Bishoy A. Gayed

The management of patients with renal cell carcinoma (RCC) with venous tumor thrombus (VTT) is challenging. We report our 15 year experience in the management of patients with RCC with VTT utilizing a multidisciplinary team approach, highlighting improved total and specifically Clavien III-V complication rates. We reviewed the records of 146 consecutive patients who underwent radical nephrectomy with venous thrombectomy between 1998 and 2012. Data on patient history, staging, surgical techniques, morbidity, and survival were analyzed. Additionally, complication rates between two surgical eras, 1998–2006 and 2006–2012, were assessed. The study included 146 patients, 97 males (66 %), and a median age of 61 years (range, 24–83). Overall complications rate was 53 %, high grade complications (Clavien III -V) occurred in 10 % of patients. Most importantly, there was a lower incidence of overall and high grade complications (45 % and 8 %, respectively) in the last 6 years compared to the earlier surgeries included in the study (67 % and 13 % respectively) [p = .008 and .03, respectively). 30 day postoperative mortality was 2.7 %. 5 year overall survival (5Y- OS) and 5 year cancer specific survival (5Y- CSS) were 51 % and 40 %, respectively. Metastasis was the only independent predictor factor for CSS (HR 3.8, CI 1.9-7.6 and p < .001) and OS (HR 2.6, CI 1.5-4.7 and p = .001) in all patients. Our data suggest that patients with RCC and VTT can be treated safely utilizing a multidisciplinary team approach leading to a decrease in complication rates.

To assess pathological correlations and temporal trends of Angiopoietin-2 (ANGPT2), vascular endothelial growth factor (VEGF) and M2 Pyruvate kinase (TuM2PK), markers of tumor vascular development and metabolism, in patients with renal cell carcinoma (RCC). We prospectively collected plasma samples from 89 patients who underwent surgical/ablative therapy for RCC and 38 patients with benign disease (nephrolithiasis, hematuria without apparent neoplastic origin, or renal cysts). In RCC patients, marker levels were compared between at least 1 preoperative and 1 postoperative time point generally 3 weeks after surgery. Marker temporal trends were assessed using the Wilcoxon sign-rank test. Plasma VEGF, ANGPT2, and TuM2PK levels were determined by ELISA and tested for association with pathological variables. Median age was comparable between groups. 83/89 (93%) of the cohort underwent surgical extirpation. 82% of the tumors were organ confined (T ≤2, N0). Only ANGPT2 exhibited significantly elevated preoperative levels in patients with RCC compared to benign disease (p = 0.046). Elevated preoperative levels of ANGPT2 and TuM2PK significantly correlated with increased tumor size and advanced grade (p < 0.05). Chromophobe RCC exhibited higher levels of ANGPT2 compared to other histologies (p < 0.05). A decline in marker level after surgery was not observed, likely due to the timing of the analyses. Our results suggest that ANGPT2 is a marker of RCC. Additionally, ANGPT2 and TuM2PK significantly correlated with several adverse pathological features. Further studies are needed to determine clinical applicability.

Prostate cancer continues to be the second leading cause of cancer related mortality in men within the United States. Despite a consistent decline in prostate cancer mortality over the past two decades, the prognosis for men with metastatic prostate cancer remains poor with no curative therapies. In this article, we review the recently approved and emerging therapeutics for patients with castrate resistant prostate cancer. An advanced search was conducted on the clinicaltrials.gov database, using search terms "metastatic prostate cancer", and limiting results to phase II-IV clinical trials. Clinically relevant emerging therapeutics were selected and a Medline search for supporting documents was performed. An emphasis was placed on newly approved and promising new therapeutics. A total of four Food and Drug Administration approved medications and eight investigational agents were chosen for review. The background and role of these therapeutics in the treatment of prostate cancer treatment is discussed. The past few years have yielded a near exponential increase in treatments for metastatic prostate cancer, many of which have a unique mechanism of action. The estimated median survival for patients with metastatic prostate cancer remains dynamic as we begin to integrate these therapeutics into clinical practice and determine the optimal sequence and timing of treatment.

525 Background: There have been multiple reports implicating the role of hydronephrosis (HN) as a predictor of outcome in patients diagnosed with upper tract urothelial carcinoma (UTUC). However, this was done in mixed populations (low-/high-grade) and degree of HN (DOH) was not taken into account. We evaluated the impact of severity of hydronephrosis on systemic and bladder relapse in patients with UTUC. Methods: We retrospectively reviewed the records of 141 patients with localized UTUC that underwent extirpative surgery. Preoperative imaging was used to evaluate ipsilateral DOH. We analyzed the association between DOH (none/mild vs. moderate/severe), pathological findings and oncological outcomes in high-grade vs. low-grade patients. Bladder recurrence was assessed separately from local or systemic (L/S) recurrence. Results: High-grade UTUC was present in 80% of patients, 35% had muscle-invasive disease (≥pT2), and 29% had non-organ-confined disease. At a median follow-up of 34 months (range, 1-149), 35% of patients experienced intravesical recurrence, 20% developed L/S recurrence, and 17% died of UTUC. No difference in outcomes was seen between patients without HN and mild HN. DOH was none/mild in 55% and moderate/severe in 45% of cases. In patients with high-grade UTUC, moderate/severe HN was associated with advanced pathologic stage (p

493 Background: Epithelial to mesenchymal transition (EMT) is thought to play a crucial role in cancer progression and development of metastasis. Thus, we evaluated dysregulation of beta-catenin as a part of EMT and its clinical implications in patients with clear cell renal cell carcinoma (ccRCC). Methods: Immunohistochemical staining was performed for beta-catenin on tissue microarrays of patients with ccRCC. Membranous and cytoplasmatic beta-catenin expression patterns were assessed separately. Beta-catenin was considered normal if none or only one component was abnormal and was considered dysregulated if both components were abnormal. Differences in pathological characteristics between both groups were investigated. Differences in recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with the Kaplan-Meier method. Uni- and multivariate Cox proportional hazard models were used to assess independent predictors of oncological outcomes. Results: 406 patients with a median follow-up of 58 months were included. Overall, 52 (12.8%) and 25 (6.2%) patients recurred and died of ccRCC. Beta-catenin was dysregulated in 70 (17.2%) patients. Dysregulation of beta-catenin was significantly associated with adverse pathologic features, such as higher T-stage, nodal positivity, higher grade, presence of tumor thrombus, sarcomatoid features, necrosis and LVI (all p

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.

198 Background: Tumor hypoxia is associated with worse pathologic features and oncological outcomes. Blood Oxygen Level Dependent (BOLD) MRI evaluates changes in endogenous contrast generated by paramagnetic deoxy-hemoglobin to non-invasively evaluate tissue oxygenation. Prior attempts using carbogen-based (95%O₂ + 5%CO₂) imaging were limited by patient tolerance. We present the first-in-man evaluation of a novel oxygen breathing challenge technique to monitor tissue oxygenation with BOLD MRI in patients with prostate cancer. Methods: Following IRB approval, 10 patients with clinically localized prostate cancer scheduled for radical prostatectomy underwent preoperative imaging with a 3-Tesla MRI scanner. Images were acquired using a 6-element SENSE body transmit coil and endorectal receive coil. T₂* signal intensity is dependent on the concentration of deoxy-hemoglobin. Signal intensity measurements were obtained at different time points. Shorter T₂* times imply the presence of hypoxia. Dynamic T₂* maps were acquired while subjects breathed air for 2 mins followed by oxygen (15 l/min). Results: 10 patients (median age: 59 years (range 48-73), median PSA 6.9 ng/ml (range 2.5-25), with prostate cancer (Gleason sum 6- 7, 8-9 in 7 and 3 patients respectively) underwent BOLD MRI within 3 weeks of definitive management with a robotic assisted laparoscopic prostatectomy. All patients tolerated BOLD MRI with oxygen challenge without difficulty. Evaluation of BOLD MRI revealed wide variation in T₂* values within the prostates from a median of 14.7 ± .71 ms to 44.5 ± 3.3ms. Surrounding muscle T₂* values were similar for all patients, indicating that heterogeneous values were specific to each patient’s prostate. Shorter T₂* values were seen in Gleason 6-7 than Gleason 8- 9 cancers, indicating more hypoxic areas in these tumors. HIF-1α staining was strongly positive in all tumors. Conclusions: BOLD MRI with oxygen challenge is well tolerated in patients and is a feasible noninvasive technique to study tissue oxygenation in tumors. Differential oxygenation patterns of prostates appear to correlate with pathological features. Further testing is needed to validate these findings.