Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model.

OBJECTIVES: To test if intravesical instillation of both an anti-programmed cell death protein 1 (PD-1) inhibitor and an oncolytic reovirus would demonstrate a greater effect than either treatment alone, as non-muscle-invasive bladder cancer that is refractory to intravesical bacillus Calmette-Guérin can be treated by systemic anti-PD-1 immunotherapy and we previously demonstrated improved overall survival (OS) with six once-weekly instillations of intravesical anti-PD-1 in a murine model. MATERIALS AND METHODS: Using an orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer, groups of 10 mice were compared between no treatment, intravesical anti-PD-1, intravesical oncolytic reovirus, or intravesical reovirus + anti-PD-1. A single intravesical treatment session was given. The primary outcome was OS, and the secondary outcomes included long-term immunity and tumour-immune profile. RESULTS: With a median follow-up of 9 months, all mice that received no treatment died with a median survival of 41 days, while the comparison median OS was not reached for reovirus (hazard ratio [HR] 14.4, 95% confidence interval [CI] 3.9-32.6; P < 0.001), anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001), and reovirus + anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001). Monotherapy with anti-PD-1 or reovirus demonstrated no significant differences in survival (P = 0.067). Mass cytometry showed that reovirus + anti-PD-1 treatment enriched monocytes and decreased myeloid-derived suppressor cells, generating an immuno-responsive tumour microenvironment. Depletion of CD8+ T cells eliminated the survival advantage provided by the intravesical treatment. CONCLUSIONS: Treatment of murine orthotopic bladder tumours with a single instillation of intravesical reovirus, anti-PD-1 antibody, or the combination confers superior survival compared to controls. Tumour-immune microenvironment differences indicated myeloid-derived suppressor cells and CD8+ T cells mediate the treatment response.

Glycemic impact of a diet and lifestyle intervention on diabetics and prediabetics during treatment for non-muscle invasive bladder cancer.

Introduction: Patients with Type II Diabetes Mellitus (DM2) have increased risk of recurrence and progression of non-muscle invasive bladder cancer (NMIBC). Glucose control through lifestyle intervention is an uninvestigated, attractive strategy to decrease risk of cancer recurrence. We test the feasibility of a diet and exercise program and its glycemic impact in patients with DM2 and NMIBC.Materials/methods: Five participants with NMIBC and pre-diabetes or DM2 were recruited for a pilot, prospective clinical trial. Each participant received dietary counseling for 16 sessions during clinical visits. The intervention included a carbohydrate-restricted (CR) diet (<130 grams per day), 30 min, walking 5×/wk, and 5000 steps daily. Diet compliance was measured with 24-hour diet recall. Exercise was monitored with accelerometer and self-report.Results: Five participants enrolled and two participants completed the 12-month intervention. Adherence was 60% to CR diet and 84% to exercise goals. Participants reduced carbohydrate consumption by 44%. Participants showed reductions in fasting blood glucose, HbA1c, glucosuria, fasting blood insulin, and body weight, and increased euglycemia on continuous glucose monitoring.Conclusions: Adherence to a CR diet and exercise goals is feasible in patients with NMIBC and DM2 and also leads improved glucose control. A phase-II trial on bladder cancer-specific outcomes is warranted.

Molecular subtyping of bladder cancer: current trends and future directions in 2019.

PURPOSE OF REVIEW: Personalized medicine portends a future where patients receive therapy based on mutational and gene expression profiles intrinsic to their tumor. Recent advances in molecular subtyping of tumors have pushed us closer to using patient-specific data to guide therapy. The purpose of this review is to understand how these advances may be used to understand tumor development and direct therapeutic regimens clinically. RECENT FINDINGS: Multiple reports have identified specific molecular subtypes present in bladder cancer. A variety of classification schemes are currently being suggested based on different groups observations on gene expression, mutational profile, and histological variability. Notably, recent novel findings indicate standard of care with neoadjuvant platinum-based chemotherapy effectively removes the basal subtype specifically, indicating clinical data largely supports the use of molecular subtyping as a way to treat tumors. SUMMARY: Although varied classifications are present in the field currently, more work is required to truly define which subtypes are responsive to specific therapies. Current data supports the idea that molecular subtyping will benefit patients; however, these data also argue in favor of combinatorial therapy and molecular profiling throughout treatment.

Perioperative Immunonutrition Modulates Inflammatory Response after Radical Cystectomy: Results of a Pilot Randomized Controlled Clinical Trial.

PURPOSE: Poor preoperative nutritional status is associated with a higher complication rate after radical cystectomy in patients with bladder cancer. Given the short interval between diagnosis and radical cystectomy, we compared the effect of short-term specialized immunonutrition to that of a standard oral nutritional supplement on the acute inflammatory response and arginine status in patients treated with radical cystectomy. MATERIALS AND METHODS: In this prospective, randomized study in 29 men 14 received specialized immunonutrition and 15 received oral nutritional supplement. Each group drank 3 cartons per day for 5 days before and 5 days after radical cystectomy. The Th1-Th2 balance, plasma interleukin-6 and plasma amino acids were measured at baseline, intraoperatively and on postoperative days 2, 14 and 30. Body composition was measured by dual energy x-ray absorptiometry at baseline and on postoperative days 14 and 30. Differences in outcomes were assessed using the generalized linear mixed model. RESULTS: In the specialized immunonutrition group there was a 54.3% average increase in the Th1-Th2 balance according to the tumor necrosis factor-α-to-interleukin-13 ratio from baseline to intraoperative day, representing a shift toward a Th1 response. In the oral nutritional supplement group the Th1-Th2 balance decreased 4.8%. The change in the Th1-Th2 balance between the specialized immunonutrition and oral nutritional supplement groups significantly differed (p <0.027). Plasma interleukin-6 was 42.8% lower in the specialized immunonutrition group compared to the oral nutritional supplement group on postoperative day 2 (p = 0.020). In the specialized immunonutrition group plasma arginine was maintained from baseline to postoperative day 2 and yet the oral nutritional supplement group showed a 26.3% reduction from baseline to postoperative day 2 (p = 0.0003). The change in appendicular muscle loss between the groups was not statistically significant. CONCLUSIONS: Th1-to-Th2 ratios, peak interleukin-6 levels and plasma arginine suggest that consuming specialized immunonutrition counteracts the disrupted T-helper balance, lowers the inflammatory response and prevents arginine depletion due to radical cystectomy.

Where are we with bladder preservation for muscle-invasive bladder cancer in 2017?

INTRODUCTION: In 2017, neoadjuvant, cisplatin-based chemotherapy followed by radical cystectomy (RC) is considered the gold standard therapy for muscle-invasive bladder based on randomized controlled trials. Across all tumor stages, this approach has been associated with the highest rates of disease-specific survival. However, RC is one of the most challenging procedures performed by urologic surgeons and carries with it significant risks of complications, hospital readmission, and even a small risk of mortality, in addition to lifestyle changes that can have long-term effects on well-being. For these reasons, bladder-sparing approaches are utilized in some highly selected patients. We reviewed the most recent evidence for bladder-sparing modalities for muscle-invasive urothelial bladder cancer and summarize those findings in this review article. METHODS: We performed a PubMed literature review utilizing the key words "bladder preservation," "trimodal therapy," "muscle-invasive bladder cancer," and "partial cystectomy" written in English, dating back to 1990. We excluded case reports. RESULTS: Our search yielded more than 2000 articles which we screened. Some articles were then rejected due to inappropriate topic. In addition, we reviewed the most recent American Urological Association, National Comprehensive Cancer Network (NCCN), and European guidelines on muscle-invasive bladder cancer. We identified fifty relevant articles which are summarized in this text. In some rare instances, recommendations are based on expert opinion. CONCLUSIONS: Bladder preservation is often considered for quality of life considerations or in the setting of multiple medical comorbidities, and this remains oncologically appropriate even in 2016 in highly selected patients with muscle-invasive urothelial carcinoma of the bladder.

Implementation of a comprehensive prehabilitation program for patients undergoing radical cystectomy.

BACKGROUND: Coordinated preoperative optimization programs for radical cystectomy (RC) are limited and non-comprehensive. We evaluated the feasibility and acceptability of a coordinated, multi-faceted prehabilitation program for RC patients at a high-volume bladder cancer referral center. METHODS: We performed a narrative literature review for prehabilitation in bladder cancer management as of December 1, 2020, with specific emphasis on examining higher-level evidence sources. We selected domains with the highest level of evidence and recruited a multidisciplinary team of experts to design our program. We implemented a comprehensive prehabilitation program with a pre-defined order set as standard of care for all patients undergoing RC beginning February 1, 2021. Demographic and clinicopathologic data were collected prospectively. Rates of adherence to the prehabilitation program services were analyzed using Stata version 13. RESULTS: A total of 82 patients were enrolled between February - December 2021, of which 67 (81%) had undergone RC at data cutoff. Mean age was 68 years (SD 11) and 63 (76%) identified as male. Neoadjuvant chemotherapy (NAC) was utilized in 48 (59%) patients. The mean Charlson Comorbidity Index was 3.8 (SD 2.3). 100% of patients were screened for malnutrition, with 82% consuming nutritional supplements. Fifty-two percent of patients attended physical therapy pre-op. The 30-day and 30- to 90-day rates of complications were 56% and 40%, respectively. Resource length of stay (RLOS) declined after implementation of prehabilitation. CONCLUSIONS: Implementation of a comprehensive prehabilitation program at a high-volume bladder cancer referral center is feasible and has a modest effect on resource consumption and complications in our early experience.

Intensity of observation with active surveillance or watchful waiting in men with prostate cancer in the United States.

BACKGROUND: Population-based studies assessing various active surveillance (AS) protocols for prostate cancer, to date, have inferred AS participation by the lack of definitive treatment and use of post-diagnostic testing. This is problematic as evidence suggests that most men do not adhere to AS protocols. We sought to develop a novel method of identifying men on AS or watchful waiting (WW) independent of post-diagnostic testing and aimed to identify possible predictors of follow-up intensity in men on AS/WW. METHODS: A predictive model was developed using SEER watchful waiting data to identify men ≥66 years on AS between 2010-2015, irrespective of post-diagnostic testing, and applied to SEER-Medicare database. AS intensity among different variables including age, prostate-specific antigen (PSA) level, number of total and positive biopsy cores, Charlson comorbidity index, race (Black vs. non-Black), US census region, and county poverty, income, and education levels were compared using multivariable regression analyses for PSA testing, surveillance biopsy, and magnetic resonance imaging (MRI). RESULTS: A total of 2238 men were identified as being on AS. Of which, 81%, 33%, and 10% had a PSA test, surveillance biopsy, and MRI scan within 1-2 years, respectively. On multivariable analyses, Black men were less likely to have a PSA test (adjusted rate ratio [ARR] 0.60, 95% CI: 0.53-0.69), MRI scan (ARR 0.40, 95% CI: 0.24-0.68), and surveillance biopsy (ARR 0.71, 95% CI: 0.55-0.92) than non-Black men. Men within the highest income quintile were more likely to undergo PSA test (ARR 1.16, 95% CI: 1.05-1.27) and MRI scan (ARR 1.60, 95% CI 1.15-2.27) compared to men with the lowest income. CONCLUSIONS: Black men and men with lower incomes on AS underwent less rigorous monitoring. Further study is needed to understand and ameliorate differences in AS rigor stemming from sociodemographic differences.

Management of anticoagulation and antiplatelet agents in the radical cystectomy patient.

BACKGROUND: Bladder cancer is a disease of the older adult, and management of comorbid conditions requiring anticoagulation (AC) or antiplatelet agents (APA) around the time of radical cystectomy (RC) is a frequent clinical challenge. It is estimated that 10% of adult surgical patients are on chronic anticoagulation medications, and considerations surrounding the perioperative disruption, resumption, and modification or substitution of AC and APA in patients undergoing radical cystectomy are critical for the practicing urologist. METHODS: In our report, we performed a comprehensive literature review using PubMed to evaluate all available studies from 1950 to present. Additionally, we reviewed current multidisciplinary guideline papers from the American College of Surgeons, American College of Cardiology, and CHEST Society regarding perioperative management of anticoagulation and antiplatelet agents. RESULTS: Our keyword search yielded 35 articles from 1950 to 2019. We identified 16 studies pertaining specifically to evaluation and perioperative management of anticoagulation in patient undergoing RC. Many of the recommendations in this realm are informed by trial data outside the RC population in the general surgical population or general adult population. Current guidelines from the American College of Surgeons, American College of Cardiology/American Heart Association, and CHEST Society inform our recommendations heavily and are summarized in Table 1. CONCLUSIONS: Radical cystectomy remains both a mainstay of therapy for patients with muscle-invasive bladder cancer and a morbid procedure. Competing risks of perioperative hemorrhage and thromboembolic events make management of anticoagulation and antiplatelet agents an important and modifiable risk factor. Our review of the current literature highlights the knowledge gap that exists in management of these agents in the radical cystectomy patient. A multi-disciplinary approach to management of this clinical challenge remains a mainstay of treatment.

Funding Peyronie's disease: funding sources for primary research literature.

The objective was to describe funding sources and publication trends for the primary literature on Peyronie's disease (PD), including direct industry research support. A search of EMBASE, PubMed, Scopus, and Web of Science was performed to identify articles published from 2006 to 2018. Articles not published in English, reviews, case reports, editorials, guidelines, and meta-analysis were excluded from analysis. Data collected included year and journal of publication, major focus, and funding sources. The US Federal Open Payments database was searched for direct industry research payments to authors. Four hundred thirty-seven articles met criteria. The median number of yearly publications was 31. The most frequent publications were Journal of Sexual Medicine (25.6%), Urology (8.9%), BJU International (7.3%), and Journal of Urology (5.7%). Plaque excision/grafting was the most common topic (16.5%) followed by pathophysiology (15.3%), and intralesional therapy (14.9%). Only 15.1% (n = 66) of articles had a funding source with only 2.3% (n = 10) articles receiving any National Institutes of Health (NIH) funding. In total, 4.1% (n = 18) of the articles were industry funded, 61.1% (n = 11) of these from Xiaflex manufacturer Endo/Auxilium. Remaining articles appeared self-funded. There were 1524 unique authors and just 13 received any direct industry funds, totaling US$718,426. Most PD research is self-funded with only a small percentage from NIH or industry.

Side Effects of Intravesical BCG and Chemotherapy for Bladder Cancer: What They Are and How to Manage Them.

Intravesical therapy for nonmuscle invasive bladder cancer decreases recurrence and progression but carries a high risk of side effects, which limit patient adherence. Appropriate management of the toxicities from intravesical therapy requires consideration of the agent used, the side effects experienced, and the timing of those side effects. Management strategies for intravesical toxicities ideally improve patient tolerance without sacrificing oncologic outcomes. This review aims to provide a comprehensive overview of the available evidence regarding the side effects of intravesical therapies for nonmuscle invasive bladder cancer and to propose practical strategies for toxicity management.

Characterization of perioperative androgen profiles in men with bladder cancer undergoing radical cystectomy.

BACKGROUND: Prior studies have demonstrated declines in androgen levels in men with cancer and patients undergoing anesthesia and surgery. In this study, we hypothesized that decreased serum androgen levels are prevalent in male patients undergoing radical cystectomy (RC) for bladder cancer and that it persists in the postoperative period. We characterized perioperative androgen hormonal profiles and examined for associated changes indicative of sarcopenia on computed tomography scans in men undergoing RC. METHODS: We implemented a prospective observational trial in men with newly diagnosed non-metastatic bladder cancer undergoing RC. Baseline pre-operative total testosterone (TT), free testosterone (FT), and luteinizing hormone (LH) were obtained on morning lab draws with 30 days of surgery. TT and FT were then repeated on postoperative days (POD) 2, 3, 30, and 90. The threshold for normal TT was defined as >300 ng/dl, consistent with the AUA Guidelines for Evaluation and Management of Testosterone Deficiency. We evaluated postoperative changes in weight and psoas muscle cross-sectional area using computed tomography scans to assess for sarcopenic changes. RESULTS: Univariable statistical analysis was performed. 25 patients were enrolled. The mean patient age was 68.9 years. The mean pre-operative TT was 308 ng/dl, and 12/23 (52.5%) patients had low testosterone. Mean TT onPOD 2 and 3 were 166 ng/dl and 161 ng/dl, respectively (range 24-345). 19/20 (95%) of men who had morning lab draws had decreased TT. The mean TT at 30 days was 253 ng/dl with 37.5% of men having low TT. Mean TT at 90 days was 306 ng/dl. The mean FT levels were 43 ng/dl, 29.25 ng/dl, 28.2 ng/dl, 40.89 ng/dl, and 42.62 ng/dl at baseline, POD 2, POD 3, POD 30, and POD 90, respectively. Mean LH at baseline was 9.9 IU/L. Average weight loss at 30- and 90- days postop was -4.29 and -4.38 kilograms, respectively. Weight loss was persistent with only 3/23 (13%) returning to their presurgery weight by 90 days. Despite significant declines in weight and perioperative TT, no significant differences in psoas muscle cross-sectional area were observed (net change -92 mm2, P= 0.13) CONCLUSIONS: Perioperative disruption of androgen levels is prevalent in men undergoing RC. Our trial demonstrates a pre-op, immediate postop, 30- and 90-day postoperative prevalence of low TT of 52%, 95%, 63%, and 37.5%, respectively. Significant changes in baseline weight were noted, although no significant changes in psoas muscle cross-sectional area were observed, limiting conclusions regarding a link between changes in androgens and sarcopenia in this setting.

Diagnostic renal mass biopsy is associated with individual categories of PADUA and RENAL nephrometry scores: Analysis of diagnostic and concordance rates with surgical resection.

BACKGROUND: Renal mass biopsy (RMB) is a safe and accurate method for diagnosis and clinical management of renal masses. However, the non-diagnostic rate is a limiting factor. We tested the hypothesis that imaging characteristics and anatomic complexity of the mass may impact RMB diagnostic outcome using the preoperative aspects and dimensions used for an anatomical (PADUA) classification and radius-exophytic/endophytic-nearness-anterior/posterior-location (RENAL) score. MATERIAL AND METHODS: Single institution, retrospective study of 490 renal masses from 443 patients collected from 2001 to 2018. Outcome measurements include (1) diagnostic and concordance rates amongst RMB types and RMB with surgical resection specimens; (2) association between diagnostic RMB and anatomical complexity of renal masses. The analysis was conducted in unselected masses and small renal masses (SRMs). RESULTS: RMB was performed by fine needle aspiration (FNA), core needle biopsy (CNB), or both (FNA+CNB). Non-diagnostic rate was significantly higher for FNA compared to CNB and FNA+CNB in both unselected and SRMs. Subset analysis in the FNA+CNB group showed similar diagnostic rates for FNA and CNB. In unselected masses, specificity for FNA, CNB, and FNA+CNB was 100%. Sensitivity was higher for CNB (90.1%, P = 0.002) and FNA+CNB (96.3%, P = 0.004) compared to FNA (66.7%). For unselected masses, endophytic growth predicted a non-diagnostic CNB. R.E.N.A.L location entirely between the polar lines (central) and entirely above the upper polar line predicted a diagnostic CNB. Sonography-guidance predicted a diagnostic FNA. For SRMs, non-diagnostic CNB was associated with endophytic growth, while diagnostic CNB was associated with renal sinus invasion and operator experience. More cystic masses were sampled by FNA, but diagnostic results were similar for FNA and CNB. CONCLUSIONS: Endophytic growth consistently predicted a non-diagnostic CNB in unselected and SRMs, whereas sonography-guidance predicted a diagnostic FNA. Cystic masses could be adequately sampled by FNA.

Contemporary Preoperative and Intraoperative Management of the Radical Cystectomy Patient.

Radical cystectomy is a morbid procedure performed on an aging and often frail population. Nonetheless, advances in preoperative and intraoperative management have significantly improved patient outcomes. Preoperative optimization includes a focus on patient education, risk factor reduction, risk stratification, nutritional optimization, and bowel motility enhancement. Intraoperative optimization focuses on maintaining normothermia, restrictive fluid administration, minimization of blood transfusions, and nonopioid pain management.

Assessment of Patient and Surgical Variables Including Residency Training Level on Adverse Events After Ureteroscopy for Ureteral Stones: A Multivariate Analysis.

PURPOSE: With advances in technology, ureteroscopy (URS) is increasingly utilized for the management of urolithiasis. Previous studies have attempted to characterize the post-operative complication and readmission rates relative to the technical difficulty of the procedure. There is limited data exploring the resident level of training and its effect on adverse outcomes in these cases. We review our experience with URS to create a model to predict factors, including resident experience, that affect rates of post-operative complications. MATERIALS AND METHODS: We reviewed ureteroscopies performed at our academic facility from January 2009 to December 2013. Ureteral-only stones were examined for demographics, stone characteristics, operative techniques, and resident training level. Post-operative adverse events requiring urology consultation, clinic or emergency department visits, hospital admission, prolonged post-operative hospitalization, or unplanned repeat surgery within 30 days of the procedure were identified and analyzed. RESULTS: Four hundred seventeen cases of URS for ureteral-only stones were included for study. We identified 53 (12.7%) involving an unexpected post-operative course. Several logistic regression models were created to make a predictive model of adverse events. One model found only lack of stone clearance to be significant for increasing the likelihood of an adverse event. A second model determined that no residency year showed higher odds of adverse outcomes. CONCLUSIONS: URS has increased in prevalence in recent years, but overall complication rates are low. Resident level of experience does not appear to impact adverse event rate. Stone clearance during initial surgery appears to be the most important in avoiding adverse events. Further expansion of the database over time will improve our ability to predict adverse outcomes in this common procedure.