术前炎症指标在肝细胞癌肝移植后肿瘤复发中的预测价值

The value of preoperative inflammatory markers in predicting recurrence of hepatocellular carcinoma after liver transplantation

目的探讨天冬氨酸转氨酶与淋巴细胞比值(ALR)、谷氨酰转移酶与淋巴细胞比值(GLR)、天冬氨酸转氨酶与丙氨酸转氨酶比值(AAR)在肝细胞癌肝移植后肿瘤复发中的预测价值。方法采用回顾性队列研究方法。收集2014年7月至2018年6月天津市第一中心医院收治的178例肝细胞癌肝移植患者的临床病理资料;男156例,女22例;年龄为(54±9)岁。所有患者为首次原位肝移植。观察指标:(1)随访情况。(2)各指标对肝细胞癌患者肝移植后肿瘤复发的预测价值及截断值。(3)影响肝细胞癌患者肝移植后肿瘤复发的危险因素分析。(4)肝细胞癌患者肝移植后肿瘤复发预测模型的建立及评价。正态分布的计量资料以x±s表示,组间比较采用t检验,偏态分布的计量资料以M(范围)表示,组间比较采用Mann-Whitney U检验;计数资料以绝对数表示,组间比较采用χ^(2)检验或Fisher确切概率法。采用Kaplan-Meier法绘制生存曲线,Log-rank检验进行生存分析。将单因素分析P<0.05的因素纳入多因素分析。单因素和多因素分析采用COX比例风险回归模型前进法。采用回归系数构建预测模型。绘制受试者工作特征曲线,以曲线下面积进行效能评价。结果(1)随访情况。178例肝细胞癌患者肝移植后均获得随访,随访时间为36(1~74)个月,其中41例随访期间死亡;61例肿瘤复发,117例无肿瘤复发。肝移植后患者3年、5年总生存率和无复发生存率分别为72.8%、69.9%和57.3%、52.8%。(2)各指标对肝细胞癌患者肝移植后肿瘤复发的预测价值及最佳截断值。受者术前血清甲胎蛋白(AFP)、肿瘤最大径、ALR、GLR、中性粒细胞与淋巴细胞比值、AAR的曲线下面积分别为0.76、0.70、0.69、0.65、0.64、0.65[95%可信区间(CI)分别为0.68~0.83、0.61~0.79、0.61~0.77、0.57~0.74、0.56~0.73、0.56~0.74,P<0.05],上述各项指标最佳截断值分别为228.00μg/L、5.25 cm、92.90、122.40、3.00、2.42。(3)影响肝细胞癌患者肝移植后肿瘤复发的危险因素分析。多因素分析结果显示:术前血清AFP>228.88μg/L、肿瘤数目为多发、肿瘤最大径>5.25 cm、ALR>92.90、AAR>2.42是影响肝细胞癌肝移植后肿瘤复发的独立危险因素(风险比=3.13、1.90、2.66、2.40、2.75,95%CI分别为1.81~5.41、1.08~3.35、1.49~4.74、1.40~4.11、1.54~4.91,P<0.05)。(4)肝细胞癌患者肝移植后肿瘤复发预测模型的建立及评价。根据多因素分析结果,纳入术前血清AFP、肿瘤数目、肿瘤最大径、ALR、AAR构建肝细胞癌肝移植后肿瘤复发预测模型;预测模型曲线下面积为0.83(95%CI为0.76~0.89,P<0.05),最佳截断值为5.5,特异度为80.3%,灵敏度为73.8%。178例患者中,110例为肝移植后肿瘤复发低风险(0~5分),68例为肝移植后肿瘤复发高风险(6~16分),高风险患者肝移植后1、3、5年无复发生存率和总生存率分别为27.7%、18.2%、18.2%和63.7%、48.9%、48.9%;低风险患者上述指标分别为92.3%、82.4%、74.6%和90.4%、87.7%、83.6%,两者无复发生存率和总生存率比较,差异均有统计学意义(χ^(2)=67.83,21.95,P<0.05)。结论术前血清AFP、肿瘤数目、肿瘤最大径、ALR、AAR是肝细胞癌患者肝移植后肿瘤复发的独立影响因素,以此构建的预测模型具有良好的预测效能。

Objective To investigate the value of aspartate aminotransferase/lymphocyte ratio(ALR),γ-glutamyltranspeptidase/lymphocyte ratio(GLR)and aspartate aminotransferase/alanine aminotransferase ratio(AAR)in predicting the recurrence of hepatocellular carcinoma after liver transplantation.Methods The retrospective cohort study was conducted.The clinicopathological data of 178 patients with hepatocellular carcinoma who underwent liver transplantation in Tianjin First Central Hospital from July 2014 to June 2018 were collected.There were 156 males and 22 females,aged(54±9)years.All patients received the first time of orthotopic liver transplantation.Observation indicators:(1)follow-up;(2)the predictive value and cutoff value of each index for tumor recur-rence of patients with hepatocellular carcinoma after liver transplantation;(3)analysis of risk factors for tumor recurrence of patients with hepatocellular carcinoma after liver transplantation;(4)cons-truction and evaluation of the predictive model for tumor recurrence of patients with hepatocellular carcinoma after liver transplantation.Measurement data with normal distribution were represented as Mean±SD,and comparison between groups was conducted using the t test.Measurement data with skewed distribution were represented as M(range),and comparison between groups was conducted using the Mann-Whitney U test.Count data were expressed as absolute numbers,and comparison between groups was conducted using the chi-square test or Fisher exact probability.The Kaplan-Meier method was used to draw survival curve and the Log-rank test was used for survival analysis.Factors with P<0.05 in univariate analysis were included in multivariate analysis.Univariate analysis and multivariate analysis were performed by COX proportional risk regression model with forward method.The regression coefficient was used to build the prediction model.The receiver operating characteristic curve was drawn,and the area under curve(AUC)was used to evaluate the predictive ability of prediction model.Results(1)Follow-up.All 178 patients with hepatocellular carcinoma were followed up for 36(range,1‒74)months after liver transplantation.During the follow-up,there were 41 patients died,61 patients with tumor recurrence and 117 cases without tumor recurrence.The 3-,5-year overall survival rates and 3-,5-year tumor recurrence free survival rates of patients after liver transplantation were 72.8%,69.9%and 57.3%,52.8%,respectively.(2)The predictive value and cutoff value of each index for tumor recurrence of patients with hepatocellular carcinoma after liver transplantation.The AUC of preoperative serum alpha fetoprotein(AFP),tumor diameter,ALR,GLR,neutrophil to lymphocyte ratio,AAR in recipients were 0.76,0.70,0.69,0.65,0.64,0.65(95%confidence interval as 0.68‒0.83,0.61‒0.79,0.61‒0.77,0.57‒0.74,0.56‒0.73,0.56‒0.74,P<0.05),and the corresponding best cutoff value of each index were 228.00μg/L,5.25 cm,92.90,122.40,3.00,2.42.(3)Analysis of risk factors for tumor recurrence of patients with hepato-cellular carcinoma after liver transplantation.Results of multivariate analysis showed the preoperative serum AFP>228.88μg/L,number of tumor as multiple,tumor diameter>5.25 cm,ALR>92.90,AAR>2.42 were indepen-dent risk factors for tumor recurrence of hepatocellular carcinoma after liver transplantation(hazard ratio=3.13,1.90,2.66,2.40,2.75,95%confidence interval as 1.81‒5.41,1.08‒3.35,1.49‒4.74,1.40‒4.11,1.54‒4.91,P<0.05).(4)Construction and evaluation of the predictive model for tumor recurrence of patients with hepatocellular carcinoma after liver transplantation.According to the results of multivariate analysis,the preoperative serum AFP,number of tumor,tumor diameter,ALR,AAR were used to construct the predictive model for tumor recurrence of hepatocellular carcinoma after liver transplantation.The AUC,best cutoff value,specificity and sensitivity of the predictive model were 0.83(95%confidence interval as 0.76‒0.89,P<0.05),5.5,80.3%and 73.8%.Of the 178 patients,there were 110 patients with low risk of tumor recurrence(scoring as 0‒5)and 68 patients with high risk of tumor recurrence(scoring as 6‒16)after liver transplantation.The 1-,3-,5-year tumor recurrence free survival rates and 1-,3-,5-year overall survival rates of patients with high risk of tumor recurrence were 27.7%,18.2%,18.2%and 63.7%,48.9%,48.9%,respectively.The above indicators of patients with low risk of tumor recurrence were 92.3%,82.4%,74.6%and 90.4%,87.7%,83.6%,respectively.There were significant differences of the above indicators between patients with high risk of tumor recurrence and low risk of tumor recurrence(χ^(2)=67.83,21.95,P<0.05).Conclusions The preoperative serum AFP,number of tumor,tumor diameter,ALR,AAR are independent influencing factors for tumor recurrence of hepato-cellular carcinoma after liver transplantation.The predictive model constructed based on the above indexes has a good prediction efficiency.