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Hepatic Events and Viral Kinetics in Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab. 使用阿特珠单抗加贝伐单抗治疗肝细胞癌患者的肝脏事件和病毒动力学分析
IF 11.6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-08-25 eCollection Date: 2023-02-01 DOI: 10.1159/000525499
Chiun Hsu, Michel Ducreux, Andrew X Zhu, Shukui Qin, Masafumi Ikeda, Tae-You Kim, Peter R Galle, Richard S Finn, Ethan Chen, Ning Ma, Youyou Hu, Lindong Li, Ann-Lii Cheng

Introduction: In the Phase 3 IMbrave150 trial (NCT03434379), atezolizumab + bevacizumab demonstrated a clinically meaningful survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (HCC), including those with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We used IMbrave150 data to investigate the safety and risk of viral reactivation or flare in infected patients treated with atezolizumab + bevacizumab or sorafenib.

Methods: Patients with unresectable HCC not previously treated with systemic therapy were randomized 2:1 to atezolizumab + bevacizumab or sorafenib. In this exploratory analysis, safety was continually evaluated, including for hepatic adverse events. Patients were monitored for HBV and HCV reactivation and flare at screening, the beginning of Cycles 5 and 9, and at treatment discontinuation.

Results: Of 501 enrolled patients, 485 were included in the safety population; 329 (68%) received atezolizumab + bevacizumab, and 156 (32%) received sorafenib. Overall, 150 (31%) and 58 (12%) patients had HBV and HCV infections, respectively. The safety profiles of atezolizumab + bevacizumab and sorafenib were consistent across patients, regardless of viral infection. Overall, hepatic serious adverse events occurred in 11% of patients receiving atezolizumab + bevacizumab and 8% receiving sorafenib. HBV or HCV reactivation occurred in 2% or 16% of atezolizumab + bevacizumab-treated patients, respectively, versus 7% or 14% with sorafenib. There were no instances of hepatitis flare with atezolizumab + bevacizumab.

Conclusions: Atezolizumab + bevacizumab had a similar hepatic safety profile in patients with and without HBV or HCV infection. Viral reactivation rates were similar between arms. Overall, these data support the use of atezolizumab + bevacizumab in patients with HCC and HBV or HCV infection without any special precaution.

简介在3期IMbrave150试验(NCT03434379)中,对于无法切除的肝细胞癌(HCC)患者(包括乙型肝炎病毒(HBV)或丙型肝炎病毒(HCV)感染者),atezolizumab+贝伐单抗比索拉非尼具有临床意义的生存获益。我们利用IMbrave150数据调查了接受阿特珠单抗+贝伐单抗或索拉非尼治疗的感染者的安全性以及病毒再激活或复发的风险:既往未接受过系统治疗的不可切除的HCC患者按2:1的比例随机接受atezolizumab+贝伐珠单抗或索拉非尼治疗。在这项探索性分析中,对安全性进行了持续评估,包括肝脏不良事件。在筛选、第5和第9周期开始以及治疗终止时,对患者的HBV和HCV再激活和复发情况进行监测:在501例入组患者中,485例被纳入安全人群;329例(68%)接受了阿特珠单抗+贝伐珠单抗治疗,156例(32%)接受了索拉非尼治疗。总体而言,分别有150名(31%)和58名(12%)患者感染了HBV和HCV。无论病毒感染与否,atezolizumab+贝伐珠单抗和索拉非尼的安全性在所有患者中都是一致的。总体而言,11%接受atezolizumab+贝伐珠单抗治疗的患者和8%接受索拉非尼治疗的患者发生了肝脏严重不良事件。接受atezolizumab+贝伐珠单抗治疗的患者中分别有2%或16%出现HBV或HCV再激活,而接受索拉非尼治疗的患者中分别有7%或14%出现HBV或HCV再激活。atezolizumab+贝伐珠单抗没有出现肝炎复发的情况:结论:阿替祖利珠单抗+贝伐珠单抗在感染和未感染HBV或HCV的患者中具有相似的肝脏安全性。两组患者的病毒再活率相似。总体而言,这些数据支持在HCC和HBV或HCV感染患者中使用阿特珠单抗+贝伐珠单抗,无需采取任何特殊预防措施。
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引用次数: 0
First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Patient-Level Network Meta-Analysis. 晚期肝细胞癌的一线系统疗法:系统综述和患者层面的网络荟萃分析。
IF 11.6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-08-23 eCollection Date: 2023-02-01 DOI: 10.1159/000526639
Khi Yung Fong, Joseph Jonathan Zhao, Rehena Sultana, Joycelyn Jie Xin Lee, Suat Ying Lee, Stephen Lam Chan, Thomas Yau, David Wai Meng Tai, Raghav Sundar, Chow Wei Too

Introduction: Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab. Thereafter, several novel first-line combination therapies have demonstrated favorable outcomes. The efficacies of these treatments in relation to current and previous standards of care are unknown, necessitating an overarching evaluation.

Methods: A systematic literature search was conducted on PubMed, EMBASE, Scopus, and the Cochrane Controlled Register of Trials for phase III randomized controlled trials investigating first-line systemic therapies for aHCC. Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were graphically reconstructed to retrieve individual patient-level data. Derived hazard ratios (HRs) for each study were pooled in a random-effects network meta-analysis (NMA). NMAs were also conducted using study-level HRs for various subgroups, according to viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion, and extrahepatic spread. Treatment strategies were ranked using p scores.

Results: Among 4,321 articles identified, 12 trials and 9,589 patients were included for analysis. Only two therapies showed OS benefit over sorafenib: combined anti-programmed-death and anti-VEGF pathway inhibitor monoclonal antibodies (Anti-PD-(L)1/VEGF Ab), including atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar (HR = 0.63, 95% CI = 0.53-0.76) and tremelimumab-durvalumab (HR = 0.78, 95% CI = 0.66-0.92). Anti-PD-(L)1/VEGF Ab showed OS benefit over all other therapies except tremelimumab-durvalumab. Low heterogeneity (I2 = 0%) and inconsistency (Cochran's Q = 0.52, p = 0.773) was observed. p scores for OS ranked Anti-PD-(L)1/VEGF Ab as the best treatment in all subgroups, except hepatitis B where atezolizumab-cabozantinib ranked highest for both OS and PFS, as well as nonviral HCC and AFP ≥400 μg/L where tremelimumab-durvalumab ranked highest for OS.

Conclusion: This NMA supports Anti-PD-(L)1/VEGF Ab as the first-line therapy for aHCC and demonstrates a comparable benefit for tremelimumab-durvalumab which also extends to certain subgroups. Results of the subgroup analysis may guide treatment according to baseline characteristics, while pending further studies.

简介索拉非尼一直是治疗晚期肝细胞癌(aHCC)的标准疗法,直到被阿特珠单抗和贝伐单抗联合疗法所取代。此后,几种新型一线联合疗法取得了良好的疗效。这些疗法的疗效与当前和以往的治疗标准相比尚不清楚,因此有必要进行总体评估:方法:在PubMed、EMBASE、Scopus和Cochrane对照试验登记册上进行了系统性文献检索,以了解研究治疗aHCC一线系统疗法的III期随机对照试验。对总生存期(OS)和无进展生存期(PFS)的卡普兰-梅耶曲线进行图形重构,以检索患者个体水平的数据。在随机效应网络荟萃分析(NMA)中对每项研究得出的危险比(HRs)进行汇总。根据病毒病因学、巴塞罗那临床肝癌(BCLC)分期、甲胎蛋白(AFP)水平、大血管侵犯和肝外播散等因素,还使用不同亚组的研究水平HR进行了NMA分析。治疗策略采用P评分进行排序:在4321篇文章中,有12项试验和9589名患者被纳入分析。与索拉非尼相比,只有两种疗法显示出OS获益:联合抗程序性死亡和抗血管内皮生长因子通路抑制剂单克隆抗体(Anti-PD-(L)1/VEGF Ab),包括atezolizumab-bevacizumab和sintilimab-bevacizumab生物类似物(HR = 0.63,95% CI = 0.53-0.76)以及tremelimumab-durvalumab(HR = 0.78,95% CI = 0.66-0.92)。除tremelimumab-durvalumab外,抗PD-(L)1/VEGF抗体的OS获益优于所有其他疗法。观察到低异质性(I2 = 0%)和不一致性(Cochran's Q = 0.52,p = 0.773)。OS的p得分将Anti-PD-(L)1/VEGF Ab列为所有亚组的最佳治疗方法,但乙型肝炎除外,atezolizumab-cabozantinib的OS和PFS均排名第一,非病毒性HCC和AFP≥400 μg/L的tremelimumab-durvalumab的OS排名第一:该NMA支持将抗-PD-(L)1/VEGF抗体作为治疗HCC的一线疗法,并证明了tremelimumab-durvalumab也能为某些亚组带来类似的获益。亚组分析结果可根据基线特征指导治疗,但仍有待进一步研究。
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引用次数: 0
Atezolizumab plus Bevacizumab Followed by Curative Conversion (ABC Conversion) in Patients with Unresectable, TACE-Unsuitable Intermediate-Stage Hepatocellular Carcinoma. 无法切除、不适合 TACE 的中晚期肝细胞癌患者的 Atezolizumab+Bevacizumab 后治愈性转换(ABC 转换)。
IF 11.6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-27 eCollection Date: 2022-09-01 DOI: 10.1159/000526163
Masatoshi Kudo
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引用次数: 0
Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma? 来自癌症相关成纤维细胞的硫酸酯酶-2:肝细胞癌的环境靶标?
IF 13.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-13 eCollection Date: 2022-12-01 DOI: 10.1159/000525375
Marco Y W Zaki, Sari F Alhasan, Ruchi Shukla, Misti McCain, Maja Laszczewska, Daniel Geh, Gillian L Patman, Despina Televantou, Anna Whitehead, João P Maurício, Ben Barksby, Lucy M Gee, Hannah L Paish, Jack Leslie, Ramy Younes, Alastair D Burt, Lee A Borthwick, Huw Thomas, Gary S Beale, Olivier Govaere, Daniela Sia, Quentin M Anstee, Dina Tiniakos, Fiona Oakley, Helen L Reeves

Introduction: Heparin sulphate proteoglycans in the liver tumour microenvironment (TME) are key regulators of cell signalling, modulated by sulfatase-2 (SULF2). SULF2 overexpression occurs in hepatocellular carcinoma (HCC). Our aims were to define the nature and impact of SULF2 in the HCC TME.

Methods: In liver biopsies from 60 patients with HCC, expression and localization of SULF2 were analysed associated with clinical parameters and outcome. Functional and mechanistic impacts were assessed with immunohistochemistry (IHC), in silico using The Cancer Genome Atlas (TGCA), in primary isolated cancer activated fibroblasts, in monocultures, in 3D spheroids, and in an independent cohort of 20 patients referred for sorafenib. IHC targets included αSMA, glypican-3, β-catenin, RelA-P-ser536, CD4, CD8, CD66b, CD45, CD68, and CD163. SULF2 impact of peripheral blood mononuclear cells was assessed by migration assays, with characterization of immune cell phenotype using fluorescent activated cell sorting.

Results: We report that while SULF2 was expressed in tumour cells in 15% (9/60) of cases, associated with advanced tumour stage and type 2 diabetes, SULF2 was more commonly expressed in cancer-associated fibroblasts (CAFs) (52%) and independently associated with shorter survival (7.2 vs. 29.2 months, p = 0.003). Stromal SULF2 modulated glypican-3/β-catenin signalling in vitro, although in vivo associations suggested additional mechanisms underlying the CAF-SULF2 impact on prognosis. Stromal SULF2 was released by CAFS isolated from human HCC. It was induced by TGFβ1, promoted HCC proliferation and sorafenib resistance, with CAF-SULF2 linked to TGFβ1 and immune exhaustion in TGCA HCC patients. Autocrine activation of PDGFRβ/STAT3 signalling was evident in stromal cells, with the release of the potent monocyte/macrophage chemoattractant CCL2 in vitro. In human PBMCs, SULF2 preferentially induced the migration of macrophage precursors (monocytes), inducing a phenotypic change consistent with immune exhaustion. In human HCC tissues, CAF-SULF2 was associated with increased macrophage recruitment, with tumouroid studies showing stromal-derived SULF2-induced paracrine activation of the IKKβ/NF-κB pathway, tumour cell proliferation, invasion, and sorafenib resistance.

Conclusion: SULF2 derived from CAFs modulates glypican-3/β-catenin signalling but also the HCC immune TME, associated with tumour progression and therapy resistance via activation of the TAK1/IKKβ/NF-κB pathway. It is an attractive target for combination therapies for patients with HCC.

简介肝脏肿瘤微环境(TME)中的肝素硫酸盐蛋白聚糖是细胞信号的关键调节因子,受硫酸酯酶-2(SULF2)调节。SULF2在肝细胞癌(HCC)中出现过表达。我们的目的是确定 SULF2 在 HCC TME 中的性质和影响:方法:在60名HCC患者的肝活检组织中,分析SULF2的表达和定位与临床参数和预后的关系。通过免疫组织化学(IHC)、利用癌症基因组图谱(TGCA)对原发性分离癌活化成纤维细胞、单培养物、三维球体以及转诊接受索拉非尼治疗的20名患者的独立队列进行了功能和机理影响评估。IHC靶标包括αSMA、glypican-3、β-catenin、RelA-P-ser536、CD4、CD8、CD66b、CD45、CD68和CD163。通过迁移试验评估了SULF2对外周血单核细胞的影响,并利用荧光激活细胞分选技术确定了免疫细胞的表型:我们报告说,在15%(9/60)的病例中,SULF2在肿瘤细胞中表达,这与肿瘤晚期和2型糖尿病有关,而SULF2在癌症相关成纤维细胞(CAFs)中表达更为常见(52%),并且与生存期缩短(7.2个月对29.2个月,p = 0.003)独立相关。基质SULF2在体外调节glypican-3/β-catenin信号,但体内相关性表明CAF-SULF2对预后的影响还存在其他机制。从人类 HCC 中分离出的 CAFS 释放了基质 SULF2。它由TGFβ1诱导,促进HCC增殖和索拉非尼耐药,CAF-SULF2与TGFβ1和TGCA HCC患者的免疫衰竭有关。在基质细胞中,PDGFRβ/STAT3 信号的自分泌激活非常明显,并在体外释放出强效的单核细胞/巨噬细胞趋化吸引剂 CCL2。在人PBMCs中,SULF2优先诱导巨噬细胞前体(单核细胞)迁移,诱导与免疫衰竭一致的表型变化。在人类HCC组织中,CAF-SULF2与巨噬细胞募集增加有关,肿瘤研究显示基质衍生的SULF2诱导了IKKβ/NF-κB通路的旁分泌激活、肿瘤细胞增殖、侵袭和索拉非尼抗性:结论:来自CAFs的SULF2不仅能调节glypican-3/β-catenin信号,还能调节HCC免疫TME,通过激活TAK1/IKKβ/NF-κB通路,与肿瘤进展和耐药性相关。它是对 HCC 患者进行联合治疗的一个有吸引力的靶点。
{"title":"Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma?","authors":"Marco Y W Zaki, Sari F Alhasan, Ruchi Shukla, Misti McCain, Maja Laszczewska, Daniel Geh, Gillian L Patman, Despina Televantou, Anna Whitehead, João P Maurício, Ben Barksby, Lucy M Gee, Hannah L Paish, Jack Leslie, Ramy Younes, Alastair D Burt, Lee A Borthwick, Huw Thomas, Gary S Beale, Olivier Govaere, Daniela Sia, Quentin M Anstee, Dina Tiniakos, Fiona Oakley, Helen L Reeves","doi":"10.1159/000525375","DOIUrl":"10.1159/000525375","url":null,"abstract":"<p><strong>Introduction: </strong>Heparin sulphate proteoglycans in the liver tumour microenvironment (TME) are key regulators of cell signalling, modulated by sulfatase-2 (SULF2). SULF2 overexpression occurs in hepatocellular carcinoma (HCC). Our aims were to define the nature and impact of SULF2 in the HCC TME.</p><p><strong>Methods: </strong>In liver biopsies from 60 patients with HCC, expression and localization of SULF2 were analysed associated with clinical parameters and outcome. Functional and mechanistic impacts were assessed with immunohistochemistry (IHC), in silico using The Cancer Genome Atlas (TGCA), in primary isolated cancer activated fibroblasts, in monocultures, in 3D spheroids, and in an independent cohort of 20 patients referred for sorafenib. IHC targets included αSMA, glypican-3, β-catenin, RelA-P-ser536, CD4, CD8, CD66b, CD45, CD68, and CD163. SULF2 impact of peripheral blood mononuclear cells was assessed by migration assays, with characterization of immune cell phenotype using fluorescent activated cell sorting.</p><p><strong>Results: </strong>We report that while SULF2 was expressed in tumour cells in 15% (9/60) of cases, associated with advanced tumour stage and type 2 diabetes, SULF2 was more commonly expressed in cancer-associated fibroblasts (CAFs) (52%) and independently associated with shorter survival (7.2 vs. 29.2 months, <i>p</i> = 0.003). Stromal SULF2 modulated glypican-3/β-catenin signalling in vitro, although in vivo associations suggested additional mechanisms underlying the CAF-SULF2 impact on prognosis. Stromal SULF2 was released by CAFS isolated from human HCC. It was induced by TGFβ1, promoted HCC proliferation and sorafenib resistance, with CAF-SULF2 linked to TGFβ1 and immune exhaustion in TGCA HCC patients. Autocrine activation of PDGFRβ/STAT3 signalling was evident in stromal cells, with the release of the potent monocyte/macrophage chemoattractant CCL2 in vitro. In human PBMCs, SULF2 preferentially induced the migration of macrophage precursors (monocytes), inducing a phenotypic change consistent with immune exhaustion. In human HCC tissues, CAF-SULF2 was associated with increased macrophage recruitment, with tumouroid studies showing stromal-derived SULF2-induced paracrine activation of the IKKβ/NF-κB pathway, tumour cell proliferation, invasion, and sorafenib resistance.</p><p><strong>Conclusion: </strong>SULF2 derived from CAFs modulates glypican-3/β-catenin signalling but also the HCC immune TME, associated with tumour progression and therapy resistance via activation of the TAK1/IKKβ/NF-κB pathway. It is an attractive target for combination therapies for patients with HCC.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"11 6","pages":"540-557"},"PeriodicalIF":13.8,"publicationDate":"2022-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9801184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10852619","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
Response to the Article on Antibiotics and Immune Checkpoint Inhibitors by Lin et al. 回应 Lin 等人撰写的关于抗生素和免疫检查点抑制剂的文章
IF 11.6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-13 eCollection Date: 2022-12-01 DOI: 10.1159/000526003
Ka Shing Cheung, Wai K Leung
{"title":"Response to the Article on Antibiotics and Immune Checkpoint Inhibitors by Lin et al.","authors":"Ka Shing Cheung, Wai K Leung","doi":"10.1159/000526003","DOIUrl":"10.1159/000526003","url":null,"abstract":"","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"11 6","pages":"578-580"},"PeriodicalIF":11.6,"publicationDate":"2022-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8c/fe/lic-0011-0578.PMC9801173.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10458349","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
Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study. 乐伐替尼治疗肝细胞癌的实际研究:RELEVANT研究。
IF 11.6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-11 eCollection Date: 2022-12-01 DOI: 10.1159/000525145
Andrea Casadei-Gardini, Margherita Rimini, Masatoshi Kudo, Shigeo Shimose, Toshifumi Tada, Goki Suda, Myung Ji Goh, Andre Jefremow, Mario Scartozzi, Giuseppe Cabibbo, Claudia Campani, Emiliano Tamburini, Francesco Tovoli, Kazuomi Ueshima, Tomoko Aoki, Hideki Iwamoto, Takuji Torimura, Takashi Kumada, Atsushi Hiraoka, Masanori Atsukawa, Ei Itobayashi, Hidenori Toyoda, Naoya Sakamoto, Takuya Sho, Wonseok Kang, Jürgen Siebler, Markus Friedrich Neurath, Valentina Burgio, Stefano Cascinu

Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes.

Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries.

Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months).

Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

简介在REFLECT试验中,发现来伐替尼的总生存率不劣于索拉非尼。在此,我们根据全球多个中心的实际经验分析了来伐替尼的效果,并找出了可能与生存结果显著相关的临床因素:研究人群来自回顾性收集的来伐替尼治疗的HCC患者数据。总体队列包括来自5个国家23个中心的西方和东方人群:我们分析了1325名接受来伐替尼治疗的HCC患者。中位OS为16.1个月。总体反应率为38.5%。OS的多变量分析显示,在所有模型中,HBsAg阳性、NLR>3和AST>38与预后不良独立相关。相反,非酒精性脂肪肝/NASH 相关病因则与良好预后独立相关。中位无进展生存期为6.3个月。无进展生存期的多变量分析显示,NAFLD/NASH、BCLC、NLR和AST是无进展生存期的独立预后因素。75.2%的患者在研究期间至少出现过一种不良反应。多变量分析显示,食欲下降≥2级与0-1级相比,是无进展生存期缩短的独立预后因素。在来伐替尼治疗期间,1325例患者中有924例(69.7%)病情进展,其中827例患者从二线治疗开始后随访时间超过2个月。在一线治疗中,来伐替尼和免疫疗法的中位生存期最长(47.0个月),其次是TACE(24.7个月)、ramucirumab(21.2个月)、索拉非尼(15.7个月)、瑞戈非尼(12.7个月)和最佳支持治疗(10.8个月):我们的研究证实,在全球大量不适合接受局部治疗的晚期HCC患者中,来恩伐替尼可达到注册研究中报告的OS和高应答率。
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引用次数: 0
Discriminatory Changes in Circulating Metabolites as a Predictor of Hepatocellular Cancer in Patients with Metabolic (Dysfunction) Associated Fatty Liver Disease. 循环代谢物的鉴别性变化是代谢(功能障碍)相关性脂肪肝患者罹患肝细胞癌的预测指标。
IF 13.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-08 eCollection Date: 2023-02-01 DOI: 10.1159/000525911
Haonan Lu, Jacob George, Mohammed Eslam, Augusto Villanueva, Luigi Bolondi, Helen L Reeves, Misti McCain, Edward Chambers, Caroline Ward, Dewi Sartika, Caroline Sands, Lynn Maslen, Matthew R Lewis, Ramya Ramaswami, Rohini Sharma

Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC.

Methods: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC.

Results: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721-0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793-0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09-1.83, p < 0.01).

Conclusion: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.

导言:代谢(功能障碍)相关性脂肪肝(MAFLD)的发病率正在上升,肝细胞癌(HCC)的发病率也在增加。代谢相关性脂肪肝及其后遗症的特点是脂质处理、炎症和线粒体损伤的紊乱。在 MAFLD 中,随着 HCC 的发展,循环脂质和小分子代谢物的轮廓特征尚不明显,在未来的研究中可用作 HCC 的生物标志物:我们采用超高效液相色谱法和高分辨质谱法评估了来自六个不同中心的 MAFLD 患者(n = 113)和 MAFLD 相关 HCC 患者(n = 144)血清中 273 种脂质和小分子代谢物的特征。利用回归模型确定了HCC的预测模型:20种脂质和1种代谢物反映了线粒体功能和鞘脂代谢的变化,它们与MAFLD背景下癌症的存在相关,准确率很高(AUC 0.789,95% CI:0.721-0.858),在模型中加入肝硬化后,准确率更高(AUC 0.855,95% CI:0.793-0.917)。特别是,在 MAFLD 亚组中,这些代谢物的存在与肝硬化相关(p < 0.001)。如果仅考虑 HCC 组群,代谢特征是总生存率的独立预测因子(HR 1.42,95% CI:1.09-1.83,p <0.01):这些探索性发现揭示了血清中的代谢特征,该特征能够准确检测出在 MAFLD 背景下是否存在 HCC。未来将进一步研究这一独特的血清特征作为MAFLD患者早期HCC生物标志物的诊断性能。
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引用次数: 0
Front & Back Matter 正面和背面
IF 13.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-01 DOI: 10.1159/000525876
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引用次数: 0
Liver Cancer Study Group of Japan Clinical Practice Guidelines for Intrahepatic Cholangiocarcinoma. 日本肝癌研究组肝内胆管癌临床实践指南。
IF 13.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-01 DOI: 10.1159/000522403
Shoji Kubo, Hiroji Shinkawa, Yoshinari Asaoka, Tatsuya Ioka, Hiroshi Igaki, Namiki Izumi, Takao Itoi, Michiaki Unno, Masayuki Ohtsuka, Takuji Okusaka, Masumi Kadoya, Masatoshi Kudo, Takashi Kumada, Norihiro Kokudo, Michiie Sakamoto, Yoshihiro Sakamoto, Hideyuki Sakurai, Tadatoshi Takayama, Osamu Nakashima, Yasushi Nagata, Etsuro Hatano, Kenichi Harada, Takamichi Murakami, Masakazu Yamamoto

This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, a high incidence of ICC has been reported in East and Southeast Asian countries, and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography, CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis (LNM) and has a single tumor, resection is the treatment of choice. If both regional LNM and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional LNM or multiple tumors, resection or drug therapy is selected, depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function.

本文介绍了由日本肝癌研究组制定的肝内胆管癌(ICC)临床实践指南的第一版。该指南包括1个治疗算法、5个背景说明、16个临床问题和1个临床主题,包括病因、分期、病理、诊断和治疗。在全球范围内,据报道,ICC在东亚和东南亚国家发病率较高,在日本和西方国家发病率逐渐上升。据报道,ICC的危险因素包括肝硬化、乙型/丙型肝炎、饮酒、糖尿病、肥胖、吸烟、非酒精性脂肪性肝炎和肝吸虫感染,以及胆道疾病,如原发性硬化性胆管炎、肝内胆管结石、先天性胆管扩张和卡罗里病。化学危险因素包括钍-232、1,2-二氯丙烷和二氯甲烷。推荐CA19-9和CEA作为早期发现和诊断ICC的肿瘤标志物。腹部超声、CT和MRI是诊断ICC的有效成像方式。如果怀疑胆管侵犯,影像学检查胆管可能是有用的。在不能切除的病例中,当认为有必要进行鉴别诊断和药物治疗选择时,应考虑肿瘤活检。Child-Pugh A级或B级肝功能患者的主要治疗方法是手术切除和药物治疗。如果患者没有区域淋巴结转移(LNM),只有一个肿瘤,切除是治疗的选择。如果同时存在区域性LNM和多发性肿瘤,药物治疗是首选的治疗方法。如果患者是区域性LNM或多发肿瘤,则根据转移的程度或肿瘤的数量选择切除或药物治疗。如果存在远处转移,药物治疗是治疗的选择。由于肝功能储备减少或合并症而不适合手术切除或药物治疗的患者可考虑经皮消融治疗。对于不可切除且无肝外转移的ICC,可考虑立体定向放疗(肿瘤大小≤5cm)或颗粒放疗(无大小限制)。ICC一般不适用于肝移植,对于Child-Pugh C级肝功能患者推荐姑息治疗。
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引用次数: 26
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IF 13.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2022-07-01 DOI: 10.1159/000525668
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引用次数: 0
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