Prostate cancer reshapes the secreted and extracellular vesicle urinary proteomes.

Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.

Pilot study to assess the feasibility of self-administered, low-dose methoxyflurane for cystoscopic procedures.

INTRODUCTION: Methoxyflurane (MEOF) (Penthrox™) is an inhaled, self-administered, non-opioid analgesic approved by Health Canada for the short-term relief of moderate to severe acute pain associated with trauma or interventional medical procedures. In this pilot study, we evaluated the feasibility of using MEOF as an anesthetic agent in 11 patients undergoing outpatient cystoscopic procedures. METHODS: The average duration of the procedure was 24 (range 20-35) minutes and this included 10 minutes of administration time of the drug and five minutes of wait time before the procedure. The average monitoring time from start to end of the procedure was 23 (range 20-35) minutes and this included 15 minutes of monitoring post-procedure. On a scale of 0-10, patients on average rated the pain 4/10 (standard deviation [SD] 2.6). RESULTS: Global performance was on average 3/4 (SD 1.3) for the patients and 3/4 (SD 1.1) for the operator. Of the 11 patients, four reported adverse events; two experienced euphoria, one experienced dizziness, and one was unable to tolerate the medication. Two patients noted their adverse events to be of moderate intensity, while the other two were of mild intensity. None of the adverse events was deemed serious. CONCLUSIONS: Our findings in this pilot study provide proof of principle for the design of a randomized control trial to evaluate MEOF as an anesthetic in an outpatient cystoscopic procedural setting. As more urologic procedures are being performed in an outpatient setting, this may offer significant clinical benefit.

Prevalence and repair patterns of vesicovaginal fistula: a large retrospective population-based cohort analysis.

PURPOSE: Vesicovaginal fistulae (VVF) have a significant negative impact on quality of life, with failed surgical repair resulting in ongoing morbidity. Our aim was to characterize the rate of VVF repair and repair failures over time, and to identify predictors of repair failure. METHODS: We completed a population-based, retrospective cohort study of all women who underwent VVF repair in Ontario, Canada, aged 18 and older between 2005 and 2018. Risk factors for repair failure were identified using multivariable cox proportional hazard analysis; interrupted time series analysis was used to determine change in VVF repair rate over time. RESULTS: 814 patients underwent VVF repair. Of these, 117 required a second repair (14%). Mean age at surgery was 52 years (SD 15). Most patients had undergone prior gynecological surgery (68%), and 76% were due to iatrogenic injury. Most repairs were performed by urologists (60%). Predictors of VVF re-repair included iatrogenic injury etiology (HR 2.1, 95% CI 1.3-3.45, p = 0.009), and endoscopic repair (HR 6.1, 95% CI 3.1-11.1, p < 0.05,); protective factors included combined intra-abdominal/trans-vaginal repair (HR 0.51, 95% CI 0.3-0.8, p = 0.009), and surgeon years in practice (21 + years-HR 0.5, 95% CI 0.3-0.9, p = 0.005). Age adjusted annual rate of VVF repair (ranging from 0.8 to 1.58 per 100,000 women) and re-repair did not change over time. CONCLUSIONS: VVF repair and re-repair rates remained constant between 2005 and 2018. Iatrogenic injury and endoscopic repair predicted repair failure; combined intra-abdominal/trans-vaginal repair, and surgeon years in practice were protective. This suggests surgeon experience may protect against VVF repair failure.

The Use of Metformin in Overactive Bladder: A Retrospective Nested Case-control, Population-based Analysis.

OBJECTIVE: To determine if metformin use is associated with a lower rate of overactive bladder (OAB) medication use. Metformin facilitates the proliferation and migration of stem cells, which have been shown to improve bladder overactivity in animal models. METHODS: We conducted a retrospective nested case-control cohort study using population-based health-care administrative databases. Our cohort included patients with diabetes mellitus type 2 (DM2) ≥69years. Cases received a prescription for an OAB medication, matched with up to 4 controls based on age, sex, and DM2 diagnosis date. Exposure was a new prescription for metformin prior to receiving an OAB medication. Adjusted odds ratios were estimated using conditional logistic regression. Sensitivity analysis was done to assess the relationship between cumulative days' supply of metformin and use of OAB medications. RESULTS: Within our cohort of 2,233,084 patients with DM2, there were 16,549 case subjects who received a prescription for an OAB medication, and 64,171 matched controls. We found a positive association between OAB medication use and metformin use (adjusted odds ratios=1.07, 95% CI=1.03-1.12). Summed days' supply of metformin was also associated with OAB medication use, except when summed metformin days was >2220. CONCLUSION: Older patients with DM2 exposed to metformin had a slightly higher rate of OAB medication use, until 2220+ days' metformin supply, whereafter no association was found. This suggests no protective role for metformin in the prevention of OAB in this patient population.

Treatment Patterns in Men Prescribed Benign Prostatic Obstruction or Overactive Bladder Medications in Canada: A Retrospective Population-based Study.

OBJECTIVE: To characterize first therapeutic change and healthcare resource utilization in older men initiating an overactive bladder (OAB) or benign prostatic obstruction (BPO) medication. METHODS: A retrospective cohort study using health administrative data from ICES in Ontario, Canada (from April 01, 2010 to December 31, 2018) was conducted in men aged ≥66 years with ≥1 OAB (ß3 agonist, antimuscarinic) or BPO (α-blocker, 5-α-reductase inhibitor) prescription and ≥1-year postindex data (index=first observed dispensation). EXCLUSIONS: prescriptions for these drugs ≤1 year preindex, a related procedure ≤5 years. Patients were grouped by condition based on index prescription. Treatment changes in relation to OAB and BPO were characterized by type. Costs and healthcare resource utilization pre- and post-index were compared. RESULTS: Age, geographic region, and income were similar between groups. The most common initial treatments were antimuscarinics (78.1%) in the OAB group and alpha-blockers (86.4%) in the BPO group. The OAB group was more likely to experience a therapeutic change and had a shorter time to first change in therapy (78 [30,231] vs 104 [30,350] days) and higher mean healthcare costs both pre- ($12,354 vs $11,497) and postindex ($14,423 vs $12,852). The most common first therapeutic change in both groups was discontinuing treatment (OAB: 75.6%; BPO: 69.9%). CONCLUSION: Men initiating OAB medications changed therapy sooner than those initiating BPO medications. Most discontinued first-line therapy without initiating further treatment, suggesting unmet need in this population.

Predicting Mirabegron Treatment Response in Patients with Overactive Bladder: A Post Hoc Analysis of Data from Clinical Trials.

BACKGROUND: Many patients discontinue overactive bladder (OAB) treatment because of unmet treatment expectations and/or tolerability issues. OBJECTIVE: To develop a model for predicting the individual treatment response to mirabegron using patient baseline characteristics. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of data from eight global phase 2/3, double-blind, randomized, placebo- or active-controlled trials of mirabegron in adult patients with OAB. INTERVENTION: Mirabegron 50 mg once-daily monotherapy for ≥12 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary efficacy outcomes were the change in the mean number of micturitions and the number of incontinence episodes/24 h after 12 wk of treatment. Secondary efficacy outcomes were the change in the mean number of urgency episodes/24 h and the change in Symptom Bother score after 12 wk of treatment. Baseline demographic characteristics, OAB-related characteristics, and intrinsic and extrinsic factor variables were used to create multivariable linear regression models to predict the primary and secondary outcomes. RESULTS AND LIMITATIONS: Data for 3627 patients were included. The predicted effect of mirabegron 50 mg was an average of 2.5 fewer micturition episodes/24 h (95% confidence interval -2.85 to -2.14) and 0.81 fewer incontinence episodes/24 h (95% confidence interval -1.15 to -0.46) from baseline to week 12. A higher number of urgency episodes was predictive of a larger reduction in micturition episodes; body mass index (BMI) ≥30 kg/m2, OAB symptoms for ≥12 mo, and incontinence at baseline were predictive of a smaller reduction. Mixed stress/urgency incontinence and more than five urgency episodes per day were predictive of greater reductions in incontinence episodes. Reductions in urgency episodes and Symptom Bother score were also predicted with mirabegron. Limitations include the exclusion of placebo groups from the analysis and the use of clinical trial rather than real-world data. CONCLUSIONS: Data from the predictive models provide new insights into the effects of modifiable factors (such as BMI) and nonmodifiable factors on treatment outcomes with mirabegron 50 mg. PATIENT SUMMARY: This study aimed to identify factors that could predict how patients with overactive bladder respond to mirabegron treatment to help doctors effectively treat this condition. Mirabegron treatment was associated with a lower number of urinations and occurrences of urinary incontinence per day. Factors associated with worse responses to the medication included being obese.

A Retrospective Look at Term Outcomes After Definitive Surgical Repair for Traumatic Pelvic Fracture Urethral Injuries - Does Initial Management Make a Difference?

OBJECTIVE: To compare the long-term outcomes of initial management of pelvic fracture urethral injury (PFUI) in a large cohort of trauma patients undergoing urethral reconstruction. MATERIALS AND METHODS: 119 patients underwent urethral reconstruction by a single surgeon for PFUI at our center between 1998-2018. We compared initial PFUI management - primary realignment vs suprapubic tube (SPT) insertion alone. Multivariable Cox proportional hazard analysis was used to assess the association between primary intervention and the risk of having a complication. RESULTS: PFUI was initially managed with primary realignment (57%) or SPT alone (43%). Ultimately, all patients underwent a primary perineal urethral anastomosis after a median of 7 months (IQR: 5-14). Overall, 27 patients (23%) had 1 or more long-term complications after a median 25 months (IQR:7-66), including urethral stricture, de novo erectile dysfunction, and urinary incontinence. On multivariable analysis, initial PFUI management did not predict for complications. CONCLUSION: No difference was found in long-term outcomes after urethral reconstruction when comparing initial PFUI management of primary realignment vs SPT insertion.

Morbidity and predictors of delayed recognition of iatrogenic ureteric injuries.

INTRODUCTION: Although intraoperative iatrogenic ureteric injuries (IUI) are rare, significant consequences can occur if they are unrecognized at the time. The focus of our study is to characterize the associated morbidity and identify predictors of delayed recognition of IUI. METHODS: Sunnybrook Health Sciences Centre Research Ethics Board approved the study. Patients with a diagnosis of IUI between 2002 and 2020 were identified through an institutional electronic medical record system. Data pertaining to the demographic characteristics, diagnosis, and management of IUI, as well as overall outcomes were collected retrospectively. RESULTS: Of the 103 patients identified, 83% were female, 52% had previous abdominal surgery, and 18% had previous radiation. The median age was 67 (range 21-88) years. Twenty percent were not recognized at the time of surgery. Although delayed recognition was not a significant predictor for poor outcome after subsequent repair (i.e., hydronephrosis, ureteric stricture/obstruction), it was associated with substantial morbidity to the patient (i.e., additional procedures) and increased cost to the healthcare system (i.e., longer hospital stay, re-admission to hospital). Patients who underwent laparoscopic surgery had an 11 times more likely chance of having an unrecognized IUI as compared to those who underwent open surgery (odds ratio 11.515, p=0.0001). CONCLUSIONS: Delayed recognition of IUI may be associated with considerable adverse effects. In this retrospective case series, we identified laparoscopic surgery as a significant predictor for delayed recognition of IUI. This information underscores the need for future studies to facilitate intraoperative identification of ureteric injuries, particularly during laparoscopic procedures.

Management of high-grade renal traumas with collecting system injuries.

INTRODUCTION: Approximately 50% of all high-grade renal traumas (HGRT, American Association for the Surgery of Trauma [AAST] grade 4/5) have associated collecting system injuries. Although most of these collecting system injuries will heal spontaneously, approximately 20-30% of these injuries are managed with ureteric stents. The objective of the study was to review the management of HGRT with collecting system injuries in a level 1 trauma center. METHODS: This was a single-center, retrospective cohort study of trauma patients with HGRT and collecting system injuries from 1998-2019. RESULTS: We identified 147 patients with HGRT. Of the 105 patients who had trauma computed tomography (CT) imaging within 24 hours, 46 were found to have collecting system injuries. Seven of these patients underwent intervention based on initial CT findings; the remaining 39 patients with urinary extravasation were conservatively managed. Of the 37 patients who underwent reimaging, 22 (59%) demonstrated a stable or resolving collection and 15 (41%) demonstrated continued urinary extravasation. Resolution of extravasation on subsequent imaging was observed in 10 of those patients, while five patients (14%) required intervention (four stents, one percutaneous drain) for symptoms/signs of urinary extravasation. CONCLUSIONS: In this study, most patients with HGRT and collecting system injuries did not require intervention unless the patient became symptomatic. The majority of collecting system injuries resolved with no intervention. This study underscores the need for future prospective trials to investigate the necessity of intervening in HGRT collecting system injuries and, secondarily, the need for routine re-imaging in these asymptomatic patients.

Diagnosis and Management of Kock Afferent Nipple Valve Obstruction.

OBJECTIVE: To characterize afferent nipple valve obstruction in Kock diversions presenting with hydronephrosis and discuss appropriate work-up and management. METHODS: We retrospectively reviewed 7 cases of afferent nipple valve obstruction. RESULTS: The median time from diversion creation to afferent nipple valve intervention was 17-years. Presentations included febrile-UTIs, worsening renal function and hydronephrosis. All patients underwent upper tract imaging confirming bilateral hydronephrosis or hydronephrosis of a solitary kidney followed by nephrostomy tube insertion to drain the obstructed kidney(s). On nephrostogram assessment afferent nipple valve obstruction was confirmed by a lack of contrast passing through the valve. In 4 of these patients the afferent valve could not be cannulated while in one patient endoscopic retrograde balloon dilation was performed but failed after 12-months. One patient had successful antegrade balloon dilation (four-years follow-up). In five patients and the one patient who failed retrograde balloon dilation open surgical repair of the afferent nipple valve was successful (median follow-up time 5-years). CONCLUSION: It is essential to consider afferent nipple valve obstruction in a patient with a Kock diversion presenting with bilateral hydronephrosis/hydronephrosis of a solitary kidney, even after many years following the original diversion. Appropriate work-up consists of upper tract imaging, endoscopy and retrograde studies or nephrostomy insertion with nephrostogram. Management options include endoscopic retrograde or antegrade balloon dilation or valve incision. Failing that, surgical repair may be successful with long-term upper tract preservation.

Urinary retention after AdVance™ Sling: A multi-institutional retrospective study.

AIMS: To identify risk factors for urinary retention following AdVance™ Sling placement using preoperative urodynamic studies to evaluate bladder contractility. METHODS: A multi-institutional retrospective review of patients who underwent an AdVance Sling for post-prostatectomy stress urinary incontinence from 2007 to 2019 was performed. Acute urinary retention (AUR) was defined as the complete inability to void or elevated post-void residual (PVR) leading to catheter placement or the initiation of intermittent catheterization at the first void trial postoperatively. Bladder contractility was evaluated based on preoperative urodynamics. RESULTS: Of the 391 patients in this study, 55 (14.1%) experienced AUR, and 6 patients (1.5%) had chronic urinary retention with a median follow-up of 18.1 months. In total, 303 patients (77.5%) underwent preoperative urodynamics, and there was no significant difference between average PdetQmax (26.4 vs. 27.4 cmH2 O), Qmax (16.6 vs. 16.2 ml/s), PVR (19.9 vs. 28.1 ml), bladder contractility index (108 vs. 103) for patients with or without AUR following AdVance Sling. Impaired bladder contractility preoperatively was not predictive of AUR. Time to postoperative urethral catheter removal was predictive of AUR (odds ratio, 0.83; 95% confidence interval, 0.73-0.94; p = .003). CONCLUSIONS: Chronic urinary retention after AdVance Sling placement is uncommon and acute retention is generally self-limiting. No demographic or urodynamic factors were predictive of AUR. Patients who developed AUR were more likely to have their void trials within 2 days following AdVance Sling placement versus longer initial catheterization periods, suggesting that a longer duration of postoperative catheterization may reduce the occurrence of AUR.

Triamcinolone acetonide injections for the treatment of recalcitrant post-radical prostatectomy vesicourethral anastomotic stenosis: A retrospective look at efficacy and safety.

INTRODUCTION: We aimed to evaluate the success of bladder neck injections of triamcinolone at the time of transurethral bladder neck incision (BNI) for prevention of recurrent vesicourethral anastomotic stenosis (VUAS) following prostate cancer treatment. METHODS: This is a retrospective cohort study examining patients with recurrent VUAS post-radical prostatectomy (RP) ± radiation treated with triamcinolone injections at the time of BNI. VUAS was diagnosed by symptoms followed by cystoscopy or urethrography. The outpatient procedures were done under general anesthesia. Cold knife incisions were made at the three, nine, and 12 o'clock BN positions, followed by triamcinolone injections (4 mg/mL) into the three and nine o'clock incision sites. Treatment outcomes were determined with cystoscopy. RESULTS: Eighteen men underwent 25 procedures over a four-year period. Median age at diagnosis of VUAS was 65 (interquartile range [IQR] 61-68); median time to VUAS from RP was eight months (IQR 5-12). Fourteen patients (78%) had radiation treatment. The cohort had 128 unsuccessful VUAS treatments, with a median of five failed treatments per patient (IQR 3-10). Failed treatments included BN dilation, BNI, BN injection of mitomycin C, and urethral stent placement. Success rate after a mean of 16.3 months (standard deviation [SD] 8.1) from the time of triamcinolone injection was 83% (15/18). Six patients went on to have successful incontinence surgery. Five patients (28%) had treatment complications (bleeding, urinary tract infection, pain, and urinary extravasation). The three non-responders are stable and awaiting re-treatment with triamcinolone injection. CONCLUSIONS: Triamcinolone bladder neck injections for post-RP VUAS are a useful and safe treatment for recurrent stenosis.

Impact of Delayed Recognition of Iatrogenic Ureteral Injury in a Retrospective Population-Based Study.

INTRODUCTION: Iatrogenic ureteral injuries (IUIs) are rare but can lead to significant consequences if unrecognized at the time of injury. We compare the impact of immediate vs delayed recognition of IUIs on clinical, cost and health care utilization outcomes. METHODS: We conducted a population-based retrospective cohort study on patients who had a diagnosis of an IUI between 2003 and 2018. The primary independent variable was the time of diagnosis of IUI. The primary clinical outcomes evaluated included renal impairment and a composite outcome: hydronephrosis or stricture. Secondary outcomes included total direct health care costs and health care utilization. RESULTS: We identified 1,193 patients who experienced an IUI, 25.2% of whom had a delay in recognition. Delayed recognition of IUI was associated with hydronephrosis or stricture within 1 year following treatment of IUI (OR 2.27, 95% CI 1.69-3.04, p <0.0001) and renal impairment within 2 years following treatment of IUI (OR 2.69, 95% CI 1.84-3.94, p <0.0001) compared to immediate diagnosis. Total health care costs (incident rate ratio [IRR] 2.06, 95% CI 1.89-2.24, p <0.0001), emergency department visits (IRR 2.07, 95% CI 1.77-2.43, p <0.0001), hospitalizations (IRR 1.62, 95% CI 1.48-1.78, p <0.0001) and outpatient urology visits (IRR 1.45, 95% CI 1.31-1.60, p <0.0001) were significantly higher in those with delayed recognition compared to immediate. Previous radiation was significantly associated with delayed recognition of IUI (OR 0.64, 95% CI 0.42-0.97, p=0.04). CONCLUSIONS: Delayed recognition of IUI is associated with significant clinical, cost and health care utilization consequences.

Urethrovaginal fistula repair with or without concurrent fascial sling placement: A retrospective review.

INTRODUCTION: We sought to review outcomes of urethrovaginal fistula (UVF) repair, with or without concurrent fascial sling placement. METHODS: All patients diagnosed with UVF at our center from 1988-2017 were included in this study. Patient charts were reviewed from a prospectively kept fistula database, and patient characteristics and surgical outcomes were described. Descriptive statistics were applied to compare complication rates between patients with or without fascial sling placement at the time of UVF repair. RESULTS: A total of 41 cases of UVF were identified, all of which underwent surgical repair. Median age at diagnosis was 49 years (interquartile range [IQR] 35-62). All patients had undergone pelvic surgery. UVF etiology was secondary to stress urinary incontinence (SUI) surgery in 17 patients (41%) and urethral diverticulum repair in seven patients (17%). The most common presenting symptom was continuous incontinence in 19 patients (46%). Nineteen patients had a fascial sling placed at the time of surgery (46%), with no significant difference in complication rates (26% vs. 23%, p=0.79). Two patients had Clavien-Dindo grade I complications (5%) and one had a grade III complication (2%). Four patients had long-term complications (10%), including urinary retention, chronic pain, and urethral stricture. Two patients had UVF recurrence (5%). Median followup after surgery was 21 months (IQR 4-72). CONCLUSIONS: UVF should be suspected in patients with continuous incontinence following a surgical procedure. Most UVF surgical repairs are successful and can be done with concurrent placement of a fascial sling.

Patients' perspective of telephone visits during the COVID-19 pandemic.

INTRODUCTION: With the cessation of non-urgent clinical office visits due to the coronavirus, there has been a rapid shift to telephone and other virtual visits in outpatient practice. We conducted a survey to evaluate patients' perspective of telephone visits during the COVID-19 pandemic. METHODS: Patients receiving a scheduled telephone call as a virtual visit from urologists at our clinic were asked to participate in a three-minute, self-administered, online questionnaire. After verbal permission was obtained, the survey was emailed to each participant. The outcomes evaluated were telephone visit satisfaction and preference for type of appointment. Non-parametric tests were used to analyze the results. The study was approved by the Sunnybrook Research Ethics Board. RESULTS: A total of 102 participants were included; 96% of participants assessed the telephone visit as a positive experience in every survey question, while 45% expressed no preference. In those who expressed a preference, this was evenly divided between in-office visits and phone visits (p=0.0614). Participants who lived more than 75 km from the hospital were less likely to prefer an in-office visit compared to those residing locally (U=433, p=0.006; odds ratio 0.29, 95% confidence interval 0.106-0.779, p=0.0142). CONCLUSIONS: In this survey, most participants assessed the telephone visit positively. Almost half had no preference and a similar proportion expressed a preference for in-office and telephone visits. Patients who resided farther from the hospital were more likely to prefer the telephone visit. This is the first study that we know of to assess patients' preferences regarding remote encounters in urology.