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Salvage cystectomy is required for some patients with intravesical recurrence after trimodality therapy. We compared postoperative outcomes between salvage cystectomy post-trimodality therapy, primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy.We included 265 patients who underwent radical cystectomy at Massachusetts General Hospital for cT1-T4 bladder cancer between 2003 and 2013. Patients were grouped as salvage cystectomy post-trimodality therapy, primary cystectomy or primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Early (≤90 days) and late (90 days) complications were compared. Disease-specific survival and overall survival were calculated using a Cox regression model, and adjusted survival curves were generated.The median followup from the time of cystectomy was 65.5 months. There was no difference in intraoperative and early complications between the groups. The detection of late complications was higher in salvage cystectomy post-trimodality therapy compared to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy (p=0.03). In multivariable Cox regression analysis, salvage cystectomy post-trimodality therapy was associated with a higher incidence of any late (HR 2.3, p=0.02) and major late complications (HR 2.1, p0.05). There was no difference in disease-specific survival (p=0.8) or overall survival (p=0.9) between the groups.Salvage cystectomy post-trimodality therapy for intravesical recurrence post-trimodality therapy has an intraoperative and early complication rate comparable to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Salvage cystectomy post-trimodality therapy is associated with a higher risk of overall and major late complications than primary cystectomy. The disease-specific survival and overall survival of patients who require salvage cystectomy post-trimodality therapy are comparable to both groups.

Mucinous adenocarcinoma of the urethra is extremely rare, even more so in a setting of postradiation therapy, with only 3 cases reported up to date including the first case published by our group in 2011. In the present study, we included the long-term follow-up on our previously reported case and report 3 additional cases. This is the first case series to date of this rare disease entity. The aim of this study is to review the clinicopathologic features of mucinous adenocarcinoma of the prostatic urethra in patients after receiving brachytherapy for prostatic adenocarcinoma. We identified 4 patients with a mean age of 72 years, and a mean interval of 14.8 years from brachytherapy for prostate carcinoma (grade group 1). Patients presented with hematuria or urinary retention. A colonoscopy was performed in three-fourth of patients and was within normal limits. Three patients underwent cystoprostatectomy and 1 had a transurethral resection of the prostate. On gross examination, only tumor formed a 3.5 cm tan-gray, ulcerated, friable, and necrotic mass and 2 displayed either irregular red granular or thickened areas within the prostatic urethra. Abundant extracellular mucin pools dissecting the prostatic stroma were present in all tumors, with clusters of tumor cells floating in the mucin. The mucin pools were lined by pleomorphic pseudostratified columnar mucinous epithelium. Tumors were diffusely positive for CK20, CDX2 (4/4), and AMACR (2/2); they focally expressed CK7 (2/4), and lacked nuclear β-catenin expression (3/3). PSA, PSAP, NKX3.1, p63, and GATA3 were negative in the tumors tested. Among the 3 patients who underwent radical surgery, 2 had stage 2 tumors (confined to the prostatic urethra and prostate), and 1 had a stage 3 tumor, with seminal vesicle involvement. All 4 patients were alive without disease with a mean follow-up of 4.9 years. In conclusion, brachytherapy-associated mucinous adenocarcinoma of the prostatic urethra displays intestinal-type features as its non-radiation-related counterpart. It appears to lack a villous adenoma component, displays a different immunohistochemical profile with diffuse CK20 and CDX2 positivity, and is associated with lower stage and less aggressive behavior.

Gleason grade (GG) on prostate biopsy is important for risk stratification and clinical decision making. Multiparametric MRI (mpMRI) improved detection of clinically significant disease and some studies suggest that MRI-fusion biopsy combined with systematic biopsy results in fewer upgrades on final surgical pathology. However, the downgrade rate is unclear and there is controversy in the literature. The objectives of this study are to assess the concordance of combination biopsy with final surgical pathology, and furthermore, to specifically determine downgrade rates.In our institutional mpMRI-ultrasound fusion biopsy database, 173 underwent targeted and systematic biopsy followed by radical prostatectomy (RP). GG on targeted, systematic and combination (targeted and systematic) biopsy were compared with GG on RP. Concordance rates between biopsy types were compared with the McNemar test. Proportion of GG upgrade or downgrade at the time of RP was also evaluated.Surgical pathology was concordant with 44.5% of systematic biopsies, 46.8% of targeted biopsies, and 56.7% of combination biopsies. Combination biopsy significantly overestimated the final GG on RP compared to systematic biopsy (16.8% vs. 8.7% RR 1.93, 95% CI 1.36-2.75, P0.001). Downgrade rate from unfavorable to favorable intermediate-risk disease was 46.2%, and from high-risk to intermediate-risk disease was 45.1%.Combination (targeted and systematic) biopsy is associated with the highest concordance rate between biopsy and RP pathology when compared with systematic or targeted biopsy alone. However, targeting MRI lesions and therefore the higher risk components, may at times overestimate the final surgical pathology which can result in overtreatment of what may truly be less aggressive disease.

Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor-mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1.22 to 2.27. Radiosensitization was correlated with the induction of potentially lethal DNA double-strand breaks (DSB) but not with RAD51 foci formation. The ability of olaparib to radiosensitize MIBC cells was linked to the extent of cell kill achieved with the drug alone. Unexpectedly, increased levels of reactive oxygen species (ROS) resulting from PARPi treatment were the cause of DSB throughout the cell cycle in vitro and in vivo. ROS originated from mitochondria and were required for the radiosensitizing effects of olaparib. Consistent with the role of TP53 in ROS regulation, loss of p53 function enhanced radiosensitization by olaparib in non-isogenic and isogenic cell line models and was associated with increased PARP-1 expression in bladder cancer cell lines and tumors. Impairment of ATM in addition to p53 loss resulted in an even more pronounced radiosensitization. In conclusion, ROS suppression by PARP-1 in MIBC is a potential therapeutic target either for PARPi combined with radiation or drug alone treatment. The TP53 and ATM genes, commonly mutated in MIBC and other cancers, are candidate biomarkers of PARPi-mediated radiosensitization.

Background Trimodality bladder-sparing therapy (TMT) is an acceptable treatment for selected patients with muscle-invasive urothelial cancer. Outcomes of TMT in histologic variants remains largely unknown. Objective To compare outcomes of pure urothelial carcinoma (PUC) to variant urothelial carcinoma (VUC) after TMT. Design, setting, and participants Retrospective study of patients treated with TMT at a single cancer center from 1993 until 2013. Outcome measurements and statistical analysis Kaplan-Meier survival probabilities, and univariate and multivariable Cox regression analysis. Results and limitations Of 303 patients treated with TMT, 66 (22%) had VUC. Fifty (76%) had VUC with squamous and/or glandular differentiation and 16 (24%) had other forms. Complete response rate after induction TMT was 83% in PUC and 82% in VUC ( p =0.9). The 5-yr and 10-yr disease-specific survival (DSS) was 75% and 67% in PUC versus 64% and 64% in VUC. The 5-yr and 10-yr overall survival (OS) was 61% and 42% in PUC versus 52% and 42% in VUC. On multivariable analysis VUC was not associated with DSS (hazard ratio: 1.3, 95% confidence interval: 0.8–2.2, p =0.3) or OS (hazard ratio: 1.2, 95% confidence interval: 0.8–1.7, p =0.4). Salvage cystectomy rates were similar (log-rank p =0.3). Limitations include retrospective design and restriction to variants of urothelial cancer. Conclusions VUC responded to TMT, and there was no significant difference in complete response, OS, DSS, or salvage cystectomy rates compared with PUC. The presence of VUC should not exclude patients from TMT. Patient summary The response of histologic variants of bladder cancer to bladder-sparing chemoradiation is largely unknown. We compared the outcomes of histologic variants of urothelial cancer to pure urothelial cancer in a large series of patients from a single institution. We found that variant histology does not significantly influence outcomes.

Background Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC). Objective Report long-term outcomes of patients with MIBC treated by TMT. Design, setting, and participants Four hundred and seventy-five patients with cT2–T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013. Intervention Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy. Outcome measurements and statistical analysis Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results and limitations Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44–0.75, DSS HR: 0.51, 95% CI: 0.36–0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46–0.81, DSS HR: 0.49, 95% CI: 0.34–0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17–2.08, DSS HR: 1.50, 95% CI: 1.03–2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986–1995 to 2005–2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%. Conclusions These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients. Patient summary Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation.

Little is known regarding the subclone evolution process in advanced bladder cancer, particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic bladder cancer through mRNA expression profiling of RNA isolated from 33 primary bladder cancer and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary bladder cancer compared with LN metastasis samples. To elucidate its function in bladder cancer, loss- and gain-of-function experiments were conducted in bladder cancer cell lines with high and low expression of TCF21, respectively. We also performed GEP in bladder cancer cell lines following TCF21 overexpression. We identified 2,390 genes differentially expressed in primary bladder cancer and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared with LN metastasis. We validated this finding with qPCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination, and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal bladder cancer cell lines decreased their invasive and metastatic potential. Implications: TCF21 is differentially overexpressed in primary bladder cancer compared with matched LN metastasis, with in vitro and in vivo studies demonstrating a metastasis suppressor function of this transcription factor.

There exists a growing debate as to whether multiparametric magnetic resonance imaging with fusion transrectal ultrasound guided prostate biopsy alone without a standard template biopsy is sufficient to evaluate patients with suspected prostate cancer. Our objective was to describe our experience with fusion targeted prostate biopsy and assess whether it could obviate the need for concomitant standard 12-core template prostate biopsy.We retrospectively reviewed our prospectively collected database of patients who underwent fusion transrectal ultrasound guided prostate biopsy. All images and lesions were graded according to the Prostate Imaging Reporting and Data System, version 2. All patients underwent targeted biopsy followed by standard 12-core double sextant biopsy within the same session. Clinically significant prostate cancer was defined as Grade Group 2 or greater prostate cancer.A total of 506 patients were included in analysis. Indications were elevated prostate specific antigen with a previous negative prostate biopsy in 46% of cases, prostate cancer on active surveillance in 35%, elevated prostate specific antigen without a prior prostate biopsy in 15% and an isolated abnormal digital rectal examination in 3%. For standard vs fusion prostate biopsy the overall cancer detection rate was 57.7% vs 54.0% (p=0.12) and the clinically significant prostate cancer detection rate was 24.7% vs 30.8% (p=0.001). Of the 185 patients diagnosed with clinically significant prostate cancer 29 (16%) would have been missed if only targeted fusion prostate biopsy had been performed.Fusion targeted prostate biopsy is associated with a higher detection rate of clinically significant prostate cancer compared to standard double sextant biopsy. However, standard double sextant biopsy should still be performed as part of the routine fusion targeted prostate biopsy procedure to avoid missing a significant proportion of clinically significant prostate cancer.

222 Background: Active surveillance (AS) is an accepted management strategy for men with very low, low, and select cases of favorable intermediate National Comprehensive Cancer Network (NCCN) risk prostate cancer (PCa). However, how patients’ risk of disease progression evolves over time during AS has not been well defined. Conditional survival measures the probability a patient will continue to survive some number of years, given that they have already survived a certain number without progression. We evaluated our AS cohort to investigate overall and conditional progression free survival on AS, stratified by the NCCN risk groups. Methods: We reviewed our institutional database of 1254 men enrolled in AS for localized PCa from 1996-2016. Our AS protocol includes prostate specific antigen (PSA) and digital rectal exam (DRE) every 4-6 months for 3 years, then annually. Mandatory confirmatory 12 core biopsy is done at 12-18 months. Multiparametric magnetic resonance imagining (mpMRI) or additional systematic or MRI-fusion biopsies are done at the discretion of physician and patient. Overall freedom from pathologic grade progression on follow-up biopsy and treatment free survival were estimated using the Kaplan-Meier method. Survival curves were compared pairwise using the Log-rank test and adjusted for false discovery rates with the Benjamini-Hochberg procedure. Three-year conditional survival estimates were derived for both outcomes from the Kaplan-Meier estimator. Results: Of 1254 men, 521 (41.6%) met criteria for very low, 606 (48.4%) for low, and 125 (10.0%) for favorable intermediate NCCN risk at diagnosis. Median follow-up time was 6.5 years (IQR 4.1-9.4). Median pathologic grade progression free survival in years was significantly longer for very low risk (7.8, 95% CI 6.8-11.2) compared to low risk men (5.6, 95% CI 4.7-6.9), however neither was significantly different from favorable intermediate risk men (5.9). There was no significant difference in treatment free survival between the three risk groups. At diagnosis, the three-year risk for pathologic grade progression (24%, 95% CI 21-27%) and progression to treatment (22%, 95% CI 20-25%) were similar. However, with increasing time of event-free AS, the conditional probability of pathologic grade progression increased, while that of progression to treatment decreased. Conclusions: Our results demonstrate that despite a mild increase in pathologic progression free survival in very low risk men, there was no clear difference in overall treatment free survival between very low, low, and select favorable intermediate NCCN risk men. Further, with increased time spent on AS, despite elevated rates of pathologic progression, patient progression to treatment decreased. This trend may be indicative of changes in goals of care as men with PCa age and should be closely monitored during AS.

We describe the incidence, clinicopathological risk factors, management and outcomes of recurrent nonmuscle invasive bladder cancer after a complete response to trimodality therapy of muscle invasive bladder cancer.We retrospectively reviewed the records of 342 patients with cT2-4aN0M0 muscle invasive bladder cancer and a complete response after trimodality therapy from 1986 to 2013. Using competing risks analyses we examined the association between baseline clinicopathological variables and nonmuscle invasive bladder cancer outcomes. Kaplan-Meier and the generalized Fleming-Harrington test were used to compare disease specific and overall survival.At a median followup of 9 years nonmuscle invasive bladder cancer recurred in 85 patients (25%) who had had a complete response. On Kaplan-Meier analysis baseline carcinoma in situ was associated with recurrent nonmuscle invasive bladder cancer (p = 0.02). However, on multivariate analysis carcinoma in situ and other baseline clinicopathological characteristics did not predict such recurrence. Patients with recurrent nonmuscle invasive bladder cancer had worse 10-year disease specific survival than those without recurrence (72.1% vs 78.4%, p = 0.002), although overall survival was similar (p = 0.66). Of the 39 patients (46%) who received adjuvant intravesical bacillus Calmette-Guérin 29 (74%) completed induction therapy and 19 (49%) reported bacillus Calmette-Guérin toxicity. Three-year recurrence-free and progression-free survival after induction bacillus Calmette-Guérin was 59% and 63%, respectively.After a complete response to trimodality therapy nonmuscle invasive bladder cancer recurred in 25% of patients, developing in some of them more than a decade after trimodality therapy. No baseline clinicopathological characteristics were associated with such recurrence after a complete response. Patients with nonmuscle invasive bladder cancer recurrence had worse disease specific survival than those without such recurrence but similar overall survival. Adjuvant intravesical bacillus Calmette-Guérin had a reasonable toxicity profile and efficacy in this population. Properly selected patients with recurrent nonmuscle invasive bladder cancer after a complete response may avoid immediate salvage cystectomy.

Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic "recycling" technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC's) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFβ pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL.

93 Background: Multiparametric MRI is increasingly used in prostate cancer detection. Previous studies have shown that detection rate of clinically significant cancer is higher in MRI targeted biopsy than systematic biopsy. However, the concordance between the Gleason score on fusion biopsy and radical prostatectomy is less well known. The objective of this study is to look for predictors of histopathologic concordance between biopsy (fusion and systematic) and radical prostatectomy. Methods: We used an institutional database of men who underwent mpMRI-ultrasound fusion targeted and systematic biopsy followed by radical prostatectomy. Gleason score on targeted, systematic and combination (targeted + systematic) biopsy were compared with Gleason score on radical prostatectomy, and concordance was recorded. The McNemar test was used to compare concordance and upgrade rates. Predictors of concordance and upgrade such as age, prostate volume, PSA, PSA density, Gleason score on biopsy, number of targets reported on mpMRI, and PI-RADS score were evaluated with Fisher’s exact test and logistic regression. Results: Surgical pathology was concordant with 47.4% of systematic biopsies, 52.0% of targeted biopsies and 58.4% of combination biopsies. There was no significant difference in concordance rates between systematic and targeted biopsy (P = 0.37). However, combination biopsy was superior to both systematic (RR 1.23, 95% CI 1.08-1.40, P = 0.03) and targeted biopsy (RR 1.12, 95% CI 1.02 – 1.24, P = 0.03) in predicting concordance with surgical pathology. Risk of upgrade to a higher Gleason score on surgical pathology was significantly lower with combination biopsy compared to systematic (RR 0.57, 95% CI 0.46-0.69, P < 0.001) or targeted biopsy alone (RR 0.72, 95% CI 0.61-0.84, P = 0.001). Upgrade rates were 43.9% for systematic biopsy, 34.7% for targeted, and 24.9% for combination. Lastly, we found no significant predictors of concordance or upgrade. Conclusions: Combination biopsy is associated with the highest concordance rate between biopsy and radical prostatectomy when compared with systematic or targeted biopsy alone. Performing targeted biopsy alone will underestimate tumour aggressiveness on surgical pathology.

Bladder cancer (BC) is a burdensome disease with significant morbidity, mortality, and cost. The development of novel plasma-based biomarkers for BC diagnosis and surveillance could significantly improve clinical outcomes and decrease health expenditures. Plasma miRNAs are promising biomarkers that have yet to be rigorously investigated in BC.To determine the feasibility and efficacy of detecting BC with plasma miRNA signatures.Plasma miRNA was isolated from 20 patients with bladder cancer and 18 noncancerous controls. Samples were analyzed with a miRNA array containing duplicate probes for each miRNA in the Sanger database. Logistic regression modeling was used to optimize diagnostic miRNA signatures to distinguish between muscle invasive BC (MIBC), non-muscle-invasive BC (NMIBC) and noncancerous controls.Seventy-nine differentially expressed plasma miRNAs (local false discovery rate [FDR]0.5) in patients with or without BC were identified. Some diagnostically relevant miRNAs, such as miR-200b, were up-regulated in MIBC patients, whereas others, such as miR-92 and miR-33, were inversely correlated with advanced clinical stage, supporting the notion that miRNAs released in the circulation have a variety of cellular origins. Logistic regression modeling was able to predict diagnosis with 89% accuracy for detecting the presence or absence of BC, 92% accuracy for distinguishing invasive BC from other cases, 100% accuracy for distinguishing MIBC from controls, and 79% accuracy for three-way classification between MIBC, NIMBC, and controls.This study provides preliminary data supporting the use of plasma miRNAs as a noninvasive means of BC detection. Future studies will be required to further specify the optimal plasma miRNA signature, and to apply these signatures to clinical scenarios, such as initial BC detection and BC surveillance.

Changes in health-related quality of life following the diagnosis and treatment of patients with non-muscle-invasive bladder cancer (NMIBC) remain poorly understood. A new study suggests that diagnosis and treatment of NMIBC might affect mental health as well as sexual, urinary and bowel function.

Purpose: A phase I trial of intravesical recombinant adenovirus mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guerin. The primary objective was to determine the safety of rAd-IFNα/Syn3. Secondary end points were demonstrated effective rAd-IFNα gene expression and preliminary evidence of clinical activity at 3 months.Materials and Methods: A total of 17 patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guerin treatment were enrolled in the study. A single treatment of rAd-IFNα (3 × 109 to 3 × 1011 particles per ml) formulated with the excipient Syn3 was administered. Patient safety was evaluated for 12 or more weeks. Efficacy of gene transfer was determined by urine IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months.Results: Intravesical rAd-IFNα/Syn3 was well tolerated as no...

Epithelial-mesenchymal transition (EMT) is a physiological process that plays important roles in tumor metastasis, "stemness," and drug resistance. EMT is typically characterized by the loss of the epithelial marker E-cadherin and increased expression of EMT-associated transcriptional repressors, including ZEB1 and ZEB2. The miR-200 family and miR-205 prevent EMT through suppression of ZEB1/2. p53 has been implicated in the regulation of miR-200c, but the mechanisms controlling miR-205 expression remain elusive. Here we report that the p53 family member and p63 isoform, ΔNp63α, promotes miR-205 transcription and controls EMT in human bladder cancer cells. ΔNp63α, E-cadherin and miR-205 were coexpressed in a panel of bladder cancer cell lines (n = 28) and a cohort of primary bladder tumors (n = 98). Stable knockdown of ΔNp63α in the "epithelial" bladder cancer cell line UM-UC6 decreased the expression of miR-205 and induced the expression of ZEB1/2, effects that were reversed by expression of exogenous miR-205. Conversely, overexpression of ΔNp63α in the "mesenchymal" bladder cancer cell line UM-UC3 induced miR-205 and suppressed ZEB1/2. ΔNp63α knockdown reduced the expression of the primary and mature forms of miR-205 and the miR-205 "host" gene (miR-205HG) and decreased binding of RNA Pol II to the miR-205HG promoter, inhibiting miR-205HG transcription. Finally, high miR-205 expression was associated with adverse clinical outcomes in bladder cancer patients. Together, our data demonstrate that ΔNp63α-mediated expression of miR-205 contributes to the regulation of EMT in bladder cancer cells and identify miR-205 as a molecular marker of the lethal subset of human bladder cancers.

Objective • To compare outcomes of hilar clamping and non-hilar clamping partial nephrectomy for tumours involving a solitary functional kidney. Patients and methods • Between 1990 and 2009, 104 partial nephrectomies, excluding bench and autotransplant procedures, were performed on solitary functional kidneys. • An institutional review board-approved retrospective review was performed analyzing patient demographics, operative data, complications, oncological outcomes and estimated glomerular filtration rate (GFR). • GFR was calculated using the abbreviated Modification of Diet in Renal Disease equation. • Preoperative GFR was compared to Early GFR (lowest measured GFR 7-100 days postoperatively) and to Late GFR (GFR 101-365 days postoperatively). • Multiple linear regression analysis was performed to assess covariates affecting Late GFR. • Kaplan-Meier estimator was utilized to compare renal cell carcinoma (RCC) specific survival and non-RCC-related survival. Results • In total, 29 partial nephrectomies with hilar clamping and 75 partial nephrectomies without hilar clamping were performed in solitary kidneys. Median follow-up was 57 months. • There was no difference in tumour size, location and the number of tumours resected between the two groups. Mean ischaemia time for the clamping group was 25 min. • Some 97% of the clamping procedures were performed with cold ischaemia. • There was no difference in intra-operative estimated blood loss, transfusion requirement or length of hospital stay. • The complication rate and spectrum of complications were similar between the two groups. • The two groups had similar preoperative GFR and Early GFR. The non-clamping group had a significantly smaller percent decrease in Late GFR (11.8% vs 27.7%, P= 0.01) than the clamping group. • The non-clamping group was significantly more likely to have a less than 10% decrease in Late GFR compared to the clamping group (60.9% vs 17.7%, P= 0.002). • On multivariate analysis, only hilar clamping was significantly associated with decreased Late GFR (estimate 15.0, P= 0.02). • Surgical margin positivity rate was higher in the clamping group (21% vs 4%, P= 0.01); however, the local recurrence rate between the two groups was similar. • The clamping and non-clamping groups had similar 5-year RCC-specific survival and 5-year non-RCC-related survival. Conclusions • Partial nephrectomy without hilar clamping in solitary kidneys provides similar cancer control compared to partial nephrectomy with hilar clamping. • Partial nephrectomy without clamping was associated with superior preservation of Late GFR. • No difference was detected in GFR early after surgery, possibly indicating that there may be ongoing renal loss after hilar clamping.

What’s known on the subject? and What does the study add? Epithelial-mesenchymal transition (EMT) is involved in tumor progression where the underlying cellular changes associated with EMT have been identified in in vitro models and confirmed in a limited number of in vivo studies. ZEB1, which targets E-cadherin repression, is a transcriptional regulator that has been implicated in EMT, and is associated with uterine and colorectal cancers. Regulation of ZEB1 expression has been shown to involve different microRNAs (miRNAs), identifying a potential role for miRNA in EMT. In the present study we have identified novel expression of ZEB1 in bladder tumours and shown a role for ZEB1 in enhanced migration and invasion potential in in vitro assays. Confirmation of ZEB1 expression in bladder tumours was shown in tissue microarrays (TMAs). OBJECTIVE To evaluate ZEB1 expression in bladder tumorigenesis and define a possible role for this transcription factor in urothelial carcinomas of the bladder (UCBs). MATERIALS and METHODS Five hundred and fifty-eight samples were assembled in 10 tissue microarrays (TMAs; 263 non-muscle-invasive Ta/T1/Tis, 295 muscle-invasive T2–T4). All tumours were transitional cell carcinomas (TCCs) and processed for immunohistochemistry to assess nuclear ZEB1 expression. Expression levels of ZEB1 were modulated in bladder carcinoma cell lines CUBIII or UM-UC-3 after forced expression or shRNA knockdown, respectively. Protein expression levels were determined using western blot analysis and transfectants were assessed for migration and invasion potential in standard in vitro assays. RESULTS Nuclear ZEB1 expression was recorded in 22.8% of non-muscle-invasive UCBs and 21.7% of muscle-invasive UCBs, including 24.1% grade I/II and 21.1% grade III tumours, and absent in normal bladder mucosa. No significant correlation was observed for tumour stage and grade, nodal involvement, vascular invasion, metastasis and overall or cancer-specific survival. The introduction or knockdown of ZEB1 expression in bladder carcinoma cell lines showed enhanced or reduced migration and invasive potential, respectively. Changes in ZEB1 expression were accompanied by altered microRNA (miRNA) expression underlying events linked to epithelial–mesenchymal transition (EMT). CONCLUSION The results in the present study showed novel expression of ZEB1 in bladder cancer in the absence of a link to clinical variables of change, including metastasis and survival. However, in vitro assays showed enhanced or reduced migration and invasion after the introduction or reduction of ZEB1, respectively, in transfected bladder cell lines. Modulation in expression of ZEB1 was closely linked to changes in the miR-200 family along with alternative known prognostic indicators of bladder tumour progression.

Given the steadily growing cancer survivor population, increasing pressure has been placed on more effective clinical approaches and biomarker assays to manage care. For bladder cancer despite the high probability of recurrence the number of patients with recurrent disease is significantly lower than the number that remains cancer free at any monitoring interval. We developed a noninvasive urine assay using a novel approach to identify patients without recurrent cancer with extremely high confidence.Previous studies show that matrix metalloproteinases are increased in the urine of patients with cancer compared to that in disease-free individuals. To determine the clinical usefulness of these markers as monitors for bladder cancer recurrence we measured and compared metalloproteinase-2, metalloproteinase-9 and metalloproteinase-9/neutrophil gelatinase-associated lipocalin by enzyme-linked immunosorbent assay and zymography in a set of 530 samples, including 84 samples from patients with bladder cancer.Initial studies using urine metalloproteinase to discriminate disease-free patients from those with bladder cancer resulted in 80% sensitivity (67 of 84) and 71% specificity (318 of 446) for metalloproteinase-9. By applying our novel Clinical Intervention Determining Diagnostic() clinical approach to metalloproteinase-9 we correctly identified 42% of cases that were cystoscopy negative with 98% negative predictive value.A noninvasive urine diagnostic assay that uses metalloproteinases with the Clinical Intervention Determining Diagnostic could lead to more efficient treatment in bladder cancer survivors by decreasing the number of negative cystoscopies (42%), allowing physicians to more selectively monitor those at high risk.

Surgical resection of renal cell carcinoma remains the mainstay for the management of patients who suffer from this disease. Five percent to 10% of renal cell carcinomas develop a tumor thrombus that propagates into the renal vein or the inferior vena cava. Radical nephrectomy and inferior vena cava thrombectomy can provide longstanding survival rates comparable to those for tumors confined to the renal parenchyma. In general the surgical approach is dictated by the cephalad extension of tumor thrombus. This article reviews the authors' experience with 243 patients who suffered from renal cell carcinoma with extension into the venous system with specific reference to the surgical techniques and the long-term outcomes.

total and fatal pathology-confirmed RCC by BMI immediately prior to diagnosis. Models were adjusted for diabetes, hypertension, smoking, alcohol intake, NSAID use, physical activity, and parity in women. Results from the two cohorts were pooled using random effects metaanalysis. RESULTS: We confirmed 351 cases of RCC, including 105 fatal cases, in NHS, and 225 cases in HPFS, with 49 fatal cases. Compared to women with normal BMI (18.5-24.9 kg/m2) immediately prior to diagnosis, obese women (BMI 30) had a non-significantly increased risk of RCC (HR 1.29, 95% CI: 0.97-1.72, p-trend1⁄40.04), adjusting for possible confounders. The HR for fatal RCC was similar (HR 1.30, 95% CI: 0.77-2.20, p-trend1⁄40.50). Obese men had a nonsignificantly increased risk of RCC (HR 1.44, 95% CI: 0.95-2.19, ptrend1⁄40.08), with a significantly increased risk of fatal RCC (HR 2.48, 95% CI: 1.08-5.72, p-trend1⁄40.16). There was no evidence of significant differences in the associations by sex. The pooled HRs for total RCC incidence were 1.21 (95% CI: 0.99-1.47) for overweight and 1.34 (95% CI: 1.05-1.69) for obese compared to normal weight, p-trend1⁄40.007. For fatal RCC, the pooled HRs were 1.11 (95% CI: 0.75-1.63) for overweight and 1.65 (0.95% CI: 0.90-3.04) for obese, p-trend1⁄40.18. CONCLUSIONS: Our results support that obesity is a risk factor for RCC incidence. Associations for fatal RCC were similar in magnitude to those for total RCC, though not statistically significant, suggesting that obesity is also adversely associated with risk of fatal RCC.

PurposeWe evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy.Materials and methodsWe identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings.ResultsWe identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p

Open partial nephrectomy is a challenging operation that requires complete tumor resection with a negative margin and maximal preservation of functioning renal parenchyma with the aim of maximizing cancer-specific survival and minimizing postoperative chronic kidney disease, morbidity, and mortality. This chapter will provide a detailed discussion of the rationale for PN as well as its current indications. The importance of minimizing renal ischemia and other predictors of postoperative CKD will be discussed. The techniques of open PN will be described.

Epithelial-mesenchymal transition (EMT) is a physiological process that plays important roles in tumor metastasis, "stemness," and drug resistance. EMT is typically characterized by the loss of the epithelial marker E-cadherin and increased expression of EMT-associated transcriptional repressors, including ZEB1 and ZEB2. The miR-200 family and miR-205 prevent EMT through suppression of ZEB1/2. p53 has been implicated in the regulation of miR-200c, but the mechanisms controlling miR-205 expression remain elusive. Here we report that the p53 family member and p63 isoform, ΔNp63α, promotes miR-205 transcription and controls EMT in human bladder cancer cells. ΔNp63α, E-cadherin and miR-205 were coexpressed in a panel of bladder cancer cell lines (n = 28) and a cohort of primary bladder tumors (n = 98). Stable knockdown of ΔNp63α in the "epithelial" bladder cancer cell line UM-UC6 decreased the expression of miR-205 and induced the expression of ZEB1/2, effects that were reversed by expression of exogenous miR-205. Conversely, overexpression of ΔNp63α in the "mesenchymal" bladder cancer cell line UM-UC3 induced miR-205 and suppressed ZEB1/2. ΔNp63α knockdown reduced the expression of the primary and mature forms of miR-205 and the miR-205 "host" gene (miR-205HG) and decreased binding of RNA Pol II to the miR-205HG promoter, inhibiting miR-205HG transcription. Finally, high miR-205 expression was associated with adverse clinical outcomes in bladder cancer patients. Together, our data demonstrate that ΔNp63α-mediated expression of miR-205 contributes to the regulation of EMT in bladder cancer cells and identify miR-205 as a molecular marker of the lethal subset of human bladder cancers.

To evaluate the role of laparoscopy for the detection and management of early postoperative complications after minimally invasive urologic surgery.From October 2003 to September 2008, data were prospectively collected for all patients needing surgical intervention within 21 days after urologic minimally invasive procedures. No patients operated on for a postoperative complication during this period were excluded. Minimally invasive surgical intervention was performed on all hemodynamically stable patients in whom pneumoperitoneum could be established safely.A total of 1962 laparoscopic or robot-assisted urologic procedures were performed. In 14 (0.7%) cases, surgical intervention was necessary for postoperative complications. Two patients underwent exploratory laparotomy because of abdominal distention and hemodynamic instability. Laparoscopic surgical intervention successfully diagnosed and treated the remaining 12 patients. There were no conversions to open surgery. No additional trocars were necessary apart from preexisting sites. Two (14%) patients had minor postexploration complications. Mean estimated blood loss was 70 mL (range 50-100 mL). The mean length of hospital stay after exploration was 2 days (range 5 hours-5 days).With surgical expertise, laparoscopic treatment of intra-abdominal complications after minimally invasive urologic procedures can be successfully and safely performed. The advantages of the minimally invasive approach may be preserved.

Ischemia-reperfusion injury caused by vascular clamping contributes to the decline in glomerular filtration rate following partial nephrectomy. Ischemia is the main modifiable factor that determines postoperative kidney function, and it is likely that a harmless duration of ischemia does not exist. Each additional minute of warm ischemia increases the odds of acute renal failure, severe chronic kidney disease (CKD) and end-stage renal disease. Our experience comparing partial nephrectomy with and without clamping in solitary kidneys suggests that renovascular clamping is the only statistically significant determinant of postoperative renal dysfunction. Studies comparing partial nephrectomy with and without clamping demonstrate that ischemia is associated with a risk of acute renal failure, advanced CKD, and renal replacement therapy. Oncologic outcomes and complications in partial nephrectomy without clamping are similar to those with clamping. Even in complex lesions, partial nephrectomy without vascular clamping is preferable when feasible.

• To compare outcomes of hilar clamping and non-hilar clamping partial nephrectomy for tumours involving a solitary functional kidney.• Between 1990 and 2009, 104 partial nephrectomies, excluding bench and autotransplant procedures, were performed on solitary functional kidneys. • An institutional review board-approved retrospective review was performed analyzing patient demographics, operative data, complications, oncological outcomes and estimated glomerular filtration rate (GFR). • GFR was calculated using the abbreviated Modification of Diet in Renal Disease equation. • Preoperative GFR was compared to Early GFR (lowest measured GFR 7-100 days postoperatively) and to Late GFR (GFR 101-365 days postoperatively). • Multiple linear regression analysis was performed to assess covariates affecting Late GFR. • Kaplan-Meier estimator was utilized to compare renal cell carcinoma (RCC) specific survival and non-RCC-related survival.• In total, 29 partial nephrectomies with hilar clamping and 75 partial nephrectomies without hilar clamping were performed in solitary kidneys. Median follow-up was 57 months. • There was no difference in tumour size, location and the number of tumours resected between the two groups. Mean ischaemia time for the clamping group was 25 min. • Some 97% of the clamping procedures were performed with cold ischaemia. • There was no difference in intra-operative estimated blood loss, transfusion requirement or length of hospital stay. • The complication rate and spectrum of complications were similar between the two groups. • The two groups had similar preoperative GFR and Early GFR. The non-clamping group had a significantly smaller percent decrease in Late GFR (11.8% vs 27.7%, P= 0.01) than the clamping group. • The non-clamping group was significantly more likely to have a less than 10% decrease in Late GFR compared to the clamping group (60.9% vs 17.7%, P= 0.002). • On multivariate analysis, only hilar clamping was significantly associated with decreased Late GFR (estimate 15.0, P= 0.02). • Surgical margin positivity rate was higher in the clamping group (21% vs 4%, P= 0.01); however, the local recurrence rate between the two groups was similar. • The clamping and non-clamping groups had similar 5-year RCC-specific survival and 5-year non-RCC-related survival.• Partial nephrectomy without hilar clamping in solitary kidneys provides similar cancer control compared to partial nephrectomy with hilar clamping. • Partial nephrectomy without clamping was associated with superior preservation of Late GFR. • No difference was detected in GFR early after surgery, possibly indicating that there may be ongoing renal loss after hilar clamping.

What's known on the subject? and What does the study add? Epithelial-mesenchymal transition (EMT) is involved in tumor progression where the underlying cellular changes associated with EMT have been identified in in vitro models and confirmed in a limited number of in vivo studies. ZEB1, which targets E-cadherin repression, is a transcriptional regulator that has been implicated in EMT, and is associated with uterine and colorectal cancers. Regulation of ZEB1 expression has been shown to involve different microRNAs (miRNAs), identifying a potential role for miRNA in EMT. In the present study we have identified novel expression of ZEB1 in bladder tumours and shown a role for ZEB1 in enhanced migration and invasion potential in in vitro assays. Confirmation of ZEB1 expression in bladder tumours was shown in tissue microarrays (TMAs).To evaluate ZEB1 expression in bladder tumorigenesis and define a possible role for this transcription factor in urothelial carcinomas of the bladder (UCBs).Five hundred and fifty-eight samples were assembled in 10 tissue microarrays (TMAs; 263 non-muscle-invasive Ta/T1/Tis, 295 muscle-invasive T2-T4). All tumours were transitional cell carcinomas (TCCs) and processed for immunohistochemistry to assess nuclear ZEB1 expression. Expression levels of ZEB1 were modulated in bladder carcinoma cell lines CUBIII or UM-UC-3 after forced expression or shRNA knockdown, respectively. Protein expression levels were determined using western blot analysis and transfectants were assessed for migration and invasion potential in standard in vitro assays.Nuclear ZEB1 expression was recorded in 22.8% of non-muscle-invasive UCBs and 21.7% of muscle-invasive UCBs, including 24.1% grade I/II and 21.1% grade III tumours, and absent in normal bladder mucosa. No significant correlation was observed for tumour stage and grade, nodal involvement, vascular invasion, metastasis and overall or cancer-specific survival. The introduction or knockdown of ZEB1 expression in bladder carcinoma cell lines showed enhanced or reduced migration and invasive potential, respectively. Changes in ZEB1 expression were accompanied by altered microRNA (miRNA) expression underlying events linked to epithelial-mesenchymal transition (EMT).The results in the present study showed novel expression of ZEB1 in bladder cancer in the absence of a link to clinical variables of change, including metastasis and survival. However, in vitro assays showed enhanced or reduced migration and invasion after the introduction or reduction of ZEB1, respectively, in transfected bladder cell lines. Modulation in expression of ZEB1 was closely linked to changes in the miR-200 family along with alternative known prognostic indicators of bladder tumour progression.

To assess the face, content, and construct validity of the dV-Trainer. The dV-Trainer is a virtual reality simulator for the da Vinci Surgical System that is in beta development.Medical students, residents, and attending surgeons were enrolled in a prospective, institutional review board-approved study. The subjects were prospectively categorized as novice or experienced. Each subject completed 2 EndoWrist modules and 2 needle-driving modules. The performance was recorded using a built-in scoring algorithm. Each subject completed a questionnaire after finishing the modules.The novice group (n = 19) consisted of 3 students (16%), 11 residents (58%), and 5 attending surgeons (26%). The novices had operated an average of 1.3 +/- 2.2 hours at the da Vinci console before using the simulator. The experienced subjects (n = 7) had performed an average of 140 robotic cases (range 30-320). Experienced robotic surgeons outperformed novices in nearly all variables, including total score, total task time, total instrument motion, and number of instrument collisions (P.01). All experienced surgeons ranked the simulator as useful for training and agreed with incorporating the simulator into a residency curriculum. The virtual reality and instrumentation achieved acceptability. The needle-driving modules did not exceed the acceptability threshold.The results of the present study have shown that the dV-Trainer has face, content, and construct validity as a virtual reality simulator for the da Vinci Surgical System. The needle-driving modules need to be refined. Studies are underway to assess the concurrent and predictive criterion validity. The dV-Trainer could become a beneficial training simulator for robotic surgery.

In addition to an increased occurrence of small, localized, incidentally discovered renal cell carcinomas (RCCs), there has been an upward trend in the incidence of advanced renal tumors per unit of population and in disease mortality worldwide. As radical nephrectomy remains the standard of care in treating localized RCC, this manuscript focuses on surgical approaches. We defined 'large renal tumors' as those greater than 7 cm or those with venous involvement. We discuss operative strategies in both open and laparoscopic surgery as well as approaches to special circumstances, including patients with tumor thrombus and the indications for nephron-sparing surgery in patients with greater than T2 RCC. The literature pertaining to controversial areas such as preoperative renal artery embolization and the clinical utility of metastectomy and cytoreductive therapy are also reviewed. The theoretical basis and potential applications of neoadjuvant therapy for larger renal tumors is examined as well.

The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly Drosophila melanogaster . Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.

Epithelial - mesenchymal transition (EMT) is a physiological process in normal tissue development and wound healing that has been shown to play important roles in tumor metastasis, “stemness,” and drug resistance. Therefore, it is critical to understand the molecular mechanisms that control EMT. EMT is typically characterized by the loss of the epithelial marker E-cadherin and gain of the transcriptional repressors of E-cadherin (Zeb1, Zeb2, Twist, SnaiI, and Slug). MicroRNAs belonging to the mir200 family and miR205 are involved in EMT through suppression of Zeb1 and Zeb2. Recently, p53 has been demonstrated to regulate EMT by transcriptionally activating the microRNA mir-200c, which in turn suppresses Zeb1; however, the mechanisms controlling miR205 remain elusive. We noticed that expression of the p53 homologue p63 correlates with the expression of E-cadherin in bladder cancer cell lines, suggesting that p63 might participate in regulating EMT. Consistent with this idea, expression of p63 and miR205 are strongly correlated with each other in a large panel of bladder cancer cell lines. Interestingly, stably knocking down (KD) p63 in two epithelial cell lines (UM-UC6 and UM-UC14) repressed the expression of miR205. Consistent with the role of miR205 in suppressing Zeb1, p63 knockdown resulted in increased expression of Zeb1 in the UM-UC6 cells, and this effect was reversed by expression of exogenous miR205. p63 knockdown reduced both the primary and mature forms of miR205, suggesting that p63 might transcriptionally activate miR205 gene expression. Intriguingly, chromatin immunoprecipitation (ChIP) revealed that p63 binds to a putative regulatory region of miR205 in UM-UC6 and UM-UC14. Furthermore, the acetylated histone H3 mark (indicative of active/open chromatin) was enriched in the region encompassing the p63 binding site. Together, our data identifies p63 as an important repressor of EMT via its ability to promote expression of miR205, which represses Zeb1 expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-472. doi:1538-7445.AM2012-LB-472

Objective The purpose of this study was to identify microRNA (miRNA) involved in the transition between the noninvasive and invasive urothelial carcinoma of the bladder (UCB) phenotype. Methods Differential expression of miRNA was identified in a microarray format between noninvasive and invasive UCB cell lines and confirmed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) within this cell panel. Normalization of qRT-PCR with miR-222 was established from the microarray data and validated within a panel of 57 UCB tumors (26 noninvasive lesions (Ta/G1) and 31 invasive lesions (T2-T4). Pre-miR constructs were transfected into appropriate UCB cell lines to establish a change in invasive potential. Results Differential expression of miRNAs was identified from microarray analysis and included reduced expression associated with miR-30b, miR-31, miR-141, miR-200a, miR-200b, miR-200c, miR-205, miR-21 in invasive lesions and elevated miR-99a in noninvasive UCB lesions. Reduced invasion potential was recorded in UM-UC-3, following pre-miR transfection, in all UCB cell lines with the exception of UM-UC-3/miR-30b transfectants. Our results identify a panel of miRNA modulated and expressed in invasive UCB tumors and demonstrates a role for them in the invasive phenotype. Conclusions The diagnostic test, based on the three most discriminatory miRNAs in our panel (miR-200c, miR-141, and miR-30b), showed a sensitivity of 100% and a specificity of 96.2%. Such a panel of miRNAs has the potential to identify invasive bladder tumors misclassified in pathologic assessment of bladder biopsy specimens.