Lee Pei-Chang, Wu Chi-Jung, Lee I-Cheng, Lee Chieh-Ju, Hou Ming-Chih, Huang Yi-Hsiang
Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
JHEP Rep. 2025 Jun 26;7(9):101491. doi: 10.1016/j.jhepr.2025.101491. eCollection 2025 Sep.
BACKGROUND & AIMS: Most patients with hepatocellular carcinoma (HCC) have underlying chronic liver disease, which may influence survival outcomes. Mac-2 binding protein glycosylation isomer (M2BPGi) is a biomarker reflecting liver fibrosis status, which in turn may be associated with survival in patients with HCC treated with immune checkpoint inhibitors (ICIs), particularly in regions where viral hepatitis is endemic.
From September 2017 to September 2022, 158 patients receiving ICIs for unresectable HCC were prospectively enrolled, and baseline serum samples were collected for M2BPGi measurement. Variables associated with overall survival (OS) were analyzed. An additional 60 consecutive patients with unresectable HCC were recruited after October 2022 for validation.
In the training cohort, serum M2BPGi level correlated strongly with Fibrosis-4 score, Child-Pugh class and ALBI (albumin-bilirubin) grade. An M2BPGi ≥1.68 COI (cut-off index) was associated with significantly reduced OS (hazard ratio 1.992, 95% CI 1.369-2.900; <0.001). By incorporating baseline alpha-fetoprotein (≥100 ng/ml), M2BPGi (≥1.68 COI), portal vein invasion, and non-HBV infection, a new Mac-2 score was developed that effectively stratified patients by OS (28.8, 13.6 and 8.3 months for scores of 0-1, 2 and 3-4, respectively, <0.001). The Mac-2 score demonstrated superior discrimination and calibration abilities (the highest AUROC, greatest homogeneity, and the lowest corrected Akaike information criterion value), and net reclassification improvement compared with the CRAFITY score, ALBI grade, and Child-Pugh class.
Serum fibrosis marker M2BPGi correlates with liver reserves and survival in patients with HCC undergoing ICI-based immunotherapy. The newly developed Mac-2 score may offer improved clinical utility in this population.
Most cases of hepatocellular carcinoma occur in patients with underlying liver fibrosis or cirrhosis, and the fibrotic microenvironment may influence the anti-tumor effects of immune checkpoint inhibitors. Serum M2BPGi reflects liver fibrosis status and liver reserve in hepatocellular carcinoma and is associated with survival outcomes in patients receiving ICI-based immunotherapy. The novel Mac-2 score, based on baseline M2BPGi levels, has the potential to enhance patient selection and guide therapeutic strategies.
大多数肝细胞癌（HCC）患者存在潜在的慢性肝病，这可能会影响生存结果。Mac-2结合蛋白糖基化异构体（M2BPGi）是一种反映肝纤维化状态的生物标志物，而肝纤维化状态反过来可能与接受免疫检查点抑制剂（ICI）治疗的HCC患者的生存相关，尤其是在病毒性肝炎流行的地区。
2017年9月至2022年9月，前瞻性纳入158例接受ICI治疗不可切除HCC的患者，并收集基线血清样本进行M2BPGi检测。分析与总生存期（OS）相关的变量。2022年10月后又招募了60例连续的不可切除HCC患者进行验证。
在训练队列中，血清M2BPGi水平与Fibrosis-4评分、Child-Pugh分级和ALBI（白蛋白-胆红素）分级密切相关。M2BPGi≥1.68 COI（临界指数）与OS显著降低相关（风险比1.992，95%CI 1.369-2.900；P<0.001）。通过纳入基线甲胎蛋白（≥100 ng/ml）、M2BPGi（≥1.68 COI）、门静脉侵犯和非HBV感染，开发了一种新的Mac-2评分，该评分可根据OS有效地对患者进行分层（0-1、2和3-4分的患者OS分别为28.8、13.6和8.3个月，P<0.001）。与CRAFITY评分、ALBI分级和Child-Pugh分级相比，Mac-2评分显示出更好的鉴别和校准能力（最高的曲线下面积、最大的同质性和最低的校正赤池信息准则值）以及净重新分类改善。
血清纤维化标志物M2BPGi与接受基于ICI的免疫治疗的HCC患者的肝脏储备和生存相关。新开发的Mac-2评分可能为该人群提供更好的临床实用性。
大多数肝细胞癌病例发生在有潜在肝纤维化或肝硬化的患者中，纤维化微环境可能会影响免疫检查点抑制剂的抗肿瘤作用。血清M2BPGi反映肝细胞癌中的肝纤维化状态和肝脏储备，并与接受基于ICI的免疫治疗的患者的生存结果相关。基于基线M2BPGi水平的新型Mac-2评分有可能改善患者选择并指导治疗策略。
