Objectives: To determine the combination of urinary protein markers for noninvasive detection of primary and recurrent urothelial bladder carcinomas. Methods: Urinary concentrations of 27 biomarkers (NSE, ATT, AFABP, Resistin, Midkine, Clusterin, Uromodulin, ZAG2, HSP27, HSP 60, NCAM1/CD56, Angiogenin, Calreticulin, Chromogranin A, CEACAM1, CXCL1, IL13Ra2, Progranulin, VEGFA, CarbAnhydIX, Annexin-V, TIM4, Galectin1, Cystatin B, Synuclein G, ApoA1 and ApoA2) were assessed by enzyme-linked immunosorbent assay or by electrochemiluminiscence immunoassay. Results: During the primary diagnostics, a group of 70 patients with primary occurrence of bladder cancer and 49 healthy control subjects were compared. For this clinical situation, the most accurate combination proved to be the combination of cytology with markers Midkine and Synuclein G (sensitivity 91.8%, specificity 97.5%). During the monitoring of patients with non-muscle invasive bladder cancer (NMIBC), a group of 44 patients with cancer recurrence was compared with the group of 61 patients with a history of NMIBC without current disease. For this clinical situation, the most accurate combination proved to be the combination of cytology and erythrocytes count in urine sediment with markers Midkine, ZAG2, CEACAM1, and Synuclein G (sensitivity 92.68%, specificity 90.16%). A lower accuracy of the diagnostic panel and the necessity to use more markers in the case of recurrence was connected with a different structure of patients. Conclusions: Multi-marker test can significantly improve the bladder cancer detection both during the primary diagnostics and monitoring of patients with NMIBC. This outcome should result in other, larger studies.

Keywords:
Urothelial urinary bladder cancer, Noninvasive detection, Urinary biomarker, Midkine, Synuclein G
1.
Sylvester RJ, van der Meijden APM, Oosterlinck W, et al: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2,596 patients from seven EORTC trials. Eur Urol 2006;49:466-477.
2.
Altieri VM, Castellucci R, Palumbo P, et al: Recurrence and progression in non-muscle-invasive bladder cancer using EORTC risk tables. Urol Int 2012;89:61-66.
3.
Holmang S, Strock V: Should follow-up cystoscopy in bacillus Calmette-Guérin-treated patients continue after five tumour-free years? Eur Urol 2012;61:503-507.
4.
Soukup V, Babjuk M, Bellmunt J, et al: Follow-up after surgical treatment of bladder cancer: a critical analysis of the literature. Eur Urol 2012;62:290-302.
5.
Oderda M, Ricceri F, Pisano F, et al: Prognostic factors including Ki-67 and p53 in Bacillus Calmette-Guérin-treated non-muscle-invasive bladder cancer: a prospective study. Urol Int 2013;90:184-190.
6.
Fahmy NM, Mahmud S, Aprikian AG: Delay in the surgical treatment of bladder cancer and survival: systematic review of the literature. Eur Urol 2006;50:1176-1182.
7.
Babjuk M, Burger M, Zigeuner R, et al: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64:639-653.
8.
Kamat AM, Hegarty PK, Gee JR, et al: ICUD-EAU international consultation on bladder cancer 2012: screening, diagnosis, and molecular markers. Eur Urol 2013;63:4-15.
9.
Schmitz-Dräger BJ, Todenhöfer T, van Rhijn B, et al: Considerations on the use of urine markers in the management of patients with low-/intermediate-risk non-muscle invasive bladder cancer. Urol Oncol 2014;32:1061-1068.
10.
Yang H, Li H, Wang Z, et al: Is urinary soluble Fas an independent predictor of non-muscle-invasive bladder cancer? A prospective chart study. Urol Int 2013;91:456-461.
11.
Yossepowitch O, Herr HW, Donat SM: Use of urinary biomarkers for bladder cancer surveillance: patient perspectives. J Urol 2007;177:1277-1282.
12.
Vriesema JL, Poucki MH, Kiemeney LA, et al: Patient opinion of urinary tests versus flexible urethrocystoscopy in follow-up examination for superficial bladder cancer: a utility analysis. Urology 2000;56:793-797.
13.
Lokeshwar VB, Habuchi T, Grossman HB, et al: Bladder tumour markers beyond cytology: international consensus panel on bladder tumor markers. Urology 2005;66:35-63.
14.
Xylinas E, Kluth LA, Rieken M, et al: Urine markers for detection and surveillance of bladder cancer. Urol Oncol 2014;32:222-229.
15.
Wadhwa N, Jatawa SK, Tiwari A: Non-invasive urine based tests for the detection of bladder cancer. J Clin Pathol 2012;65:970-975.
16.
Shimwell NJ, Bryan RT, Wei W, et al: Combined proteome and transcriptome analyses for the discovery of urinary biomarkers for urothelial carcinoma. Br J Cancer 2013;108:1854-1861.
17.
Chen YT, Chen CL, Chen HW, et al: Discovery of novel bladder cancer biomarkers by comparative urine proteomics using iTRAQ technology. J Proteome Res 2010;9:5803-5815.
18.
Wu TF, Ku WL, Tsay YG, et al: Proteome-based diagnostics and prognosis of bladder transitional cell carcinoma. Expert Rev Proteomics 2007;4:639-647.
19.
Yang N, Feng S, Shedden K, et al: Urinary glycoprotein biomarker discovery for bladder cancer detection using LC/MS-MS and label-free quantification. Clin Cancer Res 2011;17:3349-3359.
20.
Papanicolaou GN, Marshall VF: Urine sediment smears as a diagnostic procedure in cancers of the urinary tract. Science 1945;101:519-520.
21.
Layfield LJ, Elsheikh TM, Fili A, et al: Review of the state of the art and recommendations of the Papanicolaou Society of Cytopathology for urinary cytology procedures and reporting: the Papanicolaou Society of Cytopathology Practice Guidelines Task Force. Diagn Cytopathol 2004;30:24-30.
22.
Kim YK, Kim WJ: Epigenetic markers as promising prognosticators for bladder cancer. Int J Urol 2009;16:17-22.
23.
Mengual L, Burset M, Ribal MJ, et al: Gene expression signature in urine for diagnosing and assessing aggressiveness of bladder urothelial carcinoma. Clin Cancer Res 2010;16:2624-2633.
24.
Yafi FA, Brimo F, Auger M, Aprikian A, Tanguay S, Kassouf W: Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer. Urol Oncol 2014;32:27.e1-e6.
25.
Iwaki H, Kageyama S, Isono T, et al: Diagnostic potential in bladder cancer of a panel of tumor markers (calreticulin, gamma-synuclein, and catechol-o-methyltransferase) identified by proteomic analysis. Cancer Sci 2004;95:955-961.
26.
Irmak S, Tilki D, Heukeshoven J, et al: Stage-dependent increase of orosomucoid and zinc-alpha2-glycoprotein in urinary bladder cancer. Proteomics 2005;5:4296-4304.
27.
Tilki D, Singer BB, Shariat SF, et al: CEACAM1: a novel urinary marker for bladder cancer detection. Eur Urol 2010;57:648-654.
© 2015 S. Karger AG, Basel
2015
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