Mesut Remzi

358 Background: To investigate the prognostic value of PD-1 and PD-L1 expression in patients with high-grade upper tract urothelial carcinoma (UTUC). Methods: Tissue microarrays were created using 448 patients from the International UTUC collaboration who underwent extirpative surgery for high-grade UTUC and stained for PD-1 (antibody (AB): NAT105, diluted 1:250 from Ventana) and PD-L1 (AB: E1L3N prediluted from Cell Signaling). PD-1 and PD-L1 expression was assessed in a semi-quantitative fashion and any percentage of staining of the tumor cells (PD-L1) and tumor-infiltrating lymphocytes (PD-1) was considered positive. Univariate (UVA) and multivariate analyses (MVA) were performed to assess independent prognosticators of oncological outcomes. No funding was received. Results: Median age of the cohort was 69.2 years and 56.5% of patients were male. PD-L1 and PD-1 were positive in 24.1% and 37.5% of patients. PD-L1 positivity was associated with favorable pathological stage, where as PD-1 positivity was significantly associated with pelvicalyceal location, lymph node metastases, non-organ confined disease, presence of lymphovascular invasion, sessile architecture, necrosis, concomitant CIS, and history of non-muscle invasive bladder cancer. PD-L1 positivity was not significantly associated with survival outcomes. In Cox regression UVA, PD-1 positivity was associated with worse recurrence-free survival (RFS) (HR 1.5 (95%CI 1.08-2.14, p=0.016)), cancer-specific survival (CSS) (HR 1.5 (95%CI 1.07-2.19, p=0.021)), and overall survival (OS) (HR 1.5 (95%CI 1.10-1.97, p=0.009)). However in MVA, PD-1 positivity was not found to be an independent predictor of RFS, CSS or OS. Conclusions: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and was a significant prognosticator for RFS, CSS and OS on UVA in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort. In MVA, the independent prognostic value of PD-1 was not confirmed. PD-L1 positivity was associated with lower tumor stage, but not with other pathological characteristics or survival outcomes.

In recent years, new therapeutic options have brought improvements in the treatment of metastatic, castration-resistant prostate cancer. Targeted Hormone Therapy (THT) represents a novel therapeutic component for which recent studies have shown a maximum benefit in the time between failure of androgen deprivation therapy (patient is metastatic and still pain-free) and prior to chemotherapy. Prostate cancer experts of the Austrian Society of Urology and Andrology (ÖGU), the Working Group for Urologic Oncology as part of the ÖGU, and the Professional Association of Austrian Urologists (BvU) have developed recommendations for the treatment of patients with asymptomatic or mildly symptomatic metastatic, castration-resistant prostate cancer. The definition of failure of classical hormonal therapy has been based on the guidelines of the German Society of Urology (Deutsche Gesellschaft für Urologie, DGU) and the European Association of Urology (EAU). Criteria for the initiation of treatment with hormonal or chemotherapy include: Treatment should only be initiated when all of these four criteria are applicable, with the age of the patient being no exclusion criterion. First-line therapies for these patients include abiraterone, enzalutamide, and docetaxel as well as radium-223. The manuscript refers only to treatment regimens available in Austria. Selection of the initial treatment option—starting with THT or chemotherapy—should be determined based on the individual patient characteristics. When using abiraterone or enzalutamide, re-staging within 3–6 months is recommended.

371 Background: To validate the independent predictive value of Ki-67 in patients with high-grade upper tract urothelial carcinoma (UTUC). Methods: 475 patients from the international UTUC collaboration who underwent extirpative surgery for high-grade UTUC were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray (TMA) formed from this patient cohort. Ki-67 expression was assessed in a semi-quantitative fashion and considered overexpressed at a cut-off of 20%. Multivariate analyses (MVA) were performed to assess independent predictors of oncological outcomes and Harrell’s C indices (HCI) were calculated for predictive models. Results: Median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was overexpressed in 25.9% of patients. Ki-67 overexpression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ (CIS), and regional lymph node metastases. In Kaplan-Meier analyses, overexpressed Ki-67 was associated with worse recurrence-free (RFS) (HR 12.6, p<0.001) and cancer-specific survival (CSS) (HR 15.8, p<0.001). In MVA, Ki-67 was an independent predictor of RFS (HR 1.6, 95% CI 1.07-2.30, p=0.021) and CSS (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved HCI from 0.66 to 0.70 (p<0.0001) for both RFS and CSS in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for RFS and 0.81 to 0.83 (p=0.005) for CSS in our post-operative model. Conclusions: Ki-67 was validated as an independent prognostic predictor of RFS and CSS in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort.

323 Background: Alterations in the MTOR and HIF pathways may have prognostic significance in bladder carcinoma. We evaluated the predictive value of altered MTOR-pathway biomarkers in upper tract urothelial carcinoma (UTUC). Methods: Multi-institutional review of clinicopathological data on patients receiving extirpative surgery for UTUC from 1990-2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, p4E-BP, phosphorylated-AKT, PTEN, HIF-1a, Raptor and Cyclin D was performed on tissue microarrays from radical nephroureterectomy specimens. Predictive markers were identified by regression analyses. Significance of altered markers was assessed with Kaplan-Meier and Cox regression analysis. Results: 620 patients with a mean age of 69 years were included. 37% of patients had non-organ confined (T3/T4 and/or N+) disease. 74% of patients had high-grade disease and 22% had LVI on final pathology. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariable analysis, PI3K (OR 1.28, p=0.001) and Cyclin D (OR 3.45, p=0.05) were significant predictors of clinical outcomes. Cumulative marker-score was defined as low-risk (zero/one altered marker) or high-risk (Cyclin D AND PI3K altered). Patients with high-risk marker-score had a significantly higher proportion of high-grade disease (91% vs. 71%, p<0.001), non-organ confined disease (61% vs. 33%, p<0.001), LVI (35% vs. 20%, p=0.001), and lymph node metastases (22% vs. 6%, p<0.001). Kaplan-Meier analysis demonstrated a significant difference in CSM based on risk groups. On multivariable analysis for CSM incorporating non-organ confined disease, grade, LVI, tumor architecture, and marker-score, high-risk biomarker-score was an independent predictor of CSM (HR 1.5, 95%CI 1.04-2.3, p=0.03). Conclusions: Alterations in MTOR pathway correlate with established adverse pathologic features and independently predict inferior oncologic outcomes. Incorporation of MTOR-based marker profiles may allow for enhanced patient counseling, risk stratification, and individualized treatment regimens.

Through evolution in technology, endoscopic treatment has gained popularity for the treatment of upper tract urothelial carcinoma (ENDO-UTUC).