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Objective: The COVID-19 pandemic resulted in decreased prostate specific antigen (PSA) testing for prostate cancer screening and its impact remains uncharacterized. Our objective was to compare incident PSA testing rates, PSA levels, and prostate cancer treatment rates before and during the pandemic after the state of emergency (SoE) was declared., Materials and Methods: This was a population-based, retrospective cohort study among men 50-80 years of age in Ontario, Canada undergoing incident PSA testing from November 23, 2018 to July 9, 2021. Working backwards and forwards from the date of the province-wide SoE (March 17, 2020), 30-day time periods were constructed during which incident PSA testing rates were measured. Our primary outcome was the rate of incident PSA testing. Secondary endpoints included comparison of incident PSA levels and prostate cancer treatment rates., Results: We identified 835,402 men who underwent incident PSA testing. There was a 20% decrease in PSA testing after the SoE (RR = 0.80,95% CI: 0.800.81, P < .001). There was a higher proportion of extreme PSA levels after the SoE with a higher proportion of patients with a PSA >20 ng/mL (rate ratio = 1.63,95% CI: 1.54-1.73, P < .0001) and >100 ng/mL (rate ratio = 1.98,95% CI: 1.77-2.20, P < .0001). This effect was highest for those aged 50-59 years. More patients required active treatment (5,201,59.5% prior to the pandemic vs. 5,072,64.2%, P < .001 after the SoE declaration)., Conclusions: The COVID-19 SoE resulted in patients experiencing a 2-fold increase in the risk of having an extreme PSA level and higher odds of treatment. Future studies are needed to assess the impact on the rates of advanced prostate cancer and cancer-specific mortality., Competing Interests: Disclosure SH reports receiving grants from Astellas Pharma Canada, Allergan, AMI, Boston Scientific, and Pfizer all outside the submitted work. All other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Individuals with spina bifida (SB) may experience negative health outcomes because of an informal transition from pediatric to adult care that results in using the emergency room (ER ) for non-acute health problems., Methods: We conducted a retrospective, population-based cohort study of all people with SB in Ontario, Canada turning 18 years old between 2002 and 2011. These patients were followed for five years before and after age 18. Primary outcome was the annual rate of ER visits. Secondary outcomes included rates of hospitalization, surgery, primary care, and specialist outpatient care. We estimated the association between age and primary and secondary outcomes using negative binomial growth curve models, adjusting for patient-level baseline covariates., Results: Among the 1215 individuals with SB, there was no trend of ER visits seen with increasing age (relative risk [RR ] 0.99, 95% confidence interval [CI] 0.98-1.02); however, there was a significant increase in the rate of ER visits associated with turning 18 years (RR 1.14, 95% CI 1.03-1.27). Turning 18 years old was also associated with a decreased rate of hospital admissions (RR 0.79, 95% CI 0.66-0.95) and no change in surgeries (RR 0.80, 95% CI 0.64-1.02). Visits to primary care physicians remained stable over the same period (RR 0.96, 95% CI 0.90-1.01), while visits to SB-focused specialists decreased after age 18 (RR 0.81, 95% CI 0.75-0.87)., Conclusions: In patients with SB, the rate of ER visits increased significantly at 18 years old, while hospital admissions and specialist physician visits decreased at the same time. Models of transitional care can aim to reduce non-urgent ER visits and facilitate regular specialist care.

Purpose: To determine the prevalence and natural history of nmCRPC prior to the adoption of novel androgen receptor axis-targeting therapies(ARAT)., Materials and Methods: This was a retrospective population-based cohort study of men with nmCRPC in Ontario, Canada between January 2007-March 2018. Patients with prostate cancer, castrate level of testosterone(<1.7nmol/L) and a PSA>2.0ng/mL with a subsequent rise>25% from the nadir, and without metastasis were included. Annual prevalence of nmCRPC was calculated. Crude time from nmCRPC to metastasis and all-cause death are presented as medians with interquartile range(IQR). Predictors of time from nmCRPC to death were compared using univariable and multivariable cox proportional hazard models., Results: We identified 2045 patients with nmCRPC. Median age was 79(IQR:72-84). 984 patients(48.1%) received upfront hormonal therapy while 583(28.5%) received initial radiotherapy and 478(23.4%) underwent radical prostatectomy. Median time from primary treatment to nmCRPC was 6 years(IQR:3-10). The average annual prevalence of nmCRPC was 8% among men receiving ADT. Crude median time from nmCRPC to death was 37.6 months(IQR:22.1-55.4). Median time from nmCRPC to metastasis and metastasis to death was 20.0 and 8.3 months, respectively. Patients who had primary surgery experienced longer crude survival. Older patients, patients who had a higher PSA at nmCRPC, and patients with grade group 4 to 5 disease had a shorter time from nmCRPC to death., Conclusion: This is the largest population-level analysis of the prevalence and natural history of nmCRPC. The current study can be used as a historical cohort to compare how novel imaging modalities and ARAT impact prevalence and disease trajectory over time., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The differential risk of incident dementia associated with receiving various overactive bladder (OAB) drugs is unknown., Objective: To estimate the association of antimuscarinic OAB drug (exposure), compared with a β-3 agonist (mirabegron), and incident dementia., Design, Setting, and Participants: A population-based nested case-control study was conducted in patients treated with OAB medications in Ontario, Canada. A total of 11 392 patients aged ≥66 yr with a new diagnosis of dementia between 2010 and 2017, and 29 881 age- and sex-matched controls without dementia were included in the study., Intervention: Receipt of an antimuscarinic OAB drug or receipt of mirabegron, within the previous 6-12 mo., Outcome Measurements and Statistical Analysis: Cases developed dementia and Alzheimer's disease. Controls were derived from the general population and matched to cases based on important baseline characteristics. Odds ratios (ORs) for incident dementia, adjusted for demographic and health-related characteristics, were determined., Results and Limitations: Patients receiving solifenacin (OR 1.24; 95% confidence interval 1.08-1.43) and darifenacin (OR 1.30; 95% CI 1.08-1.56) in the prior 6 mo had increased odds of incident dementia compared with those receiving mirabegron. In the 6 mo to 1 yr prior to diagnosis, receipt of solifenacin (OR 1.34; 95% CI 1.11-1.60), darifenacin (OR 1.49; 95% CI 1.19-1.86), tolterodine (OR 1.21; 95% CI 1.02-1.45), and fesoterodine (OR 1.39; 95% CI 1.14-1.71) was associated with increased odds of incident dementia compared with receipt of mirabegron. No effect was seen with oxybutynin or trospium. Limitations included misclassification of the outcome and residual confounding associated with the use of health administrative databases., Conclusions: Older adults receiving solifenacin and darifenacin in the 6 mo prior to diagnosis, and those receiving solifenacin, darifenacin, tolterodine, or fesoterodine in the year prior to diagnosis, have increased odds of incident dementia, compared with those receiving mirabegron. Oxybutynin and trospium were not associated with dementia, likely due to a protopathic bias. Careful drug selection is warranted when treating patients with OAB., Patient Summary: In a large Canadian cohort of patients who developed dementia after starting an overactive bladder (OAB) medication, those taking some anticholinergic medications for OAB have an increased risk of dementia compared with those taking mirabegron., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To compare the risk of bladder cancer and bladder cancer mortality among patients with chronic bladder catheterisation (indwelling or intermittent) to patients from the general population., Design: Retrospective cohort study., Setting: Population-based study in Ontario, Canada between 2003 and 2018., Participants: Adult patients 18-90 years of age with chronic bladder catheterisation were hard matched to patients from the general population without a history of bladder catheterisation., Interventions: The presence of a chronic catheter was defined as a minimum of two physician encounters for bladder catheterisation, suprapubic tube insertion or home care for catheter care separated by at least 28 days. Urinary tract infection (UTI) rates were collected., Main Outcome Measures: Bladder cancer and bladder cancer-specific mortality after a 1-year lag period were compared between groups., Results: We identified 36 903 patients with chronic catheterisation matched to 110 709 patients without a history of catheterisation. Patients were followed for a median of 8.8 years (IQR: 5.2-11.9 years). The median age was 62 years (IQR: 50-71) and 52% were female. More patients in the catheter group developed bladder cancer (393 (1.1%) vs 304 (0.3%),p<0.001). There were 106 (0.3%) bladder cancer deaths in the catheter group and 59 (0.1%) in the comparison group (p<0.001). Chronic catheterisation (adjusted subdistribution HR (sdHR)=4.80, 95% CI: 4.26 to 5.42,p<0.001) and the number of UTIs (adjusted sdHR=1.04 per UTI, 95% CI: 1.04 to 1.05,p<0.001) were independent predictors of bladder cancer. The relative rate of bladder cancer-specific death was more than eightfold higher among patients with chronic catheterisation (adjusted sdHR=8.68, 95% CI: 6.97 to 10.81,p<0.001). Subgroup analysis among patients with neurogenic bladder and bladder calculi similarly revealed an increased risk of bladder cancer diagnosis and mortality. Bladder cancer risk was highest among patients in the two longest catheter duration quintiles (2.9-5.9 and 5.9-15.5 years)., Conclusions: This is the first study to quantify the increase in bladder cancer incidence and mortality in a large, diverse cohort of patients with chronic indwelling or intermittent bladder catheterisation. The risk was highest among patients with a chronic catheter beyond 2.9 years., Competing Interests: Competing interests: GK has acted as a consultant for Merck, Roche, Janssen and Ferring and received honoraria for lectures on behalf of Biosyent, Merck, Roche and Theralase. SH reports receiving grants from Astellas Pharma Canada, Allergan, AMI, Boston Scientific and Pfizer all outside the submitted work. All other authors have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Cystoscopic placement of ureteric stents during colorectal surgery (CRS) may aid in the intraoperative identification of the ureters and thus prevent ureteric injury, but may also be associated with prolonged operating time, increased cost and adverse events. No formal recommendations exist regarding the use of ureteric stents prior to CRS. Our aim was to determine the effect of prophylactic ureteric stent insertion on the risk of ureteric injury among adult patients undergoing CRS., Method: A systematic search using the Ovid platform was completed. The primary outcome was risk of ureteric injury. Secondary outcomes included the risk of acute kidney injury (AKI), urinary tract infection (UTI), sepsis, length of stay (LOS) and mortality. The Paule-Mandel pooling and a random effects model was used to produce odds ratios (ORs) with 95% confidence intervals (CIs) for binary outcomes. Standardized mean differences (MD) were reported for continuous variables. Analyses were completed using R3.5., Results: Nine retrospective cohort studies evaluating 98 507 patients were included. The incidence of ureteric injury was 0.6%. Overall, 5.1% of patients underwent ureteric stenting. There was no change in the odds of ureteric injury among stented patients compared with controls (OR 1.30, 95% CI 0.39-4.29, I 2  = 25%). Operating time was significantly longer (MD 49.3 min, 95% CI 35.3-63.4, I 2  = 96%) in the intervention group. There was no difference in rates of AKI, UTI, sepsis, LOS or mortality between groups., Conclusion: Given the retrospective nature of the identified studies, the benefit of prophylactic ureteric stenting remains uncertain. Prophylactic ureteric stenting was not associated with increased patient morbidity but did significantly increase operating time., (© 2020 The Association of Coloproctology of Great Britain and Ireland.)

Background: We previously identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. Expression of one of the down-regulated miRNAs, miR-139-5p, was significantly associated with a lower incidence of biochemical recurrence and metastasis. Transcriptome profiling of miR-139-expressing prostate cancer cells revealed up-regulation of genes involved in interferon (IFN) stimulation. The association between miR-139 and IFN-β was further explored in this study., Materials and Methods: We examined miR-139 transfected PC3, Du145 and LNCaP cells and the associated IFN response by transcriptome sequencing, immunoblotting and pulldown assays., Results: Treatment of prostate cancer cells by miR-139 resulted in the up-regulation of IFN-related genes. Specifically, miR-139 induced expression of the IFN-β protein. The ability of miR-139 to induce IFN-β was due to its binding to RIG-1 and the induction of IFN-related genes was found to be dependent on RIG-1 expression., Conclusion: miR-139 acts as an immune agonist of RIG-1 to enhance IFN-β response in prostate cancer cells., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Upper tract urothelial carcinoma (UTUC) is clinically understudied, and there are no definitive recommendations regarding timing of perioperative chemotherapy. The objective of this study was to compare 3 treatment pathways in UTUC: nephroureterectomy (NU) alone, neoadjuvant chemotherapy (NAC), and adjuvant chemotherapy (AC) using a microsimulation model., Patients and Methods: An individual-level state transition model was constructed using TreeAgePro software to compare treatment strategies for patients with newly diagnosed UTUC. The base case was that of a 70-year-old patient with a radiographically localized upper tract tumor. Primary outcome was quality-adjusted life expectancy. Secondary outcomes included crude overall survival, rates of adverse events, and bladder cancer diagnoses., Results: A total of 100,000 patients were simulated. NAC was preferred, with an estimated quality-adjusted life expectancy of 7.50 years versus 6.79 years with NU alone and 7.23 years with AC. Median crude overall survival was 123 months with NAC, 96 months with NU only, and 111 months with AC. Overall, 40.0% of patients in the AC group with invasive pathology completed chemotherapy. In the NAC group, 83.3% of patients completed chemotherapy. In the NAC group, 37.5% of patients experienced an adverse chemotherapy event compared to 15.1% of patients in the AC group. Bladder cancer recurrence rates were 64.9%, 65.9%, and 67.4% over the patient's lifetime for the NU, NAC, and AC strategies, respectively., Conclusion: This study supports the increased use of NAC in UTUC until robust randomized trials are completed. The ultimate choice should be based on patient and tumor factors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Patients with renal cell carcinoma (RCC) with level 3 or 4 caval thrombus have a poor prognosis, with reported five-year survival rates of 30-40%. The aim of this study was to assess the perioperative morbidity and long-term oncological outcomes for radical nephrectomy with resection of vena cava thrombus using a combined surgical approach, including extracorporeal circulation and deep hypothermic circulatory arrest., Methods: A retrospective review was performed of the institutional case log to identify all radical nephrectomies with caval thrombus performed from January 2006 to May 2020., Results: Twenty-five patients were identified with level 2 thrombus in one (4%), level 3 thrombus in eight (32%), and level 4 in 16 (64%). The median followup was 20.6 months (range 0.2-133.3). The median age at surgery was 68.4 years (range 44.2-85.5). Twenty-one (84%) patients were symptomatic at presentation. Six (24%) patients had distant metastases at diagnosis. The median circulatory arrest time was 15 minutes (range 6-35). The 30-day grade ≥3 complication rate was 8%. The 30-day mortality rate was 8%. The one-year, two-year, three-year, and five-year recurrence-free survival (RFS) rates were 53%, 18%, 10%, and 10%, respectively. The median time to systemic treatment was 7.7 months (range 1.2-25.7). The one-year, two-year, three-year, and five-year overall survival (OS) rates were 70%, 43%, 36%, and 31%, respectively., Conclusions: Radical nephrectomy with resection of vena cava thrombus using extracorporeal circulation and deep hypothermic circulatory arrest is associated with some morbidity and mortality but remains a safe and effective strategy for advanced RCC patients who would otherwise be managed palliatively.

Introduction: The aim of this study was to assess the effect of an enhanced care pathway on length of stay (LOS) for open radical prostatectomy (RP) given that robotic-assisted laparoscopic prostatectomy (RALP) is not available to all patients in Canada., Methods: A retrospective review was conducted of all RPs performed. An enhanced care pathway was established for RPs in 2011. Patients were compared in the period before (2005-2010) and after (2011-2019) the introduction of the pathway., Results: During the study period, 581 RPs were performed by a single surgeon with a median followup of 66.9 months (range 3-176). A total of 211 (36.3%) RPs were performed from 2005-2010, while 370 (63.9%) were performed from 2011-2019. The median age at RP was 65 years (range 44-81). Following the introduction of an enhanced care pathway, there were significant decreases in intraoperative blood loss (350 ml vs. 200 ml; p=0.0001) and the use of surgical drains (90% vs. 9.5%; p=0.0001). The median LOS over the whole study period was one day (range 1-7), which significantly decreased with the enhanced care pathway (3 vs. 1 day; p=0.0001). Since introducing the enhanced care pathway in 2011, 344 (93%) patients were discharged day 1 following surgery. There were no differences in post-discharge presentations to the emergency department (5.7% vs. 9%; p=0.15) or 30-day readmission rates (3.8% vs. 3.8%; p=1.00)., Conclusions: A single-night stay for open RP is safe and achievable for most patients. A dedicated, multifaceted pathway is required to attain targets for a safe and timely discharge.

Introduction: We sought to assess seven-day and 30-day complications following renal mass biopsy (RMB), including mortality, hospitalizations, emergency department (ED) visits, and operative and non-operative complications and compare these to rates in population-matched controls., Methods: We performed a population-based, matched, retrospective cohort study of patients undergoing RMB following consultation with a urologist and axial imaging from 2003-2015 in Ontario, Canada. Data on seven-day and 30-day rates of mortality, as well as operative and non operative complications after RMB were reported. The seven-day and 30-day rates of mortality, operative and non-operative interventions, hospitalizations, and ED visits were compared to matched controls using multivariable logistic regression., Results: Among 6840 patients who underwent RMB in the study period, 24 (0.4%) and 159 (2.3%) died within seven and 30 days of their biopsy, respectively. Seven- and 30-day operative intervention rates were 79 (1.2%) and 236 (3.4%), respectively. Seven- and 30-day non-operative intervention rates were 227 (3.3%) and 529 (7.7%), respectively. Thirty-day mortality (odds ratio [OR] 8.1, 95% confidence interval [CI] 5.1-13.0), hospitalizations (OR 12.6, 95% CI 10.6-15.2), and ED visits (OR 3.8, 95% CI 3.4-4.3) were more common among patients who underwent RMB than the matched controls (p<0.001 for each)., Conclusions: Patients undergoing RMB may have a small but non-negligible increased risk of mortality, hospital readmission, and ED visits compared to matched controls. However, limitations in the granularity of the dataset limits the strength of these conclusions. Further studies are needed to confirm our results. These risks should be discussed with patients for shared decision-making and considered in the risk/benefit tradeoff for the management of small renal masses.

Background/aim: We previously identified a panel of five miRNAs (including miR-139) associated with biochemical recurrence and metastasis in prostate cancer patients., Materials and Methods: We examined miR-139 transfected PC3, DU145 and LNCaP cells by morphology as well as by cell-based assays, confocal microscopy and immunoblotting., Results: We found that treatment of prostate cancer cells with miR-139 resulted in phenotypic changes characteristic of autophagic cells. MiR-139 increased the autophagy-related conversion of the microtubule-associated protein light chain 3 (LC3-I to LC3-II) that was specifically inhibited by the miR-139 antagomir. The upregulation of LC3 II was further confirmed by confocal microscopy. miR-139 regulated activation of both mTOR and Beclin1 the two important autophagy-related molecules. We found that upon miR-139 treatment, the cargo adaptor protein p62 which is degraded during autophagy, accumulates., Conclusion: These results suggest that miR-139 is inducing autophagic flux blockade leading to apoptosis in prostate cancer cells through the mTOR and Beclin-1 proteins., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The rate of primary and secondary treatment while on active surveillance (AS) for localized prostate cancer at the general population level is unknown. Our objective was to determine the patterns of secondary treatments after primary surgery or radiation for patients who undergo AS., Methods: This was a population-based retrospective cohort study of men aged 50-80 years old in Ontario, Canada, between 2008 and 2016. We identified 26 742 patients with prostate cancer, a Gleason grade score ≤7, and an index prostate-specific antigen ≤10 ng/mL. Patients were categorized as undergoing AS with or without delayed primary treatment (DT; treatment >6 months after diagnosis) versus immediate treatment (IT; treatment ≤6 months). Patients receiving DT and IT were propensity score matched and the rate of secondary treatment (surgery or radiation ± androgen deprivation treatment) was compared using Cox proportional hazards models., Results: We identified 10 214 patients who underwent AS and 11 884 patients who underwent IT. Among patients undergoing AS, 3724 (36.5%) eventually underwent DT and among them, 406 (10.9%) underwent secondary treatment. The median time to DT was 1.2 years (IQR 0.5-8.1 years). The relative rate of undergoing secondary treatment was similar in the DT vs IT group (HR 0.92; 95% CI: 0.79-1.08). The risk of death in the DT group was higher compared to patients who did not undergo treatment (HR 1.23, 95% CI: 1.01-1.49)., Conclusions: Among patients with localized prostate cancer on AS, one third undergo DT. The rate of secondary treatment was similar between the DT and IT groups. Patients in the DT group may experience a higher risk of mortality compared to those who remained on AS., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: The association of radiation and chemotherapy with the development of secondary sarcoma is known, but the contemporary risk has not been well characterized for patients with cancers of the abdomen and pelvis., Objective: To compare the risk of secondary sarcoma among patients treated with combinations of surgery, radiation, or chemotherapy with patients treated with surgery alone and the general population., Design, Setting, and Participants: This population-based cohort study included 173 580 patients in Ontario, Canada, with nonmetastatic cancer of the prostate, bladder, colon, rectum or anus, cervix, uterus, or testis. Patients were enrolled from January 1, 2002, to January 31, 2017. Data analysis was conducted from March 1, 2019, to January 31, 2020., Exposures: Treatment combinations of radiation, chemotherapy, and surgery., Main Outcome and Measures: Diagnosis of sarcoma based on histologic codes from the Ontario Cancer Registry. Time to sarcoma was compared using a cause-specific proportional hazard model., Results: Of 173 580 patients, most were men (125 080 [72.1%]), and the largest group was aged between 60 and 69 years (58 346 [33.6%]). Most patients had genitourinary cancer (86 235 [51.4%]) or colorectal cancer (69 241 [39.9%]). Overall, 64 301 (37.1%) received surgery alone, 51 220 (29.5%) received radiation alone, 15 624 (9.0%) were treated with radiation and chemotherapy, 15 252 (8.8%) received radiation with surgery, and 11 822 (6.8%) received all 3 treatments. A total of 332 patients (0.2%) had sarcomas develop during a median (interquartile range) follow-up of 5.7 (2.2-8.9) years. The incidence of sarcoma was 0.3% among those who underwent radiation alone (138 of 51 220) and radiation with chemotherapy (40 of 15 624), 0.2% among those who received radiation and surgery (36 of 15 252) and all 3 modalities (25 of 11 822), and 0.1% among those who received surgery with chemotherapy (13 of 14 861) and surgery alone (80 of 64 801). Compared with a reference group of patients who had surgery alone, the greatest risk of sarcoma was found among patients who underwent a combination of radiation and chemotherapy (cause-specific relative hazard [csRH], 4.07; 95% CI, 2.75-6.01; P < .001), followed by patients who had radiation alone (csRH, 2.35; 95% CI, 1.77-3.12; P < .001), radiation with surgery (csRH, 2.33; 95% CI, 1.57-3.46; P < .001), and all 3 modalities (csRH, 2.27; 95% CI, 1.44-3.58; P < .001). In the general population, 7987 events occurred during 46 554 803 person-years (17.2 events per 100 000 person-years). The standardized incidence ratio for sarcoma among patients treated with radiation compared with the general population was 2.41 (95% CI, 1.57-3.69; 41.3 events per 100 000 person-years). The annual number of cases of sarcoma increased from 2009 (15 per 100 000 persons) to 2016 (32 per 100 000 persons), but the annual rate did not change during the study period., Conclusions and Relevance: In this cohort study, patients treated with radiation or chemotherapy for abdominopelvic cancers had an increased rate of sarcoma. Although the absolute rate is low, patients and physicians should be aware of this increased risk of developing sarcoma.

Introduction: Our aim was to determine whether androgen deprivation therapy (ADT) with abiraterone acetate (AA) or ADT with docetaxel chemotherapy (DC) resulted in improved quality-adjusted life years (QALYs) among men with de novo metastatic castration-sensitive prostate cancer (mCSPC) and the cost effectiveness of the preferred strategy using decision analytic techniques., Methods: A microsimulation model with a lifetime time horizon was constructed. Our primary outcome was QALYs. Secondary outcomes included cost, incremental cost effectiveness ratio (ICER), unadjusted overall survival (OS), rates of second- and third-line therapy, and adverse events. A systematic literature review was used to generate probabilities and utilities to populate the model. The base case was a 65-year-old patient with de novo mCSPC., Results: A total of 100 000 microsimulations were generated. Initial AA resulted in a gain of 0.45 QALYs compared to DC (3.36 vs. 2.91 QALYs) with an ICER of $276 251.82 per QALY gained with initial AA therapy. Median crude OS was 51 months with AA and 48 months with DC. Overall, 46.6% and 42.6% of patients received second-line therapy and 8.7% and 7.9% patients received third-line therapy in the AA and DC groups, respectively. Grade 3/4 adverse events were experienced in 17.6% of patients receiving initial AA and 22.3% of patients receiving initial DC., Conclusions: Although ADT with AA results in a gain in QALYs and crude OS compared to DC, AA therapy is not a cost-effective treatment strategy to apply uniformly to all patients. The availability of AA as a generic medication may help to close this gap. The ultimate choice should be based on patient and tumor factors.

Purpose: Previous studies have shown an association between urinary incontinence and increased mortality independently of demographics and health status. However, they do not account for the effect of frailty as a state of vulnerability. We evaluated whether there is an association between urinary incontinence and mortality and, if so, whether adjustment for a frailty index would affect the association., Materials and Methods: We performed a cross-sectional study in a nationally representative sample of 2,282 community dwelling individuals 50 years old or older who were surveyed between 2003 and 2006. The study primary outcome was overall survival as reported on December 31, 2011. We used design adjusted Cox proportional hazards regression models to estimate the hazard of mortality associated with urinary incontinence. We adjusted the models for demographics and a validated 45-item frailty index incorporating an accumulation of deficits in the domains of health and independence., Results: Of the individuals 23% reported having urinary incontinence at least a few times per week. Stress urinary incontinence and urge urinary incontinence were associated with a 13.3% (95% CI 7.2-19.7) and 18.4% (95% CI 8.3-29.4) increase in the frailty index, respectively. Without controlling for frailty individuals with urinary incontinence were at higher risk for death (HR 1.39, 95% CI 1.13-1.72). When adjusted for the frailty index, the association between urinary incontinence and mortality was no longer significant (HR 1.10, 95% CI 0.89-1.36)., Conclusions: The association between urinary incontinence and mortality can be understood based on increased frailty in incontinent individuals. Urinary incontinence itself is not independently associated with mortality. In clinical practice these findings underscore the importance of screening for frailty in addition to urinary incontinence.

Background: Immunotherapy agents are an innovative oncological treatment modality and as a result their use has expanded widely. Understanding the treatment-related adverse events (AEs) of these drugs compared with traditional chemotherapy is crucial for clinical practice., Design: A systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to 14 February 2019 was conducted. Randomized clinical trials comparing immunotherapy [cytotoxic T-lymphocyte protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1)] with standard-of-care chemotherapy in the treatment of advanced solid-organ neoplasms were included if AEs were reported as an outcome. Primary outcome was AEs ≥ grade 3 in severity. Secondary outcomes were proportion of overall AEs, treatment discontinuation due to AEs, deaths due to AEs, and specific AEs [fatigue, diarrhea, acute kidney injury (AKI), colitis, pneumonitis, and hypothyroidism]. Paule-Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects., Results: Among 10 598 abstracts screened, we included 22 studies involving 12 727 patients. In the immunotherapy group, 16.5% of patients developed an AE ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm [OR = 0.26, 95% confidence interval (CI) 0.19-0.35, I 2  = 92%]. Patients receiving immunotherapy also had lower odds of developing an AE overall (OR = 0.35, 95% CI 0.28-0.44; I 2  = 77%), terminating therapy due to an AE (OR = 0.55, 95% CI 0.39-0.78, I 2  = 80%), or dying from a treatment-related AE (OR = 0.67, 95% CI 0.46-0.98, I 2  = 0%). When treated with chemotherapy versus immunotherapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhea (14.97% versus 11.13%), and AKI (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immunotherapy., Conclusions: Treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of AEs., (Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Objectives: To examine the complication rates after benign prostatic enlargement (BPE) surgery and the effects of age, comorbidity and preoperative medical therapy., Design: A retrospective, population-based cohort study using linked administrative data., Setting: Ontario, Canada., Participants: 52 162 men≥66 years undergoing first BPE surgery between 1 January 2003 to 31 December 2014., Intervention: Medical therapy preoperatively and surgery for BPE., Primary and Secondary Outcome Measures: The primary outcome was overall 30-day postoperative complication rates. Secondary outcomes included BPE-specific event rates (bleeding, infection, obstruction, trauma) and non-BPE specific event rates (cardiovascular, pulmonary, thromboembolic and renal). Multivariable analysis examined the association between preoperative medical therapy and postoperative complication rates., Results: The 30-day overall complication rate after BPE surgery was 2828 events/10 000 procedures and increased annually over the study period. Receipt of preoperative α-blocker monotherapy (relative rate (RR) 1.05; 95% CI 1.00 to 1.09; p=0.033) and antithrombotic medications (RR 1.27; 95% CI 1.22 to 1.31; p<0.0001) was associated with increased complication rates. Among the ≥80-year-old group, the rate of complications increased by 39% from 2003 to 2014 (RR 1.39; 95% CI 1.21 to 1.61; p<0.0001). The mean duration of medical and conservative management increased by a mean of 2.1 years between 2007 and 2014 (p<0.0001 for trend)., Conclusions: Thirty-day complication rates after BPE surgery have increased annually between 2003 and 2014. Preoperative medical therapy with alpha blockers or antithrombotics was independently associated with higher rates of complications. Over this time, the duration of conservative therapy also increased., Competing Interests: Competing interests: SH has received grants and personal fees from Astellas, Allergan, and Ipsen and personal fees from Pfizer and Duchesnay. SBR has acted as an advisory board member for Astellas, Pfizer, Merus, Allergan and participated in research for Astellas and Allergan. LC has participated in research and advisory board meetings for Cook MyoSite, and also serves on speakers boards for Astellas, Allergan, Pfizer, Duchesney USA and Ferring Pharmaceuticals., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next-generation sequencing-based whole miRNome sequencing and quantitative polymerase chain reaction-based validation analysis. In this study, we examined the mechanism of action of miR-139-5p, one of the downregulated miRNAs identified in the panel., Methods: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan-Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 to confirm its targets as well as examine pathways through which miR-139 may function using cell-based assays., Results: Low miR-139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR-139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33-0.82). Overexpression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR-139 based on multiple miRNA-binding sites in 3'-untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR-139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR-139 treatment, which was reversed by the addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21., Conclusions: miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components., (© 2019 Wiley Periodicals, Inc.)

Background: Previous studies have demonstrated an association between a diagnosis of cancer and the risk of suicide; however, they failed to account for psychiatric care before a cancer diagnosis, which may confound this relationship. The objective of this study was to assess the effect of a cancer diagnosis on the risk of suicide, accounting for prediagnosis psychiatric care utilization., Methods: All adult residents of Ontario, Canada who were diagnosed with cancer (1 of prostate, breast, colorectal, melanoma, lung, bladder, endometrial, thyroid, kidney, or oral cancer) between 1997 and 2014 were identified. Noncancer controls were matched 4:1 based on sociodemographics, including a psychiatric utilization gradient (PUG) score (with 0 indicating none; 1, outpatient; 2, emergency department; and 3, hospital admission). A marginal, cause-specific hazard model was used to assess the effect of cancer on the risk of suicidal death., Results: Among 676,470 patients with cancer and 2,152,682 matched noncancer controls, there were 8.2 and 11.4 suicides per 1000 person-years of follow-up, respectively. Patients with cancer had an overall higher risk of suicidal death compared with matched patients without cancer (hazard ratio, 1.34; 95% CI, 1.22-1.48). This effect was pronounced in the first 50 months after cancer diagnosis (hazard ratio, 1.60; 95% CI, 1.42-1.81); patients with cancer did not demonstrate an increased risk thereafter. Among individuals with a PUG score 0 or 1, those with cancer were significantly more likely to die of suicide compared with controls. There was no difference in suicide risk between patients with cancer and controls for those who had a PUG score of 2 or 3., Conclusions: A cancer diagnosis is associated with increased risk of death from suicide compared with the general population even after accounting for precancer diagnosis psychiatric care utilization. The specific factors underlying the observed associations remain to be elucidated., (© 2019 American Cancer Society.)

Introduction: We sought to examine the costs related to treatment and treatment-related complications for patients treated with surgery or radiation for localized prostate cancer., Methods: We performed a population-based, retrospective cohort study of men who underwent open radical prostatectomy or radiation from 2004-2009 in Ontario, Canada. Costs, including initial treatment and inpatient hospitalization, emergency room visit, outpatient consultation, physician billings, and medication costs, were determined for five years following treatment using a validated costing algorithm. Multivariable negative binomial regression was used to assess the association between treatment modality and costs., Results: A total of 28 849 men underwent treatment for localized prostate cancer from 2004- 2009. In the five years following treatment, men who underwent radiation (n=12 675) had 21% higher total treatment and treatment-related costs than men who underwent surgery ($16 716/person vs. $13 213/person). Based on multivariable analysis, while men who underwent XRT had a lower relative cost in their first year after treatment (relative rate [RR] 0.97; 95% confidence interval [CI] 0.94-1.0; p=0.025), after year 2, annual costs were significantly higher in the radiation group compared to the surgery group (total cost for year 5, RR 1.44; 95% CI 1.17-1.76; p&lt;0.0001). Our results were similar when restricted to young, healthy men and to older men., Conclusions: Men who undergo radiation have significantly higher five-year total treatment-related costs compared to men who undergo open radical prostatectomy. While surgery was associated with slightly higher initial costs, radiotherapy had higher costs in subsequent years.

Background: Among patients with cancer, prior research suggests that patients with mental illness may have reduced survival. The objective was to assess the impact of psychiatric utilisation (PU) prior to cancer diagnosis on survival outcomes., Methods: All residents of Ontario diagnosed with one of the top 10 malignancies (1997-2014) were included. The primary exposure was psychiatric utilisation gradient (PUG) score in 5 years prior to cancer: 0: none, 1: outpatient, 2: emergency department, 3: hospital admission. A multivariable, cause-specific hazard model was used to assess the effect of PUG score on cancer-specific mortality (CSM), and a Cox proportional hazard model for effect on all-cause mortality (ACM)., Results: A toal of 676,125 patients were included: 359,465 (53.2%) with PUG 0, 304,559 (45.0%) PUG 1, 7901 (1.2%) PUG 2, and 4200 (0.6%) PUG 3. Increasing PUG score was independently associated with worse CSM, with an effect gradient across the intensity of pre-diagnosis PU (vs PUG 0): PUG 1 h 1.05 (95% CI 1.04-1.06), PUG 2 h 1.36 (95% CI 1.30-1.42), and PUG 3 h 1.73 (95% CI 1.63-1.84). Increasing PUG score was also associated with worse ACM., Conclusions: Pre-cancer diagnosis PU is independently associated with worse CSM and ACM following diagnosis among patients with solid organ malignancies.

Context: Radiotherapy used for treating localized prostate cancer is effective at prolonging cancer-specific and overall survival. Still, acute and late pelvic toxicities are a concern, with gastrointestinal (GI) and genitourinary (GU) sequelae being most common as well as other pelvic complications., Objective: To present a critical review of the literature regarding the incidence and risk factors of pelvic toxicity following primary radiotherapy for prostate cancer and to provide a narrative review regarding its management., Evidence Acquisition: A collaborative narrative review of the literature from 2010 to present was conducted., Evidence Synthesis: Regardless of the modality used, the incidence of acute high-grade pelvic toxicity is low following conventionally fractionated external beam radiotherapy (EBRT). After moderate hypofractionation, the crude cumulative incidences for late grade 3 or higher (G3+) GI and GU complications are as high as 6% and 7%, respectively. After extreme hypofractionation, the 5-yr incidences of G2+ GU and GI toxicities are 3-9% and 0-4%, respectively. Following brachytherapy monotherapy, crude rates of late G3+ GU toxicity range from 6% to 8%, while late GI toxicity is rare. With combination therapy (EBRT and brachytherapy), the cumulative incidence of late GU toxicity is high, between 18% and 31%; however, the prevalence is lower at 4-14%. Whole pelvic radiotherapy remains a controversial treatment option as there is increased G3+ GI toxicity compared with prostate-only treatment, with no overall survival benefit. Proton beam therapy appears to have similar toxicity to photon therapies currently in use. With respect to specific complications, urinary obstruction and urethral stricture are the most common severe urinary toxicities. Rectal and urinary bleeding can be recurrent long-term toxicities. The risk of hip fracture is also increased following prostate radiotherapy. The literature is mixed on the risk of in-field secondary pelvic malignancies following prostate radiotherapy. Urinary and GI fistulas are rare complications. Management of these toxicities may require invasive treatment and reconstructive surgery for refractory and severe symptoms., Conclusions: There has been progress in the delivery of radiotherapy, enabling the administration of higher doses with minimal tradeoff in terms of slightly increased or equal toxicity. There is a need to focus future improvements in radiotherapy on sparing critical structures to reduce GU and GI morbidities. While complications such as fistulae, bone toxicity, and secondary malignancy are rare, there is a need for higher-quality studies assessing these outcomes and their management., Patient Summary: In this report, we review the literature regarding pelvic complications following modern primary prostate cancer radiotherapy and their management. Modern radiotherapy technologies have enabled the administration of higher doses with minimal increases in toxicity. Overall, high-grade long-term toxicity following prostate radiotherapy is uncommon. Management of late high-grade pelvic toxicities can be challenging, with patients often requiring invasive therapies for refractory cases., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Prostate cancer can be detected using a multicomponent T 2 mapping technique termed luminal water imaging. The purpose of this study is twofold: 1) To accelerate the luminal water imaging acquisition by using inner volume selection as part of a gradient and spin echo sequence, and 2) to evaluate the accuracy of luminal water fractions and multicomponent T 2 relaxation times., Methods: The accuracy of parameter estimates was assessed using Monte Carlo simulations, in phantom experiments and in the prostate (in 5 healthy subjects). Two fitting methods, nonnegative least squares and biexponential fitting with stimulated echo correction, were compared., Results: Results demonstrate that inner volume selection in a gradient and spin echo sequence is effective for accelerating prostate luminal water imaging by at least threefold. Evaluation of the accuracy shows that the estimated luminal water fractions are relatively accurate, but the short- and long-T 2 relaxation times should be interpreted with caution in noisy scenarios (SNR < 100) and when the corresponding fractions are small ( < 0.5). The mean luminal water fractions obtained at SNR above 100 are 0.27 ± 0.07 for the peripheral zone for both fitting methods, 0.16 ± 0.04 for the transition zone with nonnegative least squares, and 0.16 ± 0.03 for the transition zone with biexponential fitting including stimulated echo correction., Conclusion: The shortened scan duration allows the luminal water imaging sequence to be easily integrated into a standard multiparametric prostate MRI protocol., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: Patients with rectal cancer (RCa) and prior radiation for prostate cancer (PCa) are clinically complicated and may have worse outcomes than other RCa patients. This study investigates the impact of previous radiation for PCa on survival for patients with RCa., Method: We conducted a population-based study identifying men who underwent surgical treatment of RCa from 2002 to 2010. Patients were classified into three cohorts: no prior PCa, prior PCa treated without radiotherapy, and prior PCa treated with radiotherapy. The primary outcome was overall survival. Secondary outcomes included RCa surgical approach, ICU admission, length of stay, ER visits, and delayed formation of a new stoma., Results: Seven thousand ninety-six men underwent surgery for RCa; 6867 patients had no prior PCa, 58 had prior PCa treated without radiotherapy, and 171 had prior PCa treated with radiotherapy. The 5-year overall survival was 62% (95% CI 61-64%) for patients without prior PCa, 46% (95% CI 25-65%) for patients with prior PCa treated without radiotherapy, and 42% (95% CI 29-54%) for patients with prior PCa treated with radiotherapy (p < 0.0001). In multivariable analysis, patients with prior PCa treated with radiotherapy were at increased risk of death (aHR 1.38, 95% CI 1.12-1.69) compared to those without prior PCa. Furthermore, patients with prior PCa treated with radiotherapy had a significantly increased risk of resection with permanent stoma., Conclusions: Prior radiotherapy for PCa is a poor prognostic factor in RCa patients with significantly increased risk of death. Additionally, patients with prior radiotherapy for PCa are more likely to require a permanent stoma.

Purpose: The aim of this study was to investigate the influence of the abutment material and the connection geometry on deformation and wear at the internal implant-abutment connection area (IAC), using an optical scanner., Materials and Methods: Thirty-two internal conical titanium implants, and two types of prefabricated abutments (zirconia or titanium), each (n = 8) with different connection geometries (hexagon or nonhexagon) were prepared. The inner surfaces of the implants were optically scanned before and after loading for 100,000 cycles in a simulated wet environment. The scanned data were superimposed to calculate potential three-dimensional (3D) deviations. Surfaces of the two respective implants in each group were examined using scanning electron microscopy to observe fretting wear patterns. A two-way analysis of variance (ANOVA) was used for the statistical analysis., Results: The 3D deviation (deformation) was detected at the IAC in relation to the loading direction. The average 3D positive deviation and maximum positive and negative deviations at the IAC were significantly higher with zirconia abutments than with titanium abutments, regardless of connection geometries (all P < .05). However, the average 3D negative and standard 3D deviations were similar between the two materials (both P > .05). The effect of connection geometry was not significant (P > .05). After cyclic loading, an irregular wave-pattern furrow was observed on the connection area of the implant with the titanium abutment, whereas a long and straight groove was detected on that with the zirconia abutment., Conclusion: Based on this analysis, the deformation and the wear at the IAC could be significantly affected by the material of the prefabricated abutment.

Background/aim: This is a case control study designed to identify one or more novel microRNA sequences associated with metastasis following radical prostatectomy for clinically localized prostate cancer., Materials and Methods: Samples were obtained from patients with clinical evidence of metastatic disease following surgery (cases) and patients who showed no evidence of metastasis or biochemical recurrence at least 5 years following surgery (controls) as identified from a single-center, institutional database. Cases and controls were matched for tumor grade and duration of follow-up., Results: Whole miRNome analysis identified 2,792 expressed miRNAs in 19 patient pairs. The 497 miRNA sequences with reads per million over 10, were used for analysis, bootstrapping with backward selection identified a panel of 5-miRNA (miR-17-3p, miR-27a-3p, miR-200a-3p, miR-375, and miR-376b-3p) with a risk score strongly associated with metastasis (AUC=89.5%, 95%CI=79.5-99.5%). Methodologically, most studies use the magnitude of differential expression with or without clinical judgement for selection of predictors for inclusion in panels. In order to strengthen the predictive model, a selection strategy was employed, bootstrapping with automated backwards selection, which relied on the strength of association for inclusion., Conclusion: A genome-wide analysis of microRNA expression identified a panel of 5 miRNAs strongly associated with prostate cancer metastasis following radical prostatectomy., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: The treatment of cervical cancer can result in genitourinary morbidity. We measured selected urologic procedures after the treatment of cervical cancer with either surgery or radiation., Methods: We used administrative data from the province of Ontario Canada to identify adult women who had nonmetastatic cervical cancer and were treated with surgery or radiation between 1994 and 2014. Study outcomes were surgical or procedure codes representing ureteric repair or fistula repair. Stress incontinence surgery, minimally invasive urologic procedures, open bowel/bladder surgeries, and secondary malignancy were measured to compare between treatment modalities. Multivariable Cox proportional hazards models were used., Results: Our final cohort consisted of 7311 women (median follow-up, 7.0 years [interquartile range, 2.9-13.3 years]), of which 3354 (44.9%) underwent radiation, and 3957 (54.1%) underwent surgery. After treatment of cervical cancer, ureteral repair was less common after surgery (3.4%) compared with radiation (10.3%) (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.19-0.32). Fistula repair was uncommon (0.9%) and occurred significantly more often in the surgery and radiation group compared with the radiation-alone group (HR, 4.02; 95% CI, 1.80-9.00). Overall, stress incontinence surgery was uncommon (2.2%) but was significantly more likely after surgery versus radiation (HR, 3.73; 95% CI, 2.13-6.53). Minimally invasive urologic procedures were less common after surgery compared with radiation (HR, 0.49; 95% CI, 0.44-0.54). Open bowel/bladder surgeries were similar among treatment modalities, and secondary malignancy was less common after treatment with surgery versus radiation (HR, 0.60; 95% CI, 0.39-0.92; P = 0.02)., Conclusions: Women treated for cervical cancer undergo ureteral stricture interventions at 0.8% per year over the 20 years after their treatment; this risk is higher among women who receive radiation treatment. Fistula repair is rare after cervical cancer.

Background: Androgen-deprivation therapy (ADT) has been associated with cardiovascular risk factors and the development of cardiovascular disease in men with metastatic prostate cancer. We sought to examine the effect of ADT on nonprostate cancer mortality among patients with nonmetastatic prostate cancer., Methods: We performed a population-based, retrospective cohort study of men aged 66 years and older treated with surgery or radiotherapy for nonmetastatic prostate cancer in Ontario, Canada from 2002 to 2009 using administrative datasets (including the Ontario Cancer Registry, Ontario Drug Benefit, and Ontario Health Insurance Plan). Analysis was performed between September 2016 and April 2017. ADT exposure was operationalized as a time-varying binary and cumulative dose exposure. Primary and secondary outcomes were nonprostate cancer mortality and cardiovascular mortality, respectively. The Fine and Gray subdistribution method with generalized estimating equations was used to calculate subdistribution hazard ratios (sdHR), while accounting for competing risks., Results: We examined 20,651 men treated for nonmetastatic prostate cancer. Median follow-up was 7.4 years and median ADT exposure was 6.4 months. ADT was not significantly associated with nonprostate cancer mortality (sdHR = 0.75, 95% CI: 0.37-1.50) or cardiovascular mortality (sdHR = 1.16, 95% CI: 0.37-3.63) when operationalized as a binary time-varying exposure. Similar results were obtained when we examined ADT cumulative dose exposure., Conclusions: ADT is not associated with nonprostate cancer mortality or cardiovascular mortality in a large, population-based cohort of older men with localized prostate cancer treated by surgery or radiation therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Consultation with radiation oncologists, in addition to urologists, is advocated for patients diagnosed with prostate cancer. Treatment patterns for patients receiving consultation from radiation oncologists in addition to urologists have not previously been described., Methods: We conducted a matched cohort study of men with newly diagnosed non-metastatic prostate cancer in Ontario, Canada. Patients who underwent consultation with a radiation oncologist prior to treatment were matched 1:1 with patients managed by a urologist alone based on tumour and patient characteristics. We examined rates of active treatment (surgery or radiotherapy) within one year following diagnosis., Results: Among 5708 matched pairs (11,416 patients), those who received radiation oncology consultation were more likely to undergo active treatments whether they had intermediate or high-risk disease (88.6% vs. 65.9%, p < 0.0001; adjusted odds ratio 4.0, 95% CI: 3.6-4.4) or low-risk disease (56.1% vs. 13.3%, p < 0.0001; adjusted odds ratio 8.4, 95% CI: 6.7-10.6). This effect persisted after considering age, comorbidity, tumour volume and year of diagnosis., Conclusions: Patients newly diagnosed with prostate cancer who receive radiation oncology consultation are associated with a higher rate of active treatment, compared to patients managed by urologists only. Selection and referral biases, and unmeasured confounding such as patient preference must be considered as important factors attributing this association.

MicroRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally regulate gene expression. Dysregulation of miRNAs is frequently associated with disease and, in particular, is involved in prostate cancer progression. Next generation miRNA sequencing identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. High expression of one of these five miRNAs, miR-652, correlated significantly with an increased rate of prostate cancer biochemical recurrence. Overexpression of miR-652 in prostate cancer cells, PC3 and LNCaP, resulted in increased growth, migration and invasion. Prostate cancer cell xenografts overexpressing miR-652 showed increased tumorigenicity and metastases. We found that miR-652 directly targets the B" regulatory subunit, PPP2R3A, of the tumor suppressor PP2A, inducing epithelial-mesenchymal transition (EMT) in PC3 cells and neuroendocrine-like differentiation (NED) in LNCaP cells. The mesenchymal marker N-cadherin increased and epithelial marker E-cadherin decreased in PC3 cells overexpressing miR-652. In LNCaP cells and xenografted tumors, overexpression of miR-652 increased markers of NED, including chromogranin A, neuron specific enolase, and synaptophysin. MiR-652 may contribute to prostate tumor progression by promoting NED through decreased PP2A function. MiR-652 expression could serve as a biomarker for aggressive prostate cancer, as well as provide an opportunity for novel therapy in prostate cancer., Competing Interests: CONFLICTS OF INTEREST All authors have disclosed no potential conflicts of interest.

Objective: To assess the association between local treatment modality, surgery or radiotherapy, and non-prostate cancer and cardiovascular mortality in patients treated for nonmetastatic prostate cancer, given the high competing risk of mortality in this population., Methods: We performed a population-based, retrospective cohort study of men treated for nonmetastatic prostate cancer in Ontario, Canada, from 2002 to 2009. Patients treated with surgery and radiotherapy were matched on demographics, comorbidity, and cardiovascular risk factors. The primary outcome was non-prostate cancer mortality. Outcomes were compared using the Fine and Gray subdistribution method with generalized estimating equations. We used a previously published technique to quantify the prevalence and strength of residual confounding necessary to account for observed results., Results: We examined 5393 pairs of matched men. The 10-year cumulative incidence of non-prostate cancer mortality was higher among patients who underwent radiotherapy (12%) than surgery (8%; adjusted subdistribution hazard ratio [HR] 1.57, 95% confidence interval 1.35-1.83). Patients treated with radiotherapy also had an increased risk of cardiovascular mortality (adjusted HR 1.74, 95% confidence interval 1.27-2.37). Hypothetical residual confounders would have to be both strongly associated with non-prostate cancer mortality (HRs > 2.5) and have highly differential prevalence to nullify the observed effect., Conclusion: Among patients carefully matched on cardiovascular risk factors, those treated with radiotherapy had an increased risk of non-prostate cancer mortality and cardiovascular disease. Because of the observational nature of the data, the potential for confounding remains. The magnitude and prevalence of potential residual confounders required to account for differences in treatment effects for prostate cancer was quantified., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To assess the toxicity and effectiveness of contemporary metastatic castrate-resistant prostate cancer (mCRPC) treatments at a population level, among all patients in Ontario particularly treated with newer agents, including abiraterone, enzalutamide, docetaxel, and cabazitaxel., Methods: We performed a population-based, retrospective cohort study of 2439 men aged ≥65 years treated for mCRPC with abiraterone, enzalutamide, docetaxel, or cabazitaxel from 2003 to 2015 in Ontario, Canada. Our primary outcome was treatment-related toxicity, defined as hospitalizations and emergency room (ER) visits during mCRPC treatment. Based on toxicity profiles identified during phase III trials, we further identified specific treatment-related toxicity. We calculated hazard ratios (HRs) using multivariable Cox proportional hazards models with time-varying exposures., Results: Abiraterone and enzalutamide exposure were not associated with any-cause (P = .19 and .52, respectively) or treatment-related (P = .45 and .64, respectively) toxicities. In contrast, docetaxel exposure was associated with an increased risk of any-cause (HR 1.29, 95% confidence interval [CI] 1.15-1.44) and treatment-related (HR 1.52, 95% CI 1.33-1.74) toxicities. Cabazitaxel exposure was associated with a significant risk of treatment-related toxicity (HR 5.94, 95% CI 1.87-18.92) but not any-cause toxicity (HR 2.37, 95% CI 0.59-9.63)., Conclusion: Among patients with mCRPC, we failed to show any increased risk of hospitalizations and ER visits for treatment-related complications for abiraterone or enzalutamide. In contrast, treatment with intravenous chemotherapeutic agents was associated with an increased risk of hospitalizations and ER visits to manage these complications., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Current prostate cancer risk calculators are limited in impact because only a probability of having prostate cancer is provided. We developed the next generation of prostate cancer risk calculator that incorporates life expectancy in order to better evaluate prostate cancer risk in context to a patient's age and comorbidity., Methods: We combined two cohorts to develop the new risk calculator. The first was 5638 subjects who all underwent a prostate biopsy for prostate cancer detection. The second was 979 men diagnosed with prostate cancer with long-term survival data. Two regression models were used to create multivariable nomograms and an online prostate cancer risk calculator was developed., Results: Of the 5638 patients who underwent a prostate biopsy, 629 (11%) were diagnosed with aggressive prostate cancer (Gleason Score 7[4+3] or more). Of the 979 patients who underwent treatment for prostate cancer, the 10-year overall survival (OS) was 49.6% (95% confidence interval [CI] 46.6-52.9). The first multivariable nomogram for cancer risk had a concordance index of 0.74 (95% CI 0.72, 0.76), and the second nomogram to predict survival had a concordance index of 0.71 (95% CI 0.69-0.72). The next-generation prostate cancer risk calculator was developed online and is available at: http://riskcalc.org/ProstateCA&#95;Screen&#95;Tool., Conclusions: We have developed the next-generation prostate cancer risk calculator that incorporates a patient's life expectancy based on age and comorbidity. This approach will better evaluate prostate cancer risk. Future studies examining other populations will be needed for validation.

Background: Evaluation of treatment options for localized prostate cancer (PCa) remains among the highest priorities for comparative effectiveness research. Surgery and radiotherapy (RT) are the two interventions most commonly used., Objective: To provide a critical narrative review of evidence of the comparative effectiveness and harms of surgery and RT in the treatment of localized PCa., Evidence Acquisition: A collaborative critical narrative review of the literature was conducted., Evidence Synthesis: Evidence to clearly guide treatment choice in PCa remains insufficient. Randomized trials are underpowered for clinically meaningful endpoints and have demonstrated no difference in overall or PCa-specific survival. Observational studies have consistently demonstrated an absolute survival benefit for men treated with radical prostatectomy, but are limited by selection bias and residual confounding errors. Surgery and RT are associated with comparable health-related quality of life following treatment in three randomized trials. Randomized data regarding urinary, erectile, and bowel function show few long-term (>5 yr) differences, although short-term continence and erectile function were worse following surgery and short-term urinary bother and bowel function were worse following RT. There has been recent recognition of other complications that may significantly affect the life trajectory of those undergoing PCa treatment. Of these, hospitalization, the need for urologic, rectoanal, and other major surgical procedures, and secondary cancers are more common among men treated with RT. Androgen deprivation therapy, frequently co-administered with RT, may additionally contribute to treatment-related morbidity. Technological innovations in surgery and RT have shown inconsistent oncologic and functional benefits., Conclusions: Owing to underpowered randomized control studies and the selection biases inherent in observational studies, the question of which treatment provides better PCa control cannot be definitively answered now or in the near future. Complications following PCa treatment are relatively common regardless of treatment approach. These include the commonly identified issues of urinary incontinence and erectile dysfunction, and others including hospitalization and invasive procedures to manage complications and secondary malignancies. Population-based outcome studies, rather than clinical trial data, will be necessary for a comprehensive understanding of the relative benefits and risks of each therapeutic approach., Patient Summary: Surgery and radiotherapy are the most common interventions for men diagnosed with prostate cancer. Comparisons of survival after these treatments are limited by various flaws in the relevant studies. Complications are common regardless of the treatment approach., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Peripheral nerve injury (PNI) is a rare but preventable complication of surgery. We sought to assess whether the use of minimally invasive surgery (MIS) affects the occurrence of PNI. Using the American College of Surgeons National Surgical Quality Improvement Program database, we examined rates of PNI among patients undergoing appendectomy, hysterectomy, colectomy, or radical prostatectomy between 2005 and 2012. We assessed the effect of MIS, as compared with open surgery, on PNI occurrence using logistic regression. Among 297,532 patients, of whom 175,884 (59.1%) underwent MIS, the rate of PNI was 0.03 per cent. Forty-four patients treated using MIS had PNI (0.03%) as compared with 63 who underwent open surgery (0.05%; P = 0.0002). There was a significant decrease in the proportion of surgeries resulting in PNI (P < 0.0001) over time. In univariate analysis, MIS was associated with a decreased occurrence of PNI (odds ratio 0.48, 95% confidence interval 0.33-0.71), but this became nonsignificant on multivariable analysis (odds ratio 0.71, 95% confidence interval 0.47-1.09). Increased operative time and smoking status were the only factors independently associated with an increased risk of PNI on multivariable analysis. MIS techniques during common abdominal-pelvic surgeries do not appear to increase the risk of PNI. Prolonged operative time and smoking are independently associated with an increased risk of PNI. Quality improvement initiatives to increase awareness of PNI and identify patients at increased risk of this preventable complication should be considered.

Introduction: We sought to examine the relationship between preoperative platelet to white blood cell ratio (PLT/WBC), a hematological marker of the systemic inflammatory response, and postoperative infectious complications following radical nephrectomy for localized renal cell carcinoma., Methods: We performed a retrospective cohort study of patients treated with radical nephrectomy for localized kidney cancer between January 1, 2005 and December 31, 2014 (n=6235) using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Univariate and multivariate analyses were used to assess the association between PLT/WBC ratio and 30-day infectious complications, including surgical site infection, urinary tract infection (UTI), pneumonia, and sepsis. Secondarily, we examined major complications and bleeding requiring transfusion., Results: A lower PLT/WBC ratio was associated with an increased risk of sepsis, pneumonia, and UTI rates (p<0.05 for all). Furthermore, there was a significant trend of decreasing rates of sepsis and pneumonia with increasing PLT/WBC ratio across quintiles (p<0.05 for all). On multivariate analysis, patients with the lowest PLT/WBC ratios (Quintile 1) had a two-fold risk of having a postoperative infectious complication compared to patients in the highest quintile (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.42-2.86; p<0.0001). Patients in Quintile 5 had a higher risk of requiring blood transfusion than those in Quintiles 2-4 (p<0.05 for all)., Conclusions: The PLT/WBC ratio represents a widely available and novel index to predict risk of infectious and bleeding complications in patients undergoing radical nephrectomy. External validation is required and the biological underpinning of this phenomenon requires further study.

Importance: Antithrombotic medications are among the most commonly prescribed medications., Objective: To characterize rates of hematuria-related complications among patients taking antithrombotic medications., Design, Setting, and Participants: Population-based, retrospective cohort study including all citizens in Ontario, Canada, aged 66 years and older between 2002 and 2014. The final follow-up date was December 31, 2014., Exposures: Receipt of an oral anticoagulant or antiplatelet medication., Main Outcomes and Measures: Hematuria-related complications, defined as emergency department visit, hospitalization, or a urologic procedure to investigate or manage gross hematuria., Results: Among 2 518 064 patients, 808 897 (mean [SD] age, 72.1 [6.8] years; 428 531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were 123.95 events per 1000 person-years among patients actively exposed to antithrombotic agents vs 80.17 events per 1000 person-years among patients not exposed to these drugs (difference, 43.8; 95% CI, 43.0-44.6; P < .001, and incidence rate ratio [IRR], 1.44; 95% CI, 1.42-1.46). The rates of complications among exposed vs unexposed patients (80.17 events/1000 person-years) were 105.78 for urologic procedures (difference, 33.5; 95% CI, 32.8-34.3; P < .001, and IRR, 1.37; 95% CI, 1.36-1.39), 11.12 for hospitalizations (difference, 5.7; 95% CI, 5.5-5.9; P < .001, and IRR, 2.03; 95% CI, 2.00-2.06), and 7.05 for emergency department visits (difference, 4.5; 95% CI, 4.3-4.7; P < .001, and IRR, 2.80; 95% CI, 2.74-2.86). Compared with patients who were unexposed to thrombotic agents, the rates of hematuria-related complications were 191.61 events per 1000 person-years (difference, 117.3; 95% CI, 112.8-121.8) for those exposed to both an anticoagulant and antiplatelet agent (IRR, 10.48; 95% CI, 8.16-13.45), 140.92 (difference, 57.7; 95% CI, 56.9-58.4) for those exposed to anticoagulants (IRR, 1.55; 95% CI, 1.52-1.59), and 110.72 (difference, 26.5; 95% CI, 25.9-27.0) for those exposed to antiplatelet agents (IRR, 1.31; 95% CI, 1.29-1.33). Patients exposed to antithrombotic agents, compared with patients not exposed to these drugs, were more likely to be diagnosed as having bladder cancer within 6 months (0.70% vs 0.38%; odds ratio, 1.85; 95% CI, 1.79-1.92)., Conclusions and Relevance: Among older adults in Ontario, Canada, use of antithrombotic medications, compared with nonuse of these medications, was significantly associated with higher rates of hematuria-related complications (including emergency department visits, hospitalizations, and urologic procedures to manage gross hematuria).

Objective: To quantify the effect of immortal-time bias in an observational study examining the effect of cumulative testosterone exposure on mortality., Patients and Methods: We used a population-based matched cohort study of men aged ≥66 years, newly treated with testosterone-replacement therapy (TRT), and matched-controls from 2007 to 2012 in Ontario, Canada to quantify the effects of immortal-time bias. We used generalised estimating equations to determine the association between cumulative TRT exposure and mortality. Results produced by models using time-fixed and time-varying exposures were compared. Further, we undertook a systematic review of PubMed to identify studies addressing immortal-time bias or time-varying exposures in the urological literature and qualitatively summated these., Results: Among 10 311 TRT-exposed men and 28 029 controls, the use of a time-varying exposure resulted in the attenuation of treatment effects compared with an analysis that did not account for immortal-time bias. While both analyses showed a decreased risk of death for patients in the highest tertile of TRT exposure, the effect was overestimated when using a time-fixed analysis (adjusted hazard ratio [aHR] 0.56, 95% confidence interval [CI]: 0.52-0.61) when compared to a time-varying analysis (aHR 0.67, 95% CI: 0.62-0.73). Of the 1 241 studies employing survival analysis identified in the literature, nine manuscripts met criteria for inclusion. Of these, five used a time-varying analytical method. Each of these was a large, population-based retrospective cohort study assessing potential harms of pharmacological agents., Conclusions: Where exposures vary over time, a time-varying exposure is necessary to draw meaningful conclusions. Failure to use a time-varying analysis will result in overestimation of a beneficial effect. However, time-varying exposures are uncommonly utilised among manuscripts published in prominent urological journals., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)