA)是小肝细胞癌(HCC)的标准治疗方法,特别是肿瘤。方法:在日本的五个中心进行的多中心随机对照试验中,符合条件的参与者有多达4个肿瘤,每个肿瘤的大小达4厘米,不考虑手术。患者被随机分配接受MWA或RFA。主要终点是局部肿瘤进展率(LTP),而次要终点包括2年随访结束时的总生存期(OS)和肝内和肝外无复发生存期(RFS)。结果:从2018年7月12日至2021年12月7日,共筛选了240名参与者。4名受试者被排除在外:3名不符合纳入标准,1名在治疗期间死于未知原因。因此,119(130个病变)和117(136个病变)参与者分别接受了MWA和RFA治疗。2年随访时,MWA组LTP病变比例(20例[16.4%])明显低于RFA组(38例[30.4%])(风险比0.54;P = 0.007)。OS和肝内、肝外RFS组间无显著差异。结论:对于4cm以内的HCC肿瘤,MWA比RFA更有效地减少局部肿瘤进展。然而,在OS和RFS方面没有观察到差异。影响和启示:虽然一些随机对照试验(rct)比较了微波消融(MWA)和射频消融(RFA)治疗小肝细胞癌(HCC)的疗效,但MWA优于RFA的优势尽管在理论上有好处,但仍未得到证实。这项研究首次证明了MWA比单针RFA对HCC患者的实用性,在2年随访后,两组在局部肿瘤进展的病变比例上有显著差异。此外,这两种技术是安全的,在整个研究队列中仅报告了两种严重并发症。考虑到随机对照试验与日常临床情况略有不同,在逐个病变的基础上选择最佳技术的实用和解剖学标准是必要的。
{"title":"Microwave ablation vs. single-needle radiofrequency ablation for the treatment of HCC up to 4 cm: A randomized-controlled trial","authors":"Katsutoshi Sugimoto ,&nbsp;Kento Imajo ,&nbsp;Hidekatsu Kuroda ,&nbsp;Go Murohisa ,&nbsp;Kazue Shiozawa ,&nbsp;Kentaro Sakamaki ,&nbsp;Takuya Wada ,&nbsp;Hirohito Takeuchi ,&nbsp;Kei Endo ,&nbsp;Tamami Abe ,&nbsp;Takashi Matsui ,&nbsp;Takahiro Murakami ,&nbsp;Masato Yoneda ,&nbsp;Atsushi Nakajima ,&nbsp;Shigehiro Kokubu ,&nbsp;Takao Itoi","doi":"10.1016/j.jhepr.2024.101269","DOIUrl":"10.1016/j.jhepr.2024.101269","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Radiofrequency ablation (RFA) is the standard treatment for small hepatocellular carcinoma (HCC), specifically for tumors &lt;3 cm in size and numbering fewer than three, excluding surgical candidates. Microwave ablation (MWA) is an innovative approach believed to have theoretical benefits over RFA; however, these advantages are yet to be empirically verified. Therefore, we evaluated and compared the effectiveness of MWA and RFA in managing HCC tumors up to 4 cm in size.</div></div><div><h3>Methods</h3><div>In this multicenter randomized controlled trial conducted across five centers in Japan, eligible participants had up to 4 tumors, each up to 4 cm in size, and were not considered for surgery. Patients were randomly assigned to undergo MWA or RFA. The primary outcome was the rate of local tumor progression (LTP), whereas secondary outcomes included overall survival (OS) and intra- and extrahepatic recurrence-free survival (RFS) at the end of the 2-year follow up.</div></div><div><h3>Results</h3><div>In total, 240 participants were screened from July 12, 2018, to December 7, 2021. Four participants were excluded: three did not meet inclusion criteria, and one died from an unknown cause during treatment. Consequently, 119 (130 lesions) and 117 (136 lesions) participants were treated with MWA and RFA, respectively. The proportion of lesions with LTP at the 2-year follow up was significantly lower in the MWA group (20 [16.4%] lesions) than in the RFA group (38 [30.4%] lesions) (risk ratio, 0.54; <em>p</em> = 0.007). OS and both intra- and extrahepatic RFS did not significantly differ between groups.</div></div><div><h3>Conclusions</h3><div>MWA is more effective than RFA in reducing local tumor progression for HCC tumors up to 4 cm. However, no differences were observed in OS and RFS.</div></div><div><h3>Impact and implications:</h3><div>While some randomized control trials (RCTs) have compared the efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC), the superiority of MWA over RFA remains unverified despite its theoretical benefit. This study is the first to demonstrate the utility of MWA over single-needle RFA for patients with HCC, with a significant difference between the two groups in the proportion of lesions with local tumor progression after a 2-year follow up. Moreover, the two techniques were safe, with only two severe complications reported in the entire study cohort. Given that an RCT differs slightly from daily clinical situations, practical and anatomical criteria for selecting the optimal technique on a lesion-by-lesion basis are required.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101269"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970813","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}
引用次数: 0
Tumor burden with AFP improves survival prediction for TACE-treated patients with HCC: An international observational study☆ AFP的肿瘤负荷提高tace治疗的HCC患者的生存预测:一项国际观察性研究☆。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101216
Dongdong Xia , Wei Bai , Qiuhe Wang , Jin Wook Chung , Xavier Adhoute , Roman Kloeckner , Hui Zhang , Yong Zeng , Pimsiri Sripongpun , Chunhui Nie , Seung Up Kim , Ming Huang , Wenhao Hu , Xiangchun Ding , Guowen Yin , Hailiang Li , Hui Zhao , Jean-Pierre Bronowicki , Jing Li , Jiaping Li , Guohong Han

Background & Aims

Current prognostic models for patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) are not extensively validated and widely accepted. We aimed to develop and validate a continuous model incorporating tumor burden and biology for individual survival prediction and risk stratification.

Methods

Overall, 4,377 treatment-naive candidates for whom TACE was recommended, from 39 centers in five countries, were enrolled and divided into training, internal validation, and two external validation datasets. The novel model was developed using a Cox multivariable regression analysis and compared with our original 6-and-12 model (the largest tumor size [ts, centimetres] + tumor number [tn]) and other available models in terms of predictive accuracy.

Results

The proposed model, named the ‘6-and-12 model 2.0’, was generated as ‘ts + tn + 1.5×log10 alpha-fetoprotein (AFP)’, showed good discrimination (C-index 0.674) and calibration (Hosmer–Lemeshow test p = 0.147), and outperformed current existing models. An easy-to-use stratification was proposed according to the different AFP levels (≤100, 100–400, 400–2,000, 2,000–10,000, 10,000–40,000, and >40,000 ng/ml) along with the corresponding tumor burden cutoffs (8/14, 7/13, 6/12, 5/11, 4/10, and any tumor burden); that is, if the AFP level was 400–2,000 ng/ml, the stratification should be low-(≤6)/intermediate-(6–12)/high-risk (>12) strata. Hence, it could divide the patients into three distinct risk categories with a median overall survival of 45.0 (95% CI, 40.1–49.9), 30.0 (95% CI, 26.1–33.9), and 15.4 (95% CI, 13.4–17.4) months (p <0.001) from low-risk to high-risk strata, respectively. These findings were confirmed in validation and subgroup analyses.

Conclusions

The 6-and-12 model 2.0 significantly improved individual outcome predictions and better stratified the candidates recommended for TACE; thus, this model could be used in both clinical practice and trial design.

Impact and implications:

In this international multicentre study, we developed and internally and externally validated a novel outcome prediction model for candidates with HCC who would be ideal for TACE. The model, called the 6-and-12 model 2.0, was based on 4,377 patients from 39 centers in five countries. The model offers individualized outcome prediction, outperforming the original 6-and-12 model score and other existing metrics across all datasets and subsets. Based on different levels of alpha-fetoprotein (AFP) and corresponding cut-offs of tumor burden, patients could be stratified into three risk strata with significantly different survival prognoses, which could provide a referential framework to control study heterogeneity and define the target population in future trial designs.
背景与目的:目前肝细胞癌(HCC)经动脉化疗栓塞(TACE)患者的预后模型尚未得到广泛验证和广泛接受。我们的目标是开发和验证一个结合肿瘤负荷和生物学的连续模型,用于个体生存预测和风险分层。方法:总体而言,来自5个国家39个中心的4377名TACE推荐的初始治疗候选人入组,并分为培训、内部验证和两个外部验证数据集。新模型采用Cox多变量回归分析,并与我们的原始6和12模型(最大肿瘤大小[ts,厘米]+肿瘤数量[tn])和其他可用模型在预测准确性方面进行了比较。结果:所建模型命名为“6- 12模型2.0”,生成的模型为“ts + tn + 1.5×log10 α -胎蛋白(AFP)”,具有良好的判别性(c指数0.674)和校准性(Hosmer-Lemeshow检验p = 0.147),优于现有模型。根据不同的AFP水平(≤100、100-400、400-2,000、2,000-10,000、10,000-40,000和bbb40000 ng/ml)以及相应的肿瘤负荷截止值(8/14、7/13、6/12、5/11、4/10和任何肿瘤负荷)提出了易于使用的分层;即AFP水平为400- 2000 ng/ml时,分层应为低(≤6)/中(6-12)/高危(> -12)层。因此,它可以将患者分为三个不同的风险类别,中位总生存期为45.0 (95% CI, 40.1-49.9)、30.0 (95% CI, 26.1-33.9)和15.4 (95% CI, 13.4-17.4)个月(p)。结论:6- 12模型2.0显著提高了个体结局预测,更好地分层推荐TACE候选人;因此,该模型可用于临床实践和试验设计。影响和意义:在这项国际多中心研究中,我们开发并内部和外部验证了一种新的HCC候选人预后预测模型,该模型将是理想的TACE患者。该模型被称为6- 12模型2.0,是基于来自五个国家39个中心的4377名患者。该模型提供个性化的结果预测,在所有数据集和子集中优于原始的6和12模型得分和其他现有指标。根据不同的甲胎蛋白(AFP)水平和相应的肿瘤负荷临界值,可将患者划分为生存预后差异显著的3个风险层,为今后试验设计控制研究异质性和确定目标人群提供参考框架。
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引用次数: 0
Acknowledging our reviewers
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101244
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引用次数: 0
Hepatocellular carcinoma hosts cholinergic neural cells and tumoral hepatocytes harboring targetable muscarinic receptors 肝细胞癌宿主胆碱能神经细胞和肿瘤肝细胞含有可靶向的毒蕈碱受体。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101245
Charlotte A. Hernandez , Claire Verzeroli , Armando Andres Roca Suarez , Abud-José Farca-Luna , Laurie Tonon , Roger Esteban-Fabró , Roser Pinyol , Marie-Laure Plissonnier , Ievgeniia Chicherova , Anaëlle Dubois , Pascale Bellaud , Marine Seffals , Bruno Turlin , Alain Fautrel , Gabriel Ichim , Michel Rivoire , Guillaume Passot , Zuzana Macek-Jilkova , Thomas Decaens , Alain Viari , Romain Parent

Background & Aims

Owing to unexplained interpatient variation and treatment failure in hepatocellular carcinoma (HCC), novel therapeutic approaches remain an urgent clinical need. Hepatic neurons, belonging to the autonomic nervous system (ANS), mediate liver/whole body crosstalk. Pathological innervation of the ANS has been identified in cancer, nurturing tumor stroma and conferring stronger carcinogenic properties.

Methods

We characterized the innervation of liver tumors from the French Liver Biobank, then applied bioinformatics to TCGA (The Cancer Genome Atlas), several other datasets and a European validation cohort, to re-evaluate patient stratification. Cell biology and pharmacology studies were also performed.

Results

Densely packed nucleated DCX+, synaptophysin+, NeuN+, VAChT+, TH-, CD31-, CD45- clusters, to date undetected, were identified in human HCCs, and independently confirmed by single-cell RNA sequencing data. Using the new concept of a neuronal score, human and rat HCCs displayed tightly netrin-1-associated neural reconfiguration towards cholinergic polarity, which was associated with chronic liver disease progression, cancer onset and many features of aggressive (proliferative class) HCC, including shortened survival. This score was conditioned by tumoral hepatocytes, and predicted sorafenib efficacy in the STORM HCC phase III trial. Conversely, intratumoral adrenergic lymphocytes were enriched in TEMRA and cytotoxic phenotypes. Amongst all cholinergic transcripts, the medically targeted CHRM3 receptor was enriched and associated with pathogenic traits in HCC, as well as poor prognosis in HCC stages 1-2, while its level dropped upon experimental re-differentiation. Its pharmacological inhibition with low concentrations of anticholinergic drugs, but not cholinomimetics, decreased anchorage-independent growth and anoikis, synergized with sorafenib and lenvatinib in HCC class 1 to 3 lines, yet not in primary human hepatocytes, and preserved mature hepatocyte functions.

Conclusion

These data identify cholinergic processes as instrumental in liver carcinogenesis and support the use of EMA/FDA-approved cholinergic drugs in HCC research.

Impact and implications:

Hepatocellular carcinoma (HCC) care has long been hampered by the enigmatic nature of disease evolution, as well as of response or resistance to treatment. Hepatic neurons are likely the least studied liver cell type and mediate patients singularities from the ANS to the organ in real-time. Cholinergic inputs identified in this study as pathogenic may be targeted with the well charted pharmacopoeia of neurotropic drugs already available, for basic or clinical research purposes, with an expected high level of safety.
背景与目的:由于肝细胞癌(HCC)患者间无法解释的差异和治疗失败,新的治疗方法仍然是临床迫切需要的。肝神经元属于自主神经系统,介导肝/全身串扰。ANS的病理神经支配已经在癌症中被发现,它培育肿瘤基质并赋予更强的致癌特性。方法:我们对来自法国肝脏生物库的肝脏肿瘤的神经支配进行了表征,然后将生物信息学应用于TCGA(癌症基因组图谱),其他几个数据集和欧洲验证队列,以重新评估患者分层。细胞生物学和药理学研究也进行了。结果:在人类hcc中发现了密集排列的有核DCX+、synaptophysin+、NeuN+、VAChT+、TH-、CD31-、CD45-簇,迄今未被检测到,并通过单细胞RNA测序数据独立证实。利用神经元评分的新概念,人和大鼠HCC显示出与netrin-1密切相关的神经重构,向胆碱能极性方向发展,这与慢性肝病进展、癌症发作和侵袭性(增生性)HCC的许多特征相关,包括生存期缩短。该评分以肿瘤肝细胞为条件,并预测索拉非尼在STORM HCC III期试验中的疗效。相反,瘤内肾上腺素能淋巴细胞在TEMRA和细胞毒性表型中富集。在所有胆碱能转录本中,医学上靶向的CHRM3受体在HCC中富集,并与HCC 1-2期的致病特征和不良预后相关,而在实验中再分化后其水平下降。它与低浓度的抗胆碱能药物(而非拟胆碱药物)的药理抑制作用降低了锚定非依赖性生长和细胞增生,与索拉非尼和lenvatinib在1至3级HCC中协同作用,但对原代人肝细胞没有协同作用,并保留了成熟肝细胞的功能。结论:这些数据确定胆碱能过程在肝癌发生中起重要作用,并支持在HCC研究中使用EMA/ fda批准的胆碱能药物。影响和启示:肝细胞癌(HCC)的治疗长期以来一直受到疾病演变的神秘性质以及对治疗的反应或抵抗的阻碍。肝神经元可能是研究最少的肝细胞类型,并实时介导患者从ANS到器官的奇异性。在本研究中确定的具有致病性的胆碱能输入物,可用于基础或临床研究目的,并具有预期的高安全性,以现有的神经营养药物的药典为目标。
{"title":"Hepatocellular carcinoma hosts cholinergic neural cells and tumoral hepatocytes harboring targetable muscarinic receptors","authors":"Charlotte A. Hernandez ,&nbsp;Claire Verzeroli ,&nbsp;Armando Andres Roca Suarez ,&nbsp;Abud-José Farca-Luna ,&nbsp;Laurie Tonon ,&nbsp;Roger Esteban-Fabró ,&nbsp;Roser Pinyol ,&nbsp;Marie-Laure Plissonnier ,&nbsp;Ievgeniia Chicherova ,&nbsp;Anaëlle Dubois ,&nbsp;Pascale Bellaud ,&nbsp;Marine Seffals ,&nbsp;Bruno Turlin ,&nbsp;Alain Fautrel ,&nbsp;Gabriel Ichim ,&nbsp;Michel Rivoire ,&nbsp;Guillaume Passot ,&nbsp;Zuzana Macek-Jilkova ,&nbsp;Thomas Decaens ,&nbsp;Alain Viari ,&nbsp;Romain Parent","doi":"10.1016/j.jhepr.2024.101245","DOIUrl":"10.1016/j.jhepr.2024.101245","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Owing to unexplained interpatient variation and treatment failure in hepatocellular carcinoma (HCC), novel therapeutic approaches remain an urgent clinical need. Hepatic neurons, belonging to the autonomic nervous system (ANS), mediate liver/whole body crosstalk. Pathological innervation of the ANS has been identified in cancer, nurturing tumor stroma and conferring stronger carcinogenic properties.</div></div><div><h3>Methods</h3><div>We characterized the innervation of liver tumors from the French Liver Biobank, then applied bioinformatics to TCGA (The Cancer Genome Atlas), several other datasets and a European validation cohort, to re-evaluate patient stratification. Cell biology and pharmacology studies were also performed.</div></div><div><h3>Results</h3><div>Densely packed nucleated DCX<sup>+</sup>, synaptophysin<sup>+</sup>, NeuN<sup>+</sup>, VAChT<sup>+</sup>, TH<sup>-</sup>, CD31<sup>-</sup>, CD45<sup>-</sup> clusters, to date undetected, were identified in human HCCs, and independently confirmed by single-cell RNA sequencing data. Using the new concept of a neuronal score, human and rat HCCs displayed tightly netrin-1-associated neural reconfiguration towards cholinergic polarity, which was associated with chronic liver disease progression, cancer onset and many features of aggressive (proliferative class) HCC, including shortened survival. This score was conditioned by tumoral hepatocytes, and predicted sorafenib efficacy in the STORM HCC phase III trial. Conversely, intratumoral adrenergic lymphocytes were enriched in TEMRA and cytotoxic phenotypes. Amongst all cholinergic transcripts, the medically targeted CHRM3 receptor was enriched and associated with pathogenic traits in HCC, as well as poor prognosis in HCC stages 1-2, while its level dropped upon experimental re-differentiation. Its pharmacological inhibition with low concentrations of anticholinergic drugs, but not cholinomimetics, decreased anchorage-independent growth and anoikis, synergized with sorafenib and lenvatinib in HCC class 1 to 3 lines, yet not in primary human hepatocytes, and preserved mature hepatocyte functions.</div></div><div><h3>Conclusion</h3><div>These data identify cholinergic processes as instrumental in liver carcinogenesis and support the use of EMA/FDA-approved cholinergic drugs in HCC research.</div></div><div><h3>Impact and implications:</h3><div>Hepatocellular carcinoma (HCC) care has long been hampered by the enigmatic nature of disease evolution, as well as of response or resistance to treatment. Hepatic neurons are likely the least studied liver cell type and mediate patients singularities from the ANS to the organ in real-time. Cholinergic inputs identified in this study as pathogenic may be targeted with the well charted pharmacopoeia of neurotropic drugs already available, for basic or clinical research purposes, with an expected high level of safety.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101245"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881966","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}
引用次数: 0
Macrophage Notch1 signaling modulates regulatory T cells via the TGFB axis in early MASLD 巨噬细胞Notch1信号在早期MASLD中通过TGFB轴调节调节性T细胞。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101242
Mengya Zhang , Kun Li , Xiaoxing Huang , Dongqin Xu , Ruobin Zong , Qintong Hu , Xiaoyu Dong , Qinyong Zhang , Chaochen Jiang , Yue Ge , Changyong Li , Jie Ping

Background & Aims

Hepatic immune imbalance is crucial for driving metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the role of hepatic regulatory T cells (Tregs) in MASLD initiation and the mechanisms responsible for their change are not completely understood.

Methods

A mouse model subjected to a short-term high-fat diet (HFD) to mimic early steatosis, along with liver biopsy samples from patients with simple steatosis, and macrophage-specific Notch1-knockout mice (Notch1M-KO), were used to investigate the role of Tregs in early MASLD and the effect of hepatic macrophage Notch1 signaling on Treg frequency. The miRNAs correlated with Treg differentiation were analyzed using exosomal miRNA sequencing.

Results

A decrease in Tregs contributed to HFD-induced hepatic steatosis and insulin resistance (five/group/time point, p <0.001). Remarkably, the frequency of Tregs was negatively correlated with Notch1 activation in hepatic macrophages during hepatic steatosis (38/group, r = -0.735, p <0.001). Furthermore, Notch1 deficiency attenuated hepatic lipid deposition and reversed Treg levels (five/group, p <0.01 and <0.05, respectively). Moreover, Treg depletion in Notch1M-KO mice greatly diminished the ameliorative effect of macrophagic Notch1 deletion on hepatic steatosis. Mechanistically, macrophage Notch1 activation increased the level of exosomal miR-142a-3p (by one- to two- fold), impairing Treg differentiation by targeting transforming growth factor beta receptor 1 (TGFBR1) on T cells. Consistently, HFD-fed Notch1M-KO mice exhibited reduced miR-142a-3p levels, elevated TGFBR1 expression on T cells, and increased Treg frequency in the liver.

Conclusions

These findings highlight the crucial role of hepatic Tregs during the early stage of MASLD and add a novel, non-negligible pathway for macrophage involvement in hepatic steatosis. We identify a previously unrecognized molecular mechanism involving the macrophage Notch1/exosomal miR-142a-3p/TGFBR1 pathway in regulating Treg differentiation, providing a rationale for refined therapeutic strategies for MASLD.

Impact and implications:

The immune mechanisms driving MASLD progression, particularly during the early stages of disease, are not fully understood, which limits the development of effective interventions. This study elucidated a novel mechanism by which hepatic macrophage Notch1 signaling modulated Tregs through the exosomal miR-142a-3p/TGFBR1 axis, contributing to the progression of MASLD. These findings provide a rationale for a potential immunological approach to treat MASLD in the future.
背景与目的:肝脏免疫失衡是驱动代谢功能障碍相关脂肪变性肝病(MASLD)进展的关键因素。然而,肝调节性T细胞(Tregs)在MASLD起始中的作用及其变化机制尚不完全清楚。方法:采用短期高脂饮食(HFD)模拟早期脂肪变性的小鼠模型,以及单纯性脂肪变性患者的肝活检样本和巨噬细胞特异性Notch1敲除小鼠(Notch1M-KO),研究Tregs在早期MASLD中的作用以及肝巨噬细胞Notch1信号通路对Treg频率的影响。使用外泌体miRNA测序分析与Treg分化相关的miRNA。结果:Tregs的减少有助于hfd诱导的肝脂肪变性和胰岛素抵抗(5 /组/时间点,p p p M-KO小鼠),大大降低了巨噬细胞Notch1缺失对肝脂肪变性的改善作用。从机制上讲,巨噬细胞Notch1激活增加了外泌体miR-142a-3p的水平(1至2倍),通过靶向T细胞上的转化生长因子β受体1 (TGFBR1)来损害Treg分化。同样,hfd喂养的Notch1M-KO小鼠表现出miR-142a-3p水平降低,T细胞上TGFBR1表达升高,肝脏中Treg频率增加。结论:这些发现强调了肝脏Tregs在MASLD早期的关键作用,并为巨噬细胞参与肝脂肪变性增加了一种新的、不可忽视的途径。我们发现了一个以前未被认识的巨噬细胞Notch1/外泌体miR-142a-3p/TGFBR1通路调节Treg分化的分子机制,为改进MASLD的治疗策略提供了理论依据。影响和影响:推动MASLD进展的免疫机制,特别是在疾病早期阶段,尚未完全了解,这限制了有效干预措施的发展。本研究阐明了肝巨噬细胞Notch1信号通过外泌体miR-142a-3p/TGFBR1轴调控Tregs,促进MASLD进展的新机制。这些发现为未来潜在的免疫治疗MASLD提供了理论依据。
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引用次数: 0
The future of clinical trials of gut microbiome therapeutics in cirrhosis 肝硬化肠道微生物组治疗临床试验的未来。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101234
Patricia P. Bloom , Raymond T. Chung
The last two decades have witnessed an explosion of microbiome research, including in hepatology, with studies demonstrating altered microbial composition in liver disease. More recently, efforts have been made to understand the association of microbiome features with clinical outcomes and to develop therapeutics targeting the microbiome. While microbiome therapeutics hold much promise, their unique features pose certain challenges for the design and conduct of clinical trials. Herein, we will briefly review indications for microbiome therapeutics in cirrhosis, currently available microbiome therapeutics, and the biological pathways targeted by these therapies. We will then focus on the best practices and important considerations for clinical trials of gut microbiome therapeutics in cirrhosis.
过去二十年见证了微生物组研究的爆炸式增长,包括肝病学,研究表明肝病中微生物组成的改变。最近,人们努力了解微生物组特征与临床结果的关系,并开发针对微生物组的治疗方法。虽然微生物组疗法很有希望,但其独特的特点给临床试验的设计和实施带来了一定的挑战。在此,我们将简要回顾微生物组治疗肝硬化的适应症,目前可用的微生物组治疗,以及这些治疗的生物学途径。然后,我们将重点讨论肝硬化肠道微生物组治疗临床试验的最佳实践和重要考虑因素。
{"title":"The future of clinical trials of gut microbiome therapeutics in cirrhosis","authors":"Patricia P. Bloom ,&nbsp;Raymond T. Chung","doi":"10.1016/j.jhepr.2024.101234","DOIUrl":"10.1016/j.jhepr.2024.101234","url":null,"abstract":"<div><div>The last two decades have witnessed an explosion of microbiome research, including in hepatology, with studies demonstrating altered microbial composition in liver disease. More recently, efforts have been made to understand the association of microbiome features with clinical outcomes and to develop therapeutics targeting the microbiome. While microbiome therapeutics hold much promise, their unique features pose certain challenges for the design and conduct of clinical trials. Herein, we will briefly review indications for microbiome therapeutics in cirrhosis, currently available microbiome therapeutics, and the biological pathways targeted by these therapies. We will then focus on the best practices and important considerations for clinical trials of gut microbiome therapeutics in cirrhosis.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101234"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882002","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}
引用次数: 0
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JHEP Reports
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