Interethnic differences in the impact of body mass index on upper tract urothelial carcinoma following radical nephroureterectomy.

PURPOSE: Inconsistent prognostic implications of body mass index (BMI) in upper tract urothelial carcinoma (UTUC) have been reported across different ethnicities. In this study, we aimed to analyze the oncologic role of BMI in Asian and Caucasian patients with UTUC. METHODS: We retrospectively collected data from 648 Asian Taiwanese and 213 Caucasian American patients who underwent radical nephroureterectomy for UTUC. We compared clinicopathologic features among groups categorized by different BMI. Kaplan-Meier method and Cox regression model were used to examine the impact of BMI on recurrence and survival by ethnicity. RESULTS: According to ethnicity-specific criteria, overweight and obesity were found in 151 (23.2%) and 215 (33.2%) Asians, and 79 (37.1%) and 78 (36.6%) Caucasians, respectively. No significant association between BMI and disease characteristics was detected in both ethnicities. On multivariate analysis, overweight and obese Asians had significantly lower recurrence than those with normal weight (HR 0.631, 95% CI 0.413-0.966; HR 0.695, 95% CI 0.493-0.981, respectively), and obesity was an independent prognostic factor for favorable cancer-specific and overall survival (HR 0.521, 95% CI 0.342-0.794; HR 0.545, 95% CI 0.386-0.769, respectively). There was no significant difference in outcomes among normal, overweight and obese Caucasians, but obese patients had a relatively poorer 5-year RFS, CSS, and OS rates of 52.8%, 60.5%, and 47.2%, compared to 54.9%, 69.1%, and 54.9% for normal weight patients. CONCLUSION: Higher BMI was associated with improved outcomes in Asian patients with UTUC. Interethnic differences could influence preoperative counseling or prediction modeling in patients with UTUC.

Overcoming sociodemographic factors in the care of patients with testicular cancer at a safety net hospital.

BACKGROUND: The objective of this study was to determine whether standardized treatment of germ cell tumors (GCTs) could overcome sociodemographic factors limiting patient care. METHODS: The records of all patients undergoing primary treatment for GCTs at both a public safety net hospital and an academic tertiary care center in the same metropolitan area were analyzed. Both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center; clinicopathologic features and outcomes were analyzed. RESULTS: Between 2006 and 2018, 106 and 95 patients underwent initial treatment for GCTs at the safety net hospital and the tertiary care center, respectively. Safety net patients were younger (29 vs 33 years; P = .005) and were more likely to be Hispanic (79% vs 11%), to be uninsured (80% vs 12%; P < .001), to present via the emergency department (76% vs 8%; P < .001), and to have metastatic (stage II/III) disease (42% vs 26%; P = .025). In a multivariable analysis, an absence of lymphovascular invasion (odds ratio [OR], 0.30; P = .008) and an embryonal carcinoma component (OR, 0.36; P = .02) were associated with decreased use of adjuvant treatment for stage I patients; hospital setting was not (OR, 0.67; P = .55). For patients with stage II/III nonseminomatous GCTs, there was no difference in the performance of postchemotherapy retroperitoneal lymph node dissection between the safety net hospital and the tertiary care center (52% vs 64%; P = .53). No difference in recurrence rates was observed between the cohorts (5% vs 6%; P = .76). CONCLUSIONS: Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCTs; they may be overcome with integrated, standardized management of testicular cancer.

Prognostic significance of BAP1 expression in high-grade upper tract urothelial carcinoma: a multi-institutional study.

PURPOSE: To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies. METHODS: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0-3, with BAP1 loss defined as an average intensity of < 1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05. RESULTS: 348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS. CONCLUSIONS: BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.

Postoperative Nomogram for Relapse-Free Survival in Patients with High Grade Upper Tract Urothelial Carcinoma.

PURPOSE: We developed a prognostic nomogram for patients with high grade urothelial carcinoma of the upper urinary tract after extirpative surgery. MATERIALS AND METHODS: Clinical data were available for 2,926 patients diagnosed with high grade urothelial carcinoma of the upper urinary tract who underwent extirpative surgery. Cox proportional hazard regression models identified independent prognosticators of relapse in the development cohort (838). A backward step-down selection process was applied to achieve the most informative nomogram with the least number of variables. The L2-regularized logistic regression was applied to generate the novel nomogram. Harrell's concordance indices were calculated to estimate the discriminative accuracy of the model. Internal validation processes were performed using bootstrapping, random sampling, tenfold cross-validation, LOOCV, Brier score, information score and F1 score. External validation was performed on an external cohort (2,088). Decision tree analysis was used to develop a risk classification model. Kaplan-Meier curves were applied to estimate the relapse rate for each category. RESULTS: Overall 35.3% and 30.7% of patients experienced relapse in the development and external validation cohort. The final nomogram included age, pT stage, pN stage and architecture. It achieved a discriminative accuracy of 0.71 and 0.76, and the AUC was 0.78 and 0.77 in the development and external validation cohort, respectively. Rigorous testing showed constant results. The 5-year relapse-free survival rates were 88.6%, 68.1%, 40.2% and 12.5% for the patients with low risk, intermediate risk, high risk and very high risk disease, respectively. CONCLUSIONS: The current nomogram, consisting of only 4 variables, shows high prognostic accuracy and risk stratification for patients with high grade urothelial carcinoma of the upper urinary tract following extirpative surgery, thereby adding meaningful information for clinical decision making.

Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma.

PURPOSE: We investigated the prognostic value of PD-1 and PD-L1 expression in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: Tissue microarrays of 423 patients treated with extirpative surgery for high grade upper tract urothelial carcinoma from the International Upper Tract Urothelial Carcinoma collaboration were stained for PD-1 and PD-L1 using antibodies, including Cell Marque™ NAT105 diluted 1:250 and prediluted E1L3N® via immunohistochemistry. A 1% or greater staining rate of tumor infiltrating lymphocytes (PD-1) and tumor cells (PD-L1) was considered positive. Univariate and multivariate analyses were performed to assess independent prognosticators of survival outcomes. RESULTS: Median patient age was 70.0 years and median followup was 37.0 months. PD-1 and PD-L1 were positive in 37.2% and 26.2% of patients, respectively. PD-1 positivity was significantly associated with adverse pathological characteristics while PD-L1 positivity was associated with favorable pT stage. On univariate analysis PD-1 expression was associated with worse recurrence-free, cancer specific and overall survival. On multivariate analysis PD-1 expression was an independent prognosticator of cancer specific survival (HR 1.7, 95% CI 1.03-2.66, p = 0.039) and overall survival (HR 1.5, 95% CI 1.05-2.24, p = 0.029) but not recurrence-free survival (HR 1.4, 95% CI 0.9-2.16, p = 0.139). On univariate analysis PD-L1 expression was not significantly associated with survival outcomes. However, on multivariate analysis in patients with organ confined disease (pT2 or less, pN0/x and cM0), PD-L1 positivity was an independent prognosticator of recurrence-free survival (HR 0.2, 95% CI 0.06-0.98, p = 0.046) and overall survival (HR 0.3, 95% CI 0.11-0.63, p = 0.003). CONCLUSIONS: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and independent prognostication of worse survival outcomes. PD-L1 positivity of tumor cells was an independent prognosticator of favorable survival outcomes in cases of organ confined disease.

The Usefulness of Chest X-Rays for T1a Renal Cell Carcinoma Surveillance.

PURPOSE: The overall incidence of pulmonary metastasis of T1 renal cell carcinoma is low. We evaluated the usefulness of chest x-rays based on the current AUA (American Urological Association) guidelines and NCCN Guidelines® for T1a renal cell carcinoma surveillance. MATERIALS AND METHODS: Between 2006 and 2012, 258 patients with T1a renal cell carcinoma were treated with partial nephrectomy, radical nephrectomy or radio frequency ablation with surveillance followup at our institution. A retrospective chart review was performed to identify demographics, pathological findings and surveillance records. The primary outcome was the incidence of asymptomatic pulmonary recurrences diagnosed by chest x-ray in cases of T1a disease. Our secondary outcome was a comparison of diagnoses by treatment modality (partial nephrectomy, radical nephrectomy or radio frequency ablation). RESULTS: Pulmonary metastases developed in 3 of 258 patients (1.2%) but only 1 (0.4%) was diagnosed by standard chest x-ray surveillance. Median followup in the entire cohort was 36 months (range 6 to 152) and 193 of 258 patients (75%) had greater than 24 months of followup. A mean of 3.3 surveillance chest x-rays were completed per patient. When assessed by treatment type, there was no significant difference in the recurrence rate for partial nephrectomy (0 of 191 cases), radical nephrectomy (0 of 22) or radio frequency ablation (1 of 45 or 2.2%) (p = 0.09). CONCLUSIONS: Chest x-rays are a low yield diagnostic tool for detecting pulmonary metastasis in patients treated for T1a renal cel carcinoma. Treatment mode does not appear to influence the need for chest x-ray surveillance.

Molecular profile of urothelial carcinoma of the upper urinary tract: are pelvicalyceal and ureteral tumors different?

PURPOSE: To assess the potential biologic impact of tumor location on oncological outcomes for patients with upper tract urothelial carcinoma (UTUC), we used prospectively collected molecular signatures of high-grade UTUC. METHODS: Immunohistochemical staining for p21, p27, p53, cyclin E, and Ki-67 was prospectively performed on 96 UTUC specimens of patients with non-metastatic high-grade UTUC treated with extirpative surgery. Patients were grouped according to primary tumor location (pelvicalyceal vs. ureteral) where primary tumor was defined as the highest tumor stage and diameter. Primary outcome was assessment of differences in marker expression between groups. Secondary outcome was difference in survival according to marker status. RESULTS: Pelvicalyceal and ureteral tumors were found in 52.1 and 47.9 %, respectively, and 42.7 % of patients had non-organ-confined disease. Over a median follow-up of 22.0 months, 31.2 and 20.8 % of patients experienced disease recurrence and died of UTUC, respectively. The total number of altered markers stained for was 0-2 in 67.7 and 3-5 in 32.3 % of patients. The number of altered markers and alteration status of markers were not significantly different between patients with primary pelvicalyceal versus ureteral tumors when stratified by tumor stage and nodal status. There were no significant differences in survival outcomes between both groups when stratified by number of altered markers (0-2 and 3-5). CONCLUSIONS: The prospective assessment of selected cell cycle and proliferative markers suggests no molecular difference between UTUC of the pelvicalyceal system and that of the ureter. Our study is limited by its size and definition of location.

Multi-institutional validation of the predictive value of Ki-67 in patients with high grade urothelial carcinoma of the upper urinary tract.

PURPOSE: We validate the independent predictive value of Ki-67 in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: A total of 475 patients from the international Upper Tract Urothelial Carcinoma Collaboration who underwent extirpative surgery for high grade upper tract urothelial carcinoma were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray formed from this patient cohort. Ki-67 expression was assessed in a semiquantitative fashion and considered over expressed at a cutoff of 20%. Multivariate analyses were performed to assess independent predictors of oncologic outcomes and Harrell's C indices were calculated for predictive models. RESULTS: The median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was over expressed in 25.9% of patients. Ki-67 over expression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ and regional lymph node metastases. On Kaplan-Meier analyses over expressed Ki-67 was associated with worse recurrence-free survival (HR 12.6, p <0.001) and cancer specific survival (HR 15.8, p <0.001). On multivariate analysis Ki-67 was an independent predictor of recurrence-free survival (HR 1.6, 95% CI 1.07-2.30, p=0.021) and cancer specific survival (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved Harrell's C index from 0.66 to 0.70 (p <0.0001) for recurrence-free survival as well as cancer specific survival in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for recurrence-free survival and 0.81 to 0.83 (p=0.005) for cancer specific survival in our postoperative model. CONCLUSIONS: Ki-67 was validated as an independent predictor of recurrence-free survival and cancer specific survival in patients treated with extirpative surgery for high grade upper tract urothelial carcinoma in a large, multi-institutional cohort.

TALL score for prediction of oncological outcomes after radical nephroureterectomy for high-grade upper tract urothelial carcinoma.

PURPOSE: We created a prognostic tool for the prediction of oncologic outcomes after radical nephroureterectomy (RNU) for high-grade non-metastatic upper tract urothelial carcinoma (UTUC). METHODS: UTUC collaboration was utilized to include 586 patients who underwent RNU for non-metastatic high-grade UTUC. Survival outcomes were compared according to a score defined based on the sum of the independent prognostic variables. RESULTS: The study included 382 males with a median age 70 years (range 28-97). Independent prognostic factors included: T (t stage), A (architecture), LVI (lympho-vascular invasion) and L (lymphadenectomy). TALL score (1-7) was the sum of T (≤T1 = 1, T2 = 2, T3 = 3 and T4 = 4), A (papillary = 0 and sessile = 1), LVI (absent = 0 and present = 1) and L (lymphadenectomy = 0 and no lymphadenectomy = 1). Five-year disease-free survival (DFS) and cancer-specific survival (CSS) were stratified into four risk categories according to the TALL score: low (TALL 0-2; 86 % DFS and 90 % CSS), intermediate (TALL = 3; 71 % DFS and 75 % CSS), high (TALL = 4; 57 % DFS and 58 % CSS) and very high risk (TALL ≥ 5; 34 % DFS and 38 % CSS) using Kaplan-Meier survival analyses. TALL score was externally validated in a single-center cohort of 85 UTUC patients. CONCLUSIONS: We developed a multivariable prognostic tool for the prediction of oncological outcomes after RNU for high-grade UTUC. The score can be used for patient counseling, selection for adjuvant systemic therapies and design of clinical trials.

Prospective evaluation of plasma levels of ANGPT2, TuM2PK, and VEGF in patients with renal cell carcinoma.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Changing trends in utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer.

INTRODUCTION: To reassess use of perioperative chemotherapy in muscle-invasive bladder cancer (MIBC) following implementation of monthly multidisciplinary meetings to facilitate optimal oncologic treatment. We previously reported from 2003 to 2008 17% of eligible patients with bladder cancer received cisplatin-based neoadjuvant chemotherapy (NAC) at our institution. MATERIALS AND METHODS: A retrospective review of all patients who underwent radical cystectomy (RC) between 2008 and 2012 was performed. Information on clinical and pathologic stage, renal function, perioperative chemotherapy (CTX) use and oncologic outcomes was collected. Rationale for utilization decisions was obtained from physician encounter notes. Primary outcome was use of CTX among eligible patients. Secondary measures were type of CTX, pathologic and survival outcomes. RESULTS: Among 261 patients undergoing RC for bladder cancer, 162 were eligible for NAC. Overall 40.7% (n = 66) received NAC, and 86.4% were given platinum. Patients given NAC were younger and had more advanced clinical stage. The degree of chronic kidney disease (CKD) (0-3) did not impact likelihood of receiving NAC. NAC patients were more likely to be downstaged to non-muscle-invasive disease (21.2% versus 7.3% p < 0.01) or have a complete pathologic response (12.1% versus 3.1% p = 0.025). Receipt of NAC did not affect oncologic outcomes. Following RC 22.3% of high risk patients (n = 112) received adjuvant chemotherapy (AC). CONCLUSIONS: Our use of cisplatin-based NAC improved from 17% to 35% and overall utilization of NAC increased from 22% to 41%. NAC led to improved pT0 rates and increased pathologic downstaging. The degree of CKD (0-3) did not impact likelihood of receiving NAC. AC use decreased in part due to higher utilization of NAC.

Risk stratification of pubertal children and postpubertal adolescents with clinical stage I testicular nonseminomatous germ cell tumors.

PURPOSE: The COG (Children's Oncology Group) currently recommends surveillance for all children and adolescents with clinical stage I testicular germ cell tumors. However, up to 30% of adults with clinical stage I testicular germ cell tumors harbor occult metastatic disease. In adults with clinical stage I nonseminoma some groups advocate a risk stratified approach. Occult metastases were noted in 50% of patients with features such as lymphovascular invasion or embryonal carcinoma predominance in the orchiectomy. However, to our knowledge there are no data on the impact of high risk features in such pubertal children and postpubertal adolescents. MATERIALS AND METHODS: We reviewed an institutional testis cancer database for pubertal children and postpubertal adolescents younger than 21 years. We tested the hypothesis that lymphovascular invasion, or 40% or greater embryonal carcinoma in the orchiectomy specimen, would increase the risk of occult metastases, ie relapse during surveillance or positive nodes on retroperitoneal lymph node dissection. RESULTS: We identified 23 patients with a median age of 18.6 years (range 7.1 to 20.9) at diagnosis. Of these patients 14 (60.9%) were on surveillance, 9 (39.1%) underwent primary retroperitoneal lymph node dissection and none received initial chemotherapy. Seven patients (30.4%) had occult metastatic disease. High risk pathological features were found in the orchiectomy specimen in 12 patients (52.2%), including all 12 (52.2%) with 40% or greater embryonal carcinoma and 3 (13.0%) with lymphovascular invasion. Seven patients (58.3%) with high risk features had occult metastatic disease vs none (0%) without high risk features (log rank p = 0.031). CONCLUSIONS: Approximately half of pubertal children and postpubertal adolescents with high risk clinical stage I testicular germ cell tumors harbor occult metastatic disease. These results may be useful when discussing prognosis and treatment with patients and families.

Oncologic outcomes following surgical resection of renal cell carcinoma with inferior vena caval thrombus extending above the hepatic veins: a contemporary multicenter cohort.

PURPOSE: Suprahepatic inferior vena caval tumor thrombus in renal cell carcinoma cases has historically portended a poor prognosis. With advances in perioperative treatment of patients with high level thrombus contemporary outcomes are hypothesized to be improved. We evaluated long-term oncologic outcomes of contemporary surgical treatment of patients with renal cell carcinoma in whom level III-IV inferior vena caval thrombus was managed at high volume centers. MATERIALS AND METHODS: We examined clinical and pathological data on patients with renal cell carcinoma and level III-IV thrombus treated with surgery from January 2000 to June 2013 at 4 tertiary referral centers. Survival outcomes and associated prognostic variables were assessed by Kaplan-Meier and multivariate Cox regression analyses. RESULTS: We identified 166 patients, including 69 with level III and 97 with level IV thrombus. Median postoperative followup was 27.8 months. Patients with no evidence of nodal or distant metastasis (pN0/X, M0) had 5-year 49.0% cancer specific survival and 42.2% overall survival. There was no difference in survival based on tumor thrombus level or pathological tumor stage. Variables associated with an increased risk of death from kidney cancer on multivariate analysis were regional nodal metastases (HR 3.94, p <0.0001), systemic metastases (HR 2.39, p = 0.01), tumor grade 4 (HR 2.25, p = 0.02), histological tissue necrosis (HR 3.11, p = 0.004) and increased preoperative serum alkaline phosphatase (HR 2.30, p = 0.006). CONCLUSIONS: Contemporary surgical management achieves almost 50% 5-year survival in patients without metastasis who have renal cell carcinoma thrombus above the hepatic veins. Factors associated with increased mortality included nodal/distant metastases, advanced grade, histological necrosis and increased preoperative serum alkaline phosphatase. These findings support an aggressive surgical approach to the treatment of patients with renal cell carcinoma who have advanced tumor thrombus.

Dysregulation of ß-catenin is an independent predictor of oncologic outcomes in patients with clear cell renal cell carcinoma.

PURPOSE: Epithelial-to-mesenchymal transition is thought to have a crucial role in cancer progression and metastatic egress. We evaluated the association of ß-catenin, an important mediator of epithelial-to-mesenchymal transition, with pathological parameters and oncologic outcomes in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: Immunohistochemical staining was performed for ß-catenin on tissue microarrays of patients with nonmetastatic clear cell renal cell carcinoma. Membranous and cytoplasmic expression patterns were assessed separately. ß-Catenin was considered dysregulated if membranous as well as cytoplasmic expression was abnormal. Groups were compared based on normal vs dysregulated ß-catenin. Survival probabilities were assessed by the Kaplan-Meier method. Cox proportional hazard models were used to identify predictors of oncologic outcomes. RESULTS: Included in the study were 406 patients with a median followup of 58 months. Of the patients 52 (12.8%) and 25 (6.2%) experienced recurrence and died of clear cell renal cell carcinoma, respectively. ß-Catenin was dysregulated in 70 patients (17.2%). Dysregulation was uniformly associated with adverse pathological features, including advanced T stage, larger tumor diameter, nodal positivity, higher Fuhrman grade, tumor thrombus, sarcomatoid features, necrosis and lymphovascular invasion (each p<0.001). Patients with dysregulated ß-catenin had inferior recurrence-free and cancer specific survival (each p<0.001). On multivariate analysis adjusting for tumor stage, nodal status and grade dysregulation was an independent predictor of recurrence-free and cancer specific survival (HR 2.2, 95% CI 1.2-3.9, p=0.008 and HR 2.4, 95% CI 1.1-5.6, p=0.044, respectively). CONCLUSIONS: Dysregulation of ß-catenin may be an important phenomenon in clear cell renal cell carcinoma carcinogenesis. These findings support further study of ß-catenin, and systematic assessment of ß-catenin and epithelial-to-mesenchymal transition in clear cell renal cell carcinoma.

Prospective analysis of Ki-67 as an independent predictor of oncologic outcomes in patients with high grade upper tract urothelial carcinoma.

PURPOSE: We determined the association of the proliferation marker Ki-67 with pathological parameters and oncologic outcomes in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: Immunohistochemical staining for Ki-67 was done prospectively in 101 consecutive patients undergoing radical nephroureterectomy/ureterectomy for high grade upper tract urothelial carcinoma. Data were compared based on Ki-67 status (normal vs over expressed). Survival was assessed by the Kaplan-Meier method. Cox regression analysis was done to identify independent predictors of time dependent outcomes. RESULTS: Median patient age was 70.0 years and median followup was 22.0 months (range 1 to 77). Overall, 30.2% of the population experienced recurrence and 24.8% died of upper tract urothelial carcinoma. Organ confined disease (T2 or less and lymph node negative), lymphovascular invasion and sessile architecture were present in 56.3%, 33.3% and 20.8% of patients, respectively. Ki-67 was over expressed in 73.3% of patients and associated with adverse pathological features. Patients with over expressed Ki-67 had significantly worse recurrence-free survival (43.2 vs 69.0 months, p = 0.006) and cancer specific survival (48.9 vs 68.9 months, p = 0.031) than patients with normal Ki-67. Patients with nonmetastatic disease similarly had worse recurrence-free survival (40.7 vs 71.8 months, p = 0.003) and cancer specific survival (41 months vs not attained, p = 0.008) for over expressed vs normal Ki-67. After adjusting for the effects of organ vs nonorgan confined disease Ki-67 over expression was an independent predictor of recurrence-free survival in the total cohort (HR 4.3, p = 0.05) and in patients with nonmetastatic disease (HR 8.5, p = 0.038). CONCLUSIONS: Ki-67 over expression was associated with adverse pathological features in cases of upper tract urothelial carcinoma. It was also an independent predictor of recurrence-free survival in patients with high grade upper tract urothelial carcinoma.

Prospective comparison of molecular signatures in urothelial cancer of the bladder and the upper urinary tract--is there evidence for discordant biology?

PURPOSE: Upper tract urothelial carcinoma is rare and less well studied than bladder cancer. It remains questionable if findings in bladder cancer can safely be extrapolated to upper tract urothelial carcinoma. We prospectively evaluate molecular profiles of upper tract urothelial carcinoma and bladder cancer using a cell cycle biomarker panel. MATERIALS AND METHODS: Immunohistochemical staining for p21, p27, p53, cyclin E and Ki-67 was prospectively performed for 96 patients with upper tract urothelial carcinoma and 159 patients with bladder cancer with nonmetastatic high grade urothelial carcinoma treated with extirpative surgery. Data were compared between the groups according to pathological stage. Primary outcome was assessment of differences in marker expression. Secondary outcome was difference in survival according to marker status. RESULTS: During a median followup of 22.0 months 31.2% of patients with upper tract urothelial carcinoma and 28.3% of patients with bladder cancer had disease recurrence, and 20.8% and 27.7% died of upper tract urothelial carcinoma and bladder cancer, respectively. The number of altered markers was not significantly different between the study groups. Overall 34 patients (35.4%) with upper tract urothelial carcinoma and 62 (39.0%) with bladder cancer had an unfavorable marker score (more than 2 markers altered). There were no significant differences between upper tract urothelial carcinoma and bladder cancer in the alteration status of markers, the number of altered markers and biomarker score when substratified by pathological stage. There were no significant differences in survival outcomes between patients with upper tract urothelial carcinoma and those with bladder cancer according to the number of altered markers and biomarker score. CONCLUSIONS: Our results demonstrate the molecular similarity of upper tract urothelial carcinoma and bladder cancer in terms of cell cycle and proliferative tissue markers. These findings have important implications and support the further extrapolation of treatment paradigms established in bladder cancer to upper tract urothelial carcinoma.

Prospective evaluation of a preoperative biomarker panel for prediction of upstaging at radical cystectomy.

OBJECTIVES: To prospectively test whether a panel of biomarkers could identify patients with organ-confined disease likely to be upstaged at radical cystectomy (RC), as retrospective studies have found that cell-cycle- and proliferation-related biomarkers can help improve prognostic accuracy after RC. PATIENTS AND METHODS: We prospectively performed p53, p21, p27, Ki67, and cyclin E1 immunohistochemical staining on transurethral resection of the bladder (TURB) specimens from 87 patients treated with RC for organ-confined urothelial carcinoma of the bladder (UCB). The number of altered biomarkers was categorised as 'favourable' (≤2 altered markers) or 'unfavourable' (>2). RESULTS: Expression of p53, p21, p27, cyclin E1, and Ki67 were altered in 61 (70%), 19 (22%), 26 (30%), four (5%), and 70 (80%) patients, respectively. The median number of positive markers was two. In all, 47 (54%) patients were upstaged when T-stage was considered alone and 49 (56%) when T- and/or N-stage were considered both as upstaging. In multivariable analyses that adjusted for the effects of age, clinical stage, concomitant carcinoma in situ, and time from TURB to RC, an 'unfavourable' biomarker score was independently associated with T-stage upstaging (hazard ratio [HR] 3.3, P = 0.024) but not T- and/or N-stage upstaging (HR 2.76, P = 0.06). Addition of p27, number of positive markers, and biomarker score each increased the discrimination of a base model for prediction of T-stage upstaging (5%, 6%, and 5%, respectively) and T- and/or N-stage upstaging (4%, 6%, and 3%, respectively). CONCLUSIONS: Cell-cycle- and proliferation-related markers in the TURB specimen improve the prediction of upstaging at RC. Such a marker panel may help identify patients with non-muscle-invasive UCB who are clinically under-staged needing RC and patients with muscle-invasive UCB who are likely to be non-organ-confined thereby potentially benefiting from neoadjuvant chemotherapy.

A comparison of pediatric, adolescent, and adult testicular germ cell malignancy.

BACKGROUND: Testicular germ cell tumors (T-GCTs) occur from infancy to adulthood, and are the most common solid tumor in adolescent and young adult males. Traditionally, pediatric T-GCTs were perceived as more indolent than adult T-GCTs. However, there are few studies comparing these groups and none that specifically evaluate adolescents. METHODS: An institutional database of T-GCT patients was reviewed and patients were categorized into Pediatric, aged 0-12 years, Adolescent, aged 13-19 years, and Adult, older than 20 years, cohorts. Demographics, tumor characteristics, disease stage, treatment, event-free survival (EFS), and overall survival (OS) were compared between groups. RESULTS: Overall, 413 patients (20 pediatric, 39 adolescent, 354 adult) met study criteria and were followed for a median of 2.0 years (0.1-23.6). Adolescents presented with more advanced stage than children (P = 0.018) or adults (P = 0.008). There was a higher rate of events in Adolescents (13, 33.3%) than in Adults (61, 17.2%) or Children (2, 10.0%). Three-year EFS was 87.2% in the Pediatric group, 59.9% in Adolescents and 80.0% in Adults (P = 0.011). In a multivariate analysis, controlling for stage, IGCCCG risk, and histology, the hazard ratio (HR) for an event was: 1 (Reference) for Adults, HR = 0.82 (95% CI 0.19-3.46; P = 0.33) for the Pediatric group, and HR = 2.22 (95% CI 1.21-4.07; P = 0.01) for Adolescents. Five-year OS was 100% in the Pediatric group, 84.8% in Adolescents, and 92.8% in Adults (P = 0.388). CONCLUSION: Lower EFS in adolescent T-GCT patients was observed than in either children or adults. Elucidating factors associated with inferior outcomes in adolescents is an important focus of future research.

Preoperative pulmonary embolism does not predict poor postoperative outcomes in patients with renal cell carcinoma and venous thrombus.

PURPOSE: Patients with renal cell carcinoma who present with pulmonary embolism and venous thrombus may not be offered surgery because of presumed poor postoperative outcomes. In this multicenter study we evaluated perioperative mortality, recurrence and cancer specific survival in patients with renal cell carcinoma and venous thrombus diagnosed with preoperative pulmonary embolism. MATERIALS AND METHODS: We reviewed consecutive patient records from our 3 tertiary hospitals to identify patients with renal cell carcinoma and venous thrombus treated with surgery from 2000 to 2011. Univariate and multivariate Cox proportional hazards analysis was used to evaluate whether preoperative pulmonary embolism or other clinical variables were associated with postoperative disease recurrence or cancer specific survival. RESULTS: Pulmonary embolism was identified preoperatively in 35 of 782 patients (4.4%) with renal cell carcinoma. Those with pulmonary embolism preoperatively were more likely to have higher level thrombus and higher T stage (p <0.01). No differences were found in other clinical or pathological features between the groups. There was no difference in 90-day mortality in patients diagnosed with pulmonary embolism preoperatively. Of 395 patients without metastasis preoperatively 147 (37.2%) showed metastatic renal cell carcinoma at a median followup of 22 months. There was no difference in the recurrence rate of renal cell carcinoma in patients with pulmonary embolism (p = 0.36). Recurrence in the lung was not more common in patients with vs without pulmonary embolism preoperatively (p = 0.71). Also, preoperative pulmonary embolism was not predictive of worse cancer specific survival (p = 0.58). CONCLUSIONS: Preoperative pulmonary embolism is not associated with worse early mortality, recurrence or cancer specific survival in patients with renal cell carcinoma and tumor thrombus.

Lymphovascular invasion is independently associated with bladder cancer recurrence and survival in patients with final stage T1 disease and negative lymph nodes after radical cystectomy.

OBJECTIVE: To determine the outcomes of patients with final pathological stage T1N0 disease after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) and to determine whether lymphovascular invasion (LVI) is an independent predictor of prognosis in these patients. PATIENTS AND METHODS: Records of 958 consecutive patients who underwent RC at three academic centres were reviewed. A total of 101 patients with negative lymph nodes and with final stage (the higher of the pre-RC clinical/transurethral resection [TUR] and post-RC pathological stages) T1 UCB were identified. The median (range) follow-up was 38 (0.4-177) months and the median (range) number of nodes examined was 19 (9-80). RESULTS: Overall, 12/101 (11.9%) patients experienced cancer recurrence and 7/101 (6.9%) died from their cancer. The 3-year recurrence-free survival probability (SD) was 0.89 (0.04) and 3-year cancer-specific survival probability (SD) was 0.96 (0.02). Six of 101 (6%) patients had LVI, of whom four experienced disease recurrence and three died from bladder cancer. All recurrences and deaths occurred in patients who had either LVI and/or concomitant carcinoma in situ. On multivariable analysis, LVI (hazard ratio [HR] 4.9, P = 0.01) and higher pathological stage (HR 8.5, P = 0.04) predicted cancer recurrence and LVI (HR 6.7, P = 0.01) predicted cancer-specific survival. CONCLUSIONS: LVI helps identify patients with final pathological T1N0 UCB who are at significantly increased risk of bladder cancer recurrence and death. These patients should be considered for close monitoring after cystectomy.