联合应用抗程序性死亡配体1与抗血管内皮生长因子（VEGF）抗体已成为难以手术的肝细胞癌（uHCC）的标准治疗方法。我们旨在确定预测循环生物标志物，预测uHCC患者联合治疗的结果/反应。这项前瞻性多中心研究招募70名接受atezolizumab和bevacizumab（Atez/Bev）治疗的uHCC患者。我们使用多重珠式免疫分析和酶联免疫吸附试验在第1和第6周治疗前后评估血清中的47种循环蛋白质。作为对照，我们分析了62名uHCC患者接受Lenvatinib（LEN）治疗前和健康志愿者（HVs）的血清。疾病控制率为77.1%。中位无进展生存期为5.7个月（95%置信区间[CI] = 3.8-9.5）。运用Atez/Bev治疗之前，uHCC患者骨钙蛋白（OPN），血管生成素2，VEGF，可溶性程序性细胞死亡-1，可溶性CD163以及14种细胞因子/趋化因子的血清水平更高。其中，运用Atez/Bev时，OPN的前治疗水平在PD组中高于非PD组。高OPN组中PD率高于低OPN组。多因素分析确定高前治疗OPN和高α-胎蛋白水平是PD的独立预测因子。在Child-Pugh A级患者的亚组分析中，高OPN组的PFS也比低OPN组短。运用LEN治疗时，前治疗OPN水平与治疗反应无关。在uHCC患者中，高血清OPN水平与Atez/Bev反应不佳有关。©2023年。日本胃肠病学学会。

Combination therapy with anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for un-resectable hepatocellular carcinoma (uHCC). We aimed to identify predictive circulating biomarkers for the outcome/response of the combination therapy in uHCC patients.This prospective multicenter study enrolled 70 patients with uHCC who received atezolizumab and bevacizumab (Atez/Bev). We evaluated 47 circulating proteins in sera before and after 1 and 6 weeks of Atez/Bev therapy by multiplex bead-based immunoassay and ELISA. As controls, we analyzed the sera from 62 uHCC patients before treatment of lenvatinib (LEN) and healthy volunteers (HVs).The disease control rate was 77.1%. Median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI] = 3.8-9.5). The pretreatment levels of osteopontin (OPN), angiopoietin-2, VEGF, S100-calcium-binding protein A8/S100-calcium-binding protein A9, soluble programmed cell death-1, soluble CD163, and 14 cytokines/chemokines were higher in patients with uHCC than in HVs. Among these, pretreatment OPN levels were higher in PD group than in non-PD group for Atez/Bev. The PD rate was higher in high OPN group than in low OPN group. Multivariate analysis identified high pretreatment OPN and high α-fetoprotein levels as independent predictors of PD. In the sub-analysis of Child-Pugh class A patients, PFS was also shorter in the high OPN group than in the low OPN group. Pretreatment OPN level was not associated with treatment response for LEN.High serum OPN levels were associated with poor response to Atez/Bev in patients with uHCC.© 2023. Japanese Society of Gastroenterology.