title: Neuropilin-2 and its ligand VEGF-C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients.
abstract: The standard treatment for invasive bladder cancer is radical cystectomy. In selected patients, bladder-sparing therapy can be performed by transurethral resection (TURBT) and radio-chemotherapy (RCT) or radiotherapy (RT). Our published in vitro data suggest that the Neuropilin-2 (NRP2)/VEGF-C axis plays a role in therapy resistance. Therefore, we studied the prognostic impact of NRP2 and VEGF-C in 247 bladder cancer patients (cN0M0) treated with TURBT and RCT (n = 198) or RT (n = 49) and a follow-up time up to 15 years. A tissue microarray was analyzed by immunohistochemistry. NRP2 expression emerged as a prognostic factor in overall survival (OS; HR: 3.42; 95% CI: 1.48 - 7.86; p = 0.004) and was associated with a 3.85-fold increased risk of an early cancer specific death (95% CI: 0.91 - 16.24; p = 0.066) in multivariate analyses. Cancer specific survival (CSS) dropped from 166 months to 85 months when NRP2 was highly expressed (p = 0.037). Patients with high VEGF-C expression have a 2.29-fold increased risk of shorter CSS (95% CI: 1.03-5.35; p = 0.043) in univariate analysis. CSS dropped from 170 months to 88 months in the case of high VEGF-C expression (p = 0.041). Additionally, NRP2 and VEGF-C coexpression is a prognostic marker for OS in multivariate models (HR: 7.54; 95% CI: 1.57-36.23; p = 0.012). Stratification for muscle invasiveness (T1 vs. T2-T4) confirmed the prognostic role of NRP2 and NRP2/VEGF-C co-expression in patients with T2-T4 but also with high risk T1 disease. In conclusion, immunohistochemistry for NRP2 and VEGF-C has been determined to predict therapy outcome in bladder cancer patients prior to TURBT and RCT.
authors.affiliation: Department of Urology, University Hospital Erlangen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Keck
authors.forename: S
authors.initials: S
authors.lastname: Wach
authors.forename: H
authors.initials: H
authors.lastname: Taubert
authors.forename: S
authors.initials: S
authors.lastname: Zeiler
authors.forename: O J
authors.initials: OJ
authors.lastname: Ott
authors.forename: F
authors.initials: F
authors.lastname: Kunath
authors.forename: A
authors.initials: A
authors.lastname: Hartmann
authors.forename: S
authors.initials: S
authors.lastname: Bertz
authors.forename: C
authors.initials: C
authors.lastname: Weiss
authors.forename: P
authors.initials: P
authors.lastname: Hönscheid
authors.forename: S
authors.initials: S
authors.lastname: Schellenburg
authors.forename: C
authors.initials: C
authors.lastname: Rödel
authors.forename: G B
authors.initials: GB
authors.lastname: Baretton
authors.forename: R
authors.initials: R
authors.lastname: Sauer
authors.forename: R
authors.initials: R
authors.lastname: Fietkau
authors.forename: B
authors.initials: B
authors.lastname: Wullich
authors.forename: F S
authors.initials: FS
authors.lastname: Krause
authors.forename: K
authors.initials: K
authors.lastname: Datta
authors.forename: M H
authors.initials: MH
authors.lastname: Muders
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002278:Carcinoma in Situ / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D039943:Neuropilin-2 / Q000378:metabolism*; D059351:Organ Sparing Treatments; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D039943:Neuropilin-2; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C581308:neuropilin-2, human
keywords: Neuropilin-2; TURBT; VEGF-C; bladder cancer; radiochemotherapy