Publications by authors named "David Aaronson"

51 Publications

A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility.

Cancer Res 2021 04 8;81(7):1695-1703. Epub 2020 Dec 8.

Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, California.

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 (), as well as a novel candidate gene (), 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 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, = 2.55 × 10). 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..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137514PMC
April 2021

Catheter Balloon-trauma: Design, Development, and Ex-vivo Studies Using Intact Human Penis Specimens.

Urology 2020 Dec 1;146:287-292. Epub 2020 Sep 1.

Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA; Department of Urology, University of California San Francisco; San Francisco, CA; Department of Anatomy, University of California San Francisco; San Francisco, CA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.urology.2020.08.035DOI Listing
December 2020

Selecting Active Surveillance: Decision Making Factors for Men with a Low-Risk Prostate Cancer.

Med Decis Making 2019 11 21;39(8):962-974. Epub 2019 Oct 21.

Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

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. To determine clinical and decision-making factors predicting treatment selection. Prospective cohort study. Kaiser Permanente Northern California (KPNC). Men newly diagnosed with low-risk PCa between 2012 and 2014 who remained enrolled in KPNC for 12 months following diagnosis. 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. The average age of the 1171 subjects was 61.5 years ( = 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. Results may be less generalizable to other types of health care systems and to more diverse populations. 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.
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http://dx.doi.org/10.1177/0272989X19883242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895433PMC
November 2019

Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men.

J Sex Med 2019 03;16(3):410-417

Department of Urology, Kaiser Permanente, Oakland Medical Center, Oakland, CA, USA.

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. Hsiao W, Bertsch RA, Hung Y-Y, et al. Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men. J Sex Med 2019;16:410-417.
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http://dx.doi.org/10.1016/j.jsxm.2019.01.011DOI Listing
March 2019

AUTHOR REPLY.

Urology 2019 03;125:229

Kaiser Permanente Center for Health Research, Portland, OR.

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http://dx.doi.org/10.1016/j.urology.2018.11.023DOI Listing
March 2019

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.

Cancer Causes Control 2019 Feb 17;30(2):187-193. Epub 2019 Jan 17.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

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.
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http://dx.doi.org/10.1007/s10552-019-1130-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422041PMC
February 2019

Factors That Influence Selectionof Urinary Diversion Among Bladder Cancer Patients in 3 Community-based Integrated Health Care Systems.

Urology 2019 03 22;125:222-229. Epub 2018 Nov 22.

Kaiser Permanente Center for Health Research, Portland, OR.

Objective: To assess the relative contributions of patient and surgeon factors for predicting selection of ileal conduit (IC), neobladder (NB), or continent pouch (CP) urinary diversions (UD) for patients diagnosed with muscle-invasive/high-risk nonmuscle invasive bladder cancer. This information is needed to enhance research comparing cancer survivors' outcomes across different surgical treatment options.

Methods: Bladder cancer patients' age ≥21 years with cystectomy/UD performed from January 2010 to June 2015 in 3 Kaiser Permanente regions were included. All patient and surgeon data were obtained from electronic health records. A mixed effects logistic regression model was used treating surgeon as a random effect and region as a fixed effect.

Results: Of 991 eligible patients, 794 (80%) received IC. One hundred sixty-nine surgeons performed the surgeries and accounted for a sizeable proportion of the variability in patient receipt of UD (intraclass correlation coefficient = 0.26). The multilevel model with only patient factors showed good fit (area under the curve = 0.93, Hosmer-Lemeshow test P = .44), and older age, female sex, estimated glomerular filtration rate <45, 4+ comorbidity index score, and stage III/IV tumors were associated with higher odds of receiving an IC vs neobladder/continent pouch. However, including surgeon factors (annual cystectomy volume, specialty training, clinical tenure) had no association (P = .29).

Conclusion: In this community setting, patient factors were major predictors of UD received. Surgeons also played a substantial role, yet clinical training and experience were not major predictors. Surgeon factors such as beliefs about UD options and outcomes should be explored.
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http://dx.doi.org/10.1016/j.urology.2018.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389399PMC
March 2019

Perioperative Intravesical Chemotherapy for Patients WithNon-Muscle-invasive Bladder Cancer: Understanding the Extent of and Sources of Variation in Guideline-recommended Use.

Urology 2019 02 23;124:107-112. Epub 2018 Oct 23.

Kaiser Permanente Northern California Division of Research, Oakland, CA.

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.
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http://dx.doi.org/10.1016/j.urology.2018.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202079PMC
February 2019

Risk of diabetes complications among those with diabetes receiving androgen deprivation therapy for localized prostate cancer.

Cancer Causes Control 2018 08 29;29(8):785-791. Epub 2018 Jun 29.

Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

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.
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http://dx.doi.org/10.1007/s10552-018-1050-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660131PMC
August 2018

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

Urology 2018 Sep 12;119:70-78. Epub 2018 Jun 12.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, USA, CA.

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.
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http://dx.doi.org/10.1016/j.urology.2018.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080272PMC
September 2018

Quality of life among men with low-risk prostate cancer during the first year following diagnosis: the PREPARE prospective cohort study.

Transl Behav Med 2018 03;8(2):156-165

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

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.
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http://dx.doi.org/10.1093/tbm/ibx005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256951PMC
March 2018

Decision-making processes among men with low-risk prostate cancer: A survey study.

Psychooncology 2018 01 13;27(1):325-332. Epub 2017 Jul 13.

Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

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 to 2014. We analyzed subjects 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 the responses across treatment groups with χ 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 of 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.

Conclusions: 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.
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http://dx.doi.org/10.1002/pon.4469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849389PMC
January 2018

Physicians' Perceptions of Factors Influencing the Treatment Decision-making Process for Men With Low-risk Prostate Cancer.

Urology 2017 09 25;107:86-95. Epub 2017 Apr 25.

Department of Oncology, Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC.

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.
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http://dx.doi.org/10.1016/j.urology.2017.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880528PMC
September 2017

Physicians' perspectives on the informational needs of low-risk prostate cancer patients.

Health Educ Res 2017 04;32(2):134-152

Department of Oncology, Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington DC 20007, USA.

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.
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http://dx.doi.org/10.1093/her/cyx035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914350PMC
April 2017

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer.

Nat Commun 2017 01 31;8:14248. Epub 2017 Jan 31.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA.

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<5 × 10) 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.
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http://dx.doi.org/10.1038/ncomms14248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290311PMC
January 2017

5-Alpha Reductase Inhibitors and the Risk of Prostate Cancer Mortality in Men Treated for Benign Prostatic Hyperplasia.

Mayo Clin Proc 2016 Dec 27;91(12):1717-1726. Epub 2016 Oct 27.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA.

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.
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http://dx.doi.org/10.1016/j.mayocp.2016.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080281PMC
December 2016

Mortality and Androgen Deprivation Therapy as Salvage Treatment for Biochemical Recurrence after Primary Therapy for Clinically Localized Prostate Cancer.

J Urol 2017 06 19;197(6):1448-1454. Epub 2016 Dec 19.

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.

Purpose: Androgen deprivation therapy is often used as salvage treatment in men with rising prostate specific antigen after initial radical prostatectomy or radiotherapy for clinically localized prostate cancer. Given the lack of evidence from general practice, we examined the association of salvage androgen deprivation therapy with mortality in an observational cohort study.

Materials And Methods: From 3 managed care organizations we assembled a retrospective cohort of all 5,804 men with newly diagnosed localized prostate cancer from 1995 to 2009 who had a prostate specific antigen increase (biochemical recurrence) after primary radical prostatectomy or radiotherapy. The main outcomes were all-cause and prostate cancer specific mortality. We used Cox proportional hazards models to estimate mortality with salvage androgen deprivation therapy as a time dependent predictor.

Results: Overall salvage androgen deprivation therapy was not associated with all-cause or prostate cancer specific mortality in the prostatectomy cohort (HR 0.97, 95% CI 0.70-1.35 or HR 1.18, 95% CI 0.68-2.07) or in the radiotherapy cohort (HR 0.84, 95% CI 0.70-1.01 or HR 1.06, 95% CI 0.80-1.40, respectively). Among men with prostate specific antigen doubling time less than 9 months after the prostate specific antigen rise, salvage androgen deprivation therapy was statistically significantly associated with a decreased risk of all-cause and prostate cancer specific mortality in the prostatectomy cohort (HR 0.35, 95% CI 0.20-0.63 and HR 0.43, 95% CI 0.21-0.91) and in the radiotherapy cohort (HR 0.62, 95% CI 0.48-0.80 and HR 0.65, 95% CI 0.47-0.90, respectively).

Conclusions: We found no association of salvage androgen deprivation therapy with all-cause or cause specific mortality in most men with biochemical recurrence after primary radical prostatectomy or radiotherapy for clinically localized prostate cancer. Men with quickly progressed disease may derive a clinical benefit from salvage androgen deprivation therapy.
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http://dx.doi.org/10.1016/j.juro.2016.12.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433922PMC
June 2017

Treatment Preferences for Active Surveillance versus Active Treatment among Men with Low-Risk Prostate Cancer.

Cancer Epidemiol Biomarkers Prev 2016 08 2;25(8):1240-50. Epub 2016 Jun 2.

Division of Research, Kaiser Permanente Northern California.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970911PMC
August 2016

Sociodemographic and Clinical Predictors of Switching to Active Treatment among a Large, Ethnically Diverse Cohort of Men with Low Risk Prostate Cancer on Observational Management.

J Urol 2016 Sep 14;196(3):734-40. Epub 2016 Apr 14.

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.

Purpose: 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.

Materials And Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.juro.2016.04.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094279PMC
September 2016

Use of androgen deprivation therapy as salvage treatment after primary therapy for clinically localized prostate cancer.

World J Urol 2016 Dec 15;34(12):1611-1619. Epub 2016 Apr 15.

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3300 Whitehaven Street, NW, Suite 4100, Washington, DC, 20007, USA.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065786PMC
http://dx.doi.org/10.1007/s00345-016-1823-5DOI Listing
December 2016

A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences.

Cancer Discov 2015 Aug 1;5(8):878-91. Epub 2015 Jun 1.

National Cancer Institute, NIH, Bethesda, Maryland.

Unlabelled: 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.
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http://dx.doi.org/10.1158/2159-8290.CD-15-0315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527942PMC
August 2015

National incidence and outcomes of postoperative urinary retention in the Surgical Care Improvement Project.

Am J Surg 2012 Aug 3;204(2):167-71. Epub 2012 May 3.

Department of Urology, University of California San Francisco, San Francisco, CA, USA.

Background: The national incidence of postoperative urinary retention (POUR), its risk factors, and associated outcomes are not well understood.

Methods: We identified patients undergoing one of the Surgical Care Improvement Project surgeries using the National Inpatient Sample. By using International Classification of Diseases, 9th revision, Clinical Modification codes (ICD-9-CM), we identified POUR and the outcomes urinary tract infection, noninfectious catheter-related complications, length of stay, and posthospitalization care. Multivariable analysis identified predictors of POUR and its associated outcomes.

Results: A total of 415,409 patients, representing 2,077,045 nationally, underwent one of the Surgical Care Improvement Project procedures with 43,030 (2.1%) developing POUR. Age, sex, type of surgery, and medical comorbidities were predictive of POUR with a .71 area under the curve. Patients with POUR had greater odds of having urinary tract infections (odds ratio [OR], 2.3; 95% confidence interval [CI], 2.2-2.5), suffering catheter-related complications (OR, 5.2; 95% CI, 3.8-7.0), and needing additional posthospitalization care (OR, 1.3; 95% CI, 1.25-1.4), and they had a greater length of stay (.24 extra days).

Conclusions: Patients at risk for POUR can be identified, and they may benefit from interventions to prevent POUR.
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http://dx.doi.org/10.1016/j.amjsurg.2011.11.012DOI Listing
August 2012

Prediction of hospital acute myocardial infarction and heart failure 30-day mortality rates using publicly reported performance measures.

J Healthc Qual 2013 Mar-Apr;35(2):15-23. Epub 2011 Nov 11.

University of California, San Francisco, CA, USA.

Objective: To 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.

Setting: A 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).

Design: Observational 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 Collection: Data were prospectively collected from hospitalcompare.gov.

Results: Percentage 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 < .001).

Conclusion: Public reports focused on 30-day risk-adjusted mortality rate may more directly address policymakers' goals of facilitating consumer identification of hospitals with better outcomes.
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http://dx.doi.org/10.1111/j.1945-1474.2011.00173.xDOI Listing
January 2014

Safer urethral catheters: how study of catheter balloon pressure and force can guide design.

BJU Int 2012 Apr 22;109(7):1110-4. Epub 2011 Aug 22.

Department of Urology, University of California, San Francisco, CA 94143-0320, USA.

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.
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http://dx.doi.org/10.1111/j.1464-410X.2011.10510.xDOI Listing
April 2012

Use of Google Insights for Search to track seasonal and geographic kidney stone incidence in the United States.

Urology 2011 Aug 3;78(2):267-71. Epub 2011 Apr 3.

Department of Urology, University of California, San Francisco, CA 94143, USA.

Objective: To determine whether Internet search volume for kidney stones has seasonal and geographic distributions similar to known kidney stone incidence.

Material And Methods: Google Insights for Search analyzes a portion of Google web searches from all Google domains to compute how many searches are performed for a given term relative to the total number of searches done over a specific time interval and geographic region. Selected terms related to kidney stones were examined to determine which most closely tracked kidney stone incidence. Google Insights for Search data were correlated with hospital admissions for the emergent treatment of nephrolithiasis found through the Nationwide Inpatient Sample. Ambient temperature in Seattle and New York were compared with search volume for these regions to display qualitative relationships.

Results: The term "kidney stones" had the highest seasonal correlation of terms examined (r = .81, P = .0014). Google Insights for Search output and national Inpatient Sample admissions also correlated when regions were compared (r = .90, P = .005). Qualitative relationships between ambient temperatures and kidney stone search volume do exist.

Conclusions: Internet search volume activity for kidney stones correlates with temporal and regional kidney stone insurance claims data. In the future, with improved modeling of search detection algorithms and increased Internet usage, search volume has the potential to serve as a surrogate for kidney stone incidence.
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http://dx.doi.org/10.1016/j.urology.2011.01.010DOI Listing
August 2011
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