Safety, Tolerability, and Preliminary Efficacy of TAR-200 in Patients With Muscle-invasive Bladder Cancer Who Refused or Were Unfit for Curative-intent Therapy: A Phase 1 Study.

PURPOSE: Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy. MATERIALS AND METHODS: Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over 84 days. The primary end points were safety and tolerability at 84 days. Secondary end points included rates of clinical complete response and partial response as determined by cystoscopy, biopsy, and imaging; duration of response; and overall survival. RESULTS: Median age of the 35 enrolled patients was 84 years, and most were male (24/35, 68.6%). Treatment-emergent adverse events related to TAR-200 occurred in 15 patients. Two patients experienced treatment-emergent adverse events leading to removal of TAR-200. At 3 months, complete response and partial response rates were 31.4% (11/35) and 8.6% (3/35), respectively, yielding an overall response rate of 40.0% (14/35; 95% CI 23.9-57.9). Median overall survival and duration of response were 27.3 months (95% CI 10.1-not estimable) and 14 months (95% CI 10.6-22.7), respectively. Progression-free rate at 12 months was 70.5%. CONCLUSIONS: TAR-200 was generally safe, well tolerated, and had beneficial preliminary efficacy in this elderly and frail cohort with limited treatment options.

Bladder Cancer Extracellular Vesicles Elicit a CD8 T Cell-Mediated Antitumor Immunity.

Tumor-derived extracellular vesicles (TEVs) play crucial roles in mediating immune responses, as they carry and present functional MHC-peptide complexes that enable them to modulate antigen-specific CD8+ T-cell responses. However, the therapeutic potential and immunogenicity of TEV-based therapies against bladder cancer (BC) have not yet been tested. Here, we demonstrated that priming with immunogenic Extracellular Vesicles (EVs) derived from murine MB49 BC cells was sufficient to prevent MB49 tumor growth in mice. Importantly, antibody-mediated CD8+ T-cell depletion diminished the protective effect of MB49 EVs, suggesting that MB49 EVs elicit cytotoxic CD8+ T-cell-mediated protection against MB49 tumor growth. Such antitumor activity may be augmented by TEV-enhanced immune cell infiltration into the tumors. Interestingly, MB49 EV priming was unable to completely prevent, but significantly delayed, unrelated syngeneic murine colon MC-38 tumor growth. Cytokine array analyses revealed that MB49 EVs were enriched with pro-inflammatory factors that might contribute to increasing tumor-infiltrating immune cells in EV-primed MC-38 tumors. These results support the potential application of TEVs in personalized medicine, and open new avenues for the development of adjuvant therapies based on patient-derived EVs aimed at preventing disease progression.

Tenascin-C expression in the lymph node pre-metastatic niche in muscle-invasive bladder cancer.

BACKGROUND: Markers of stromal activation at future metastatic sites may have prognostic value and may allow clinicians to identify and abolish the pre-metastatic niche to prevent metastasis. In this study, we evaluate tenascin-C as a marker of pre-metastatic niche formation in bladder cancer patient lymph nodes. METHODS: Tenascin-C expression in benign lymph nodes was compared between metastatic (n = 20) and non-metastatic (n = 27) patients with muscle-invasive bladder cancer. Urinary extracellular vesicle (EV) cytokine levels were measured with an antibody array to examine potential correlation with lymph node inflammation. The ability of bladder cancer EVs to activate primary bladder fibroblasts was assessed in vitro. RESULTS: Lymph node tenascin-C expression was elevated in metastatic patients vs. non-metastatic patients, and high expression was associated with worse survival. Urinary EVs contained four cytokines that were positively correlated with lymph node tenascin-C expression. Bladder cancer EVs induced tenascin-C expression in fibroblasts in an NF-κB-dependent manner. CONCLUSIONS: Tenascin-C expression in regional lymph nodes may be a good predictor of bladder cancer metastasis and an appropriate imaging target. It may be possible to interrupt pre-metastatic niche formation by targeting EV-borne tumour cytokines or by targeting tenascin-C directly.

TRAIL-coated leukocytes to kill circulating tumor cells in the flowing blood from prostate cancer patients.

BACKGROUND: Radical surgery is the first line treatment for localized prostate cancer (PC), however, several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream. METHODS: The number and temporal fluctuations of circulating tumor cells (CTC), cancer associated fibroblasts (CAF) and CTC cluster present in each blood sample was determined. RESULTS: The results show that both CTC and CTC cluster levels significantly increased immediately following primary tumor resection, but returned to baseline within 2 weeks post-surgery. In contrast, the CAF level decreased over time. In patients who experienced PC recurrence within months after resection, CTC, CAF, and cluster levels all increased over time. Based on this observation, we tested the efficacy of an experimental TNF-related apoptosis-inducing ligand (TRAIL)-based liposomal therapy ex-vivo to induce apoptosis in CTC in blood. The TRAIL-based therapy killed approximately 75% of single CTCs and CTC in cluster form. CONCLUSION: Collectively, these data indicate that CTC cluster and CAF levels can be used as a predictive biomarker for cancer recurrence. Moreover, for the first time, we demonstrate the efficacy of our TRAIL-based liposomal therapy to target and kill prostate CTC in primary patient blood samples, suggesting a potential new adjuvant therapy to use in combination with surgery.

Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells.

The field cancerization effect has been proposed to explain bladder cancer's multifocal and recurrent nature, yet the mechanisms of this effect remain unknown. In this work, using cell biology, flow cytometry, and qPCR analyses, along with a xenograft mouse tumor model, we show that chronic exposure to tumor-derived extracellular vesicles (TEVs) results in the neoplastic transformation of nonmalignant human SV-HUC urothelial cells. Inhibition of EV uptake prevented this transformation. Transformed cells not only possessed several oncogenic properties, such as increased genome instability, loss of cell-cell contact inhibition, and invasiveness, but also displayed altered morphology and cell structures, such as an enlarged cytoplasm with disrupted endoplasmic reticulum (ER) alignment and the accumulation of smaller mitochondria. Exposure of SV-HUC cells to TEVs provoked the unfolded protein response in the endoplasmic reticulum (UPRER). Prolonged induction of UPRER signaling activated the survival branch of the UPRER pathway, in which cells had elevated expression of inositol-requiring enzyme 1 (IRE1), NF-κB, and the inflammatory cytokine leptin, and incurred loss of the pro-apoptotic protein C/EBP homologous protein (CHOP). More importantly, inhibition of ER stress by docosahexaenoic acid prevented TEV-induced transformation. We propose that TEVs promote malignant transformation of predisposed cells by inhibiting pro-apoptotic signals and activating tumor-promoting ER stress-induced unfolded protein response and inflammation. This study provides detailed insight into the mechanisms underlying the bladder cancer field effect and tumor recurrence.

Local Recurrence Following Resection of Intermediate-High Risk Nonmetastatic Renal Cell Carcinoma: An Anatomical Classification and Analysis of the ASSURE (ECOG-ACRIN E2805) Adjuvant Trial.

PURPOSE: We describe what is to our knowledge a novel classification system for local recurrence after surgery of renal cell carcinoma. We assessed its prognostic implications using prospective, randomized controlled data. MATERIALS AND METHODS: We queried the ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed By Surgery) (ECOG-ACRIN [Eastern Cooperative Oncology Group-American College of Radiology Imaging Network] E2805) trial data for patients with fully resected, intermediate-high risk, nonmetastatic renal cell carcinoma with local recurrence. We used certain definitions, including type I-single recurrence in a remnant kidney or ipsilateral renal fossa, type II-single recurrence in the ipsilateral vasculature, the ipsilateral adrenal gland or a lymph node, type III-single recurrence in other intra-abdominal soft tissues or organs and type IV-any combination of types I-III or multiple recurrences of a single type. Multivariable logistic regression and the log rank test were performed to identify clinicopathological predictors and compare survival, respectively. RESULTS: Of the 1,943 patients 300 (15.4%) had local recurrence, which was type I, II, III and IV in 66 (22.0%), 97 (32.3%), 87 (29.0%) and 50 (16.7%), respectively. Surgical modality (minimally invasive vs open) and type of surgery (partial vs radical) did not predict any local recurrence. Five-year cancer specific survival and overall survival were worse in patients with type IV recurrence (each p <0.001). There was no difference in survival among patients with types I to III recurrence. CONCLUSIONS: In patients with intermediate-high risk nonmetastatic renal cell carcinoma local recurrence appears to be a function of biology more than of surgical modality or surgery type. The prognosis for solitary intra-abdominal local recurrences appear similar regardless of location (types I-III). Local recurrences involving multiple sites and/or subdivisions are associated with worse survival (type IV).

Evaluation of the Fluorescence In Situ Hybridization Test to Predict Recurrence and/or Progression of Disease after bacillus Calmette-Guérin for Primary High Grade Nonmuscle Invasive Bladder Cancer: Results from a Prospective Multicenter Trial.

PURPOSE: Single center studies have shown that positive UroVysion® fluorescence in situ hybridization results were associated with recurrence of nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. Our goal was to validate these findings. MATERIALS AND METHODS: We performed a prospective, multicenter diagnostic trial to determine whether the fluorescence in situ hybridization test could predict recurrence or progression in patients with primary high grade nonmuscle invasive bladder cancer who were scheduled to receive bacillus Calmette-Guérin. Fluorescence in situ hybridization testing was performed prior to the first bacillus Calmette-Guérin instillation, prior to the sixth instillation and at 3-month cystoscopy. The performance of fluorescence in situ hybridization was evaluated. RESULTS: A total of 150 patients were enrolled in analysis, including 68 with Ta disease, 41 with T1 disease, 26 with carcinoma in situ alone and 15 with papillary carcinoma plus carcinoma in situ. At 9 months of followup there were 46 events, including 37 recurrences and 9 progressions. For events with positive fluorescence in situ hybridization findings the HR was 2.59 (95% CI 1.42-4.73) for the baseline test, 1.94 (95% CI 1.04-3.59) for the 6-week test and 3.22 (95% CI 1.65-6.27) at 3 months. Patients with positive results at baseline, 6 weeks and 3 months had events 55% of the time and patients with negative results at each time point had no event 76% of the time. CONCLUSIONS: The study validated that a positive UroVysion fluorescence in situ hybridization test was associated with a 3.3-fold increased risk of recurrence. The test may be useful to risk stratify patients entering clinical trials in whom induction therapy fails. However, using the test to change management decisions is limited due to the discordance between results and outcomes as well as the variance of tests results with time.

SIU-ICUD consultation on bladder cancer: treatment of muscle-invasive bladder cancer.

PURPOSE: To provide a comprehensive overview and update of the Joint Société Internationale d'Urologie-International Consultation on Urological Diseases (SIU-ICUD) Consultation on Bladder Cancer for muscle-invasive presumably node-negative bladder cancer (MIBC). METHODS: Contemporary literature was analyzed for the latest evidence in treatment options, outcomes, including radical surgery, neoadjuvant and adjuvant treatment modalities, and bladder-sparing approaches. An international multi-disciplinary expert panel evaluated and graded the data according to guidelines from the Oxford Centre for Evidence-Based Medicine. RESULTS: Radical cystectomy (RC) is the standard of care for MIBC patients considered to be surgical candidates. While associated with substantial morbidity and mortality, this has been mitigated with improved technique, minimally invasive technology, and better perioperative care pathways (e.g., enhanced recovery after surgery). Neoadjuvant (NA) cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥ cT2N0 patients. Adjuvant (Adj) cisplatin-based combination chemotherapy may be considered, particularly for pT3-4 and/or pN+ disease without prior NA chemotherapy. Trimodal bladder-preserving treatment via maximum transurethral resection of bladder tumor followed by concurrent chemoradiation is safe and, when combined with early salvage RC for recurrence, offers long-term survival rates in selected patients comparable to RC. Immunotherapy is still experimental and is given either alone or in combination with chemotherapy and/or radiation. CONCLUSION: A multi-disciplinary approach is paramount to achieving optimal outcomes for MIBC patients, irrespective of their age, performance and nutritional status, fitness/frailty, renal and other organ function, or disease severity.

Multi-institutional nomogram predicting benign prostate pathology on magnetic resonance/ultrasound fusion biopsy in men with a prior negative 12-core systematic biopsy.

BACKGROUND: Prostate multiparametric magnetic resonance imaging (mpMRI) may be recommended for patients with a prior negative systematic biopsy (SB). However, a proportion of these patients will continue to have no prostate cancer (PCa) identified on magnetic resonance/ultrasound fusion biopsy (FB) despite abnormal mpMRI findings. METHODS: In this multi-institutional, retrospective study, clinical and mpMRI parameters were assessed for 285 consecutive patients with at least 1 prior negative biopsy who underwent FB for a Prostate Imaging Reporting and Data System (PI-RADS) score of 3 to 5 at the University of Rochester Medical Center from December 2014 to December 2016, or at the University of Alabama at Birmingham from February 2014 to February 2017. Nomograms were generated for predicting benign prostate pathology on both the targeted biopsy and the concurrent SB. RESULTS: Benign pathology was found in 132 of 285 patients (46.3%). In a multivariate analysis, the predictors of benign prostate pathology on FB were age, prostate-specific antigen, prostate volume, and PI-RADS score. The predicted probabilities were plotted on a receiver operating characteristic curve, and the area under the curve was 0.825. The nomogram demonstrated excellent calibration and a high net benefit in a decision curve analysis. With a theoretical cutoff probability of ≥0.7 used to recommend deferment of FB, 61 of 285 patients (21.4%) would have avoided an unnecessary biopsy, and only 4 of 285 patients (1.4%) with PCa with a Gleason score ≥ 3 + 4 would have been missed. CONCLUSIONS: False-positive mpMRI examinations may occur in up to 46.3% of patients with a prior negative biopsy. Thus, a multi-institutional nomogram has been developed and validated for predicting benign pathology after FB in patients with a prior negative biopsy, and this may help to reduce the number of unnecessary biopsies in the setting of abnormal mpMRI findings. Cancer 2018;124:278-85. © 2017 American Cancer Society.

A Comprehensive Analysis of Cribriform Morphology on Magnetic Resonance Imaging/Ultrasound Fusion Biopsy Correlated with Radical Prostatectomy Specimens.

PURPOSE: Recently a large body of evidence has emerged indicating that cribriform morphology is an aggressive prostate cancer morphological pattern associated with higher cancer specific mortality. In a comprehensive analysis we compared traditional and contemporary prostate biopsy techniques to detect prostate cancer with cribriform morphology with radical prostatectomy serving as the reference standard. MATERIALS AND METHODS: We queried a retrospectively maintained, single institution, multiparametric magnetic resonance imaging database of 1,001 patients to identify 240 who underwent magnetic resonance imaging-ultrasound fusion targeted biopsy and concurrent systematic biopsy from December 2014 to December 2016. Of the 3,978 biopsy cores obtained 694 positive cores were rereviewed by a genitourinary pathologist for pattern 4 subtype (cribriform, fused and poorly formed glands). Using paired analysis pathological results among 3 biopsy methods (systematic biopsy, targeted biopsy and systematic plus targeted biopsy) were compared. Prostatectomy specimens were also pathologically reviewed. RESULTS: Systematic plus targeted biopsy was superior to systematic biopsy alone or targeted biopsy alone to detect cribriform morphology (all p <0.0001). On final histopathology cribriform tumor foci were associated with an increased percent of pattern 4 involvement and extraprostatic extension (p <0.0001 and 0.003, respectively). Only 17.4% of cribriform tumors in pure form were visible on multiparametric magnetic resonance imaging. Based on final histopathology the sensitivity of systematic biopsy, targeted biopsy and systematic plus targeted biopsy for cribriform morphology was 20.7%, 28.6% and 37.1%, respectively. CONCLUSIONS: Although systematic plus targeted biopsy was the most accurate biopsy method to detect cribriform morphology, biopsy sensitivity and specificity remained poor.

Retroperitoneal Lymphadenectomy for High Risk, Nonmetastatic Renal Cell Carcinoma: An Analysis of the ASSURE (ECOG-ACRIN 2805) Adjuvant Trial.

PURPOSE: Lymphadenectomy is a well established practice for many urological malignancies but its role in renal cell carcinoma is less clear. Our primary objective was to determine whether lymphadenectomy impacted survival in patients with fully resected, high risk renal cell carcinoma. MATERIALS AND METHODS: Patients with fully resected, high risk, nonmetastatic renal cell carcinoma were randomized to adjuvant sorafenib, sunitinib or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial. Lymphadenectomy was performed for cN+ disease or at surgeon discretion. Patients treated with lymphadenectomy were compared to patients in the trial who did not undergo lymphadenectomy. The primary outcome was overall survival associated with lymphadenectomy. Secondary outcomes were disease free survival, factors associated with performing lymphadenectomy and surgical complications. RESULTS: Of the 1,943 patients in ASSURE 701 (36.1%) underwent lymphadenectomy, including all resectable patients with cN+ and 30.1% of those with cN0 disease. A median of 3 lymph nodes (IQR 1-8) were removed and the rate of pN+ disease in the lymphadenectomy group was 23.4%. There was no overall survival benefit for lymphadenectomy relative to no lymphadenectomy (HR 1.14, 95% CI 0.93-1.39, p = 0.20). In patients with pN+ disease who underwent lymphadenectomy no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy did not confer an increased risk of surgical complications (14.2% vs 13.4%, p = 0.63). CONCLUSIONS: The benefit of lymphadenectomy in patients undergoing surgery for high risk renal cell carcinoma remains uncertain. Future strategies to answer this question should include a prospective trial in which patients with high risk renal cell carcinoma are randomized to specific lymphadenectomy templates.

Validation of GEMCaP as a DNA Based Biomarker to Predict Prostate Cancer Recurrence after Radical Prostatectomy.

PURPOSE: We aimed to validate GEMCaP (Genomic Evaluators of Metastatic Cancer of the Prostate) as a novel copy number signature predictive of prostate cancer recurrence. MATERIALS AND METHODS: We randomly selected patients who underwent radical prostatectomy at Cleveland Clinic or University of Rochester from 2000 to 2005. DNA isolated from the cancer region was extracted and subjected to high resolution array comparative genomic hybridization. A high GEMCaP score was defined as 20% or greater of genomic loci showing copy number gain or loss in a given tumor. Cox regression was used to evaluate associations between the GEMCaP score and the risk of biochemical recurrence. RESULTS: We report results in 140 patients. Overall 38% of patients experienced recurrence with a median time to recurrence of 45 months. Based on the CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical) score 39% of the patients were at low risk, 42% were at intermediate risk and 19% were at high risk. The GEMCaP score was high (20% or greater) in 31% of the cohort. A high GEMCaP score was associated with a higher risk of biochemical recurrence (HR 2.69, 95% CI 1.51-4.77) and it remained associated after adjusting for CAPRA-S score and age (HR 1.94, 95% CI 1.06-3.56). The C-index of GEMCaP alone was 0.64, which improved when combined with the CAPRA-S score and patient age (C-index = 0.75). CONCLUSIONS: A high GEMCaP score was associated with biochemical recurrence in 2 external cohorts. This remained true after adjusting for clinical and pathological factors. The GEMCaP biomarker could be an efficient and effective clinical risk assessment tool to identify patients with prostate cancer for early adjuvant therapy.

The conundrum of recurrent low-grade tumours: to treat or to observe?

PURPOSE OF REVIEW: To describe the importance of risk stratification and the role of more conservative management like office fulguration, office laser ablation and active surveillance in recurrent low-grade Ta tumours. RECENT FINDINGS: Updated models have been designed for risk stratification of intermediate-risk tumours. Conservative forms of management like office fulguration or laser ablation and even active surveillance seem well tolerated; however, randomized, controlled trials are lacking. In patients who have been tumour free for 5 years, late recurrences have been described. SUMMARY: Recurrent low-grade Ta tumours are classified in the intermediate risk group, which is a heterogeneous group. Therefore, risk stratification should be done by updated models or patients should be stratified in a risk group sub-classification. Recurrent low-grade Ta patients have a favourable prognosis and consequently are prone to overtreatment. Office fulguration or laser ablation or even active surveillance could be implemented in strictly selected patients. For active surveillance, Miyake et al. proposed a helpful flowchart with criteria for patient selection and for intervention. Follow up using cystoscopy and cytology is essential, but an optimal scheme has not been identified. As late recurrences are not infrequent and recurrent low-grade Ta patients can even die from bladder cancer, long term follow-up should be performed yearly, by cystoscopy and cytology.

Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial.

Importance: Low-grade non-muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). Objective: To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non-muscle-invasive urothelial cancer compared with saline. Design, Setting, and Participants: Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non-muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. Interventions: Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. Main Outcomes and Measures: The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. Results: Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non-muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower. Conclusions and Relevance: Among patients with suspected low-grade non-muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. Trial Registration: clinicaltrials.gov Identifier: NCT00445601.

Impact of Gleason Subtype on Prostate Cancer Detection Using Multiparametric Magnetic Resonance Imaging: Correlation with Final Histopathology.

PURPOSE: We determined whether Gleason pattern 4 architecture impacts tumor visibility on multiparametric magnetic resonance imaging and correlates with final histopathology. MATERIALS AND METHODS: A total of 83 tumor foci were identified in 22 radical prostatectomy specimens from patients with a prior negative biopsy who underwent magnetic resonance/ultrasound fusion biopsy followed by radical prostatectomy from January 2015 to July 2016. A genitourinary pathologist rereviewed tumor foci for Gleason architectural subtype. Each prostate imaging reporting and data system category 3 to 5 lesion on multiparametric magnetic resonance imaging was paired with its corresponding pathological tumor focus. Univariable and multivariable analyses were performed to determine predictors of tumor visibility. RESULTS: Of the 83 tumor foci identified 26 (31%) were visible on multiparametric magnetic resonance imaging, 33 (40%) were Gleason score 3+3 and 50 (60%) were Gleason score 3+4 or greater. Among tumor foci containing Gleason pattern 4, increasing tumor size and noncribriform predominant architecture were the only independent predictors of tumor detection on multivariable analysis (p = 0.002 and p = 0.011, respectively). For tumor foci containing Gleason pattern 4, 0.5 cm or greater, multiparametric magnetic resonance imaging detected 10 of 13 (77%), 5 of 14 (36%) and 9 of 10 (90%) for poorly formed, cribriform and fused architecture, respectively (p = 0.01). The size threshold for the detection of cribriform tumors was higher than that of other architectural patterns. Furthermore, cribriform pattern was identified more frequently on systematic biopsy than on targeted biopsy. CONCLUSIONS: Reduced visibility of cribriform pattern on multiparametric magnetic resonance imaging has significant ramifications for prostate cancer detection, surveillance and focal therapy.

Reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2 ) at first transurethral resection of bladder tumour is a significant predictor of subsequent recurrence and progression.

OBJECTIVE: To evaluate if moderate chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 ] is associated with high rates of non-muscle-invasive bladder cancer (NMIBC) recurrence or progression. PATIENTS AND METHODS: A multi-institutional database identified patients with serum creatinine values prior to first transurethral resection of bladder tumour (TURBT). The CKD-epidemiology collaboration formula calculated patient eGFR. Cox proportional hazards models evaluated associations with recurrence-free (RFS) and progression-free survival (PFS). RESULTS: In all, 727 patients were identified with a median (interquartile range [IQR]) patient age of 69.8 (60.1-77.6) years. Data for eGFR were available for 632 patients. During a median (IQR) follow-up of 3.7 (1.5-6.5) years, 400 (55%) patients had recurrence and 145 (19.9%) patients had progression of tumour stage or grade. Moderate or severe CKD was identified in 183 patients according to eGFR. Multivariable analysis identified an eGFR of <60 mL/min/1.73 m2 (hazard ratio [HR] 1.5, 95% confidence interval [CI]: 1.2-1.9; P = 0.002) as a predictor of tumour recurrence. The 5-year RFS rate was 46% for patients with an eGFR of ≥60 mL/min/1.73 m2 and 27% for patients with an eGFR of <60 mL/min/1.73 m2 (P < 0.001). Multivariable analysis showed that an eGFR of <60 mL/min/1.73 m2 (HR 3.7, 95% CI: 1.75-7.94; P = 0.001) was associated with progression to muscle-invasive disease. The 5-year PFS rate was 83% for patients with an eGFR of ≥60 mL/min/1.73 m2 and 71% for patients with an eGFR of <60 mL/min/1.73 m2 (P = 0.01). CONCLUSION: Moderate CKD at first TURBT is associated with reduced RFS and PFS. Patients with reduced renal function should be considered for increased surveillance.

Quality Improvement in Cystectomy Care with Enhanced Recovery (QUICCER) study.

OBJECTIVES: To determine if patients managed with a cystectomy enhanced recovery pathway (CERP) have improved quality of care after radical cystectomy (RC), as defined by a decrease in length of hospital stay (LOS) without an increase in complications or readmissions compared with those not managed with CERP. SUBJECTS AND METHODS: The Quality Improvement in Cystectomy Care with Enhanced Recovery (QUICCER) study was a non-randomized quasi-experimental study. Data were collected between June 2011 and April 2015. The CERP was implemented in July 2013. The primary endpoint was LOS. Secondary endpoints were quality scores, complications and readmissions. Multivariable regression was performed. Propensity score matching was carried out to further simulate randomized clinical trial conditions. A CERP quality composite score was created and evaluated with regard to adherence to CERP elements. RESULTS: The study included 79 patients managed with CERP and 121 who were not managed with CERP. After matching, there were 75 patients in the non-CERP group. The LOS was significantly different between the groups: the median LOS was 5 and 8 days for the CERP and non-CERP group, respectively (P < 0.001). Multivariable linear regression showed that any complication was the most significant predictor of total LOS at 90 days after RC. The higher the quality composite score the shorter the LOS (P < 0.001). There was no association between CERP and a greater number of complications or readmissions. CONCLUSIONS: Audited quality measures in the CERP are associated with a reduction in LOS with no increase in readmissions or complications. The CERP is important for the future improvement of peri-operative care for RC and provides an opportunity to improve the quality of care provided.

Microscopic haematuria at time of diagnosis is associated with lower disease stage in patients with newly diagnosed bladder cancer.

OBJECTIVES: To determine whether the severity of haematuria (microscopic or gross) at diagnosis influences the disease stage at presentation in patients diagnosed with bladder cancer. PATIENTS AND METHODS: We conducted a multi-institutional observational cohort study of patients who were newly diagnosed with bladder cancer between August 1999 and May 2012. We reviewed the degree of haematuria, demographic information, clinical and social history, imaging, and pathology. The association of haematuria severity with incident tumour stage and grade was evaluated using logistic regression. RESULTS: Patients diagnosed with bladder cancer presented with gross haematuria (GH; 1 083, 78.3%), microscopic haematuria (MH; 189, 13.7%) or without haematuria (112, 8.1%). High-grade disease was found in 64% and 57.1% of patients presenting with GH and MH, respectively, and severity of haematuria was not associated with higher grade disease. Stage of disease at diagnosis for patients presenting with MH was Ta/carcinoma in situ (CIS) in 68.8%, T1 in 19.6%, and ≥T2 in 11.6%. Stage of disease at diagnosis for patients presenting with GH was Ta/CIS in 55.9%, T1 in 19.6%, and ≥T2 in 17.9%. On multivariate analyses, GH was independently associated with ≥T2 disease at diagnosis (odds ratio 1.69, 95% confidence interval 1.05-2.71, P = 0.03). CONCLUSIONS: Among patients with newly diagnosed bladder cancer, presentation with GH is associated with a more advanced pathological stage. Earlier detection of disease, before development of GH, could influence survival in patients with bladder cancer. Type of haematuria at presentation does not impact grade of disease.

Soy food frequency questionnaire does not correlate with baseline isoflavone levels in patients with bladder cancer.

BACKGROUND: The isoflavone genistein, a natural soy product with receptor tyrosine kinase-inhibiting activity, as well as phytoestrogenic and other potential anticarcinogenic effects, is being studied as an anticancer agent. Since isoflavones are commonly consumed in food products containing soy proteins, a method to control for baseline isoflavone consumption is needed. METHODS: HPLC was used to evaluate baseline plasma and urine concentrations of isoflavone in fifty-four participants with bladder cancer enrolled on a phase II chemoprevention study of G-2535. The soy food frequency questionnaire was used to assess participant's baseline soy intake. The association between baseline isoflavone concentrations and intakes for genistein and daidzein was assessed by the Spearman's rank correlation coefficient. RESULTS: The majority of participants had no detectable genistein or daidzein in plasma at baseline. The median and range of values were 0 (0-1480) nmol/L for genistein, and 0 (0-1260) nmol/L for daidzein. In urine, the median and range of values were 91.0 (0-9030) nmol/L for genistein and 623 (0-100,000) nmol/L for daidzein. The median and range of weekly estimated genistein intake was 0 (0-236) mg/wk; the median and range of weekly estimated daidzein intake was 0 (0-114) mg/wk. There was no relationship to soy intake as measured by the food frequency questionnaire and baseline isoflavone levels in plasma or urine and the Spearman's rank correlation coefficients were not significant. CONCLUSION: The soy food frequency questionnaire did not correlate with plasma or urine concentrations of either isoflavone. IMPACT: Alternative methods for controlling for soy consumption, including measuring plasma and urine concentrations, in isoflavone chemoprevention trials should be considered.