尿白细胞介素-2、肿瘤坏死因子-α对高危非肌层浸润性膀胱癌患者卡介苗膀胱灌注治疗效果的预测价值

Values of urinary interleukin-2and tumor necrosis factor-αto the prediction of Bacillus Calmette-Guérin bladder perfusion in patients with high-risk non-muscle-invasive bladder cancer

目的观察高危非肌层浸润性膀胱癌(non-muscle invasive bladder cancer,NMIBC)患者卡介苗(Bacillus Calmette-Guérin,BCG)膀胱诱导灌注前、后尿白细胞介素-2(interleukin-2,IL-2)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平变化,探讨尿IL-2、TNF-α对治疗效果的预测价值。方法178例高危NMIBC患者均行经尿道膀胱肿瘤切除术,术后行BCG膀胱灌注治疗1年,包括诱导灌注、强化灌注、维持灌注,共19次。依据BCG膀胱灌注治疗结束时是否复发将178例患者分为复发组39例和未复发组139例,比较2组患者膀胱癌复发病史、二次经尿道膀胱肿瘤切除术、膀胱灌注治疗史、肿瘤最大直径等临床资料,诱导灌注前、后血清谷丙转氨酶、总胆红素、肌酐及尿白细胞计数等实验室指标;采用ELISA法检测2组诱导灌注前、后尿IL-2、TNF-α水平,计算诱导灌注前后尿IL-2、TNF-α差值及比值。采用多因素logistic回归分析高危NMIBC患者BCG膀胱灌注治疗后复发的影响因素;绘制ROC曲线,评估诱导灌注前后尿IL-2比值、TNF-α比值预测高危NMIBC患者BCG膀胱灌注治疗后复发的效能。结果BCG膀胱灌注治疗结束时178例患者中39例患者复发,复发率为21.91%。复发组膀胱癌复发病史、二次经尿道膀胱肿瘤切除术、膀胱灌注治疗史比率(51.28%、46.15%、35.90%)均高于未复发组(24.46%、20.86%、19.42%)(P<0.05),肿瘤最大直径[(4.13±0.97)cm]大于未复发组[(3.79±0.74)cm](t=2.019,P=0.047)。复发组诱导灌注前、后血白细胞计数、血红蛋白水平,血清谷丙转氨酶、总胆红素、肌酐水平,尿白细胞计数及诱导灌注前尿IL-2、TNF-α水平与未复发组比较差异均无统计学意义(P>0.05),诱导灌注后尿IL-2[(6.32±4.79)pg/L]、TNF-α[(88.84±42.88)ng/L]水平均低于未复发组[(7.43±4.01)pg/L、(125.47±72.81)ng/L](P<0.05);复发组诱导灌注前后尿IL-2差值及比值[(5.65±4.77)pg/L、8.51±3.32]、TNF-α差值及比值[(68.08±38.97)ng/L、4.62±1.71]均低于未复发组[(6.73±3.83)pg/L、10.59±3.62、(106.14±68.48)ng/L、6.42±2.66](P<0.05);2组诱导灌注后血清谷丙转氨酶、总胆红素、肌酐水平,尿白细胞计数及尿IL-2、TNF-α水平均高于诱导灌注前(P<0.05),血白细胞计数、血红蛋白水平与诱导灌注前比较差异均无统计学意义(P>0.05)。膀胱癌复发病史(OR=2.781,95%CI:1.901~8.585,P=0.034)及诱导灌注前后尿IL-2比值(OR=0.058,95%CI:0.017~0.784,P<0.001)、尿TNF-α比值(OR=0.021,95%CI:0.009~0.635,P=0.001)是高危NMIBC患者BCG膀胱灌注治疗后复发的独立影响因素。诱导灌注前后尿IL-2比值、尿TNF-α比值以0.121、0.217为最佳截断值,预测高危NMIBC患者BCG膀胱灌注治疗后复发的AUC分别为0.725(95%CI:0.614~0.837,P<0.001)、0.768(95%CI:0.669~0.866,P<0.001),灵敏度分别为76.37%、63.29%,特异度分别为53.42%、54.33%;二者联合预测高危NMIBC患者BCG膀胱灌注治疗后复发的AUC为0.904(95%CI:0.846~0.961,P<0.001),灵敏度为87.98%,特异度为92.41%;二者联合预测的AUC均大于单独预测(Z=5.724,P=0.013;Z=5.637,P=0.015)。结论高危NMIBC患者BCG膀胱诱导灌注后尿IL-2、TNF-α水平降低提示肿瘤易复发,诱导灌注前后尿IL-2比值、尿TNF-α比值联合预测BCG膀胱灌注治疗效果有较高价值。

Objective To observe the changes of the urinary levels of interleukin-2(IL-2)and tumor necrosis factor-α(TNF-α)before and after Bacillus Calmette-Guérin (BCG)bladder inductive perfusion in patients with high-risk non-muscle invasive bladder cancer(NMIBC)and to investigate their values to the prediction of the treatment results.Methods A total of 178 high-risk NMIBC patients received one-year BCG bladder perfusion after transurethral resection of bladder tumor(TURBT)including 19 times of inductive perfusion,intensive perfusion and maintenance perfusion.According to recurrence after BCG bladder perfusion,178 patients were divided into recurrence group (n=39)and non-recurrence group(n=139).The general data as recurrence history of bladder cancer,secondary TURBT,bladder perfusion history,maximum diameter of cancer,and laboratory indexes as serum glutamic-pyruvic transaminase,serum total bilirubin,serum creatinine and urinary white blood cell count before and after inductive perfusion were recorded.The levels of urinary IL-2 and TNF-αwere detected by ELISA.The differences and ratios of IL-2 and TNF-αwere calculated before and after inductive perfusion.Multivariate logistic regression analysis was done to evaluate the influencing factors of recurrence after BCG bladder perfusion in high-risk NMIBC patients.ROC curves were drawn to analyze the efficiencies of urinary IL-2 ratio and TNF-αratio before and after inductive perfusion on predicting recurrence after BCG bladder perfusion in high-risk NMIBC patients.Results In 178 patients,39 patients recurred after BCG bladder perfusion,with the recurrence rate of 21.91%.The percentages of patients with recurrence history,secondary TURBT and bladder perfusion history were higher in recurrence group (51.28%,46.15%,35.90%)than those in non-recurrence group (24.46%,20.86%,19.42%)(P<0.05),and the maximum tumor diameter was longer in recurrence group[(4.13±0.97)cm]than that in non-recurrence group[(3.79±0.74)cm](t=2.019,P=0.047).There were no significant differences in the serum white blood cell count,serum hemoglobin,serum glutamic-pyruvic transaminase,serum total bilirubin,serum creatinine,and urinary white blood cell count before and after inductive perfusion,as well as urinary IL-2 and TNF-αbefore inductive perfusion between two groups(P>0.05).The levels of urinary IL-2 and TNF-αwere lower in recurrence group[(6.32±4.79)pg/L,(88.84±42.88)ng/L]than those in non-recurrence group[(7.43±4.01)pg/L,(125.47±72.81)ng/L]after inductive perfusion (P<0.05).The differences and ratios of IL-2[(5.65±4.77)pg/L,8.51±3.32]and TNF-α[(68.08±38.97)ng/L,4.62±1.71]before and after inductive perfusion in recurrence group were lower than those in non-recurrence group[(6.73±3.83)pg/L,10.59±3.62;(106.14±68.48)ng/L,6.42±2.66](P<0.05),the levels of serum glutamic-pyruvic transaminase,serum total bilirubin,serum creatinine,urinary white blood cell count,urinary IL-2 and urinary TNF-αin both groups after inductive perfusion were higher than those before inductive perfusion (P<0.05),and there were no significant differences in the serum white blood cell count and hemoglobin after inductive perfusion compared with those before inductive perfusion (P>0.05).Recurrence history of bladder cancer (OR=2.781,95%CI:1.901-8.585,P=0.034),urinary IL-2 ratio before and after inductive perfusion(OR=0.058,95%CI:0.017-0.784,P<0.001),and urinary TNF-αratio before and after inductive perfusion (OR=0.021,95%CI:0.009-0.635,P=0.001)were the independent influencing factors of recurrence after BCG bladder perfusion in high-risk NMIBC patients.When the optimal cut-offvalues of urinary IL-2 ratio and urinary TNF-αratio before and after inductive perfusion were 0.121 and 0.217,the AUCs of single and combined detection of them for predicting recurrence after BCG bladder perfusion in high-risk NMIBC patients were 0.725(95%CI:0.614-0.837,P<0.001),0.768(95%CI:0.669-0.866,P<0.001),and 0.904(95%CI:0.846-0.961,P<0.001),the sensitivities were 76.37%,63.29% and 87.98%,and the specificities were 53.42%,54.33% and 92.41%,respectively.The AUCof combined detection was greater than that of single detection(Z=5.724,P=0.013;Z=5.637,P=0.015).Conclusion The decreased levels of urinary IL-2 and urinary TNF-αafter inductive perfusion indicate a tendency of recurrence,and combined detection of urinary IL-2 ratio and TNF-αratio before and after inductive perfusion has a high value to the prediction of efficacy of BCG bladder perfusion in high-risk NMIBC patients.