The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Environmental and Occupational Exposures and Prognosis in Patients with Non-Muscle Invasive Bladder Cancer in the Be-Well Study.

Bladder cancer is primarily diagnosed as non-muscle invasive bladder cancer (NMIBC) with high recurrence and progression rates. Environmental and occupational exposures to carcinogens are well-known risk factors for developing bladder cancer, yet their effects on prognosis remain unknown. In the Be-Well Study, a population-based prospective cohort study of 1,472 patient with newly diagnosed NMIBC from 2015 to 2019, we examined history of environmental and occupational exposures in relation to tumor stage and grade at initial diagnosis by multivariable logistic regression, and subsequent recurrence and progression by Cox proportional hazards regression. Exposure to environmental and occupational carcinogens was significantly associated with increased risk of progression (HR = 1.79; 95% CI: 1.04, 3.09), specifically increased progression into muscle-invasive disease (HR = 2.28; 95% CI: 1.16, 4.50). Exposure to asbestos and arsenic were associated with increased odds of advanced stage at diagnosis (asbestos: OR = 1.43; 95% CI: 1.11, 1.84; arsenic, OR = 1.27; 95% CI: 1.01, 1.63), and formaldehyde exposure was associated with increased risk of recurrence (HR = 1.38; 95% CI: 1.12, 1.69). Our findings suggest that history of these exposures may benefit current risk stratification systems to tailor clinical care and improve prognosis in patients with NMIBC.

Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria.

PURPOSE: Microhematuria is a prevalent condition and the American Urological Association has developed a new risk-stratified approach for the evaluation of patients with microhematuria. Our objective was to provide the first evaluation of this important guideline. MATERIALS AND METHODS: This multinational cohort study combines contemporary patients from 5 clinical trials and 2 prospective registries who underwent urological evaluation for hematuria. Patients were stratified into American Urological Association risk strata (low, intermediate or high risk) based on sex, age, degree of hematuria, and smoking history. The primary end point was the incidence of bladder cancer within each risk stratum. RESULTS: A total of 15,779 patients were included in the analysis. Overall, 727 patients (4.6%) were classified as low risk, 1,863 patients (11.8%) were classified as intermediate risk, and 13,189 patients (83.6%) were classified as high risk. The predominance of high risk patients was consistent across all cohorts. A total of 857 bladder cancers were diagnosed with a bladder cancer incidence of 5.4%. Bladder cancer was more prevalent in men, smokers, older patients and patients with gross hematuria. The cancer incidence for low, intermediate and high risk groups was 0.4% (3 patients), 1.0% (18 patients) and 6.3% (836 patients), respectively. CONCLUSIONS: The new risk stratification system separates hematuria patients into clinically meaningful categories with differing likelihoods of bladder cancer that would justify evaluating the low, intermediate and high risk groups with incremental intensity. Furthermore, it provides the relative incidence of bladder cancer in each risk group which should facilitate patient counseling regarding the risks and benefits of evaluation for bladder cancer.

The Be-Well Study: a prospective cohort study of lifestyle and genetic factors to reduce the risk of recurrence and progression of non-muscle-invasive bladder cancer.

PURPOSE: Bladder cancer is one of the top five cancers diagnosed in the U.S. with a high recurrence rate, and also one of the most expensive cancers to treat over the life-course. However, there are few observational, prospective studies of bladder cancer survivors. METHODS: The Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study) is a National Cancer Institute-funded, multi-center prospective cohort study of non-muscle-invasive bladder cancer (NMIBC) patients (Stage Ta, T1, Tis) enrolled from the Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health care systems, with genotyping and biomarker assays performed at Roswell Park Comprehensive Cancer Center. The goal is to investigate diet and lifestyle factors in recurrence and progression of NMIBC, with genetic profiles considered, and to build a resource for future NMIBC studies. RESULTS: Recruitment began in February 2015. As of 30 June 2018, 1,281 patients completed the baseline interview (774 KPNC, 511 KPSC) with a recruitment rate of 54%, of whom 77% were male and 23% female, and 80% White, 6% Black, 8% Hispanic, 5% Asian, and 2% other race/ethnicity. Most patients were diagnosed with Ta (69%) or T1 (27%) tumors. Urine and blood specimens were collected from 67% and 73% of consented patients at baseline, respectively. To date, 599 and 261 patients have completed the 12- and 24-month follow-up questionnaires, respectively, with additional urine and saliva collection. CONCLUSIONS: The Be-Well Study will be able to answer novel questions related to diet, other lifestyle, and genetic factors and their relationship to recurrence and progression among early-stage bladder cancer patients.

Evaluation of microscopic hematuria and risk of urologic cancer in female patients.

BACKGROUND: Urologic cancer has a lower prevalence in women compared with men; however, there are no differences in the recommended evaluation for women and men with microscopic hematuria. OBJECTIVES: The purpose of this study was to identify risk factors that are associated with urologic cancer in women with microscopic hematuria and to determine the applicability of a hematuria risk score for women. STUDY DESIGN: We conducted a retrospective cohort study within an integrated healthcare system in Southern California. All urinalyses with microscopic hematuria (>3 red blood cells per high-power field) that were performed from 2009-2015 were identified. Women who were referred for urologic evaluation were entered into a prospective database. Clinical and demographic variables that included the presence of gross hematuria in the preceding 6 months were recorded. The cause of the hematuria, benign or malignant, was entered into the database. Cancer rates were compared with the use of chi-square and logistic regression models. Adjusted risk ratios of urologic cancer were estimated with the use of multivariate regression analysis. We also explored the applicability of a previously developed, gender nonspecific, hematuria risk score in this female cohort. RESULTS: A total of 2,705,696 urinalyses were performed in women during the study period, of which 552,119 revealed microscopic hematuria. Of these, 14,539 women were referred for urologic evaluation; clinical data for 3573 women were entered into the database. The overall rate of urologic cancer was 1.3% (47/3573). In women <60 years old, the rate of urologic cancer was 0.6% (13/2053) compared with 2.2% (34/1520) in women ≥60 years old (P<.01). In women who reported a history of gross hematuria, the rate of urologic cancer was 5.8% (20/346) compared with a 0.8% (27/3227) in women with no history of gross hematuria (P<.01). In multivariate analysis, > 60 years old (odds ratio, 3.1; 95% confidence interval, 1.6-5.9), a history of smoking (odds ratio, 3.2; 95% confidence interval, 1.8-5.9), and a history of gross hematuria in the previous 6 months (odds ratio, 6.2; 95% confidence interval, 3.4-11.5) were associated with urologic cancers. A higher microscopic hematuria risk score was associated with an increased risk of cancer in this test cohort (P<.01). Women in the highest risk group had a urologic cancer rate of 10.8% compared with a rate of 0.5% in the lowest risk group. CONCLUSIONS: In this female population, >60 years old and a history of smoking and/or gross hematuria were the strongest predictors of urologic cancer. Absent these risk factors, the rate of urologic cancer did not exceed 0.6%. A higher hematuria risk score correlated significantly with the risk of urologic cancer in this female test cohort.

Health-related quality of life outcomes from a contemporary prostate cancer registry in a large diverse population.

OBJECTIVE: To assess the health-related quality of life (HRQoL) of patients with prostate cancer up to 24 months after treatment in a contemporary large diverse population. PATIENTS AND METHODS: Patients with newly diagnosed prostate cancer from March 2011 to January 2014 in our healthcare system were included. The Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire was administered before treatment, and at 1, 3, 6, 12, 18, and 24 months after treatment up to November 2014 for all methods of treatment. The Kruskall-Wallis test was used to compare the distribution of each EPIC-26 domain score at each time point, and mixed models were used to assess the overall scores over the period after treatment. RESULTS: In all, 5 727 patients were included. There were data for 3 422, 2 329, 2 017, 1 922, 1 772, 1 260, and 837 patients before treatment, and at 1, 3, 6, 12, 18, and 24 months after treatment, respectively. At 1 month, bowel scores were the lowest for patients that had had radiation therapy, and urinary irritative symptoms were the lowest for those who had had brachytherapy. There were sexual function declines for all the treatment methods, with surgery having the steepest decline; open radical prostatectomy (ORP) had a greater decline than robot-assisted laparoscopic prostatectomy (RALP). Patients who underwent RALP had a better return of sexual function, approaching that of brachytherapy and radiation therapy at 24 months. Urinary incontinence (UI) also declined the most in surgical patients, with RALP patients improving slightly more than ORP patients at 12-24 months. CONCLUSIONS: Patients' HRQoL after prostate cancer treatment varies by treatment method. Notably, sexual function recovers most for RALP patients. UI remains worse at 24 months after surgery, compared to other methods of prostate cancer treatment.

Progression and treatment of incident lower urinary tract symptoms (LUTS) among men in the California Men's Health Study.

OBJECTIVES: To characterise the progression and treatment of lower urinary tract symptoms (LUTS) among men aged 45-69 years in the California Men's Health Study. PATIENTS AND METHODS: A total of 39,222 men, aged 45-69 years, enrolled in the Southern California Kaiser Permanente Health Plan were surveyed in 2002-2003 and again in 2006-2007. Those men who completed both surveys who did not have a diagnosis of benign prostatic hyperplasia (BPH) and were not on medication for LUTS at baseline were included in the study (N = 19,505). Among the men with no or mild symptoms at baseline, the incidence of moderate/severe LUTS (American Urological Association Symptom Index [AUASI] score ≥8) and odds of progression to severe LUTS (AUASI score ≥20) was estimated during 4 years of follow-up. RESULTS: Of the 9640 men who reported no/mild LUTS at baseline, 3993 (41%) reported moderate/severe symptoms at follow-up and experienced a 4-point change in AUASI score on average. Of these men, 351 (8.8%) had received a pharmacological treatment, eight (0.2%) had undergone a minimally invasive or surgical procedure and 3634 (91.0%) had no treatment recorded. Men who progressed to severe symptoms (AUASI score ≥20; n = 165) were more likely to be on medication for BPH (odds ratio [OR] 8.09, 95% confidence interval [CI] 5.77-11.35), have a BPH diagnosis (OR 4.74, 95% CI 3.40-6.61) or have seen a urologist (OR 2.49, 95% CI 1.81-3.43) when compared with men who did not progress to severe symptoms (AUASI score <20). CONCLUSION: These data show that the majority of men who experienced progression did not have pharmacological or surgical therapy for their symptoms and, therefore, may prove to be good candidates for a self-management plan.

Modifying Effects of Genetic Variations on the Association Between Dietary Isothiocyanate Exposure and Non-muscle Invasive Bladder Cancer Prognosis in the Be-Well Study.

SCOPE: Dietary isothiocyanate (ITC) exposure from cruciferous vegetable (CV) intake may improve non-muscle invasive bladder cancer (NMIBC) prognosis. This study aims to investigate whether genetic variations in key ITC-metabolizing/functioning genes modify the associations between dietary ITC exposure and NMIBC prognosis outcomes. METHODS AND RESULTS: In the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study), a prospective cohort of 1472 incident NMIBC patients, dietary ITC exposure is assessed by self-reported CV intake and measured in plasma ITC-albumin adducts. Using Cox proportional hazards regression models, stratified by single nucleotide polymorphisms (SNPs) in nine key ITC-metabolizing/functioning genes, it is calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression. The rs15561 in N-acetyltransferase 1 (NAT1) is alter the association between CV intake and progression risk. Multiple SNPs in nuclear factor E2-related factor 2 (NRF2) and nuclear factor kappa B (NFκB) are modify the associations between plasma ITC-albumin adduct level and progression risk (pint < 0.05). No significant association is observed with recurrence risk. Overall, >80% study participants are present with at least one protective genotype per gene, showing an average 65% reduction in progression risk with high dietary ITC exposure. CONCLUSION: Despite that genetic variations in ITC-metabolizing/functioning genes may modify the effect of dietary ITCs on NMIBC prognosis, dietary recommendation of CV consumption may help improve NMIBC survivorship.

Changes in serum prostate-specific antigen levels and the identification of prostate cancer in a large managed care population.

OBJECTIVE: To determine whether the rate of change in total serum prostate-specific antigen (PSA) levels accurately detects prostate cancer and to evaluate whether it adds any predictive value to a single measurement of serum PSA alone, in general practice settings. MATERIALS AND METHODS: A retrospective cohort of 219,388 community-dwelling men, aged ≥45 years, enrolled in the Kaiser Permanente Southern California health plan, with no history of prostate cancer and at least three PSA measurements, were followed from 1 January 1998 to 31 December 2007, for the development of biopsy-confirmed prostate cancer. Annual percent changes in total serum PSA levels were estimated using linear mixed models. The accuracy of prostate cancer prediction was assessed for prostate cancer overall and for aggressive disease (Gleason score ≥7) and compared with that of a single measure of PSA level using area under the receiver-operating characteristic curves (AUCs). RESULTS: The men in this cohort experienced a mean change of 2.9% in PSA levels per year and the rate of change in PSA increased modestly with age (P ≤ 0.001). Annual percent changes in PSA accurately predicted the presence of prostate cancer (AUC = 0.963) and aggressive disease (AUC = 0.955) and had more predictive accuracy for aggressive disease than did a single measurement of PSA alone (AUC = 0.727). CONCLUSIONS: Longitudinal measures of PSA improve the accuracy of aggressive prostate cancer detection when compared with a single measurement of PSA alone. Findings from this study provide insight into the usefulness of PSA velocity as a detection marker for aggressive prostate cancer.

Associations of dietary isothiocyanate exposure from cruciferous vegetable consumption with recurrence and progression of non-muscle-invasive bladder cancer: findings from the Be-Well Study.

BACKGROUND: High recurrence and progression rates are major clinical challenges for non-muscle-invasive bladder cancer (NMIBC). Dietary isothiocyanates (ITCs), phytochemicals primarily from cruciferous vegetables (CV), show strong anticancer activities in preclinical BC models, yet their effect on NMIBC prognosis remains unknown. OBJECTIVES: This study aimed to investigate the associations of dietary ITC exposure at diagnosis with NMIBC recurrence and progression. METHODS: The study analyzed 1143 participants from the Be-Well study, a prospective cohort of newly diagnosed NMIBC cases in 2015-2019 with no prior history of BC. Dietary ITC exposure was indicated by self-reported CV intake, estimated ITC intake, urinary metabolites, and plasma ITC-albumin adducts. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression, and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for delayed and multiple recurrence. RESULTS: Over a mean follow-up of 25 mo, 347 (30%) developed recurrence and 77 (6.7%) had disease progression. Despite no significant associations with the overall risk of recurrence, urinary ITC metabolites (OR: 1.96; 95% CI: 1.01, 4.43) and dietary ITC intake (OR: 2.13; 95% CI: 1.03, 4.50) were associated with late recurrence after 12-mo postdiagnosis compared with before 12-mo postdiagnosis. Raw CV intake was associated with reduced odds of having ≥2 recurrences compared with having one (OR: 0.34; 95% CI: 0.16, 0.68). Higher plasma concentrations of ITC-albumin adducts were associated with a reduced risk of progression, including progression to muscle-invasive disease (for benzyl ITC, HR: 0.40; 95% CI: 0.17, 0.93; for phenethyl ITC, HR: 0.40; 95% CI: 0.19, 0.86). CONCLUSIONS: Our findings indicate the possible beneficial role of dietary ITCs in NMIBC prognosis. Given the compelling preclinical evidence, increasing dietary ITC exposure with CV intake could be a promising strategy to attenuate recurrence and progression risks in patients with NMIBC.

Population-based study of erectile dysfunction and polypharmacy.

UNLABELLED: Study Type - Symptom prevalence (population cohort). Level of Evidence 1b. What's known on the subject? and What does the study add? It is known that medical conditions such as diabetes, high blood pressure, high cholesterol, smoking and prescribed medications cause erectile dysfunction (ED). This has been studied at the molecular level and reported in population studies. The present study shows that, after accounting for known medical problems, there is a dose-response relationship, in which worsening degrees of ED are seen when a greater number of medications are taken, regardless if they are prescribed or over the counter. The study can help primary care doctors and urologists to make a differential diagnosis of ED and it can also help improve patient's erectile function by tailoring and curtailing current medication use to maximize therapeutic benefit but minimize ED side effects in men, thus improving health-related quality of life. OBJECTIVE: • To study the association between erectile dysfunction (ED) and polypharmacy use in a large, ethnically and racially diverse cohort of men enrolled in the California Men's Health Study (CMHS). PATIENTS AND METHODS: • Men from the Kaiser Permanente Southern California (KPSC) health plan, enrolled in the CMHS in 2002, had an age range of 45-69 years. ED and comorbidities of these subjects were identified by questionnaire responses. • The number of drugs taken was determined from the year before enrollment through electronic pharmacy records and questionnaire responses. RESULTS: • Among the 37 712 (KPSC) subjects, 10 717 (29%) reported moderate or severe ED. • Across all age groups, ED was more prevalent as the number of medications increased. • In men taking 0-2, 3-5,6-9 and ≥ 10 medications, the percentage of men reporting moderate ED was 15.9, 19.7, 25.5 and 30.9%, respectively (P < 0.001). • With adjustment for age, race, smoking, diabetes, hypertension, hyperlipidaemia, peripheral vascular disease, coronary artery disease and body mass index, men taking >10 drugs were more likely to have ED (odds ratio = 2.32, 95% confidence interval 2.14-2.52) with evidence of a dose-response relationship. CONCLUSION: • These data suggest that the number of medications a man takes is associated with worse ED, even after comorbidities have been taken into account.

Smoking Behaviors and Prognosis in Patients With Non-Muscle-Invasive Bladder Cancer in the Be-Well Study.

Importance: Tobacco smoking is an established risk factor associated with bladder cancer, yet its impact on bladder cancer prognosis is unclear. Objective: To examine associations of use of tobacco (cigarettes, pipes, and cigars), e-cigarettes, and marijuana with risk of recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) and to explore use of smoking cessation interventions. Design, Setting, and Participants: The Be-Well Study is a prospective cohort study of patients with NMIBC diagnosed from 2015 to 2019 and followed-up for 26.4 months in the Kaiser Permanente Northern and Southern California integrated health care system. Eligibility criteria were age at least 21 years, first NMIBC diagnosis (stages Ta, Tis, or T1), alive, and not in hospice care. Exclusion criteria were previous diagnosis of bladder cancer or other cancer diagnoses within 1 year prior to or concurrent with NMIBC diagnosis. Data were analyzed from April 1 to October 4, 2022. Exposures: Use of cigarettes, pipes, cigars, e-cigarettes, and marijuana was reported in the baseline interview. Use of smoking cessation interventions (counseling and medications) was derived from electronic health records. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs of recurrence and progression of bladder cancer were estimated by multivariable Cox proportional hazards regression. Results: A total of 1472 patients (mean [SD] age at diagnosis, 70.2 [10.8%] years; 1129 [76.7%] male patients) with NMIBC were enrolled at a mean (SD) of 2.3 (1.3) months after diagnosis, including 874 patients (59.4%) who were former smokers and 111 patients (7.5%) who were current cigarette smokers; 67 patients (13.7%) smoked pipes and/or cigars only, 65 patients (4.4%) used e-cigarettes, 363 patients (24.7%) used marijuana. Longer cigarette smoking duration and more pack-years were associated with higher risk of recurrence in a dose-dependent manner, with the highest risks for patients who had smoked for 40 or more years (HR, 2.36; 95% CI, 1.43-3.91) or 40 or more pack-years (HR, 1.97; 95% CI, 1.32-2.95). There was no association of having ever smoked, being a former or current cigarette smoker, and years since quit smoking with recurrence risk. No associations with pipes, cigars, e-cigarettes, or marijuana were found. Of 102 patients offered a smoking cessation intervention, 57 (53.8%) received an interventions after diagnosis, with female patients more likely than male patients to engage in such interventions (23 of 30 female patients [76.7%] vs 34 of 76 male patients [44.7%]; P = .003). Conclusions and Relevance: These findings suggest that longer duration and more pack-years of cigarette smoking were associated with higher risk of NMIBC recurrence. Cigarette smoking remains a critical exposure before and after diagnosis in survivors of NMIBC.

Association of hematuria on microscopic urinalysis and risk of urinary tract cancer.

PURPOSE: We determined the incidence of urinary tract cancer in patients with hematuria, stratified risk by age, gender and hematuria degree, and examined current best policy recommendations. MATERIALS AND METHODS: We performed a large, retrospective population based cohort study of patients who underwent microscopic urinalysis during 2004 and 2005 in a large managed care organization. Patients were followed for 3 years for urinary tract cancer. RESULTS: We identified 772,002 patients who underwent urinalysis during the study period. After exclusions due to previous hematuria, age less than 18 years, pregnancy, urinary tract infection, inpatient status and prior urinary tract cancer 309,402 patients were available for analysis, of whom 156,691 had hematuria. The overall 3-year incidence of urinary tract cancer in those with hematuria was 0.68%. Older age (greater than 40 years OR 17.0, 95% CI 11.2-25.7), greater hematuria (greater than 25 red blood cells per high power field OR 4.0, 95% CI 3.5-4.5) and male gender (OR 4.8, 95% CI 4.2-5.6) were associated with a higher risk of cancer. The American Urological Association definition of microhematuria had 50% sensitivity, 84% specificity and 1.3% positive predictive value. CONCLUSIONS: The incidence of urinary tract cancer is low even in individuals with microhematuria. Thus, current best policy recommendations do not perform well. Since older age, male gender and greater hematuria are associated with a higher risk of cancer, future studies should evaluate strategies that target these populations.

Regular nonsteroidal anti-inflammatory drug use and erectile dysfunction.

PURPOSE: Previous data suggest a potential relationship between inflammation and erectile dysfunction. If it is causal, nonsteroidal anti-inflammatory drug use should be inversely associated with erectile dysfunction. To this end we examined the association between nonsteroidal anti-inflammatory drug use and erectile dysfunction in a large, ethnically diverse cohort of men enrolled in the California Men's Health Study. MATERIALS AND METHODS: This prospective cohort study enrolled male members of the Kaiser Permanente managed care plans who were 45 to 69 years old beginning in 2002. Erectile dysfunction was assessed by questionnaire. Nonsteroidal anti-inflammatory drug exposure was determined by automated pharmacy data and self-reported use. RESULTS: Of the 80,966 men in this study 47.4% were considered nonsteroidal anti-inflammatory drug users based on the definitions used and 29.3% reported moderate or severe erectile dysfunction. Nonsteroidal anti-inflammatory drug use and erectile dysfunction strongly correlated with age with regular drug use increasing from 34.5% in men at ages 45 to 49 years to 54.7% in men 60 to 69 years old with erectile dysfunction increasing from 13% to 42%. The unadjusted OR for the association of nonsteroidal anti-inflammatory drugs and erectile dysfunction was 2.40 (95% CI 2.27, 2.53). With adjustment for age, race/ethnicity, smoking status, diabetes mellitus, hypertension, hyperlipidemia, peripheral vascular disease, coronary artery disease and body mass index, a positive association persisted (adjusted OR 1.38). The association persisted when using a stricter definition of nonsteroidal anti-inflammatory drug exposure. CONCLUSIONS: These data suggest that regular nonsteroidal anti-inflammatory drug use is associated with erectile dysfunction beyond what would be expected due to age and comorbidity.

Population Management Approach to Kidney Stone Care Improves Patient Compliance to Preventive Measures and Reduces Resource Utilization in Patients at High Risk for Stone Recurrence.

INTRODUCTION: Nephrolithiasis is a chronic condition with 5 to 10-year recurrence rates as high as 50%. Stone recurrence can be reduced by implementing American Urological Association kidney stone medical management guidelines, which recommend additional metabolic testing for high risk, recurrent and interested first-time stone formers. However, clinician adherence to guidelines is variable, and patient compliance with preventive evaluations is low. We evaluated our kidney stone population management program's role in patient compliance with completing American Urological Association metabolic studies. We assessed the program's impact on office encounters, operating room procedures and emergency department visits for known high risk kidney stone patients. METHODS: A retrospective review of electronic medical records between 2009 and 2017 identified 4,029 kidney stone patients. A total of 873 patients were at high risk for kidney stone recurrence. In 2013, we established a population management program in which high risk patients were referred and followed by a nurse case manager. Patients were contacted by email or telephone if metabolic serum and urine collections were incomplete. Office, operating room and emergency department visits were compared before and after the program's implementation. RESULTS: Metabolic evaluation orders increased from 17% to 35% in our institution's urology department. Patient compliance with recommended studies improved from <10% to 82%, and reductions in office visits by 48%, surgical procedures by 38% and emergency department encounters by 40% were observed. CONCLUSIONS: Our program improved patient compliance with American Urological Association recommended studies for high risk kidney stone patients. Reductions in stone events may have been due to our program but require further study in the future.

Disparities in Stage at Diagnosis in an Equal-access Integrated Delivery System: A Retrospective Cohort Study of 7244 Patients With Bladder Cancer.

BACKGROUND: Disparities in bladder cancer survival by race/ethnicity and gender are likely related to differences in diagnosis. We assessed disparities in stage at diagnosis and potential contributing factors within a large, integrated delivery system. PATIENTS AND METHODS: We conducted a retrospective cohort study of 7244 patients with bladder cancer age ≥ 21 years diagnosed from January 2001 to June 2015 within Kaiser Permanente Southern California. Bivariate analyses compared stage at diagnosis - as well as comorbidities, health plan membership length, and health care utilization prior to diagnosis - by race/ethnicity, gender, and age. Multivariable generalized linear mixed models with urologist as a random effect were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for diagnosis of muscle-invasive bladder cancer (MIBC) versus non-muscle-invasive bladder cancer. RESULTS: In multivariable analyses, stage at diagnosis varied significantly by race/ethnicity (P < .001). Non-Hispanic black patients had significantly higher odds of being diagnosed with MIBC than non-Hispanic white patients (OR, 1.33; 95% CI, 1.05-1.67), whereas Asian patients had significantly lower odds (OR, 0.67; 95% CI, 0.49-0.91). Women were significantly more likely to be diagnosed with MIBC than men (OR, 1.40; 95% CI, 1.22-1.61). Non-Hispanic black women had the highest proportion (39%) of MIBC diagnoses. Among Hispanic and Asian patients, a greater proportion of diagnoses occurred at younger ages. CONCLUSIONS: Health care coverage within an equal-access system did not eliminate disparities in stage at diagnosis by race/ethnicity or gender. Studies are needed to identify etiologic factors and aspects of care delivery (eg, patient-physician interactions) that may affect the diagnostic process to inform efforts to improve health equity.

Care Quality and Variability in the Use of Intravesical Therapy for Initial Treatment of Nonmuscle Invasive Bladder Cancer Within a Large, Diverse Integrated Delivery System.

OBJECTIVES: To examine treatment variability, disparities, and quality among newly diagnosed nonmuscle invasive bladder cancer (NMIBC) patients, and to identify factors associated with treatment use in a large, diverse integrated delivery system. METHODS: Retrospective cohort study of 5386 NMIBC patients diagnosed between January 2001 and June 2015 within Kaiser Permanente Southern California. Electronic health data were used to identify treatment outcomes and patient, provider, and tumor characteristics. Outcomes were use of (1) postoperative intravesical chemotherapy, (2) induction Bacille Calmette-Guérin (BCG) immunotherapy, and (3) any intravesical therapy. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized linear mixed models with a binary outcome and urologist as a random effect. RESULTS: From 2001 to 2015, 41% of newly diagnosed NMIBC patients were treated with intravesical therapy. Postoperative chemotherapy use increased significantly over this period (OR per-year = 1.16, 95% CI: 1.07-1.25). BCG use was strongly associated with tumor characteristics: patients with high-grade or carcinoma in situ tumors were more likely to receive BCG (OR = 10.10, 95% CI: 8.39-12.16). Few treatment differences were found by sex or race/ethnicity, but were observed by age. Wide treatment variability across urologists was observed, with some urologists never using intravesical therapy as part of initial treatment while others almost always used it. Differences across urologists accounted for more variability in postoperative chemotherapy (intraclass correlation coefficient = 0.52) than BCG immunotherapy (intraclass correlation coefficient = 0.11) use. CONCLUSION: Substantial variability in initial treatment of NMIBC was observed across urologists, accounting for tumor, patient, and provider characteristics. Results suggest a considerable opportunity for quality improvement programs to reduce unwanted treatment variability and improve care for patients.

Association between 5-alpha reductase inhibition and risk of hip fracture.

CONTEXT: For more than 15 years, 5-alpha reductase inhibitors, which block the conversion of testosterone to dihydrotestosterone, have been used in the treatment of benign prostatic hyperplasia (BPH). Short-term studies show no effects of these agents on bone metabolism,but long-term data are not available. OBJECTIVE: To assess the association between use of 5-alpha reductase inhibitors (eg, finasteride) for BPH and occurrence of hip fracture. DESIGN, SETTING, AND PATIENTS: Population-based case-control study using data from Kaiser Permanente Southern California, a managed care organization with more than 3 million members. Case patients included 7076 men 45 years and older with incident hip fracture from 1997-2006. Control patients were 7076 men without incident hip fracture, optimally matched at a 1:1 ratio to case patients on age and medical center. Electronic information on pharmaceutical use was used to identify use of finasteride from 1991 forward. RESULTS: Overall, 2547 (36%) and 2488 (35%) case and control patients, respectively, had a diagnosis of BPH (P = .30), and 109 (1.5%) and 141 (2.0%) of case and control patients, respectively, had been exposed to finasteride prior to the index date (matched odds ratio, 0.77; 95% confidence interval, 0.59-1.00; P = .04). There was no suggestion of a dose-response relationship between exposure to 5-alpha reductase inhibitors when the exposure was stratified into tertiles of total exposure (P = .12). By contrast, there was a slightly higher prevalence of alpha-blocker use in case vs control patients (32% vs 30%, respectively; P = .04). CONCLUSIONS: Exposure to 5-alpha reductase inhibitors was not associated with increased risk of hip fracture. The reduction in risk observed with exposure to 5-alpha reductase inhibitors and the modest increase in risk associated with exposure to alpha-blockers require replication and warrant further investigation.

The Use of 5-Alpha Reductase Inhibitors to Manage Benign Prostatic Hyperplasia and the Risk of All-cause Mortality.

OBJECTIVE: To compare the risk of mortality among men treated for benign prostatic hyperplasia (BPH) with 5 alpha-reductase inhibitors (5ARI) to those treated with alpha-blockers (AB) in community practice settings. METHODS: We employed a retrospective matched cohort study in 4 regions of an integrated healthcare system. Men aged 50 years and older who initiated pharmaceutical treatment for BPH and/or lower urinary tract symptoms between 1992 and 2008 and had at least 3 consecutive prescriptions that were eligible and followed through 2010 (N = 174,895). Adjusted hazard ratios were used to estimate the risk of mortality due to all-causes associated with 5ARI use (with or without concomitant ABs) as compared to AB use. RESULTS: In this large and diverse sample with 543,523 person-years of follow-up, 35,266 men died during the study period, 18.9% of the 5ARI users and 20.4% of the AB users. After adjustment for age, medication initiation year, race, region, prior AB history, Charlson score, and comorbidities, 5ARI use was not associated with an increased risk of mortality when compared to AB use (Adjusted hazard ratios: 0.64, 95% confidence interval: 0.62, 0.66). CONCLUSION: Among men receiving medications for BPH in community practice settings, 5ARI use was not associated with an increased risk of mortality when compared to AB use. These data provide reassurance about the safety of using 5ARIs in general practice to manage BPH and/or lower urinary tract symptoms.

Ten-Year Trends in Preventive Service Use Before and After Prostate Cancer Diagnosis: A Comparison with Noncancer Controls.

CONTEXT: Few studies have assessed the longer-term quality of preventive care in prostate cancer (PCa) survivors. OBJECTIVE: To compare the rates of preventive services among PCa survivors five years before and after diagnosis, to men without PCa. DESIGN: Men enrolled in Kaiser Permanente Southern California with newly diagnosed PCa (2002-2008) were matched 1:1 to men without a PCa diagnosis on age, race, and timing of prostate-specific antigen test (N = 31,180). The use of preventive services, including colorectal cancer screening, diabetes tests, lipid panels, and influenza and pneumococcal vaccinations was assessed 5 years before and after diagnosis (or index date for controls). MAIN OUTCOME MEASURES: Relative rates (RRs) of use were calculated for cases and controls separately and compared using Poisson regression, adjusting for comorbidities and outpatient utilization in 2014. RESULTS: Overall, the rates of preventive services were lower among men with PCa vs men without PCa. However, in the 5 years after diagnosis, rates of preventive service use for all services were greater among PCa survivors vs men without PCa (colorectal cancer: RR = 1.05, 95% confidence interval [CI] = 1.01-1.10; lipids: RR = 1.10, 95% CI = 1.08-1.11; hemoglobin A1C: RR = 1.17, 95% CI = 1.14-1.19; glucose: RR = 1.24, 95% CI = 1.23-1.26; influenza vaccine: RR = 1.05, 95% CI = 1.03-1.07; pneumococcal vaccine: RR = 1.03, 95% CI = 0.97-1.09). CONCLUSION: Delivery of preventive care improved after PCa diagnosis, with survivors receiving comparable preventive care to men without PCa during the five years following diagnosis.