Chen Li-Mei, Chang Myron, Dai Yunfeng, Chai Karl X, Dyrskjøt Lars, Sanchez-Carbayo Marta, Szarvas Tibor, Zwarthoff Ellen C, Lokeshwar Vinata, Jeronimo Carmen, Parker Alexander S, Ross Shanti, Borre Michael, Orntoft Torben F, Jaeger Tobias, Beukers Willemien, Lopez Luis E, Henrique Rui, Young Paul R, Urquidi Virginia, Goodison Steve, Rosser Charles J
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida.
Department of Biostatistics, The University of Florida, Gainesville, Florida.
Cancer Epidemiol Biomarkers Prev. 2014 Sep;23(9):1804-12. doi: 10.1158/1055-9965.EPI-14-0029. Epub 2014 Jun 11.
Because of the faltering sensitivity and/or specificity, urine-based assays currently have a limited role in the management of patients with bladder cancer. The aim of this study was to externally validate our previously reported protein biomarker panel from multiple sites in the United States and Europe.
This multicenter external validation study included a total of 320 subjects (bladder cancer = 183). The 10 biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SDC1, and SERPINE1) were measured using commercial ELISA assays in an external laboratory. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values.
Utilizing the combination of all 10 biomarkers, the area under the ROC for the diagnostic panel was noted to be 0.847 (95% confidence interval, 0.796-0.899), outperforming any single biomarker. The multiplex assay at optimal cutoff value achieved an overall sensitivity of 0.79, specificity of 0.79, positive prediction value of 0.73, and negative prediction value of 0.84 for bladder cancer classification. Sensitivity values of the diagnostic panel for high-grade bladder cancer, low-grade bladder cancer, muscle invasive bladder cancer, and non-muscle invasive bladder cancer were 0.81, 0.90, 0.95, and 0.77, respectively.
Urinary levels of the biomarker panel enabled discrimination of patients with bladder cancer and controls, and the levels of biomarker subsets were associated with advancing tumor grade and stage.
If proven to be reliable, urinary diagnostic biomarker assays can detect bladder cancer in a timely manner such that the patient can expect improvements in overall survival and quality of life.
由于敏感性和/或特异性不稳定，目前基于尿液的检测在膀胱癌患者管理中的作用有限。本研究的目的是在美国和欧洲的多个地点对外验证我们之前报告的蛋白质生物标志物组。
这项多中心外部验证研究共纳入320名受试者（膀胱癌患者 = 183名）。在外部实验室中使用商业ELISA检测法对10种生物标志物（IL8、MMP9、MMP10、SERPINA1、VEGFA、ANG、CA9、APOE、SDC1和SERPINE1）进行检测。使用受试者操作特征曲线（ROC）和描述性统计值评估生物标志物组的诊断性能。
利用全部10种生物标志物的组合，诊断组的ROC曲线下面积为0.847（95%置信区间，0.796 - 0.899），优于任何单一生物标志物。在最佳临界值下的多重检测对膀胱癌分类的总体敏感性为0.79，特异性为0.79，阳性预测值为0.73，阴性预测值为0.84。诊断组对高级别膀胱癌、低级别膀胱癌、肌层浸润性膀胱癌和非肌层浸润性膀胱癌的敏感性分别为0.81、0.90、0.95和0.77。
生物标志物组的尿液水平能够区分膀胱癌患者和对照组，生物标志物亚组的水平与肿瘤分级和分期进展相关。
如果被证明可靠，尿液诊断生物标志物检测可以及时检测出膀胱癌，从而使患者有望提高总生存率和生活质量。
