Repeat Transurethral Resection of Muscle-invasive Bladder Cancer Prior to Radical Cystectomy is Prognostic but Not Therapeutic.

PURPOSE: We sought to evaluate the impact of repeat transurethral resection of bladder tumor prior to radical cystectomy on oncologic outcomes in a contemporary cohort at a tertiary care center. MATERIALS AND METHODS: An Institutional Review Board approved review of 657 patients diagnosed with muscle-invasive bladder cancer who underwent radical cystectomy at our institution for clinical stage T2 urothelial carcinoma between 2005 and 2017 was performed. Patients with and without repeat transurethral resection of bladder tumor were matched 1-to-1 by propensity score. Matching was done by age, gender, receipt of neoadjuvant chemotherapy, preoperative hydronephrosis, variant histology, lymphovascular invasion, or carcinoma in situ on index transurethral resection of bladder tumor. RESULTS: A total of 548 patients with muscle-invasive bladder cancer were included after matching (2 groups of 274 patients). Kaplan-Meier estimates of recurrence-free and overall survival demonstrated no significant difference based upon performance of repeat transurethral resection of bladder tumor (P = 1.0 and P = .3, respectively). When outcomes were stratified by pathology of repeat transurethral resection of bladder tumor specimens, those with pT0 had superior recurrence-free and overall survival compared to those with residual muscle invasive disease (P < .001 and P = .001, respectively). Notably, more than 60% of patients who were pT0 on repeat transurethral resection of bladder tumor had residual disease at the time of radical cystectomy. CONCLUSIONS: Repeat transurethral resection of bladder tumor prior to radical cystectomy, irrespective of receipt of neoadjuvant chemotherapy, was not associated with improved survival outcomes in this propensity score matched muscle-invasive bladder cancer cohort. The absence of residual tumor on pathological evaluation of repeat transurethral resection of bladder tumor specimen was prognostic and was associated with improved survival outcomes. However, a large percentage of patients with pT0 disease on repeat transurethral resection of bladder tumor had residual disease on radical cystectomy pathology.

All High-Grade Ta Tumors Should Be Classified as High Risk: Bacillus Calmette-Guérin Response in High-Grade Ta Tumors.

PURPOSE: There is variation amongst guidelines with respect to risk stratification of Ta tumors, specifically high-grade (HG) Ta tumors. We sought to investigate the response of all Ta tumors to bacillus Calmette-Guérin (BCG) and compare response rates based on European Association of Urology (EAU) classification as intermediate- (IR) or high-risk (HR). MATERIALS AND METHODS: An institutional review of all patients who received adequate BCG from 2000-2018 was conducted. EAU 2021 prognostic risk groups were used to stratify patients including by the newly proposed adverse risk factors. RESULTS: When patient with Ta tumors were stratified into IR and HR, 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. BCG unresponsiveness developed in 13% of HR HG Ta tumors and 14% of IR HG Ta tumors compared to 0.0% of IR LG Ta tumors (p=0.003). While no patients with IR LG Ta tumors progressed, progression rates were similar in HR HG Ta and IR HG Ta tumors (≥T2: 5.9% and 6.5%; [Formula: see text]T1: 13% and 13%, respectively). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of number of EAU risk factors present (p=0.9, p=0.8 and p=0.9, respectively). CONCLUSIONS: All HG Ta tumors, regardless of EAU risk stratification, have inferior response to BCG and increased rates of progression compared to IR LG Ta tumors. EAU clinical risk factors did not improve prediction of oncologic outcomes among HG Ta patients who received adequate BCG. These data support consideration of all HG tumors as high risk.

Critical analysis of quality of life and cost-effectiveness of enhanced recovery after surgery (ERAS) for patient's undergoing urologic oncology surgery: a systematic review.

PURPOSE: Enhanced recovery after surgery (ERAS) protocols have been implemented across a variety of disciplines to improve outcomes. Herein we describe the impact of ERAS on quality of life (QOL) and cost for patients undergoing urologic oncology surgery. METHODS: A systematic literature search using the MEDLINE, Scopus, Clinictrials.gov, and Cochrane Review databases for studies published between 1946 and 2020 was conducted. Articles were reviewed and assigned a risk of bias by two authors and were included if they addressed ERAS and either QOL or cost-effectiveness for patients undergoing urologic oncology surgery. RESULTS: The literature search yielded a total of 682 studies after removing duplicates, of which 10 (1.5%) were included in the review. Nine articles addressed radical cystectomy, while one addressed ERAS and QOL for laparoscopic nephrectomy. Six publications assessed the impact of ERAS on QOL domains. Questionnaires used for assessment of QOL varied across studies, and timing of administration was heterogeneous. Overall, ERAS improved patient QOL during early phases of recovery within the realms of bowel function, physical/social/cognitive functioning, sleep and pain control. Costs were assessed in 4 retrospective studies including 3 conducted in the United States and one from China all addressing radical cystectomy. Studies demonstrated either decreased costs associated with ERAS as a result of decreased length of stay or no change in cost based on ERAS implementation. CONCLUSION: While limited studies are published on the subject, ERAS implementation for radical cystectomy and laparoscopic nephrectomy improved patient-reported QOL during early phases of recovery. For radical cystectomy, there was a decreased or neutral overall financial cost associated with ERAS. Further studies assessing QOL and cost-effectiveness over the entire global period of care in a variety of urologic oncology surgeries are warranted.

100 years of Bacillus Calmette-Guérin immunotherapy: from cattle to COVID-19.

Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.

Current Therapy and Emerging Intravesical Agents to Treat Non-Muscle Invasive Bladder Cancer.

Transurethral resection of bladder tumor remains the cornerstone of non-muscle invasive bladder cancer management, proper risk stratification, and appropriate selection of adjuvant therapy. A single, postoperative dose of intravesical chemotherapy is used for low-risk patients; patients with high-grade, high-risk disease should receive intravesical bacillus Calmette-Guérin (BCG) induction and maintenance therapy. For patients who develop BCG-unresponsive disease, cystectomy remains the standard of care. Pembrolizumab and valrubicin are approved in the BCG failure setting and as alternative treatments to cystectomy. Nadofaragene firadenovec, vicinium, hyperthermic chemotherapy, and various combination therapies are under investigation as treatment options for patients in the salvage setting.

Impact of upper tract urothelial carcinoma on response to BCG in patients with non-muscle-invasive bladder cancer.

OBJECTIVE: To evaluate the impact of upper tract urothelial carcinoma (UTUC) on bacillus Calmette-Guerin (BCG) response and progression in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We performed an institutional review board-approved review of patients with NMIBC treated with adequate intravesical BCG, as defined by the US Food and Drug Administration, at our institution between 2000 and 2018. Patients were stratified by presence of any UTUC and time of UTUC diagnosis (preceding vs synchronous to NMIBC diagnosis or metachronous disease after NMIBC diagnosis). Descriptive statistics were used to summarize the data overall and by groups, and t-tests or Wilcoxon's rank sum tests and Pearson's chi-squared or Fisher's exact tests were used to analyse continuous and categorical data, respectively. RESULTS: Of 541 patients with NMIBC treated with adequate BCG, 59 (10.9 %) were diagnosed with UTUC. Of these, 34 had a history of UTUC prior to NMIBC (UTUC-P; median [interquartile range {IQR}] 13.1 [7.4-27.6] months prior), while 25 developed UTUC after diagnosis of NMIBC (six synchronous and 19 metachronous; median [IQR] 12.1 [1.7-28.1] months after). Compared to the non-UTUC group, patients with UTUC-P were more likely to exhibit Tis without papillary tumour in the bladder (20.6% vs 5.0%; P < 0.001), but were less likely to have T1 disease on index transurethral resection (8.8% vs 49.4%; P < 0.001). Patients with UTUC-P developed more recurrences (55.9% vs 34.0%; P = 0.010), any stage/grade progression (23.5% vs 9.8%; P = 0.012) and progression to muscle-invasive or metastatic disease (17.6% vs 6.4%; P = 0.014). The presence of high-grade UTUC-P compared to low-grade UTUC-P was associated with increased NMIBC recurrence (68.2% vs 25.0%; P = 0.049). There was no significant difference in rates of recurrence or progression based on timing of UTUC with respect to the index bladder tumour, although this analysis was limited by small numbers. CONCLUSIONS: Presence of UTUC prior to a diagnosis of NMIBC was associated with an almost twofold increased recurrence and progression rates after adequate BCG therapy. This should be considered when counselling patients and designing cohorts for clinical trials.

The association of Coronavirus Disease-19 mortality and prior bacille Calmette-Guerin vaccination: a robust ecological analysis using unsupervised machine learning.

Population-level data have suggested that bacille Calmette-Guerin (BCG) vaccination may lessen the severity of Coronavirus Disease-19 (COVID-19) prompting clinical trials in this area. Some reports have demonstrated conflicting results. We performed a robust, ecologic analysis comparing COVID-19 related mortality (CRM) between strictly selected countries based on BCG vaccination program status utilizing publicly available databases and machine learning methods to define the association between active BCG vaccination programs and CRM. Validation was performed using linear regression and country-specific modeling. CRM was lower for the majority of countries with a BCG vaccination policy for at least the preceding 15 years (BCG15). CRM increased significantly for each increase in the percent population over age 65. A higher total population of a country and BCG15 were significantly associated with improved CRM. There was a consistent association between countries with a BCG vaccination for the preceding 15 years, but not other vaccination programs, and CRM. BCG vaccination programs continued to be associated with decreased CRM even for populations < 40 years old where CRM events are less frequent.

Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design.

PURPOSE: Recurrent disease after bacillus Calmette-Guérin treatment presents a therapeutic challenge. To aid trial development, the U.S. Food and Drug Administration defined "adequate bacillus Calmette-Guérin" therapy and adopted the "bacillus Calmette-Guérin unresponsive" disease state. Available data for efficacy benchmark comparison are outdated, leading to concerns about appropriate control arms and sample size calculations. We describe a contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with intravesical bacillus Calmette-Guérin, and provide benchmark outcomes data. MATERIALS AND METHODS: We retrospectively reviewed patients receiving adequate bacillus Calmette-Guérin therapy at a tertiary cancer center between January 2004 and August 2018. Unadjusted univariable analysis was conducted using the Pearson chi-square test. Kaplan-Meier estimates for recurrence-free survival-high grade, progression-free survival-muscle-invasive bladder cancer and overall survival were used to create survival curves and compared using the log-rank test. RESULTS: Of the 542 patients who received adequate bacillus Calmette-Guérin, 518 (90%) had European Association Urology high risk disease, with carcinoma in situ present in 175 (32%). With a median followup of 47.8 months, freedom from high grade recurrence at 1, 3 and 5 years was 81%, 76% and 74%, respectively, and progression-free survival was 97%, 93% and 92%. Progression to muscle invasion at 5 years was exclusively seen in patients with high risk disease (progression-free survival 91%; log-rank test, p=0.024). CONCLUSIONS: A contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with adequate bacillus Calmette-Guérin demonstrated markedly better outcomes than seen in prior studies. These data could be used in the design of clinical trials, to guide power calculations, as well as serve as benchmarks for comparison to evaluate nonrandomized studies.

The obesity paradox: defining the impact of body mass index and diabetes mellitus for patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin.

OBJECTIVES: To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette-Guérin (BCG) in a contemporary cohort. PATIENTS AND METHODS: We performed an Institutional Review Board-approved database review to identify patients with non-muscle-invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. RESULTS: A total of 579 patients (median follow-up 4.6 years) received BCG induction for NMIBC; 90% had high-grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and ß-blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. CONCLUSION: Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted.

The role of the urologist, BCG vaccine administration, and SARS-CoV-2: An overview.

OBJECTIVES: To summarize the available literature regarding bacillus Calmette-Guerin (BCG) administration, severe acute respiratory syndrome conoravirus-2 (SARS-CoV-2), and the resulting clinical condition coronavirus disease (COVID-19) in light of recent epidemiologic work suggesting decreased infection severity in BCG immunized populations while highlighting the potential role of the urologist in clinical trials and ongoing research efforts. MATERIALS AND METHODS: We reviewed the available literature regarding COVID-19 and BCG vaccination. Specifically, the epidemiologic evidence for decreased COVID-19 morbidity in countries with BCG vaccination programs, current clinical trials for BCG vaccination to protect against COVID-19, potential mechanisms and rationale for this protection, and the role of the urologist and urology clinic in providing support and/or leading ongoing efforts. RESULTS: Epidemiologic evidence suggests that the crude case fatality rates are lower for countries with BCG vaccination compared to those without such programs. Four prospective, randomized clinical trials for BCG vaccination were identified including NCT04348370 (BADAS), NCT04327206 (BRACE), NCT04328441 (BCG-CORONA), and NCT04350931. BCG administration may contribute to innate and adaptive immune priming with several opportunities for translational research. CONCLUSIONS: The urologist's expertise with BCG and the infrastructure of urologic clinics may afford several opportunities for collaboration and leadership to evaluate and understand the potential role of BCG in the current COVID-19 pandemic.

Patterns of metastases of prostatic ductal adenocarcinoma.

BACKGROUND: The current study was conducted to investigate the patterns of metastases in men with metastatic prostatic ductal adenocarcinoma (DAC) and recurrence patterns after therapy. METHODS: All patients with a new diagnosis of DAC with de novo metastases and those with localized disease who developed metastases after treatment and were treated at the study institution from January 2005 to November 2018 were included. All patient and tumor characteristics and outcome data were collected. RESULTS: A total of 164 patients (37.7%) had metastatic DAC, including 112 with de novo metastases and 52 who developed metastases after treatment. Men with de novo metastases were found to have a significantly higher median prostate-specific antigen level and International Society of Urological Pathology grade but a lower cT3 and/or T4 classification compared with those with metastases that developed after treatment (all P < .05). Approximately 87% of men with de novo metastases progressed despite multiple systemic therapies, 37.6% required intervention for the palliation of symptoms, and 10.1% responded to systemic therapy and underwent treatment of the primary tumor. Men with de novo metastatic DAC and those who developed metastases after treatment had multiple metastatic sites (including bone and viscera), with higher rates of lung metastases noted in the posttreatment group (23.2% vs 44.2%; P = .01). A total of 45 patients who were treated with curative intent developed metastases at a median of 22 months (range, 0.9-74.8 months) after treatment, at low prostate-specific antigen levels (median, 4.4 ng/mL [interquartile range, 1.7-11.1 ng/mL]). CONCLUSIONS: The current study described the metastatic patterns of DAC in both patients with de novo metastatic disease and those who later progress to metastases. Men receiving treatment for DAC with curative intent require stringent long-term follow-up with imaging modalities, including chest imaging given the predilection toward lung metastases noted among these patients.

Combination Intravesical Therapy.

After Bacillus Calmette-Guerin (BCG) failure, there is likely a 6- to 24-month window whereby salvage intravesical therapy might allow for preservation of the bladder without disease worsening. Combination intravesical, salvage therapy for nonmuscle invasive bladder cancer represents a promising avenue for treatment in patients unfit or unwilling to undergo cystectomy. BCG with concomitant immune stimulating agents or immune checkpoint inhibitors, combination chemotherapy regimens, such as gemcitabine and docetaxol, and novel agents currently in clinical trials provide hope for a bladder-sparing alternative for patients after BCG failure.

Nongenitourinary complications associated with robot-assisted laparoscopic and radical retropubic prostatectomy: A single institution assessment of 1,100 patients over 11 years.

OBJECTIVES: Robot-assisted laparoscopic prostatectomy (RALP) and radical retropubic prostatectomy (RRP) provide similar outcomes in terms of biochemical recurrence, postoperative continence, and erectile function. Little is known about other complications of these procedures. To further address this, we examined patient outcomes at our institution over an 11-year period. METHODS: A retrospective review of 1,113 prostatectomies (646 RALP and 467 RRP) performed over 11 years by 9 different urologists at a single U.S. academic center was undertaken. Preoperative data collected included age, body mass index (BMI), prostate-specific antigen (PSA), biopsy Gleason score, and tumor (T) stage. Postoperative data included pelvic lymph node dissection (PLND), intensive care unit (ICU) admission rate, length of stay (LOS), ileus, wound infection rate, umbilical hernia occurrence, inguinal hernia occurrence, ophthalmic complications, upper and lower extremity complications, postoperative neuropathy, residual cancer, and cancer recurrence. RESULTS: Significant differences between RRP and RALP included performance of PLND (54.1% vs. 35.9%, P < 0.0001 respectively), umbilical hernia rates (2.4% vs. 6.5%, P = 0.0015, respectively), inguinal hernia rates (5.4% vs. 2.5%, P = 0.0101, respectively), and LE complications (9.0% vs. 5.1%, P = 0.016, respectively). No difference was observed regarding ICU admission, LOS, ileus, wound infection, and ophthalmic or upper extremities complications. CONCLUSIONS: RRP patients were more likely to have lower extremity complications and inguinal herniae, whereas RALP patients had an increased umbilical hernia rate and a trend toward more corneal abrasions.

Pilot Study to Determine Optimal Stent Duration Following Ureteroscopy: Three versus Seven days.

BACKGROUND/AIMS: Many providers elect to place a stent following ureteroscopy for nephrolithiasis, but little data exists on the optimal duration to leave a stent. We sought to determine whether there are any differences in post-operative outcomes for patients with a 3 versus 7-day stent following ureteroscopy. METHODS: We retrospectively reviewed 247 patients who underwent unilateral ureteroscopy with lithotripsy, 79 of whom removed a stent with an extraction string at 3 or 7 days post-operatively. These 2 groups were compared with regard to demographic information, pre-operative variables, and post-operative outcomes. RESULTS: Of all patients, 33% experienced a post-procedure related event (phone call, extra clinic visit, and emergency department visit) within 30 days of their procedure, 39% of 3-day stent patients compared to 21% of 7-day patients (p = 0.11). Within the 3 days following stent removal, 3-day stent patients were significantly more likely to have a post-procedure related event than 7-day patients (23 vs. 3%, p = 0.026). CONCLUSION: One third of patients with a post-operative ureteral stent will seek medical care in the 30 days following ureteroscopy. Leaving a stent for 3 versus 7 days may lead to worse outcomes with regard to post-operative events and fank pain.

Increasing the size of ureteral access sheath during retrograde intrarenal surgery improves surgical efficiency without increasing complications.

PURPOSE: To directly compare intraoperative and post-operative outcomes and complications between three groups undergoing ureteroscopy: no ureteral access sheath, 12/14 Fr and larger 14/16 Fr ureteral access sheaths (UAS). METHODS: We retrospectively reviewed demographic, pre-operative, intraoperative, and post-operative data of 257 patients who underwent ureteroscopy for nephrolithiasis by a single surgeon from January 2013 through July 2015. Patients were separated into three groups: no UAS, a 12/14 Fr UAS, or 14/16 Fr UAS. Outcomes included differences in stone-free rate, post-procedure-related events (PRE), ureteral injury rate (measured by early post-operative hydronephrosis), and post-operative complications. RESULTS: A UAS was used in 65.4% (168/257) patients, with 73.8% (124/168) utilizing a 12/14 Fr UAS and 26.2% (44/168) utilizing a 14/16 Fr UAS. Those patients in whom a 14/16 Fr UAS was employed had greater stone burden compared to the 12/14 Fr UAS group (180.8 ± 18.0 vs. 104 ± 9.1 mm2, p < 0.001). When comparing 12/14 Fr and 14/16 Fr ureteral access sheaths, there was no significant difference in ureteral injury rate, complications (10.5 vs. 11.4%, respectively; p = 0.87), or overall stone-free rate (78.1 vs. 81.3%, p = 0.70). The mean amount of stone burden treated per minute of operative time was more than 30% higher in the 14/16 Fr UAS group compared to 12/14 Fr UAS group (2.11 vs. 1.62 mm2/min; p = 0.01). CONCLUSION: The use of a 14/16 Fr UAS allows for similar stone-free rate and improved operative efficiency with no increased risk of ureteral injury or post-operative complications when compared to the 12/14 Fr UAS.

Testosterone Therapy: Review of Clinical Applications.

Testosterone therapy is increasingly common in the United States, and many of these prescriptions are written by primary care physicians. There is conflicting evidence on the benefit of male testosterone therapy for age-related declines in testosterone. Physicians should not measure testosterone levels unless a patient has signs and symptoms of hypogonadism, such as loss of body hair, sexual dysfunction, hot flashes, or gynecomastia. Depressed mood, fatigue, decreased strength, and a decreased sense of vitality are less specific to male hypogonadism. Testosterone therapy should be initiated only after two morning total serum testosterone measurements show decreased levels, and all patients should be counseled on the potential risks and benefits before starting therapy. Potential benefits of therapy include increased libido, improved sexual function, improved mood and well-being, and increased muscle mass and bone density; however, there is little or mixed evidence confirming clinically significant benefits. The U.S. Food and Drug Administration warns that testosterone therapy may increase the risk of cardiovascular complications. Other possible risks include rising prostate-specific antigen levels, worsening lower urinary tract symptoms, polycythemia, and increased risk of venous thromboembolism. Patients receiving testosterone therapy should be monitored to ensure testosterone levels rise appropriately, clinical improvement occurs, and no complications develop. Testosterone therapy may also be used to treat hypoactive sexual desire disorder in postmenopausal women and to produce physical male sex characteristics in female-to-male transgender patients.

Bladder Neck Contracture Following Radical Retropubic versus Robotic-Assisted Laparoscopic Prostatectomy.

INTRODUCTION: Radical retropubic prostatectomy (RRP) and robotic-assisted laparoscopic prostatectomy (RALP) are co-standard surgical therapies for localized prostatic adenocarcinoma. These surgical modalities offer similar outcomes; however, lower rate of bladder neck contracture (BNC) is amongst the touted benefits of RALP. The differences between approaches are largely elucidated through multiple-surgeon comparisons, which can be biased by differential experience and practice patterns. We aimed to eliminate inter-surgeon bias through this single-surgeon comparison of BNC rates following RRP and RALP. MATERIALS AND METHODS: We retrospectively reviewed all RRPs and RALPs performed by one surgeon over 4 years. We compared clinical characteristics, intraoperative and postoperative outcomes. RESULTS: RRP patients had more advanced cancer and a higher biochemical recurrence rate. No significant differences were noted between groups in rates of anastomotic leakage, BNC, or 12-month postoperative pad-free continence. CONCLUSION: RRP offers similar outcomes to RALP with regard to postoperative urinary extravasation, urinary continence, and BNC.