基于中介分析预测术前血清学肿瘤标志物阳性数对肝内胆管癌患者手术方式及预后的影响

Predict the effect of the number of positive preoperative serum tumor markers on the surgical method and prognosis of intrahepatic cholangiocarcinoma patients based on mediation analysis

目的探讨术前血清学肿瘤标志物阳性数对肝内胆管癌患者手术方式及预后的影响。方法回顾性病例系列研究。回顾性收集2010年10月至2019年4月我国10家三级甲等医院收治的548例根治性切除术后肝内胆管癌患者的相关数据。男性277例,女性271例;年龄(57.8±10.2)岁(范围:23~84岁)。426例(77.7%)患者术前血清学肿瘤标志物至少有一项阳性。收集的数据包括4项术前血清学肿瘤标志物检测结果、其他术前指标(前驱症状5项、既往病史6项、术前血清学指标8项、术前影像学指标5项、术前病理学检查指标14项)、患者基线数据(性别和年龄)、手术方式和预后随访数据。将4项术前血清学肿瘤标志物检测结果和手术方式转换为分类变量。利用中介分析方法,将术前血清学肿瘤标志物阳性数作为处理变量,手术方式为中介变量,生存时间为结局变量,采用单因素和多因素分析的方法筛选同时是手术方式和患者独立预后因素的其他术前指标作为协变量,分析中介效应。结果纳入研究的548例患者中,176例(32.1%)患者行单纯部分肝切除术,151例(27.5%)患者行单纯半肝切除术,221例(40.3%)患者行部分肝切除或半肝切除术联合其他治疗方法。单因素和多因素分析结果显示,术前血清学肿瘤标志物阳性数、肝内胆管扩张、门静脉侵犯、分化程度、病理学类型、血管侵犯、T分期、N分期和肿瘤最大径是手术方式的独立影响因素(P值均<0.05);肝内胆管扩张、分化程度和T分期是肝内胆管癌患者的独立预后因素(P值均<0.05)。将肝内胆管扩张、分化程度和T分期作为协变量纳入中介效应模型,结果显示,术前血清学肿瘤标志物阳性数对肝内胆管癌患者的生存时间有负向预测作用(β=-0.092,P=0.039),同时对所采用的手术方式具有正向预测作用(β=0.244,P<0.01);将手术方式代入模型后,术前血清学肿瘤标志物阳性数对肝内胆管癌患者的生存时间有负向预测作用(β=-0.151,P=0.002);直接效应和间接效应分别占总效应的71.3%和28.7%。结论术前肿瘤标志物阳性数越多,肝内胆管癌患者的预后越差。阳性数既可直接影响患者的预后,也可能通过影响手术方式间接影响患者预后。

Objective:To investigate the effect of the number of positive preoperative serological tumor markers on the surgical approach and prognosis of patients with intrahepatic cholangiocarcinoma.Methods:This is a retrospective case-series study.Data from 548 patients with intrahepatic cholangiocarcinoma after radical resection from October 2010 to April 2019 were retrospectively collected in 10 hospitals of China.There were 277 males and 271 females with an age of(57.8±10.2)years(range:23 to 84 years).Four hundred and twenty-six patients(77.7%)had at least one positive preoperative serum tumor marker.The data collection included the results of 4 preoperative serological tumor markers,other preoperative indicators(5 prodromal symptoms,6 medical history,8 preoperative serological indicators,5 preoperative imaging indicators,and 14 preoperative pathological examination indicators),baseline data(gender and age),surgical methods,and prognostic follow-up data.Four preoperative results of serologic tumor marker and surgical procedure were converted into categorical variables.The number of positive preoperative serum tumor markers was used as the treatment variable,the surgical method was used as the mediating variable,and the survival time was used as the outcome variable.Univariate and multivariate analysis were used to screen for other preoperative indicators which were independent factors that influenced the surgical procedure and the prognosis of patients as covariates to analyze the mediating effect.Results:Of the 548 patients included in the study,176 patients(32.1%)underwent partial hepatectomy,151 patients(27.5%)underwent hemihepatectomy,and 221 patients(40.3%)underwent partial hepatectomy or hemihepatectomy combined with other treatments.The results of the univariate and multivariate analysis showed that the number of positive serum tumor markers,intrahepatic bile duct dilatation,portal vein invasion,pathological differentiation,pathological type,vascular invasion,T stage,N stage and maximum tumor diameter were independent factors influencing the surgical procedure(all P<0.05).Intrahepatic bile duct dilatation,pathological differentiation and T stage were independent prognostic factors for patients with intrahepatic cholangiocarcinoma(all P<0.05).Intrahepatic bile duct dilatation,differentiation and T stage were included as covariates in the mediation effect model.The results showed that the number of positive serum tumor markers before surgery had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma(β=-0.092,P=0.039),and had a positive predictive effect on the surgical method(β=0.244,P<0.01).The number of positive serum tumor markers had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma(β=-0.151,P=0.002).Direct and indirect effects accounted for 71.3%and 28.7%of total effects,respectively.Conclusions:The higher the positive number of preoperative tumor markers,the worse the prognosis of patients with intrahepatic cholangiocarcinoma.The number of positive cells not only directly affects the prognosis of patients,but also indirectly affects the prognosis of patients by affecting the surgical method.