Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells.

Epidemiological evidence suggests that cadmium (Cd) is one of the causative factors of prostate cancer, but the effect of Cd on benign prostatic hyperplasia (BPH) remains unclear. This study aimed to determine whether Cd exposure could malignantly transform BPH1 cells and, if so, to dissect the mechanism of action. We deciphered the molecular signaling responsible for BPH1 transformation via RNA-sequencing and determined that Cd induced the expression of zinc finger of the cerebellum 2 (ZIC2) in BPH1 cells. We noted Cd exposure increased ZIC2 expression in the Cd-transformed BPH1 cells that in turn promoted anchorage-independent spheroids and increased expression of stem cell drivers, indicating their role in stem cell renewal. Subsequent silencing of ZIC2 expression in transformed cells inhibited spheroid formation, stem cell marker expression, and tumor growth in nude mice. At the molecular level, ZIC2 interacts with the glioma-associated oncogene family (GLI) zinc finger 1 (GLI1), which activates prosurvival factors (nuclear factor NFκB, B-cell lymphoma-2 (Bcl2), as well as an X-linked inhibitor of apoptosis protein (XIAP)) signaling in Cd-exposed BPH1 cells. Conversely, overexpression of ZIC2 in BPH1 cells caused spheroid formation confirming the oncogenic function of ZIC2. ZIC2 activation and GLI1 signaling induction by Cd exposure in primary BPH cells confirmed the clinical significance of this oncogenic function. Finally, human BPH specimens had increased ZIC2 versus adjacent healthy tissues. Thus, we report direct evidence that Cd exposure induces malignant transformation of BPH via activation of ZIC2 and GLI1 signaling.

Association of Distance to Treatment Facility With Survival and Quality Outcomes After Radical Cystectomy: A Multi-Institutional Study.

BACKGROUND: We sought to determine the effect of the travel distance on mortality and quality outcomes after radical cystectomy in a large multi-institutional cohort. PATIENTS AND METHODS: A total of 3957 patients who had undergone radical cystectomy for urothelial carcinoma at 6 North American tertiary care institutions were included. The association of travel distance with quality-of-care endpoints, 90-day mortality, and long-term survival were evaluated. RESULTS: The median patient age was 69 years (interquartile range, 61-76 years), and most patients were men (80%). Most patients had clinical stage T2 (45.2%) and T1 (24.7%) tumors. The median distance to the treatment facility was 102.9 miles (interquartile range, 24-271 miles). Patients residing in the first quartile of travel distance to treatment facility (< 24 miles) had lower usage of neoadjuvant chemotherapy compared with patients in the fourth distance quartile (adjusted odds ratio, 1.58; 95% confidence interval, 1.22-2.05; P = .001). Patients in the first distance quartile were also less likely to experience a delay in time to cystectomy (> 3 months) compared with patients with a greater travel distance (adjusted odds ratio, 0.673; 95% confidence interval, 0.532-0.851). Distance to the treatment facility was not associated with 90-day mortality or cancer-specific or all-cause mortality on multivariate analysis. CONCLUSION: Despite the potential health care disparities for bladder cancer patients residing distant to a regional surgical oncology facility, the study results suggest that the travel distance is not a barrier to appropriate oncologic care at regional tertiary care centers.

Prognostic value of tissue-based biomarker signature in clear cell renal cell carcinoma.

OBJECTIVE: To improve risk stratification for recurrence prognostication in patients with localised clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: In all, 367 patients with non-metastatic ccRCC were included. The cohort was divided into a training and validation set. Using tissue microarrays, immunostaining was performed for 24 biomarkers representative of key pathways in ccRCC. Using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, we identified several markers that were used to construct a risk classifier for risk of disease recurrence. RESULTS: The median (interquartile range) follow-up was 63.5 (24.0-85.3) months. Five out of 24 markers were selected by LASSO Cox regression for the risk classifier: N-cadherin, E-cadherin, Ki67, cyclin D1 and phosphorylated eukaryotic initiation factor 4E binding protein-1 (p-4EBP1). Patients were classified as either low, intermediate or high risk of disease recurrence by tertiles of risk score. The 5-year recurrence-free survival (RFS) was 93.8%, 87.7% and 70% for patients with low-, intermediate- and high-risk scores, respectively (P < 0.001). Patients with a high marker score had worse RFS on multivariate analysis adjusted for age, gender, race and the Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score (hazard ratio 3.66, 95% confidence interval 1.58-8.49, P = 0.003 for high vs low marker score in the overall cohort). The five-marker classifier increased the concordance index of the clinical model in both the training and validation sets. CONCLUSION: We developed a five-marker-based prognostic tool that can effectively classify patients with ccRCC according to risk of disease recurrence after surgery. This tool, if prospectively validated, could provide individualised risk estimation for patients with ccRCC.

Anti-inflammatory use may not negatively impact oncologic outcomes following intravesical BCG for high-grade non-muscle-invasive bladder cancer.

PURPOSE: To evaluate whether anti-inflammatory agents affect outcomes in patients receiving intravesical BCG therapy for high-grade (HG) non-muscle-invasive bladder cancer (NMIBC). METHODS: We reviewed the records of 203 patients in a prospective database of HG NMIBC from 2006 to 2012 at a single institution. Patients who had muscle-invasive disease (n = 32), low-grade pathology (n = 4), underwent early cystectomy within 3 months (n = 25), had <3 months of follow-up (n = 11), or did not receive an induction course of intravesical BCG (n = 32) were excluded. Clinicopathologic data were tabulated including demographics, comorbidities, pathologic stage and grades, intravesical therapy, and concomitant use of aspirin, NSAIDs, COX inhibitors, and statins. Multivariate Cox regression analysis explored predictive factors for recurrence, progression (stage progression or progression to cystectomy), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Ninety-nine patients with HG NMIBC who received at least one induction course of intravesical BCG were identified, with median follow-up of 31.4 months. There were 20 (20.2 %) deaths, including 6 (6.1 %) patients with bladder cancer-related mortality. 13 % patients experienced tumor progression and 27 % underwent cystectomy following failure of intravesical therapy. Anti-inflammatory use included statins (65 %), aspirin (63 %), or non-aspirin NSAIDs/COX inhibitors (26 %). Anti-inflammatory use was not significantly predictive of recurrence, progression, or mortality outcomes on Cox regression. CIS stage was associated with higher progression, while age, BMI, and Charlson score were independent predictors of overall mortality. CONCLUSION: Despite speculation of inhibitory effects on BCG immunomodulation there was no evidence that anti-inflammatory agents impacted oncologic outcomes in patients receiving BCG for HG NMIBC.

Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer.

Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordance-index, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.

Comparing Changes in Renal Function After Radical Surgery for Upper Tract Urothelial Carcinoma and Renal Cell Carcinoma.

OBJECTIVE: To compare changes in renal function after radical nephrectomy for renal cell carcinoma (RCC) and radical nephroureterectomy for upper tract urothelial carcinoma (UTUC), and assess their effects on non-cancer-specific mortality (CSM). METHODS: Clinicopathologic data from 1114 patients with RCC or UTUC treated surgically from 1997 to 2013 were compiled. Patients who underwent nephron-sparing surgeries, had bilateral disease, received chemotherapy, or had <1 month of follow-up were excluded. Renal function (estimated glomerular filtration rate [eGFR]) was calculated preoperatively, 3 months postoperatively, and at last follow-up. Events were defined as ≥25% decline in eGFR from baseline. Event-free survival and non-CSM were assessed using Kaplan-Meier analysis. Multivariable Cox regression was performed to identify predictors of events. RESULTS: Four hundred thirty-five patients were included (317 radical nephrectomy, 118 radical nephroureterectomy). Median follow-up was 38.2 months. UTUC patients were older (P < .001), had worse Charlson score (P < .001), and more frequently used tobacco (P = .006). Median baseline eGFR was lower in UTUC patients (58.4 vs 74.9, P < .001). RCC patients experienced a larger event rate following surgery at first (56.8% vs 31.4%, P < .001) and last (51.7% vs 35.6%, P = .003) follow-up than UTUC patients. On Kaplan-Meier analysis, UTUC patients exhibited worse non-CSM (P < .001). Postsurgical decline in renal function was a significant predictor of non-CSM in RCC patients at first (hazard ratio = 4.71, P = .041) and last (hazard ratio = 4.56, P = .018) follow-up, whereas this was not the case for UTUC patients. CONCLUSION: UTUC patients had worse baseline eGFR and overall health status than RCC patients. RCC patients experienced greater postsurgical declines in renal function. These results shed light on differences in patient characteristics between these forms of kidney cancer and guide expectations for postoperative renal function.

Prognostic serum markers in patients with high-grade upper tract urothelial carcinoma.

INTRODUCTION: The role of preoperative serum-based markers in predicting survival outcomes of patients has been reported for several cancer types; however, their association with upper tract urothelial carcinoma (UTUC) prognosis is unclear. We evaluated the role of systemic serum-based markers in predicting adverse pathological features and survival outcomes in patients surgically treated for high-grade (HG) UTUC. METHODS: We retrospectively reviewed all patients undergoing surgery for HG UTUC between June 2006 and July 2013 at our institution. Comprehensive clinicopathologic data and preoperative serum-based markers including hemoglobin, white blood cell count, platelet count, serum albumin, calcium, and liver function tests were recorded. Associations of serum markers with pathologic features and recurrence-free survival (RFS) were determined by logistic and Cox regression analyses, respectively. The concordance index for the oncologic outcomes model was determined. RESULTS: In total, 101 patients were identified with a median follow-up of 18.5 months (range: 1-74mo). In all, 60% of patients had pT2 or less and 11% had nodal metastases. Preoperative elevated alkaline phosphatase (ALP) (≥116IU/l) was associated with multiple adverse pathologic features including advanced T stage, lymphovascular invasion, and histologic necrosis. On univariate analysis, serum markers independently associated with RFS included hemoglobin≤12.9 (hazards ratio [HR] = 2.51; 95% CI: 1.17-5.36, P = 0.018), albumin≤4g/dl (HR = 4.4; 95% CI: 2.04-9.30; P<0.0001), ALP≥116U/l (HR = 13.3; 95% CI: 5.3-33.52, P<0.0001), alanine transaminase≥27 (HR = 2.63, 95% CI: 1.11-6.21, P = 0.028), serum aspartate transaminase≥20 (HR = 2.21, 95% CI: 1.04-4.69, P = 0.038), and corrected calcium≥9.3 (HR = 2.45, 95% CI: 1.01-5.93, P = 0.047). The 2 strongest predictors, albumin and ALP, were combined to form an AA score (range: 0-2), which improved the baseline preoperative clinical model concordance index for prediction of RFS from 0.626 to 0.799. CONCLUSION: In HG UTUC, elevated preoperative ALP was associated with adverse pathologic features. Additionally, elevated ALP and low albumin were independently associated with worse RFS and overall survival. These serum-based markers are often measured in the preoperative workup of UTUC, and thus they can be included in future prognostic models to risk stratify patients.

Gossypiboma manifesting as urachal mass.

Gossypiboma (retained surgical sponge) occurs between 1 in 1000 and 1 in 1500 of all intra-abdominal operations. Patients with gossypibomas may present asymptomatically or with nonspecific symptoms, such as abdominal pain or bloating; identification frequently relies on imaging. Results of imaging alone, however, may appear nonspecific, and the gossypiboma may mimic other masses, such as neoplasms, hematomas, or abscesses. They require surgical removal for definitive diagnosis and treatment. Herein we present an unusual case of gossypiboma masquerading as an urachal mass in a 75-year-old woman. Diagnostic evaluation, natural history, and prevention of retained surgical materials are discussed.

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.

Statin Use and Serum Lipid Levels Are Associated With Survival Outcomes After Surgery for Renal Cell Carcinoma.

OBJECTIVE: To evaluate the association of statin use and preoperative serum lipid parameters with oncologic outcomes following surgery for renal cell carcinoma. METHODS: A total of 850 patients who underwent surgery for localized renal cell carcinoma at our institution from 2000 to 2012 were included. Use of statins, preoperative serum lipid profile, and comprehensive clinicopathologic features were retrospectively recorded. Kaplan-Meier analysis and multivariate Cox proportional hazards model were employed to compare survival outcomes. RESULTS: There were 342 statin users and 508 non-users. Median follow-up was 25.0 months. Statin users were older, had greater body mass index, and had worse performance status than non-users. Tumor pathologic characteristics were balanced between groups. Five-year recurrence free survival (RFS) was 77.9% for non-users compared with 87.6% for statin users (P = .004). After adjustment for clinicopathologic variables, statin use was independently associated with improved RFS (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.33-0.86, P = .011) and overall survival (HR 0.45, 95%CI 0.28-0.71, P = .001). In patients with available serum lipid parameters (n = 193), 5-year RFS was 83.8% for patients with triglycerides <250 mg/dL compared with 33.3% for those with triglycerides >250 mg/dL (P <.0001). Elevated serum triglycerides (>250 mg/dL) was independently associated with worse RFS (HR 2.69, 95%CI 1.22-5.93, P = .015) on multivariate analysis. CONCLUSION: Statin use was independently associated with improved survival, whereas elevated serum triglyceride levels correlated with worse oncologic outcomes in this cohort. These findings warrant validation in prospective studies.

Preoperative multivariable prognostic models for prediction of survival and major complications following surgical resection of renal cell carcinoma with suprahepatic caval tumor thrombus.

OBJECTIVE: Surgical resection for renal cell carcinoma (RCC) with suprahepatic inferior vena cava tumor thrombus is associated with significant morbidity, yet there are currently no tools for preoperative prognostic evaluation. Our goal was to develop a preoperative multivariable model for prediction of survival and risk of major complications in patients with suprahepatic thrombi. METHODS: We identified patients who underwent surgery for RCC with suprahepatic tumor thrombus extension from 2000 to 2013 at 4 tertiary centers. A Cox proportional hazard model was used for analysis of overall survival (OS) and logistic regression was used for major complications within 90 days of surgery (Clavien ≥ 3A). Nomograms were internally calibrated by bootstrap resampling method. RESULTS: A total of 49 patients with level III thrombus and 83 patients with level IV thrombus were identified. During median follow-up of 24.5 months, 80 patients (60.6%) died and 46 patients (34.8%) experienced major complication. Independent prognostic factors for OS included distant metastases at presentation (hazard ratio = 2.52, P = 0.002) and Eastern Cooperative Oncology Group (ECOG) performance status (hazard ratio = 1.84, P<0.0001). Variables associated with increased risk of major complications on univariate analysis included preoperative systemic symptoms, level IV thrombus, and elevated preoperative alkaline phosphatase and aspartate transaminase levels; however, only systemic symptoms (odds ratio = 8.45, P<0.0001) was an independent prognostic factor. Preoperative nomograms achieved a concordance index of 0.72 for OS and 0.83 for major complications. CONCLUSIONS: We have developed and internally validated multivariable preoperative models for the prediction of survival and major complications in patients with RCC who have a suprahepatic inferior vena cava thrombus. If externally validated, these tools may aid in patient selection for surgical intervention.

Decision analysis model comparing cost of multiparametric magnetic resonance imaging vs. repeat biopsy for detection of prostate cancer in men with prior negative findings on biopsy.

PURPOSE: We compared cost of multiparametric magnetic resonance imaging (MP-MRI) vs. repeat biopsy in detection of prostate cancer (PCa) in men with prior negative findings on biopsy. METHODS: A decision tree model compared the strategy of office-based transrectal ultrasound-guided biopsy (TRUS) for men with prior negative findings on biopsy with a strategy of initial MP-MRI with TRUS performed only in cases of abnormal results on imaging. Study end points were cost, number of biopsies, and cancers detected. Cost was based on Medicare reimbursement. Cost of sepsis and minor complications were incorporated into analysis. Sensitivity analyses were performed by varying model assumptions. RESULTS: The baseline model with 24% PCa found that the overall cost for 100 men was $90,400 and $87,700 for TRUS and MP-MRI arms, respectively. The MP-MRI arm resulted in 73 fewer biopsies per 100 men but detected 4 fewer cancers (16 vs. 20.4) than the TRUS arm did. A lower risk of PCa resulted in lower costs for the MP-MRI arm and a small difference in detected cancers. At lower cancer rates, MP-MRI is superior to TRUS over a wide range of sensitivity and specificity of MRI. A lower sensitivity of MP-MRI decreases the cost of the MP-MRI, as fewer biopsies are performed, but this also reduces the number of cancers detected. CONCLUSIONS: The use of MP-MRI to select patients for repeat biopsy reduced the number of biopsies needed by 73% but resulted in a few cancers being missed at lower cost when compared with the TRUS arm. Further studies are required to determine whether cancers missed represent clinically significant tumors.

Tumour and patient factors in renal cell carcinoma-towards personalized therapy.

Renal cell carcinoma (RCC) comprises a heterogeneous group of histologically and molecularly distinct tumour subtypes. Current targeted therapies have improved survival in patients with advanced disease but complete response occurs rarely, if at all. The genomic characterization of RCC is central to the development of novel targeted therapies. Large-scale studies employing multiple 'omics' platforms have led to the identification of key driver genes and commonly altered pathways. Specific molecular alterations and signatures that correlate with tumour phenotype and clinical outcome have been identified and can be harnessed for patient management and counselling. RCC seems to be a remarkably diverse malignancy with significant intratumour and intertumour genetic heterogeneity. The tumour microenvironment is increasingly recognized as a vital regulator of RCC tumour biology. Patient factors, including immune response and drug metabolism, vary widely, which can lead to widely divergent responses to drug therapy. Intratumour heterogeneity poses a significant challenge to the development of personalized therapies in RCC as a single biopsy might not accurately represent the clonal population ultimately responsible for aggressive biologic behaviour. On the other hand, the diversity of genomic alterations in RCC could also afford opportunities for targeting unique pathways based on analysis of an individual tumour's molecular composition.

Association of distance to treatment facility on quality and survival outcomes after radical cystectomy for bladder cancer.

OBJECTIVE: To examine the association of travel distance on quality and survival outcome measures for bladder cancer patients undergoing radical cystectomy for urothelial carcinoma. METHODS: Four hundred eight patients who underwent radical cystectomy for bladder cancer at a single institution from 2007 to 2013 were included. Multivariate logistic regression was used to determine the association of distance from treatment facility with 90-day mortality and quality-of-care endpoints including neoadjuvant chemotherapy use and time to cystectomy. Survival was assessed by multivariate Cox regression. RESULTS: Fifty-seven percent of patients lived within 50 miles of the treatment facility. There was no difference in time to cystectomy or the utilization of neoadjuvant chemotherapy between patients in different distance groups. On multivariate analysis, distance to treatment facility was the only predictor of 90-day mortality (odds ratio, 11.20; 95% confidence interval, 2.27-55.43; P = .003, for patients traveling >150 vs <50 miles). Although there was no difference in recurrence and cancer-specific survival between distance groups, greater distance was associated with worse overall survival on multivariate analysis (hazard ratio, 1.59; 95% confidence interval, 0.99-2.56; P = .05, for patients traveling >150 vs <50 miles). CONCLUSION: Distance to treatment facility did not impact quality measures including time to cystectomy or use of neoadjuvant chemotherapy, and there was no difference in cancer-specific mortality between distance groups. There was a detrimental association of increased travel distance with 90-day mortality, which could reflect disparities in access to care after cystectomy.

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.

Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma.

BACKGROUND: This was an external validation of the prognostic benefit of mammalian target of rapamycin (mTOR) marker panel in patients with clear cell renal cell carcinoma (ccRCC). METHODS: Immunohistochemistry for 5 mTOR pathway markers was performed on tissue microarrays of patients with nonmetastatic ccRCC treated surgically at 4 centers. The markers employed were phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), phosphorylated-mTOR (p-mTOR), phosphorylated-S6 (p-S6), and phosphorylated 4E-binding protein-1 (p-4EBP1). Cox regression was used to correlate marker status and oncologic outcomes. Discrimination of the models was determined using area under the curve and net reclassification improvement. RESULTS: Five hundred twenty-eight patients with a median follow-up of 56.5 months were included. Expression of PI3K, PTEN, p-mTOR, p-4EBP1, and p-S6 was altered in 52%, 78%, 25%, 86%, and 30% of patients, respectively. The number of altered biomarkers predicted recurrence-free survival (RFS) in multivariate analysis adjusted for stage, grade, and lymph node status (HR, 3.20; P = .02 for patients with 4-5 altered biomarkers compared with 0-1 altered markers). A biomarker panel consisting of only 2 markers (p-S6 and p-4EBP1) independently predicted for worse RFS (HR, 4.38; P = .003 for patients with 2 altered markers compared to patients with 0 altered markers). The biomarker score increased predictive accuracy when added to the clinical Cox regression model. CONCLUSIONS: m-TOR pathway biomarkers add prognostic information in addition to standard clinicopathologic variables in ccRCC patients and may identify patients who could benefit from additional treatments or closer postoperative surveillance.

Degree of hydronephrosis predicts adverse pathological features and worse oncologic outcomes in patients with high-grade urothelial carcinoma of the upper urinary tract.

OBJECTIVE: To evaluate degree of hydronephrosis (HN) as a surrogate for adverse pathological features and oncologic outcomes in patients with high-grade (HG) and low-grade (LG) upper tract urothelial carcinomas (UTUCs). METHODS: We retrospectively reviewed 141 patients with localized UTUCs that underwent extirpative surgery at a tertiary referral center. Preoperative imaging was used to evaluate presence and degree of ipsilateral HN. We evaluated degree of HN (none/mild vs. moderate/severe), pathological findings, and oncologic outcomes. RESULTS: HG UTUC was present in 113 (80%) patients, muscle-invasive disease (≥pT2) in 49 (35%), and non-organ-confined disease (≥pT3) in 41 (29%). At a median follow-up of 34 months, 49 (35%) patients experienced intravesical recurrence, 28 (20%) developed local/systemic recurrence, and 24 (17%) died of UTUC. HN was graded as none/mild in 77 (55%) patients and moderate/severe in 64 (45%). In patients with HG UTUC, but not LG, degree of HN was associated with advanced pathological stage (P<0.001), positive lymph nodes (P = 0.01), local/systemic recurrence-free survival (hazard ratio [HR] = 5.5, P = 0.02), and cancer-specific survival (HR = 5.2, P = 0.02). On multivariable analysis of preoperative factors, degree of HN in patients with HG UTUC was associated with muscle invasion (HR = 9.3; 95% CI: 3.08-28.32; P<0.001), non-organ-confined disease (HR = 4.5; 95% CI: 1.66-12.06; P = 0.003), local/systemic recurrence-free survival (HR = 2.5; 95% CI: 1.07-5.64; P = 0.04), and cancer-specific survival (HR = 2.6; 95% CI: 1.05-6.22; P = 0.04). CONCLUSIONS: Degree of HN can serve as a surrogate for advanced disease and predict worse oncologic outcomes in HG UTUC. Degree of HN was not predictive of intravesical or local/systemic recurrence in LG UTUC.