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Highly sensitive and specific urinary biomarkers for the early detection of bladder cancer (BC) to improve the performance of urinary cytology are needed.To investigate the usefulness of methylation markers in voided urine to identify BC presence and grade.Using genome-wide methylation strategies in Toronto, Canada and Liège, Belgium, we have identified differentially methylated genes (TWIST1, RUNX3, GATA4, NID2, and FOXE1) in low-grade vs. high-grade BC tissue and urine. We accrued urine samples from 313 patients using a 2:1 ratio in a case-control setting from Toronto, Canada, Halifax, Canada, and Zurich, Switzerland. We studied the usefulness of these 5 methylated genes to identify BC and discriminate cancer grade in voided urine specimens. Urinary cell sediment DNA was evaluated using qPCR-based MethyLight assay. Multivariable logistic regression prediction models were created.We included 211 BC patients (180 nonmuscle invasive) and 102 controls. In univariate analyses, all methylated genes significantly predicted BC vs. no BC, and high grade vs. low grade (all P0.05). In multivariable analysis, NID2, TWIST1, and age were independent predictors of BC (all P0.05). Sensitivity of NID2 and TWIST1 to predict BC and BC grade was 76.2% and 77.6%, respectively, whereas specificity was 83.3% and 61.1%, respectively. Multivariable models predicting BC overall and discriminating between high-grade and low-grade BC reached area under the receiver operating characteristics curves of 0.89 and 0.78, respectively.This multi-centric study in a real life scenario (different countries, techniques, and pathologists) supports the promise of epigenetic urinary markers in noninvasively detecting BC. With sensitivities and specificities in the range of 80%, the overall performance characteristics of this panel of methylated genes probably does not allow such signature to significantly alter clinical care at this stage but is worth further studying for instance in BC surveillance or screening in high-risk populations.

Objectives: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort. Patients and methods: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS). Results: pT-stage was

Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer., Biomarkers of prostate cancer metastasis have been difficult to determine with confidence. Here the authors analyse mutation prevalence in 1844 prostate cancers and show that ZNRF3 loss is enriched in metastatic, castration-resistant prostate cancer and associated with metastasis of localized disease.

INTRODUCTION AND OBJECTIVE:Papillary Renal Cell Carcinomas (pRCC) are divided histologically into type 1 (pRCC1) and type 2 (pRCC2), but there are histological subtypes of pRCC that are unclassifia...

INTRODUCTION AND OBJECTIVE:Prostate cancer (PCa) incidence in Asia is among the lowest in the world, although it has grown rapidly in recent years. We investigated the impact of race [Asian (ASI) o...

INTRODUCTION AND OBJECTIVE:Lynch syndrome (LS) is an autosomal dominant disorder caused by mutations in DNA mismatch repair (MMR) genes that predisposes affected individuals to a variety of cancers...

Intraductal carcinoma and cribriform (IDC/C) tumor features are well-established prognosticators of biochemical recurrence (BCR), metastasis, and prostate cancer (PCa)-specific mortality. However, approximately 70% of PCa patients undergoing a radical prostatectomy are IDC/C negative, yet up-to 20% of these patients progress and experience BCR. Thus, tumor histopathologic characteristics such as IDC/C alone are limited in their ability to predict disease progression. Conversely, several nomograms such as Cancer of the Prostate Risk Assessment-Surgery (CAPRA-S) have been developed to aid in the prognostication of BCR, but not yet widely applied in clinical settings.In this study, we assessed the combined prognostic utility of IDC/C, and CAPRA-S for BCR in 3 PCa patient cohorts.CAPRA-S+IDC/C improved the predictive accuracy of BCR in all 3 cohorts (P.001). Specifically, among IDC/C negative cases, CAPRA-S improved the prognostication of BCR in low-risk (Cohort 1; P.001, Cohort 2; P.001, Cohort 3; P = .003), intermediate (Cohort 1; P.001, Cohort 2; P = .006, Cohort 3; P = .03) and high-risk (Cohort 1-3; P.001) patients. Conversely, IDC/C improved the prognostication of BCR among CAPRA-S low-risk (Cohorts 1; P.001 and Cohort 3; P = .003) patients.Our results suggest the investigation of histopathological IDC/C features in CAPRA-S low-risk patients and conversely, nomogram CAPRA-S among IDC/C negative patients improves the identification of patients likely to experience BCR, which would otherwise be missed through current assessment regimens. These patients can be offered more intensive monitoring and adjuvant therapies upfront to circumvent the development of recurrent cancer or overtreatment at the time of surgery.

In our study the Bladder Cancer Molecular Taxonomy Group collaborated to extend a first consensus report, addressing the need for a consensus molecular classification for muscle-invasive bladder cancer (MIBC) that would support basic research and clinical trials. We provide such a consensus classification and offer a single-sample classifier (http://cit.ligue-cancer.net:3838/apps/consensusMIBC_web).

Patients with bladder cancer who undergo intestinal urinary diversion may be at increased risk for bone fractures thought to be secondary to chronic metabolic acidosis and ensuing bone loss. Our main objective was to assess whether patients who undergo intestinal urinary diversion are at increased risk for fracture.Patients who underwent intestinal urinary diversion between 1994 and 2014 in Ontario, Canada were identified using linked administrative databases. Patients were categorized as undergoing diversion for bladder cancer or nonbladder cancer causes and matched 4:1 to a healthy cohort. We determined incidence rates of the incidence of fractures per 100 person-years. Multivariable Cox proportional hazards models were used to evaluate the impact of intestinal urinary diversion on the risk of fracture.Overall 4,301 patients with and 907 without bladder cancer underwent intestinal urinary diversion. The fracture incidence rate was significantly greater in the bladder cancer and nonbladder cancer cohorts compared to respective matched controls. In the bladder cancer cohort vs matched controls there were 4.41 vs 2.63 fractures per 100 person-years and in the nonbladder cancer cohort vs matched controls there were 5.67 vs 3.51 fractures per 100 person-years (each p0.001). On multivariable analysis patients who underwent intestinal urinary diversion for bladder cancer or nonbladder cancer reasons had significantly shorter fracture-free survival compared to the respective matched cohorts (HR 1.48, IQR 1.35-1.63, and HR 1.48, IQR 1.31-1.69, respectively).Our results demonstrated that regardless of age patients with intestinal urinary diversion are at increased risk for bone fractures compared to the general population. Our findings are in line with previous reports and support the need for bone health monitoring.

Tumor intraductal carcinoma/cribriform architecture (IDC/C) is associated with an unfavorable prognosis and biochemical recurrence (BCR) in prostate cancer (PCa). Up to 70% of PCa patients are IDC/C-negative, but it is estimated that 20% of these cases still experience BCR. Thus, biomarkers for better detection of aggressive disease in IDC/C-negative patients are required.To investigate tumor-specific methylation of the transcription factor GBX2 as a novel prognosticator and predictor of BCR in PCa patients stratified by histopathologic features including IDC/C.Using genome-wide methylome profiling, we identified higher GBX2 methylation in grade group (GG) 4 tumors compared to GG1 (discovery cohort). The prognostic nature of GBX2 methylation was validated in silico using The Cancer Genome Atlas data (n=478) and a quantitative methylation assay for radical prostatectomy samples (n=254). Regulation of GBX2 methylation was investigated in prostate cells using methyl-CpG-binding domain sequencing and methylation analysis in functional knockouts of TET2, a key epigenetic player in prostate carcinogenesis.The association of GBX2 methylation with Gleason score (GS), pathologic stage (pT), IDC/C, and BCR was analyzed using Kruskal-Wallis and Mann-Whitney tests. Univariate and multivariate Cox regression analyses were used to predict BCR.GBX2 methylation was associated with GS (p0.05), pT (p0.01), and BCR (p0.05). GBX2 methylation (p=0.004), GS (p0.001), pT (p=0.012), and prostate-specific antigen (p=0.005) were independent predictors of BCR. Among IDC/C-negative patients, GBX2 methylation improved prediction of BCR (p=0.002). Loss of TET2 in prostate cells resulted in greater GBX2 methylation.We identified GBX2 methylation as a novel prognostic factor in PCa and an independent predictor of BCR. We demonstrated the additive value of GBX2 methylation in predicting BCR among IDC/C-negative patients and elucidated a novel TET2-mediated upstream epigenetic regulatory mechanism of GBX2.We identified GBX2 methylation as a promising prognostic biomarker that could improve the identification of prostate cancer patients at higher risk of biochemical recurrence.

Urinary diversions are surgical procedures that reconstruct the lower urinary tract following cystectomy. The 2 common surgical approaches are based on the continence status of the urinary tract. Incontinent diversions have continuous urine drainage through a cutaneous stoma, whereas continent diversions offer the patient the ability to self-void either via stoma catheterization or with the patient's own urethra. Given the large number of diversion procedures available, postsurgical anatomy may be complex. Multiple imaging modalities can be used to assess the postprocedural anatomy, potential complications, and for on-going oncologic monitoring. The purpose of this review is to describe the common surgical techniques and associated complications.