血浆精氨酸酶-1与肝细胞癌患者经导管动脉化疗栓塞抵抗及预后的关系

Relationships of plasma arginase-1 with transcatheter arterial chemoembolization resistance and prognosis in patients with hepatocellular carcinoma

目的观察肝细胞癌患者经导管动脉化疗栓塞(transcatheter arterial chemoembolization,TACE)治疗前血浆精氨酸酶-1(arginase-1,Arg-1)水平,探讨其与患者TACE抵抗及预后的关系。方法112例不可切除肝细胞癌患者均行TACE治疗,首次TACE治疗前采用ELISA法检测血浆Arg-1水平,记录巴塞罗那分期、Child-Pugh分级、肿瘤数量、肿瘤最大直径、甲胎蛋白、红细胞计数、血小板计数等指标。112例患者根据随访1年内是否出现TACE抵抗分为抵抗组67例和无抵抗组45例,比较2组巴塞罗那分期、肿瘤数量等临床资料。采用多因素logistic回归分析肝细胞癌患者TACE治疗后1年内发生TACE抵抗的影响因素;采用限制性立方样条模型分析血浆Arg-1与肝细胞癌患者TACE治疗后1年内发生TACE抵抗风险的关系;绘制ROC曲线,评估血浆Arg-1预测肝细胞癌患者TACE治疗后1年内发生TACE抵抗的效能;以血浆Arg-1最佳截断值54.985μg/L为界,将112例患者分为Arg-1高表达组(Arg-1>54.985μg/L)47例和Arg-1低表达组(Arg-1≤54.985μg/L)65例,绘制Kaplan-Meier生存曲线,比较Arg-1高、低表达组TACE治疗后1年内无TACE抵抗生存率。结果112例患者随访截至2022年3月,失访19例,发生TACE抵抗93例(其中死亡15例)。抵抗组巴塞罗那分期B期(56.7%)、肿瘤数量≥3个(35.8%)比率均高于无抵抗组(22.2%、6.7%)(χ^(2)=13.079,P<0.001;χ^(2)=12.506,P<0.001),肿瘤最大直径[(7.25±3.91)cm]长于无抵抗组[(5.37±2.36)cm](t=2.876,P=0.005),血小板计数[(124.18±40.49)×10^(9)/L]、血浆Arg-1水平[(41.38±29.24)μg/L]均低于无抵抗组[(155.33±39.27)×10^(9)/L、(55.25±25.97)μg/L](t=-4.041,P<0.001;t=-2.571,P=0.011),Child-Pugh分级、肿瘤部位、TACE次数、甲胎蛋白≥400μg/L比率及红细胞计数、谷丙转氨酶、谷草转氨酶、总胆红素、白蛋白水平与无抵抗组比较差异均无统计学意义(P>0.05)。巴塞罗那分期B期(OR=0.342,95%CI:0.135~0.867,P=0.024)、血小板计数(OR=1.014,95%CI:1.003~1.025,P=0.014)、血浆Arg-1(OR=1.016,95%CI:1.000~1.031,P=0.046)是肝细胞癌患者TACE治疗后1年内发生TACE抵抗的影响因素。血浆Arg-1与肝细胞癌患者TACE治疗后1年内发生TACE抵抗风险呈线性关系,随血浆Arg-1水平增高,发生TACE抵抗的风险逐渐下降。血浆Arg-1以54.985μg/L为最佳截断值,预测肝细胞癌患者TACE治疗后1年内发生TACE抵抗的AUC为0.632(95%CI:0.528~0.735,P=0.018),灵敏度为57.8%,特异度为68.7%。Arg-1高表达组TACE治疗后1年内无TACE抵抗生存率(61.9%)高于Arg-1低表达组(31.7%)(χ^(2)=14.852,P<0.001)。结论巴塞罗那分期B期、血小板计数、血浆Arg-1是肝细胞癌患者TACE治疗后1年内发生TACE抵抗的影响因素;低血浆Arg-1水平提示肝细胞癌患者TACE抵抗风险增高,预后不良。

Objective To observe the plasma arginase-1(Arg-1)level in patients with hepatocellular carcinoma before transcatheter arterial chemoembolization(TACE),and to investigate its relationships with TACE resistance and prognosis.Methods Totally 112patients with unresectable hepatocellular carcinoma received TACE.The plasma Arg-1level was measured by ELISA before TACE,and indicators such as Barcelona Clinic Liver Cancer(BCLC)stage,Child-Pugh classification,tumor number,maximum tumor diameter,alpha-fetoprotein,red blood cell count and platelet count were recorded.Totally 112patients were divided into resistant group(n=67)and non-resistant group(n=45)according to whether TACE resistance developed in one-year follow-up survey,and BCLC stage,Child-Pugh classification and other data were compared between two groups.Multivariate logistic regression analysis was done to evaluate the influencing factors of TACE resistance in one year after TACE.The relationship of plasma Arg-1with the risk of TACE resistance was analyzed by using restricted cubic spline model in hepatocellular carcinoma patients in one year after TACE.ROC curves were plotted to evaluate the efficiency of plasma Arg-1 on predicting TACE resistance in hepatocellular carcinoma patients in one year after TACE.Taking the optimal cut-off value of plasma Arg-1(54.985μg/L)as the boundary,112patients were divided into 47patients with Arg-1>54.985μg/L(Arg-1high expression group)and 65patients with Arg-1≤54.985μg/L(Arg-1low expression group).The Kaplan-Meier method was used to compare the TACE resistance-free survival rate in one year after TACE between Arg-1high and low expression groups.Results Totally 112patients were followed up till March 2022,in which 19 were lost,and 93developed TACE resistance including 15deaths.The percentages of patients with BCLC stage B and the number of tumor≥3were higher in resistant group(56.7%,35.8%)than those in non-resistant group(22.2%,6.7%)(χ^(2)=13.079,P<0.001;χ^(2)=12.506,P<0.001),the maximum tumor diameter was longer in resistant group[(7.25±3.91)cm]than that in non-resistant group[(5.37±2.36)cm](t=2.876,P=0.005),the platelet count and plasma Arg-1level were lower in resistant group[(124.18±40.49)×10^(9)/L,(41.38±29.24)μg/L]than those in non-resistant group[(155.33±39.27)×10^(9)/L,(55.25±25.97)μg/L](t=-4.041,P<0.001;t=-2.571,P=0.011),and Child-Pugh classification,tumor site,frequency of TACE,percentage of patients with alpha fetoprotein≥400μg/L,red blood cell count,and levels of glutamic-pyruvic transaminase,glutamic-oxaloacetic transaminase,total bilirubin and albumin showed no significant differences between two groups(P>0.05).BCLC stage B(OR=0.342,95%CI:0.135-0.867,P=0.024),platelet count(OR=1.014,95%CI:1.003-1.025,P=0.014),and plasma Arg-1(OR=1.016,95%CI:1.000-1.031,P=0.046)were the influencing factors of TACE resistance in hepatocellular carcinoma patients in one year after TACE.The plasma Arg-1was linearly associated with the risk of TACE resistance in one year after TACE in patients with hepatocellular carcinoma.The risk of TACE resistance decreased gradually with the increase of plasma Arg-1level.When the optimal cut-off value of plasma Arg-1 was 54.985μg/L,the AUCfor predicting TACE resistance was 0.632(95%CI:0.528-0.735,P=0.018),with a sensitivity of 57.8%and a specificity of 68.7%.The TACE resistance-free survival rate in one year after TACE was higher in Arg-1high expression group(61.9%)than that in Arg-1low expression group(31.7%)(χ^(2)=14.852,P<0.001).Conclusions BCLC stage B,platelet count and plasma Arg-1are the influencing factors of TACE resistance in hepatocellular carcinoma patients in one year after TACE.The low plasma Arg-1level indicates a increase of risk of TACE resistance and a poor prognosis.