World Journal of Urology

, Volume 26, Issue 1, pp 5–11 | Cite as

Guidelines for development of diagnostic markers in bladder cancer

  • Peter J. Goebell
  • Susan L. Groshen
  • Bernd J. Schmitz-Dräger
Topic Paper



Advances in understanding cancer at the molecular level have identified numerous alterations associated with cancer development and progression. The efforts in evaluating these putative biomarkers in clinical studies of patients with cancer are increasing in order to improve the clinical management of the disease. However, despite numerous attempts, the results of such biomarker studies are frequently inconsistent and sometimes even contradictory. Aim of this work is to discuss some of the recognized problems which have impeded our understanding of the role of new markers and prevented the introduction of these markers into patient management.


These Problems include standardization issues, selection of patient cohorts and endpoints and statistical considerations. In order to improve and standardize marker development a stepwise procedure in four phases, analogous to clinical trials is proposed. Furthermore, a common terminology, considerations on the population to study as well as general recommendations for planning and conducting the evaluation of markers will be presented.


The implementation of this discussion may foster the integration of new tools and strategies screening, diagnosis and surveillance of patients with bladder cancer.


Marker Bladder Cancer Phases 


Conflict of interest statement

There is no conflict of interest.


  1. 1.
    Malkin A (1992) Tumor markers. In: Tannock IF, Hill RP (eds) The basic science of oncology, 2nd edn. McGraw-Hill, New YorkGoogle Scholar
  2. 2.
    Gudjónsson S, Isfoss BL, Hansson K, Domanski AM, Warenholt J, Soller W, Lundberg LM, Liedberg F, Grabe M, Månsson W (2007) The value of the urovysion((R)) Assay for surveillance of non-muscle-invasive bladder cancer. Eur Urol [Epub ahead of print]Google Scholar
  3. 3.
    Birkhahn M, Mitra AP, Cote RJ (2007) Molecular markers for bladder cancer: the road to a multimarker approach. Expert Rev Anticancer Ther 7:1717–1727PubMedCrossRefGoogle Scholar
  4. 4.
    Herrmann E, Eltze E, Bierer S, Köpke T, Görge T, Neumann J, Hertle L, Wülfing C (2007) VEGF-C, VEGF-D and Flt-4 in transitional bladder cancer: relationships to clinicopathological parameters and long-term survival. Anticancer Res 27:3127–3133PubMedGoogle Scholar
  5. 5.
    Tsai YS, Tzai TS, Chow NH (2007) Does HER2 immunoreactivity provide prognostic information in locally advanced urothelial carcinoma patients receiving adjuvant M-VEC chemotherapy? Urol Int 79:210–216PubMedCrossRefGoogle Scholar
  6. 6.
    Knowles MA (2007) Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target. World J Urol 25:581–593PubMedCrossRefGoogle Scholar
  7. 7.
    Mohammed A, Khan Z, Zamora I, Bhatti A (2008) Biological markers in the diagnosis of recurrent bladder cancer: an overview. Expert Rev Mol Diagn 8:63–72PubMedCrossRefGoogle Scholar
  8. 8.
    Droller MJ (2001) Cancer heterogeneity and its biologic implications in the grading of urothelial carcinoma. J Urol 165:696–697PubMedCrossRefGoogle Scholar
  9. 9.
    Lokeshwar VB, Civantos F (2004) Tumor markers: current status. In: Droller MJ (eds) American cancer society atlas of clinical oncology: bladder cancer. Hamilton, Ontario, pp 160–205Google Scholar
  10. 10.
    Konety BR, Getzenberg RH (2001) Urine based markers of urological malignancy. J Urol 165:600–611PubMedCrossRefGoogle Scholar
  11. 11.
    Glas AS, Roos D, Deutekom M, Zwinderman AH, Bossuyt PM, Kurth KH (2003) Tumor markers in the diagnosis of primary bladder cancer. A systematic review. J Urol 169:1975–1982PubMedCrossRefGoogle Scholar
  12. 12.
    Babjuk M, Kostírová M, Mudra K, Pecher S, Smolová H, Pecen L, Ibrahim Z, Dvorácek J, Jarolím L, Novák J, Zima T (2002) Qualitative and quantitative detection of urinary human complement factor H-related protein (BTA stat and BTA TRAK) and fragments of cytokeratins 8, 18 (UBC rapid and UBC IRMA) as markers for transitional cell carcinoma of the bladder. Eur Urol 41:34–39PubMedCrossRefGoogle Scholar
  13. 13.
    Gibanel R, Ribal MJ, Filella X, Ballesta AM, Molina R, Alcaraz A, Alcover JB (2002) BTA TRAK urine test increases the efficacy of cytology in the diagnosis of low-grade transitional cell carcinoma of the bladder. Anticancer Res 22:1157–1160PubMedGoogle Scholar
  14. 14.
    Serretta V, Pomara G, Rizzo I, Esposito E (2000) Urinary BTA-stat, BTA-trak and NMP22 in surveillance after TUR of recurrent superficial transitional cell carcinoma of the bladder. Eur Urol 38:419–425PubMedCrossRefGoogle Scholar
  15. 15.
    Lokeshwar VB, Soloway MS (2001) Current bladder tumor tests: does their projected utility fulfill clinical necessity? J Urol 165:1067–1077PubMedCrossRefGoogle Scholar
  16. 16.
    Chiong E, Gaston KE, Grossman HB (2007) Urinary markers in screening patients with hematuria. World J Urol [Epub ahead of print]Google Scholar
  17. 17.
    Nguyen CT, Jones JS (2007) Defining the role of NMP22 in bladder cancer surveillance. World J Urol [Epub ahead of print]Google Scholar
  18. 18.
    Black PC, Brown GA, Dinney CP (2006) Molecular markers of urothelial cancer and their use in the monitoring of superficial urothelial cancer. J Clin Oncol 24:5528–5535PubMedCrossRefGoogle Scholar
  19. 19.
    Tritschler S, Scharf S, Karl A, Tilki D, Knuechel R, Hartmann A, Stief CG, Zaak D (2007) Validation of the diagnostic value of NMP22 BladderChek test as a marker for bladder cancer by photodynamic diagnosis. Eur Urol 51:403–407PubMedCrossRefGoogle Scholar
  20. 20.
    Shariat SF, Marberger MJ, Lotan Y, Sanchez-Carbayo M, Zippe C, Lüdecke G, Boman H, Sawczuk I, Friedrich MG, Casella R, Mian C, Eissa S, Akaza H, Serretta V, Huland H, Hedelin H, Raina R, Miyanaga N, Sagalowsky AI, Roehrborn CG, Karakiewicz PI (2006) Variability in the performance of nuclear matrix protein 22 for the detection of bladder cancer. J Urol 176:919–926PubMedCrossRefGoogle Scholar
  21. 21.
    Moonen PM, Kiemeney LA, Witjes JA (2005) Urinary NMP22 BladderChek test in the diagnosis of superficial bladder cancer. Eur Urol 48:951–956PubMedCrossRefGoogle Scholar
  22. 22.
    Shariat SF, Zippe C, Lüdecke G, Boman H, Sanchez-Carbayo M, Casella R, Mian C, Friedrich MG, Eissa S, Akaza H, Sawczuk I, Serretta V, Huland H, Hedelin H, Rupesh R, Miyanaga N, Sagalowsky AI, Wians F Jr, Roehrborn CG, Lotan Y, Perrotte P, Benayoun S, Marberger MJ, Karakiewicz PI (2005) Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder. J Urol 173:1518–1525PubMedCrossRefGoogle Scholar
  23. 23.
    Chang YH, Wu CH, Lee YL, Huang PH, Kao YL, Shiau MY (2004) Evaluation of nuclear matrix protein-22 as a clinical diagnostic marker for bladder cancer. Urology 64:687–692PubMedCrossRefGoogle Scholar
  24. 24.
    May M, Hakenberg OW, Gunia S, Pohling P, Helke C, Lübbe L, Nowack R, Siegsmund M, Hoschke B (2007) Comparative diagnostic value of urine cytology, UBC-ELISA, and fluorescence in situ hybridization for detection of transitional cell carcinoma of urinary bladder in routine clinical practice. Urology 70:449–453PubMedCrossRefGoogle Scholar
  25. 25.
    Friedrich MG, Toma MI, Hellstern A, Pantel K, Weisenberger DJ, Noldus J, Huland H (2003) Comparison of multitarget fluorescence in situ hybridization in urine with other noninvasive tests for detecting bladder cancer. BJU Int 92:911–914PubMedCrossRefGoogle Scholar
  26. 26.
    Toma MI, Friedrich MG, Hautmann SH, Jäkel KT, Erbersdobler A, Hellstern A, Huland H (2004) Comparison of the ImmunoCyt test and urinary cytology with other urine tests in the detection and surveillance of bladder cancer. World J Urol 22:145–149PubMedCrossRefGoogle Scholar
  27. 27.
    Greene KL, Berry A, Konety BR (2006) Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol Fall 8:190–197Google Scholar
  28. 28.
    Schmitz-Dräger BJ, Tirsar LA, Schmitz-Dräger C, Dörsam J, Mellan Z, Bismarck E, Ebert T (2007) Immunocytology in the assessment of patients with asymptomatic hematuria. World J Urol [Epub ahead of print]Google Scholar
  29. 29.
    Mian C, Maier K, Comploj E, Lodde M, Berner L, Lusuardi L, Palermo S, Vittadello F, Pycha A (2006) uCyt+/ImmunoCyt in the detection of recurrent urothelial carcinoma: an update on 1991 analyses. Cancer 108:60–65PubMedCrossRefGoogle Scholar
  30. 30.
    Lodde M, Mian C, Comploj E, Palermo S, Longhi E, Marberger M, Pycha A (2006) uCyt+ test: alternative to cystoscopy for less-invasive follow-up of patients with low risk of urothelial carcinoma. Urology 67:950–954PubMedCrossRefGoogle Scholar
  31. 31.
    Szarvas T, Kovalszky I, Bedi K, Szendroi A, Majoros A, Riesz P, Füle T, László V, Kiss A, Romics I (2007) Deletion analysis of tumor and urinary DNA to detect bladder cancer: urine supernatant versus urine sediment. Oncol Rep 18:405–409PubMedGoogle Scholar
  32. 32.
    Frigerio S, Padberg BC, Strebel RT, Lenggenhager DM, Messthaler A, Abdou MT, Moch H, Zimmermann DR (2007) Improved detection of bladder carcinoma cells in voided urine by standardized microsatellite analysis. Int J Cancer 121:329–338PubMedCrossRefGoogle Scholar
  33. 33.
    Burger M, Burger SJ, Denzinger S, Wild PJ, Wieland WF, Blaszyk H, Obermann EC, Stoehr R, Hartmann A (2006) Elevated microsatellite instability at selected tetranucleotide repeats does not correlate with clinicopathologic features of bladder cancer. Eur Urol 50:770–775PubMedCrossRefGoogle Scholar
  34. 34.
    Fornari D, Steven K, Hansen AB, Jepsen JV, Poulsen AL, Vibits H, Horn T (2006) Transitional cell bladder tumor: predicting recurrence and progression by analysis of microsatellite loss of heterozygosity in urine sediment and tumor tissue. Cancer Genet Cytogenet 167:15–19PubMedCrossRefGoogle Scholar
  35. 35.
    Eissa S, Swellam M, Ali-Labib R, Mansour A, El-Malt O, Tash FM (2007) Detection of telomerase in urine by 3 methods: evaluation of diagnostic accuracy for bladder cancer. J Urol 178:1068–1072PubMedCrossRefGoogle Scholar
  36. 36.
    Liu BC (2006) Urine telomerase and bladder cancer detection. JAMA 295:998PubMedCrossRefGoogle Scholar
  37. 37.
    Weikert S, Christoph F, Miller K (2006) Urine telomerase and bladder cancer detection. JAMA 295:998–999PubMedCrossRefGoogle Scholar
  38. 38.
    Gilbert SM, Veltri RW, Sawczuk A, Shabsigh A, Knowles DR, Bright S, O’Dowd GJ, Olsson CA, Benson MC, Sawczuk IS (2003) Evaluation of DD23 as a marker for detection of recurrent transitional cell carcinoma of the bladder in patients with a history of bladder cancer. Urology 61:539–543PubMedCrossRefGoogle Scholar
  39. 39.
    Bonner RB, Liebert M, Hurst RE, Grossman HB, Bane BL, Hemstreet GP 3rd (1996) Characterization of the DD23 tumor-associated antigen for bladder cancer detection and recurrence monitoring. Marker Network for Bladder Cancer. Cancer Epidemiol Biomarkers Prev 5:971–978PubMedGoogle Scholar
  40. 40.
    Sawczuk IS, Pickens CL, Vasa UR, Ralph DA, Norris KA, Miller MC, Ng AY, Grossman HB, Veltri RW (2002) DD23 biomarker. A prospective clinical assessment in routine urinary cytology specimens from patients being monitored for TCC. Urol Oncol 7:185–190PubMedCrossRefGoogle Scholar
  41. 41.
    Shariat SF, Karam JA, Lerner SP (2008) Molecular markers in bladder cancer. Curr Opin Urol 18:1–8PubMedCrossRefGoogle Scholar
  42. 42.
    Sanchez-Carbayo M, Socci ND, Richstone L, Corton M, Behrendt N, Wulkfuhle J, Bochner B, Petricoin E, Cordon-Cardo C (2007) Genomic and proteomic profiles reveal the association of gelsolin to TP53 status and bladder cancer progression. Am J Pathol 171:1650–1658PubMedCrossRefGoogle Scholar
  43. 43.
    Mhawech-Fauceglia P, Fischer G, Alvarez V Jr, Ahmed A, Herrmann FR (2007) Predicting outcome in minimally invasive (T1a and T1b) urothelial bladder carcinoma using a panel of biomarkers: a high throughput tissue microarray analysis. BJU Int 100:1182–1187PubMedGoogle Scholar
  44. 44.
    Dyrskjot L, Zieger K, Orntoft TF (2007) Recent advances in high-throughput molecular marker identification for superficial and invasive bladder cancers. Front Biosci 12:2063–2073PubMedCrossRefGoogle Scholar
  45. 45.
    Wild PJ, Herr A, Wissmann C, Stoehr R, Rosenthal A, Zaak D, Simon R, Knuechel R, Pilarsky C, Hartmann A (2005) Gene expression profiling of progressive papillary noninvasive carcinomas of the urinary bladder. Clin Cancer Res 11:4415–4429PubMedCrossRefGoogle Scholar
  46. 46.
    Sánchez-Carbayo M, Cordon-Cardo C (2003) Applications of array technology: identification of molecular targets in bladder cancer. Br J Cancer 89:2172–2177PubMedCrossRefGoogle Scholar
  47. 47.
    Zaharieva BM, Simon R, Diener PA, Ackermann D, Maurer R, Alund G, Knönagel H, Rist M, Wilber K, Hering F, Schönenberger A, Flury R, Jäger P, Fehr JL, Mihatsch MJ, Gasser T, Sauter G, Toncheva DI (2003) High-throughput tissue microarray analysis of 11q13 gene amplification (CCND1, FGF3, FGF4, EMS1) in urinary bladder cancer. J Pathol 201:603–608PubMedCrossRefGoogle Scholar
  48. 48.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) Statistics Subcommittee of NCI-EORTC Working Group on Cancer Diagnostics. Reporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235PubMedCrossRefGoogle Scholar
  49. 49.
    Real FX (2007) p53: it has it all, but will it make it to the clinic as a marker in bladder cancer? J Clin Oncol 25:5341–5344PubMedCrossRefGoogle Scholar
  50. 50.
    Kyzas PA, Denaxa-Kyza D, Ioannidis JP (2007) Almost all articles on cancer prognostic markers report statistically significant results. Eur J Cancer 43:2559–2579PubMedGoogle Scholar
  51. 51.
    Kyzas PA, Denaxa-Kyza D, Ioannidis JP (2007) Quality of reporting of cancer prognostic marker studies: association with reported prognostic effect. J Natl Cancer Inst 99:236–243PubMedCrossRefGoogle Scholar
  52. 52.
    Habuchi T, Marberger M, Droller MJ, Hemstreet GP III, Grossman HB, Schalken JA, Schmitz-Dräger BJ, Murphy WM, Bono AV, Goebell P, Getzenberg RH, Hautmann SH, Messing E, Fradet Y, Lokeshwar VB (2005) Prognostic markers for bladder cancer: International Consensus Panel on bladder tumor markers. Urology 66(6 Suppl 1):64–74PubMedCrossRefGoogle Scholar
  53. 53.
    Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet GP 3rd, Bono AV, Getzenberg RH, Goebell P, Schmitz-Dräger BJ, Schalken JA, Fradet Y, Marberger M, Messing E, Droller MJ (2005) Bladder tumor markers beyond cytology: international consensus panel on bladder tumor markers. Urology 66(6 Suppl 1):35–63PubMedCrossRefGoogle Scholar
  54. 54.
    Altman DG, Lausen B, Sauerbrei W, Schumacher M (1994) Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 86:829–835PubMedCrossRefGoogle Scholar
  55. 55.
    Schmoor C, Sauerbrei W, Schumacher M (2000) Sample size considerations for the evaluation of prognostic factors in survival analysis. Stat Med 19:441–52PubMedCrossRefGoogle Scholar
  56. 56.
    Pajak TF, Clark GM, Sargent DJ et al (2000) Statistical issues in tumor marker studies. Arch Pathol Lab Med 124:1011–1015PubMedGoogle Scholar
  57. 57.
    Altman DG, Royston P (2000) What do we mean by validating a prognostic model? Stat Med 19:453–473PubMedCrossRefGoogle Scholar
  58. 58.
    Begg CB, Cramer LD, Venkatraman ES, Rosai J (2000) Comparing tumour staging and grading systems: a case study and a review of the issues, using thymoma as a model. Stat Med 19:1997–2014PubMedCrossRefGoogle Scholar
  59. 59.
    Simon R, Altman DG (1994) Statistical aspects of prognostic factor studies in oncology. Br J Cancer 69:979–985PubMedGoogle Scholar
  60. 60.
    McGuire WL (1991) Breast cancer prognostic factors: evaluation guidelines. J Natl Cancer Inst 83:154–155PubMedCrossRefGoogle Scholar
  61. 61.
    Stockler MR, Boyd NF, Tannock IF (1998) Guide to studies of diagnostic tests, prognostic factors, and treatments. In: Tannockand H (ed) The basic science of oncology, 3rd edn. McGraw-Hill, New YorkGoogle Scholar
  62. 62.
    Drew PJ, Ilstrup DM, Kerin MJ, Monson JR (1998) Prognostic factors: guidelines for investigation design and state of the art analytical methods. Surg Oncol 7:71–76PubMedCrossRefGoogle Scholar
  63. 63.
    Grossman HB (2000) The first and second international workshops on diagnostic and prognostic markers in bladder cancer. Urol Oncol 5:183–184PubMedCrossRefGoogle Scholar
  64. 64.
    Goebell PJ, Groshen S, Schmitz-Dräger BJ, Sylvester R, Kogevinas M, Malats N, Sauter G, Grossman HB, Waldman F, Cote RJ (2004) The International Bladder Cancer Bank—proposal for a new study concept. Urol Oncol 22:277–284PubMedGoogle Scholar
  65. 65.
    Lotan/Malats this issue WJUGoogle Scholar
  66. 66.
    Amling CL (2000) Diagnosis and management of superficial bladder cancer. Curr Probl Cancer 25:219–278Google Scholar
  67. 67.
    van der Poel HG, Debruyne FM (2001) Can biological markers replace cystoscopy? An update. Curr Opin Urol 11:503–509PubMedCrossRefGoogle Scholar
  68. 68.
    Heney NM (1992) Natural history of superficial bladder cancer. Prognostic features and long-term disease course. Urol Clin North Am 19:429–433PubMedGoogle Scholar
  69. 69.
    Holmäng S, Johansson SL (2006) Impact of diagnostic and treatment delay on survival in patients with renal pelvic and ureteral cancer. Scand J Urol Nephrol 40:479–484PubMedCrossRefGoogle Scholar
  70. 70.
    Araki M, Nieder AM, Manoharan M, Yang Y, Soloway MS (2007) Lack of progress in early diagnosis of bladder cancer. Urology 69:270–274PubMedCrossRefGoogle Scholar
  71. 71.
    Bergman J, Reznichek RC, Rajfer J (2008) Surveillance of patients with bladder carcinoma using fluorescent in-situ hybridization on bladder washings. BJU Int 101:26–29PubMedGoogle Scholar
  72. 72.
    Tomera KM (2004) NMP22 BladderChek test: point-of-care technology with life- and money-saving potential. Expert Rev Mol Diagn 4:783–94PubMedCrossRefGoogle Scholar
  73. 73.
    Agarwal PK, Black PC, Kamat AM (2007) Considerations on the use of diagnostic markers in management of patients with bladder cancer. World J Urol Dec 19 [Epub ahead of print]Google Scholar
  74. 74.
    Sarosdy MF, Kahn PR, Ziffer MD, Love WR, Barkin J, Abara EO, Jansz K, Bridge JA, Johansson SL, Persons DL, Gibson JS (2006) Use of a multitarget fluorescence in situ hybridization assay to diagnose bladder cancer in patients with hematuria. J Urol 176:44–47PubMedCrossRefGoogle Scholar
  75. 75.
    Chiong E, Gaston KE, Grossman HB (2007) Urinary markers in screening patients with hematuria. World J Urol. 4 December 2007 [Epub ahead of print]Google Scholar
  76. 76.
    Schmitz-Dräger BJ, Tirsar LA, Schmitz-Dräger C, Dörsam J, Mellan Z, Bismarck E, Ebert T (2007) Immunocytology in the assessment of patients with asymptomatic hematuria. World J Urol. 12 December 2007 [Epub ahead of print]Google Scholar
  77. 77.
    Schmitz-Dräger BJ, Beiche B, Tirsar LA, Schmitz-Dräger C, Bismarck E, Ebert T (2007) Immunocytology in the assessment of patients with asymptomatic microhaematuria. Eur Urol 51:1582–1588PubMedCrossRefGoogle Scholar
  78. 78.
    Goodman GE, Thornquist MD, Edelstein C, Omenn GS (2006) Biorepositories: let’s not lose what we have so carefully gathered! Cancer Epidemiol Biomarkers Prev 15:599–601PubMedCrossRefGoogle Scholar
  79. 79.
    Holland NT, Pfleger L, Berger E, Ho A, Bastaki M (2005) Molecular epidemiology biomarkers–sample collection and processing considerations. Toxicol Appl Pharmacol 206:261–268PubMedCrossRefGoogle Scholar
  80. 80.
    van Gils MP, Stenman UH, Schalken JA, Schröder FH, Luider TM, Lilja H, Bjartell A, Hamdy FC, Pettersson KS, Bischoff R, Takalo H, Nilsson O, Mulders PF, Bangma CH (2005) Innovations in serum and urine markers in prostate cancer current European research in the P-Mark project. Eur Urol 48:1031–1041PubMedCrossRefGoogle Scholar
  81. 81.
    Baker SG (2000) Identifying combinations of cancer markers for further study as triggers for early intervention. Biometrics 56:1082–1087PubMedCrossRefGoogle Scholar
  82. 82.
    Pepe MS (2000) Reciever operating characteristics methodology. J Am Stat Assoc 95:308–311CrossRefGoogle Scholar
  83. 83.
    Swets JA, Pickett RM (1982) Evaluation of diagnostic systems: methods from signal detection theory. Academic Press, New YorkGoogle Scholar
  84. 84.
    Pepe MS, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M, Winget M, Yasui Y (2001) Phases of biomarker development for early detection of cancer. JNCI 93:1054–1061PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Peter J. Goebell
    • 1
  • Susan L. Groshen
    • 2
  • Bernd J. Schmitz-Dräger
    • 3
  1. 1.Department of UrologyFriedrich-Alexander University of ErlangenErlangenGermany
  2. 2.Department of Preventive Medicine Norris Comprehensive Cancer CenterUniversity of Southern California, Keck School of MedicineLos AngelesUSA
  3. 3.Department of UrologyEuromedClinicFürthGermany

Personalised recommendations