Search

To describe the risk of multiple recurrences in intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) and their impact on progression. Prognostic studies of IR-NMIBC have focused on initial recurrences, yet little is known about subsequent recurrences and their impact on progression.IR-NMIBC patients from the Be-Well Study, a prospective cohort study of NMIBC patients diagnosed from 2015-2019 at Kaiser Permanente Northern California, were identified. The frequency of first, second, and third intravesical recurrences of urothelial carcinoma were characterized using conditional Kaplan-Meier analyses and random-effects shared-frailty models. The association of multiple recurrences with progression was examined.In 291 patients with IR-NMIBC (median follow-up 38 months), the 5-year risk of initial recurrence was 54.4%. After initial recurrence (n=137), 60.1% of patients had a second recurrence by 2 years. After second recurrence (n=70), 51.5% of patients had a third recurrence by 3 years. In multivariable analysis, female sex (Hazard Ratio 1.51, p0.01), increasing tumor size (HR 1.14, p0.01) and number of prior recurrences (HR 1.24, p0.01) were associated with multiple recurrences; whereas maintenance BCG (HR 0.66, p=0.03) was associated with reduced recurrences. The 5-year risk of progression varied significantly (p0.01) by number of recurrences: 9.5%, 21.9%, and 37.9% for patients with 1, 2, and 3+ recurrences, respectively.Multiple recurrences are common in IR-NMIBC and are associated with progression. Female sex, larger tumors, number of prior recurrences, and lack of maintenance BCG were associated with multiple recurrences. Multiple recurrences may prove useful as a clinical trial endpoint for IR-NMIBC.

ImportanceTobacco smoking is an established risk factor associated with bladder cancer, yet its impact on bladder cancer prognosis is unclear.ObjectiveTo 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 ParticipantsThe 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.ExposuresUse 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 MeasuresHazard ratios (HRs) and 95% CIs of recurrence and progression of bladder cancer were estimated by multivariable Cox proportional hazards regression.ResultsA 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 RelevanceThese 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.

INTRODUCTION AND OBJECTIVE:Even though non-muscle invasive bladder cancer (NMIBC) has high costs care, the patient-level impact of this cost (“financial toxicity”) has been understudied. We describ...

INTRODUCTION AND OBJECTIVE:Historically, prognostic studies of intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) have focused on the risk of initial recurrence, yet little is known ab...

INTRODUCTION AND OBJECTIVE:The transurethral resection of bladder tumor (TURBT) is a common urologic procedure with a reported complication rate of about 5% according to administrative data. Howeve...

Introduction Tighter blood pressure control is widely thought to be associated with better erectile function, although the preponderance of data is limited to dichotomous representations of hypertension without an attempt to look at degree of blood pressure control. Aim To determine the association between optimal blood pressure control over time and the development of erectile dysfunction (ED) in a cohort of potent men. Methods We performed a retrospective cohort study of newly diagnosed hypertensive men without major medical comorbidities in an integrated healthcare system. Patients were stratified by exposure to hypertension, with varying levels of blood pressure control, as measured by ordinal categories of systolic blood pressure and deviation from the mean systolic pressure. Main Outcome Measures Incidence of ED was defined by at least 2 primary care or urology diagnoses of ED in our electronic health records within 2 years, at least 2 filled prescriptions for ED medications within 2 years, or 1 diagnosis of ED and 2 filled prescriptions for ED medications. Results We identified 39,320 newly diagnosed hypertensive men. The overall incidence for ED was 13.9%, with a mean follow-up of 55.1 ± 28.7 months. Higher average systolic blood pressure was associated with a higher risk of ED in a dose-dependent manner (trend test, P < .001). Wide variation in blood pressure control was associated with a higher incidence of ED (OR [95% CI]; 1.359 [1.258–1.469]) and a shorter time to the development of ED (log rank, P < .0001). Clinical Implications We believe these data may serve as a motivator for hypertensive men to better adhere to their hypertension treatment regimen. Strength & Limitations The retrospective nature of our study precludes us from drawing more than an association between tighter blood pressure control and ED. Strengths of our study include the large sample size, community cohort, and completeness of follow-up. Conclusion Among adults diagnosed with hypertension, tighter blood pressure control, as measured by average systolic blood pressure and deviation from the average, is associated with a lower incidence and a longer time to the development of ED.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. Significance: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer. See related commentary by Lachance, p. 1637

Objective To present a novel urethral catheter design with a pilot balloon to reduce intraurethral retention balloon inflation pressures and to provide a visual alert during catheter placement. Methods We manufactured our pilot balloon prototype from both molded and extruded silicone components. Various pilot balloon thicknesses were tested in order to determine the ideal compliance. We studied the filling pressures of the retention balloon of our prototype in a mechanical urethral model. The prototype catheter was then tested in ex-vivo human penis specimens obtained from gender affirming surgery and changes in the size of the retention balloon were measured under fluoroscopy. Results The thickness of the pilot balloon was directly related to the inflation pressure of the retention balloon in the mechanical urethral model. The thickness chosen for the pilot balloon in our prototype was based on a retention balloon pressure of 70 kPa. In the ex-vivo human penis model, the presence of the pilot balloon resulted in a 40% reduction in the cross-sectional area of the retention balloon compared to a standard urinary catheter. Conclusion The prototype urinary catheter appears to decrease the filling pressure and size of an improperly positioned retention balloon inside a urethra. This can potentially reduce the risk of iatrogenic urethral catheter injuries. In addition, the prototype urinary catheter may act as a visual warning sign for the healthcare practitioner.

INTRODUCTION AND OBJECTIVE:Epstein-barr virus (EBV) infection may lead to a stronger host response in adults, infectious mononucleosis (IM), than the primarily asymptomatic or mild symptomatic cour...

The potential association between rare germline genetic variants and prostate cancer (PrCa) susceptibility has been understudied due to challenges with assessing rare variation. Furthermore, although common risk variants for PrCa have shown limited individual effect sizes, their cumulative effect may be of similar magnitude as high penetrance mutations. To identify rare variants associated with PrCa susceptibility, and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we analyzed large population-based cohorts, custom genotyping microarrays, and imputation reference panels in an integrative study of PrCa genetic etiology. In particular, 11,649 men (6,196 PrCa cases, 5,453 controls) of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health, ProHealth Study, and California Men’s Health Study were genotyped and meta-analyzed with 196,269 European-ancestry male subjects (7,917 PrCa cases, 188,352 controls) from the UK Biobank. Six novel loci were genome-wide significant in our meta-analysis, including two rare variants (minor allele frequency < 0.01, at 3p21.31 and 8p12). Gene-based rare variant tests implicated a previously discovered PrCa gene (HOXB13) as well as a novel candidate (ILDR1) highly expressed in prostate tissue. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants atHOXB13and other loci, reflecting their evolutionary history. Furthermore, a polygenic risk score (PRS) of 187 known, largely common PrCa variants was strongly associated with risk in non-Hispanic whites (90thvs. 10thdecile OR = 7.66,P= 1.80*10-239). Many of the 187 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a six-fold difference in log-probability of Androgen Receptor binding at the variant rs2680708 (17q22). Our finding of two novel rare variants associated with PrCa should motivate further consideration of the role of low frequency polymorphisms in PrCa, while the considerable effect of PrCa PRS profiles should prompt discussion of their role in clinical practice.

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.

PURPOSE: Androgen deprivation therapy (ADT), used increasingly in the treatment of localized prostate cancer, is associated with substantial long-term adverse consequences, including incident diabetes. While previous studies have suggested that ADT negatively influences glycemic control in existing diabetes, its association with diabetes complications has not been investigated. In this study, we examined the association between ADT use and diabetes complications in prostate cancer patients. METHODS: A retrospective cohort study was conducted among men with newly diagnosed localized prostate cancer between 1995 and 2008, enrolled in three integrated health care systems. Men had radical prostatectomy or radiotherapy (curative intent therapy), existing type II diabetes mellitus (T2DM), and were followed through December 2010 (n = 5,336). Cox proportional hazards models were used to examine associations between ADT use and diabetes complications (any complication), and individual complications (diabetic neuropathy, diabetic retinopathy, diabetic amputation or diabetic cataract) after prostate cancer diagnosis. RESULTS: ADT use was associated with an increased risk of any diabetes complication after prostate cancer diagnosis (adjusted hazard ratio, AHR, 1.12, 95% CI 1.03–1.23) as well as an increased risk of each individual complication compared to non-use. CONCLUSION: ADT use in men with T2DM, who received curative intent therapy for prostate cancer, was associated with an increased risk of diabetes complications. These findings support those of previous studies, which showed that ADT worsened diabetes control. Additional, larger studies are required to confirm these findings and to potentially inform the development of a risk-benefit assessment for men with existing T2DM, before initiating ADT.

As many as 40% of men diagnosed with prostate cancer have low-risk disease, which results in the need to decide whether to undergo active treatment (AT) or active surveillance (AS). The treatment decision can have a significant effect on general and prostate-specific quality of life (QOL). The purpose of this study was to assess the QOL among men with low-risk prostate cancer during the first year following diagnosis. In a prospective cohort study, we conducted pretreatment telephone interviews (N = 1,139; 69.3% response rate) with low-risk PCa patients (PSA ≤ 10, Gleason ≤ 6) and a follow-up assessment 6-10 months postdiagnosis (N = 1057; 93%). We assessed general depression, anxiety, and physical functioning, prostate-specific anxiety, and prostate-specific QOL at both interviews. Clinical variables were obtained from the medical record. Men were 61.7 (SD = 7.2) years old, 82% white, 39% had undergone AT (surgery or radiation), and 61.0% had begun AS. Linear regression analyses revealed that at follow-up, the AS group reported significantly better sexual, bowel, urinary, and general physical function (compared to AT), and no difference in depression. However, the AS group did report greater general anxiety and prostate-specific anxiety at follow-up, compared to AT. Among men with low-risk PCa, adjusting for pretreatment functioning, the AS group reported better prostate-related QOL, but were worse off on general and prostate-specific anxiety compared to men on AT. These results suggest that, within the first year postdiagnosis, men who did not undergo AT may require additional support in order to remain comfortable with this decision and to continue with AS when it is clinically indicated.

Despite the evidence indicating that decision aids (DA) improve informed treatment decision making for prostate cancer (PCa), physicians do not routinely recommend DAs to their patients. We conducted semi-structured interviews with urologists (n = 11), radiation oncologists (n = 12) and primary care physicians (n = 10) about their methods of educating low-risk PCa patients regarding the treatment decision, their concerns about recommending DAs, and the essential content and format considerations that need to be addressed. Physicians stressed the need for providing comprehensive patient education before the treatment decision is made and expressed concern about the current unevaluated information available on the Internet. They made recommendations for a DA that is brief, applicable to diverse populations, and that fully discloses all treatment options (including active surveillance) and their potential side effects. Echoing previous studies showing that low-risk PCa patients are making rapid and potentially uninformed treatment decisions, these results highlight the importance of providing patient education early in the decision-making process. This need may be fulfilled by a treatment DA, should physicians systematically recommend DAs to their patients. Physicians’ recommendations for the inclusion of particular content and presentation methods will be important for designing a high quality DA that will be used in clinical practice.

Background. Men with a low-risk prostate cancer (PCa) should consider observation, particularly active surveillance (AS), a monitoring strategy that avoids active treatment (AT) in the absence of disease progression. Objective. To determine clinical and decision-making factors predicting treatment selection. Design. Prospective cohort study. Setting. Kaiser Permanente Northern California (KPNC). Patients. Men newly diagnosed with low-risk PCa between 2012 and 2014 who remained enrolled in KPNC for 12 months following diagnosis. Measurements. We used surveys and medical record abstractions to measure sociodemographic and clinical characteristics and psychological and decision-making factors. Men were classified as being on observation if they did not undergo AT within 12 months of diagnosis. We performed multivariable logistic regression analyses. Results. The average age of the 1171 subjects was 61.5 years ( s = 7.2 years), and 81% were white. Overall, 639 (57%) were managed with observation; in adjusted analyses, significant predictors of observation included awareness of low-risk status (odds ratio 1.75; 95% confidence interval 1.04–2.94), knowing that observation was an option (3.62; 1.62–8.09), having concerns about treatment-related quality of life (1.21, 1.09–1.34), reporting a urologist recommendation for observation (8.20; 4.68–14.4), and having a lower clinical stage (T1c v. T2a, 2.11; 1.16–3.84). Conversely, valuing cancer control (1.54; 1.37–1.72) and greater decisional certainty (1.66; 1.18–2.35) were predictive of AT. Limitations. Results may be less generalizable to other types of health care systems and to more diverse populations. Conclusions. Many participants selected observation, and this was associated with tumor characteristics. However, nonclinical decisional factors also independently predicted treatment selection. Efforts to provide early decision support, particularly targeting knowledge deficits, and reassurance to men with low-risk cancers may facilitate better decision making and increase uptake of observation, particularly AS.

INTRODUCTION AND OBJECTIVES:Hematuria is prevalent, with over 2 million US patients referred to urologists annually. Historical U.S. guidelines recommend CT for all adults with any degree of hematuria, whereas international guidelines recommend ultrasound, explicitly citing concerns about cost effectiveness and radiation harms. Against this backdrop, physicians in Kaiser Permanente (KP) developed a new risk-stratified guideline for hematuria, with CT restricted to patients at highest risk [gross hematuria (GH)], renal ultrasound for patients with microhematuria and risk factors [(MHRF) tobacco exposure, men, women >50 years old)] and no evaluation for nonsmoking women

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 June 30, 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.

We determined the clinical and sociodemographic predictors of beginning active treatment in an ethnically diverse population of men with low risk prostate cancer initially on observational treatment.We retrospectively studied men diagnosed with low risk prostate cancer between 2004 and 2012 at Kaiser Permanente Northern California who did not receive any treatment within the first year of diagnosis and had at least 2 years of followup. We used Cox proportional hazards regression models to determine factors associated with time from diagnosis to active treatment.We identified 2,228 eligible men who were initially on observation, of whom 27% began active treatment during followup at a median of 2.9 years. NonHispanic black men were marginally more likely to begin active treatment than nonHispanic white men independent of baseline and followup clinical measures (HR 1.3, 95% CI 1.0-1.7). Among men who remained on observation nonHispanic black men were rebiopsied within 24 months of diagnosis at a slightly lower rate than nonHispanic white men (HR 0.70, 95% CI 0.6-1.0). Gleason grade progression (HR 3.3, 95% CI 2.7-4.1) and PSA doubling time less than 48 months (HR 2.9, 95% CI 2.3-3.7) were associated with initiation of active treatment independent of race.Sociodemographic factors such as ethnicity and education may independently influence the patient decision to pursue active treatment and serial biopsies during active surveillance. These factors are important for further studies of prostate cancer treatment decision making.

Background: Due to the concerns about the overtreatment of low-risk prostate cancer, active surveillance (AS) is now a recommended alternative to the active treatments (AT) of surgery and radiotherapy. However, AS is not widely utilized, partially due to psychological and decision-making factors associated with treatment preferences. Methods: In a longitudinal cohort study, we conducted pretreatment telephone interviews (N = 1,140, 69.3% participation) with newly diagnosed, low-risk prostate cancer patients (PSA ≤ 10, Gleason ≤ 6) from Kaiser Permanente Northern California. We assessed psychological and decision-making variables, and treatment preference [AS, AT, and No Preference (NP)]. Results: Men were 61.5 (SD, 7.3) years old, 24 days (median) after diagnosis, and 81.1% white. Treatment preferences were: 39.3% AS, 30.9% AT, and 29.7% NP. Multinomial logistic regression revealed that men preferring AS (vs. AT) were older (OR, 1.64; CI, 1.07–2.51), more educated (OR, 2.05; CI, 1.12–3.74), had greater prostate cancer knowledge (OR, 1.77; CI, 1.43–2.18) and greater awareness of having low-risk cancer (OR, 3.97; CI, 1.96–8.06), but also were less certain about their treatment preference (OR, 0.57; CI, 0.41–0.8), had greater prostate cancer anxiety (OR, 1.22; CI, 1.003–1.48), and preferred a shared treatment decision (OR, 2.34; CI, 1.37–3.99). Similarly, men preferring NP (vs. AT) were less certain about treatment preference, preferred a shared decision, and had greater knowledge. Conclusions: Although a substantial proportion of men preferred AS, this was associated with anxiety and uncertainty, suggesting that this may be a difficult choice. Impact: Increasing the appropriate use of AS for low-risk prostate cancer will require additional reassurance and information, and reaching men almost immediately after diagnosis while the decision-making is ongoing. Cancer Epidemiol Biomarkers Prev; 25(8); 1240–50. ©2016 AACR.

Objective To examine intravesical chemotherapy (IVC) use according to non–muscle-invasive bladder cancer patient disease risk, and the contributions of multilevel factors to variation in proficient use among patients with low-intermediate disease. Methods This study included 988 patients diagnosed with non–muscle-invasive bladder cancer in an integrated health system in Northern California from 2015-2017. We calculated IVC receipt by disease risk, and among patients with low-intermediate risk disease, assessed the relationship between multilevel factors and IVC receipt using a logistic regression model with random intercepts for provider and service area, and patient-, provider-, and service area-level fixed effects. We further assessed the association of provider- and service area-level factors with IVC use by examining intraclass correlation coefficients. Results Similar proportions of low-intermediate (36%) and high-risk (34%) patients received IVC. In the multivariate analysis, including low-intermediate risk patients, service area volume was strongly and statistically significantly associated with IVC use (adjusted odds ratio, high- vs low-volume: 0.08, 95% Confidence Interval: 0.01-0.58). Provider- and service area-level intraclass correlation coefficients were large, (38%, P = .0009 and 39% P = .03, respectively) indicating that much of the variance in IVC use was explained by factors at these levels. Conclusion Our findings highlight opportunities to improve proficient use of IVC. Future research should assess provider- and practice-level barriers to IVC use among low-intermediate risk patients.

A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa—such as genetics—can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P−8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Numerous observational studies have assessed the clinical predictors of switching from active surveillance (AS) to active treatment (AT), but few have assessed psychological and decisional predictors. In a prospective, comparative effectiveness cohort study of men newly diagnosed with low-risk PCa, we assessed whether psychological and decisional factors predicted switching to AT after adjusting for clinical factors. We conducted pre-treatment telephone interviews (N = 1,139; 69.3% participation) with low-risk PCa patients (PSA < 10, Gleason < 7) and a follow-up assessment 6–10 months post-diagnosis (N = 1057; 93%). Clinical variables were obtained from the medical record. The current analysis included men who were on AS for up to 24 months (N = 515), compared to men on AS for >12 months who switched to AT between 12–24 months (N = 86). In Cox proportional hazard models, we included 2 time-dependent covariates measured between diagnosis and 24-months post-diagnosis: PSA ( 10 (HR 5.6, 2.4–13.1), Gleason 7+ (HR 20.2, 12.2–33.4), and the urologist's initial recommendation of AT (HR 2.1, 1.04–4.2). The psychological variables, including preference for making independent treatment decisions (HR 2.7, 1.07–6.9) and concern that disease progression will not be detected (HR 1.5, 0.95–2.4), were independently associated with undergoing AT. After adjusting for clinical evidence of disease progression over the first two years post-diagnosis, men's concerns that disease progression will not be detected and preference for making their own treatment decision each independently predicted undergoing AT. These findings suggest the need to provide information and assistance to men who may be uncertain about remaining on AS, particularly when AS remains clinically indicated.

Objective To assess physicians' attitudes regarding multiple factors that may influence recommendations for active surveillance (AS) vs active treatment (AT) given the central role physicians play in the treatment decision-making process. Materials and Methods We conducted semistructured interviews to assess factors that physicians consider important when recommending AS vs AT, as well as physicians' perceptions of what their patients consider important in the decision. Participants included urologists (N = 11), radiation oncologists (N = 12), and primary care physicians (N = 10) from both integrated and fee-for-service healthcare settings. Results Across the specialties, quantitative data indicated that most physicians reported that their recommendations for AS were influenced by patients' older age, willingness and ability to follow a surveillance protocol, anxiety, comorbidities, life expectancy, and treatment preferences. Qualitative findings highlighted physicians' concerns about malpractice lawsuits, given the possibility of disease progression. Additionally, most physicians noted the role of the healthcare setting, suggesting that financial incentives may be associated with AT recommendations in fee-for-service settings. Finally, most physicians reported spouse or family opposition to AS due to their own anxiety or lack of understanding of AS. Conclusion We found that patient and physician preferences, healthcare setting, and family or spouse factors influence physicians' treatment recommendations for men with low-risk PCa. These were consistent themes across physician subspecialties in both an Health Maintenance Organization and in fee-for-service settings.

Objective To characterize decision-making processes and outcomes among men expressing early treatment preferences for low-risk prostate cancer. Methods We conducted telephone surveys of men newly diagnosed with low-risk prostate cancer in 2012-14. We analyzed subject who had discussed prostate cancer treatment with a clinician and expressed a treatment preference. We asked about decision-making processes, including physician discussions, prostate-cancer knowledge, decision-making styles, treatment preference, and decisional conflict. We compared responses across treatment groups with chi-square tests or ANOVA. Results Participants (n=761) had a median age of 62; 82% were white, 45% had a college education, and 35% had no comorbidities. Surveys were conducted at a median 25 days (range 9-100) post diagnosis. Overall, 55% preferred active surveillance (AS), 26% preferred surgery, and 19% preferred radiotherapy. Participants reported routinely considering surgery, radiotherapy, and AS. Most were aware of their low-risk status (97%) and the option for AS (96%). However, men preferring active treatment (AT) were often unaware of treatment complications, including sexual dysfunction (23%) and urinary complications (41%). Most men (63%) wanted to make their own decision after considering the doctor's opinion, and about 90% reported being sufficiently involved in the treatment discussion. Men preferring AS had slightly more uncertainty about their decisions than those preferring AT. Conclusion Subjects were actively engaged in decision making and considered a range of treatments. However, we found knowledge gaps about treatment complications among those preferring AT and slightly more decisional uncertainty among those preferring AS suggesting the need for early decision support.

Objective To compare the risk of prostate cancer mortality among men treated with 5- alpha reductase inhibitors (5-ARIs) with those treated with alpha-adrenergic blockers (ABs) in community practice settings. Patients and Methods A retrospective matched cohort (N=174,895) and nested case-control study (N=18,311) were conducted in 4 regions of an integrated health care system. Men 50 years and older who initiated pharmaceutical treatment for benign prostatic hyperplasia between January 1, 1992, and December 31, 2007, and had at least 3 consecutive prescriptions were followed through December 31, 2010. Adjusted subdistribution hazard ratios, accounting for competing risks of death, and matched odds ratios were used to estimate prostate cancer mortality associated with 5-ARI use (with or without concomitant ABs) as compared with AB use. Results In the cohort study, 1,053 men died of prostate cancer (mean follow-up, 3 years), 15% among 5-ARI users (N= 25,388) and 85% among AB users (N=149,507) (unadjusted mortality rate ratio, 0.80). After accounting for competing risks, it was found that 5-ARI use was not associated with prostate cancer mortality when compared with AB use (adjusted subdistribution hazard ratio, 0.85; 95% CI, 0.72-1.01). Similar results were observed in the case-control study (adjusted matched odds ratio, 0.95; 95% CI, 0.78-1.17). Conclusion Among men being pharmaceutically treated for benign prostatic hyperplasia, 5-ARI use was not associated with an increased risk of prostate cancer–specific mortality when compared with AB use. The increased prevalence of high-grade lesions at the time of diagnosis noted in our study and the chemoprevention trials may not result in increased prostate cancer mortality.

The optimal use of androgen deprivation therapy as salvage treatment (sADT) for men after initial prostatectomy or radiotherapy for clinically localized prostate cancer is undefined. We describe patterns of sADT use and investigate clinical and sociodemographic characteristics of insured men who received sADT versus surveillance in managed care settings. Using comprehensive electronic health records and cancer registry data from three integrated health plans, we identified all men with newly diagnosed clinically localized prostate cancer between 1995 and 2009 who received either prostatectomy (n = 16,445) or radiotherapy (n = 19,531) as their primary therapy. We defined sADT based on the timing of ADT following primary therapy and stage of cancer. We fit Cox proportional hazard models to identify sociodemographic characteristics and clinical factors associated with sADT. With a median follow-up of 6 years (range 2–15 years), 13 % of men who underwent primary prostatectomy or radiotherapy received sADT. After adjusting for selected covariates, sADT was more likely to be used in men who were older (e.g., HR 1.70, 95 % CI 1.48–1.96 or HR 1.33, 95 % CI 1.17–1.52 for age 70+ relative to age 35–59 for primary prostatectomy or radiotherapy, respectively), were African-American, had a short PSA doubling time, had a higher pre-treatment risk of progression, had more comorbidities, and received adjuvant ADT for initial disease. In men with localized prostate cancer in community practice initially treated with prostatectomy or radiotherapy, sADT after primary treatment was more frequent for men at greater risk of death from prostate cancer, consistent with practice guidelines.

What's known on the subject? and What does the study add? The urethal catheter is a ubiquitous device that has not been modified or improved for safety in the last 20 years, although it can be associated with significant patient harm. This study utilizes force and pressure measurements of the urethral catheter in order to aid in future safety modifications. OBJECTIVES • To better define urethral catheter balloon pressures and extraction forces during traumatic placement and removal of urethral catheters. • To help guide design for safer urethral catheters. MATERIALS AND METHODS • Measurements of balloon pressure were made upon filling within the urethra vs the bladder. • Extraction forces were measured upon removal of a catheter with a filled balloon from the bladder. • Models for the bladder and urethra included an ex vivo model (funnel, ‘bladder’, attached to a 30 F tube, ‘urethra’) and fresh human male cadavers. • The mean (sem) balloon pressures and extraction forces were calculated. RESULTS • In the ex vivo model, the mean (sem) pressures upon filling the balloon with 10 mL were on average three-times higher within the ex vivo‘urethra’ (177 [6] kPa) vs ‘bladder’ (59 [2] kPa) across multiple catheter types. • In the human cadaver, the mean balloon pressure was 1.9-times higher within the urethra (139 [11] kPa) vs bladder (68 [4] kPa). • Balloon pressure increased non-linearly during intraurethral filling of both models, resulting in either balloon rupture (silicone catheters) or ‘ballooning’ of the neck of the balloon filling port (latex catheters). • Removal of a filled balloon per the ex vivo model ‘urethra’ and cadaveric urethra, similarly required increasing force with greater balloon fill volumes (e.g. 9.34 [0.44] N for 5 mL vs 41.37 [8.01] N for 10 mL balloon volume). CONCLUSIONS • Iatrogenic complications from improper urethral catheter use is common. • Catheter balloon pressures and manual extraction forces associated with urethral injury are significantly greater than those found with normal use. • The differences in pressure and force may be incorporated into a safer urethral catheter design, which may significantly reduce iatrogenic urethral injury associated with catheterization.

Introduction Medical practitioners should be aware of genital piercing and its potential complications. General piercings are associate with complications common to all piercings as well as some unique to urethral piercings. Specifically, the association between carcinoma and genital piercing is not well recognized. Aim The present study is a report of two cases describing squamous cell carcinoma associated with genital piercing. Methods Case reports of two men admitted to an academic medical center. Results A 60-year-old man with a history of HIV and hepatitis C as well as a Prince Albert piercing presented for treatment of a urethrocutaneous fistula. A biopsy of indurated granulation tissue surrounding the fistula revealed invasive, moderately-differentiated squamous cell carcinoma. A 56-year-old man with a history of HIV, hepatitis C, and a Prince Albert piercing presented following a single episode of gross hematuria. He also reported splitting of his urinary stream. On physical examination, areas of necrosis were noted on the glans penis; biopsy revealed invasive, poorly-differentiated squamous cell carcinoma. Conclusions The present study is the first to suggest a possible association between squamous cell carcinoma of the penis/urethra and genital piercing. Patients with genital piercings, especially those with concurrent risk factors such as HIV and HCV, should be counselled about this rare complication. Edlin RS, Aaronson DS, Wu AK, Blaschko SD, Yang G, Erickson BA, and McAninch JW. Squamous cell carcinoma at the site of a Prince Albert's piercing.

In this study we evaluated the effect of major kidney injury on renal function.A retrospective cross-sectional analysis was conducted of all patients who sustained renal trauma between 1977 and 2008 at San Francisco General Hospital, and underwent post-injury dimercapto-succinic acid renal scan (67). Decrease in renal function was defined as the absolute percentage difference between the affected and unaffected kidney on dimercapto-succinic acid scan. Univariate (Spearman rank correlation) and multivariate (linear regression) analyses of the American Association for the Surgery of Trauma renal injury grade, patient age, mechanism of injury (blunt vs penetrating), side of injury, treatment used (nonoperative vs surgery), shock, gender, presence of gross hematuria, serum creatinine on hospital admission, postoperative complications and associated injuries were performed.Of the 67 renal injuries 23 (34%) were managed nonoperatively. There were 43 (64%) injuries due to penetrating trauma and 24 (36%) due to blunt injury. Mean decrease in renal function for grade III, IV and V injuries was 15%, 30% and 65%, respectively. Univariate analysis demonstrated a significant association between decrease in renal function and injury grade (rho 0.43, p0.005). There was no difference in the decrease in kidney function between parenchymal and vascular causes for grade IV and V injuries. Although the right kidney demonstrated a greater decrease in function (rho 0.26, p = 0.033) on univariate analysis, multivariate analysis showed that only American Association for the Surgery of Trauma injury grade correlated with decreased function (correlation coefficient 14.3, 95% CI 4.7-24.8, p0.005).Decrease in kidney function is directly correlated with American Association for the Surgery of Trauma renal injury grade.

Treatment decision-making can be difficult and complex for patients with low-risk prostate cancer. To the authors' knowledge, there is no consensus regarding an optimal treatment strategy and the choice of therapy involves tradeoffs between differing harms and benefits that are sensitive to patient values. In such situations, patients are often asked to participate actively in the decision-making process, and high-quality decisions require a well-informed patient whose values and preferences have been taken into consideration. Prior studies have indicated that patients have poor knowledge and unrealistic expectations regarding treatment, and physician judgments concerning patient preferences are often inaccurate. Decision aids (DAs) have been developed to help inform patients with low-risk prostate cancer about treatment options and assist in the decision-making process; however, little is currently known regarding the effects of such programs in this population. Thirteen studies of DAs for patients with prostate cancer were reviewed and it was found that the use of DAs can improve knowledge, encourage more active patient involvement in decision-making, and decrease levels of anxiety and distress. The effect of DAs on treatment choice was less clear, although fewer patients chose surgery compared with historical controls, particularly in Europe. Further studies are needed to determine how best to implement DAs into practice, and whether they improve the consistency between patient preferences and treatment choice.

OBJECTIVE To assess our experience with salvage permanent perineal radioactive-seed implantation (SPPI) as a possible therapeutic option for recurrent prostate adenocarcinoma, as salvage therapies for recurrences after definitive external beam radiotherapy (EBRT) for localized adenocarcinoma of the prostate are associated with significant morbidity and biochemical failure. PATIENTS AND METHODS We retrospectively analysed on patients who had SPPI for localized recurrent prostate adenocarcinoma from 1996 to 2007 after primary treatment with EBRT. Excluded were patients who had other primary treatment or had no follow-up. Primary outcomes were time to biochemical relapse-free survival, using the Phoenix definition of a prostate-specific antigen (PSA) nadir +2 ng/mL, and cancer-specific survival. Secondary outcomes were the International Prostate Symptom Score (IPSS), the International Index of Erectile Function-5 score (IIEF-5), and complications based on Common Terminology Criteria for Adverse Events (version 3). RESULTS In all, 37 patients had SPPI during this period; after applying inclusion and exclusion criteria, 24 remained for analysis. At the time of salvage therapy, the median time to the diagnosis of local recurrence was 49 months, the median PSA level was 3.36 ng/mL, the median PSA doubling time was 20 months, and all patients were clinically re-staged at ≤T2 with negative transrectal ultrasonography and/or magnetic resonance spectroscopy. The original Gleason score was ≤6 in nine patients, 7 in eight and ≥8 in three (not recorded in two). The median follow-up after SPPI was 30 months; the cancer-free survival was 96% (one death) and biochemical relapse-free survival was 88% (three patients). The PSA level was higher than the levels before SPPI at 3 months in all three failures, but lower in all 21 patients considered relapse-free. Complications included one urethral stricture, one grade 3 rectal haemorrhage and five grade 2 gross haematuria that resolved with conservative management. Insufficient data were available to assess the IPSS or IIEF-5 scores. CONCLUSION With a short-term follow-up SPPI appears to provide excellent prostate cancer control with an acceptable rate of complications for patients with local recurrence of prostate cancer after EBRT. An extended follow-up is necessary to determine the long-term durability and safety of SPPI.

While there is a large body of evidence supporting the procedure volume-outcome relationship for surgical therapy for bladder cancer, to our knowledge it is not known whether expertise with this surgery can predict better quality of care for other urological procedures. We hypothesized that the hospital volume of radical cystectomy is an important predictor of complications of other urological procedures.We explored data from the Health Care Utilization Project Nationwide Inpatient Sample. All patients who underwent any common urological procedure as the primary procedure were selected for analysis. Any complication was the outcome variable of interest, whereas radical cystectomy hospital volume was the independent variable of interest. Logistic regression models were fitted using the generalized estimating equations method to adjust for the effects of clustering of similar outcomes within hospitals. The covariates were patient age, gender, procedure type, comorbidities and procedure year.We observed a dose-response type of relationship for 2 urological oncology procedures. Compared to hospitals where a high volume of radical cystectomies was performed hospitals where cystectomy was not performed were associated with a higher risk of complications after nephrectomy and radical prostatectomy (OR 1.16, p = 0.02 and OR 1.49, p0.001, respectively). This was not seen for the other general or subspecialized urological procedures examined.A higher hospital radical cystectomy volume appears to lead to a lower risk of complications only after other common urological oncological procedures, namely radical prostatectomy and nephrectomy, but not after nononcological urology procedures.

OBJECTIVES Endoscopic subureteral injection for the management of vesicoureteral reflux has become a well-established first-line minimally invasive treatment strategy. One potential pitfall is the creation of ureteral obstruction. No predictors are available to determine which patients will develop this rare, but real, complication. METHODS A retrospective evaluation of 2 girls, aged 3 and 4 years, with grade 4 and 3 reflux, respectively, and documented ureteral obstruction after endoscopic treatment with dextranomer/hyaluronic acid copolymer. Before treatment, both patients had had refluxing megaureters with a distal aperistaltic segment. RESULTS Ultimately, they both required open, cross-trigonal ureteral reimplantation with resolution of vesicoureteral reflux and ureteral obstruction. CONCLUSIONS Congenital refluxing megaureter with a distal aperistaltic segment might be a relative contraindication to endoscopic subureteral injection of a bulking agent for the management of vesicoureteral reflux.

Ras GTPases include the isoforms H-Ras, K-Ras, and N-Ras. Despite their great biochemical and biological similarities, evidence is mounting suggesting that Ras proteins may not be functionally redundant. A widespread strategy for studying small GTPases is the utilization of dominant inhibitory mutants that specifically block the activation of their respective wild-type proteins. As such, H-Ras N17 has proved to be extremely valuable as a tool to probe Ras functions. However, a comparative study on the inhibitory specificities of H-, K-, and N-Ras N17 mutants has not been approached thus far. Herein, we demonstrate that H-, K-, and N-Ras N17 mutants exhibit markedly distinct inhibitory effects toward H-, K-, and N-Ras. H-Ras N17 can effectively inhibit the activation of all three isoforms. K-Ras N17 completely blocks the activation of K-Ras and is only slightly inhibitory on H-Ras. N-Ras N17 can mainly inhibit N-Ras activation. In light of the recent data on the compartmentalization of H-Ras and K-Ras in the plasma membrane, here we present for the first time a description of N-Ras cellular microlocalization. Overall, our results on Ras N17 mutants specificities exhibit a marked correlation with the localization of the Ras isoforms to distinct membrane microdomains.

Activation of signal transduction kinase cascades has been shown to alter androgen receptor (AR) activity. Although it has been suggested that changes in AR phosphorylation might be directly responsible, the basal and regulated phosphorylations of the AR have not been fully determined. We have identified the major sites of AR phosphorylation on ARs expressed in COS-1 cells using a combination of peptide mapping, Edman degradation, and mass spectrometry. We describe the identification of seven AR phosphorylation sites, show that the phosphopeptides seen with exogenously expressed ARs are highly similar to those seen with endogenous ARs in LNCaP cells and show that specific agonists differentially regulate the phosphorylation state of endogenous ARs in LNCaP prostate cancer cells. Treatment of LNCaP cells with the synthetic androgen, R1881, elevates phosphorylation of serines 16, 81, 256, 308, 424, and 650. Ser-94 appears constitutively phosphorylated. Forskolin, epidermal growth factor, and phorbol 12-myristate 13-acetate increase the phosphorylation of Ser-650. The kinetics of phosphorylation of most sites in response to hormone or forskolin is temporally delayed, reaching a maximum at 2 h post-stimulation. The exception is Ser-81, which continues to display increasing phosphorylation at 6 h. These data provide a basis for analyzing mechanisms of cross-talk between growth factor signaling and androgen in prostate development, physiology, and cancer.

Prostate cancer (PrCa) is documented to be highly heritable. But many known prostate cancer loci are not associated with aggressive prostate cancer phenotypes such as high-grade cancer or biochemical failure. Previous efforts have been largely underpowered or not replicated. We conducted a study of 6,321 men with PrCa and 5,663 controls of European ancestry recruited from Kaiser Permanente (KP) matched by age and self-reported race. Phenotype data combined patient-level demographic, clinical, and tumor data from KP databases with data from 1994 to 2016. High-grade PrCa was defined using Gleason score: low-grade defined as ≤ 7 (3+4), high-grade defined as ≥ 7 (4+3). Biochemical failure was defined for cases using post-treatment prostate specific antigen (PSA) values: post-surgery failure if PSA ≥ 0.4 ng/mL; post-radiation failure if PSA value ≥ 2 ng/mL + nadir; and no failure if PSA did not reach specified threshold. Early-onset disease was defined as age < 55 years at diagnosis. Men were genotyped for over 650,000 SNPs using an ethnic-specific Affymetrix Axiom array and imputed to 1000 Genomes. We tested genetic associations for multiple aggressive phenotypes (410 early-onset cases, 1324 biochemical failure cases, and 886 high grade cases) in both a case-only (e.g., high vs. low grade) and case-control (e.g., high grade vs. no prostate cancer controls) analysis using logistic regression adjusting for ancestry principal components, age, BMI, and kit for batch effects. PrCa specific mortality was too rare to be evaluated. We identified several known and novel loci. Case-control analyses highlighted known prostate cancer loci at 8q24, 10q11, 11q13, 16q22, and 19q13. Previous reports of case-only analyses also identified 8q24, 20p13 and the gene, KLK3 in 19q13, to be associated with high-grade PrCa; we confirmed these signals in our study. Previous family-based studies identified 15q11 as a familial or early-onset prostate cancer locus. These aggressive-specific variants could perform better in predicting clinically actionable prostate cancers than variants for overall prostate cancer and can improve the predictive ability of pre-diagnostic PSA. Citation Format: Caroline G. Tai, Nima C. Emami, Thomas J. Hoffmann, Lori C. Sakoda, Eric Jorgenson, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Chun R. Chao, Nirupa R. Ghai, David Aaronson, Joseph Presti, Catherine Schaefer, Neil Risch, Stephen K. Van Den Eeden, John S. Witte. Germline genetic signals across multiple aggressive prostate cancer phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1316. doi:10.1158/1538-7445.AM2017-1316

e16028 Background: For patients diagnosed with non-muscle invasive bladder cancer (NMIBC), guidelines recommend that those with high-grade (HG) T1 disease and potentially those with lower risk HG Ta disease receive a repeat resection within six weeks of initial resection. For these patients, repeat resection has diagnostic, prognostic, and therapeutic value and is critical for informing treatment decision-making, and ultimately optimizing outcomes. Current rates of repeat resection in practice are unknown. Methods: We conducted a retrospective analysis of patients diagnosed with HG T1 and HG Ta NMIBC between 1/1/2015 and 3/1/2016 using cancer registry-linked electronic medical record data. Our analysis included 118 patients with HG T1 disease and 114 patients with HG Ta disease who did not undergo a cystectomy. We used modified Poisson regression with clustered standard errors to assess the associations of patients’ clinical and socio-demographic characteristics and providers’ characteristics with patients’ receipt of repeat resection. We present adjusted risk ratios (aRR) and 95% confidence intervals (CI). Results: 40% of HG patients (55% of T1 patients; 24% of Ta patients) underwent repeat resection, with no differences in receipt by patient age, gender, race, or comorbidity burden. In addition to HG T1 (vs. HG Ta) disease (aRR: 2.20, 95% CI: 1.53-3.22), higher census-tract median household income was associated with increased likelihood of repeat resection (aRR highest vs. lowest income quartile: 1.42, 95% CI: 1.08-2.23). At the treating urologist level, more time in practice was negatively associated with likelihood of repeat resection receipt (aRR highest vs. lowest quartile of number of years in practice: 0.56, 95% CI: 0.41-0.77). Conclusions: Our data suggest that a large proportion of potentially eligible HG patients did not undergo a repeat resection, and that variation in practice is driven by patients’ social characteristics and treating urologist characteristics. Further research is needed to understand whether the variation observed reflects a quality improvement need versus patient-centered decision-making that accounts for preferences and treatment eligibility.

The Ras guanine-nucleotide exchange factor Ras-GRF/Cdc25(Mn) harbors a complex array of structural motifs that include a Dbl-homology (DH) domain, usually found in proteins that interact functionally with the Rho family GTPases, and the role of which is not yet fully understood. Here, we present evidence that Ras-GRF requires its DH domain to translocate to the membrane, to stimulate exchange on Ras, and to activate mitogen-activated protein kinase (MAPK). In an unprecedented fashion, we have found that these processes are regulated by the Rho family GTPase Cdc42. We show that GDP- but not GTP-bound Cdc42 prevents Ras-GRF recruitment to the membrane and activation of Ras/MAPK, although no direct association of Ras-GRF with Cdc42 was detected. We also demonstrate that catalyzing GDP/GTP exchange on Cdc42 facilitates Ras-GRF-induced MAPK activation. Moreover, we show that the potentiating effect of ionomycin on Ras-GRF-mediated MAPK stimulation is also regulated by Cdc42. These results provide the first evidence for the involvement of a Rho family G protein in the control of the activity of a Ras exchange factor.

Author(s): Aaronson, David S; Bardach, Naomi S; Lin, Grace A; Chattopadhyay, Arpita; Goldman, L Elizabeth; Dudley, R Adams | Abstract: ObjectiveTo identify an approach to summarizing publicly reported hospital performance data for acute myocardial infarction (AMI) or heart failure (HF) that best predicts current year hospital mortality rates.SettingA total of 1,868 U.S. hospitals reporting process and outcome measures for AMI and HF to the Centers for Medicare and Medicaid Services (CMS) from July 2005 to June 2006 (Year 0) and July 2006 to June 2007 (Year 1).DesignObservational cohort study measuring the percentage variation in Year 1 hospital 30-day risk-adjusted mortality rate explained by denominator-based weighted composite scores summarizing hospital Year 0 performance.Data collectionData were prospectively collected from hospitalcompare.gov.ResultsPercentage variation in Year 1 mortality was best explained by mortality rate alone in Year 0 over other composites including process performance. If only Year 0 mortality rates were reported, and consumers using hospitals in the highest decile of mortality instead chose hospitals in the lowest decile of mortality rate, the number of deaths at 30 days that potentially could have been avoided was 1.31 per 100 patients for AMI and 2.12 for HF (p l .001).ConclusionPublic reports focused on 30-day risk-adjusted mortality rate may more directly address policymakers' goals of facilitating consumer identification of hospitals with better outcomes.

Background: Bladder cancer is one of the top 10 incident cancers. Most cases (75%) are diagnosed as non-muscle invasive disease (NMID), yet NMID typically recurs (70%) and a subset (25%) progresses to muscle-invasive disease. The Be-Well Study is an NCI-funded collaborative, multi-center prospective cohort study, with NMID bladder cancer patients enrolled at Kaiser Permanente Northern (KPNC) and Southern California (KPSC) and bioassays performed at Roswell Park Cancer Institute (RPCI). The goal is to examine diet and lifestyle factors and prognosis, with an emphasis on cruciferous vegetable (CV) intake and their unique isothiocyanate (ITC) content, the modifying effect of polymorphisms of ITC-metabolizing genes, and interactions with treatment. Our prior work suggests that dietary ITCs may prevent disease recurrence and progression in NMID patients. Methods: Newly-diagnosed patients with NMID (Ta, Tis, T1), who are English-speaking, KP members, and ≥21 years of age, are ascertained rapidly from electronic pathology reports and enrolled on average 2.6 months post-diagnosis. Baseline participation consists of a telephone interview including a food frequency questionnaire focused on CV intake, and providing blood and urine samples. Patients will be contacted for follow-up interviews and urine samples at 12 and 24 months. Smoking, medication use, occupational exposures, physical activity, quality of life, and urinary function are also queried. Biospecimens are processed and assayed at RPCI. Strong support for Be-Well by KP urologists will promote dissemination of study results in patient care and recommendations. Results: Recruitment began in February 2015. To date, 222 patients have completed the baseline interview, representing 78% male and 22% female, and 81% White, 7% Black, 5% Hispanic, 3% Asian, and 4% Other. Urine specimens have been collected from 82% of consented patients. Blood specimens have been collected from 85% of KPNC patients, and collection at KPSC began in November 2015. The 12-month follow-up interview and outcome ascertainment for disease recurrence and progression are scheduled to begin in February 2016. Conclusions: The Be-Well Study is poised to be the largest and most comprehensive study to answer critical questions related to prognosis, quality of life, and care in patients diagnosed with early-stage bladder cancer. Citation Format: Marilyn L. Kwan, Lawrence H. Kushi, Virginia P. Quinn, Nirupa R. Ghai, Janise M. Roh, Tracy Becerra, Adriana Martinez, Kimberly L. Cannavale, Alexander S. Carruth, Valerie S. Lee, Isaac J. Ergas, Ronald K. Loo, David S. Aaronson, Yuesheng Zhang, Christine B. Ambrosone, Li Tang. Identifying lifestyle and genetic factors to prevent recurrence of non-muscle invasive bladder cancer in a prospective cohort study at Kaiser Permanente (The Be-Well Study). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3415.

e296 Background: Bladder cancer is one of the top 10 incident cancers. Most cases (75%) are diagnosed as non-muscle invasive disease (NMID), yet NMID typically recurs (70%) and a subset (25%) progresses to muscle-invasive disease. Be-Well is a 5-year, NCI-funded prospective cohort study of NMID bladder cancer patients at Kaiser Permanente Northern (KPNC) and Southern California (KPSC). The goal is to examine diet and lifestyle factors and prognosis, with an emphasis on cruciferous vegetable (CV) intake and their unique isothiocyanate (ITC) content, the modifying effect of polymorphisms of ITC-metabolizing genes, and interactions with treatment. Our prior work suggests that dietary ITCs may prevent disease recurrence and progression in NMID patients. Methods: Newly-diagnosed patients with NMID (Ta, Tis, T1), who are English-speaking, KP members, and ≥ 21 years of age, are rapidly ascertained from electronic pathology reports and enrolled on average 2.6 months post-diagnosis. Baseline participation consists of a telephone interview including a food frequency questionnaire focused on CV intake, and providing blood and urine samples. Patients will be contacted for follow-up interviews and urine samples at 12 and 24 months. Smoking, medication use, occupational exposures, physical activity, quality of life, and urinary function are also queried. Biospecimens are processed and assayed at Roswell Park Cancer Institute. Strong support for Be-Well by KP urologists will promote dissemination of study results in patient care and recommendations. Results: Recruitment began in February 2015. To date, 159 patients have completed the baseline interview, representing 76% male and 24% female, and 80% White, 8% Black, 6% Hispanic, 3% Asian, and 3% Other. Urine specimens have been collected from 87% of consented patients. Blood specimens have been collected from 87% of KPNC patients, with collection at KPSC to begin in Fall 2015. Conclusions: The Be-Well Study is poised to be the largest and most comprehensive study to answer critical questions related to prognosis, quality of life, and care in patients diagnosed with early-stage bladder cancer.