Abstract. The aim of the present study was to investigate the clinical significance of TNF receptor-associated factor 6 (TRAF6) expression in urothelial bladder cancer. TRAF6 expression was detected by immunohistochemistry in 126 samples of patients with urothelial bladder cancer. The association between clinicopathological factors and TRAF6 expression was analyzed by χ 2 test. The association between TRAF6 expression, overall survival rate and the recurrence-free survival rate was evaluated in univariate analysis with Kaplan-Meier test and in multivariate analysis with Cox-regression model. In the cohort tested, the rate of high TRAF6 expression was 61.9% (78/126). TRAF6 expression was demonstrated to be significantly associated with positive metastasis (P=0.001) with χ 2 test. Furthermore, TRAF6 expression was demonstrated to be associated with overall survival rate (P=0.016) and recurrence-free survival rate (P=0.016). With Cox-regression model, it was indicate that TRAF6 high expression was an independent predictive factor of poor prognosis (P=0.037) and high recurrence (P=0.011). High TRAF6 expression may predict unfavorable prognosis and high recurrence in urothelial bladder cancer, indicating that TRAF6 may be a potential and promising therapeutic target in urothelial bladder cancer.

Results: The cohort was 60% male and was comprised of 62% pT1 and 65% grade 2-3 tumors. 51% of patients were current or former smokers. Median age was 58.5 (range: 20-87 years). With a median follow-up of 58 months (range: 3-131 months), 13 (16%) patients developed a relapse. The site of first relapse was isolated local in 5 patients, isolated regional in 2 patients, and combined locoregional in 6 patients. No patients developed a distant recurrence, either isolated or combined, at the time of first relapse. Regional recurrences were ipsilateral in 75% and contralateral in 25% of patients. Overall, the 5-year rates for local control (LC), regional control (RC), locoregional control (LRC), disease-free survival (DFS), diseasespecific survival (DSS), and overall survival (OS) were 89%, 91%, 86%, 80%, 93%, 87%, respectively. Pathologic T2 status was a predictor for worse outcomes across all endpoints. Perineural invasion (PNI) was a predictor for worse RC (pZ0.04), DSS (pZ0.001), and OS (pZ0.001). Margin 2mm was a predictor for worse LC (pZ0.0001) and PFS (pZ0.0011). Nine of the 49 (18%) patients with depth of invasion (DOI) !4mm suffered locoregional relapses (LRR). Of the 5 patients with pT2 and PNI, 2 (40%) developed isolated regional relapses. Of the 24 patients with pT2 and DOI !4mm, 5 (21%) had regional failures. Patients who developed neck recurrences experienced a significantly worse DSS (5year: 38% vs 100%; p<0.0001) and OS (5-year: 38% vs 92%; p<0.0001) compared to those who did not. All relapses underwent further salvage treatment; 8 (62%) patients were successfully salvaged with no evidence of disease at last follow-up. Conclusion: At our institution, patients with early stage, pT1-2N0 OTSCC exhibited relatively low rates of LRR and good overall prognosis. Regional relapse, however, significantly impacts OS adversely. Patients with pT2 disease who have PNI and/or DOI !4mm appear to be at considerable risk of regional relapse and should be counseled regarding PORT. When feasible, wider margins >2mm should be obtained surgically.