Search

Purpose: The impact of nonurological factors on male lower urinary tract symptoms (LUTS) remains unclear. We investigated cross-sectional and longitudinal associations among anxiety, depression, physical function, sleep quality and urinary symptom subdomains., Materials and Methods: Data from 518 men in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study were analyzed to identify associations between Patient-Reported Outcomes Measurement Information System® (PROMIS®) depression, anxiety, sleep disturbance and physical function measures and LUTS subdomains, as derived from the American Urological Association Symptom Index and LUTS Tool. Multivariable linear regression was used to assess the relationships between PROMIS measures and LUTS subdomains at baseline and at 3- and 12-month followup., Results: Baseline depression and anxiety were associated with urinary incontinence (p <0.001), voiding symptoms (p <0.001) and quality of life (p=0.002), whereas baseline sleep disturbance was associated with voiding and storage symptoms and quality of life (p <0.001 for all). Urinary symptom severity improved in all subdomains at 3 and 12 months. Similar associations between PROMIS measures and LUTS subdomains were observed at all time points, but baseline depression, anxiety, sleep disturbance and physical function measures were not associated with longitudinal trajectories of LUTS., Conclusions: Urinary symptom subdomains are independently associated with modifiable clinical variables including sleep quality and depression at all time points, but these variables do not predict the degree of improvement in LUTS following urological evaluation and treatment over the medium term. Bidirectional assessment and randomized experiments may improve our understanding of these relationships.

We present a methodology for subtyping of persons with a common clinical symptom complex by integrating heterogeneous continuous and categorical data. We illustrate it by clustering women with lower urinary tract symptoms (LUTS), who represent a heterogeneous cohort with overlapping symptoms and multifactorial etiology. Data collected in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN), a multi-center observational study, included self-reported urinary and non-urinary symptoms, bladder diaries, and physical examination data for 545 women. Heterogeneity in these multidimensional data required thorough and non-trivial preprocessing, including scaling by controls and weighting to mitigate data redundancy, while the various data types (continuous and categorical) required novel methodology using a weighted Tanimoto indices approach. Data domains only available on a subset of the cohort were integrated using a semi-supervised clustering approach. Novel contrast criterion for determination of the optimal number of clusters in consensus clustering was introduced and compared with existing criteria. Distinctiveness of the clusters was confirmed by using multiple criteria for cluster quality, and by testing for significantly different variables in pairwise comparisons of the clusters. Cluster dynamics were explored by analyzing longitudinal data at 3- and 12-month follow-up. Five clusters of women with LUTS were identified using the developed methodology. None of the clusters could be characterized by a single symptom, but rather by a distinct combination of symptoms with various levels of severity. Targeted proteomics of serum samples demonstrated that differentially abundant proteins and affected pathways are different across the clusters. The clinical relevance of the identified clusters is discussed and compared with the current conventional approaches to the evaluation of LUTS patients. The rationale and thought process are described for the selection of procedures for data preprocessing, clustering, and cluster evaluation. Suggestions are provided for minimum reporting requirements in publications utilizing clustering methodology with multiple heterogeneous data domains., Competing Interests: The authors have declared that no competing interests exist.

Autoimmune (AI) diseases can affect many organs; however, the prostate has not been considered to be a primary target of these systemic inflammatory processes. Here, we utilize medical record data, patient samples, and in vivo models to evaluate the impact of inflammation, as seen in AI diseases, on prostate tissue. Human and mouse tissues are used to examine whether systemic targeting of inflammation limits prostatic inflammation and hyperplasia. Evaluation of 112,152 medical records indicates that benign prostatic hyperplasia (BPH) prevalence is significantly higher among patients with AI diseases. Furthermore, treating these patients with tumor necrosis factor (TNF)-antagonists significantly decreases BPH incidence. Single-cell RNA-seq and in vitro assays suggest that macrophage-derived TNF stimulates BPH-derived fibroblast proliferation. TNF blockade significantly reduces epithelial hyperplasia, NFκB activation, and macrophage-mediated inflammation within prostate tissues. Together, these studies show that patients with AI diseases have a heightened susceptibility to BPH and that reducing inflammation with a therapeutic agent can suppress BPH., (© 2022. The Author(s).)

Aquablation has been well-studied in prostates sizes up to 150 mL. Recently, American Urological Association guidelines distinguish surgical interventions for men with large prostates (80 mL-150 mL) and now very large prostates (> 150 mL). Readers will gain an understanding of how to use Aquablation in the very large prostate size category.

Background: Germline mutations in DNA repair genes and KLK3 have been associated with adverse prostate cancer (PCa) outcomes in separate studies but never jointly. The objective of this study is to simultaneously assess these two types of germline mutations., Methods: Germline rare pathogenic mutations (RPMs) in 9 commonly tested DNA repair genes and KLK3 variants were tested for their associations with PCa progression in two PCa cohorts: (1) hospital-based PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH, N = 1943), and (2) population-based PCa patients in the UK Biobank (UKB, N = 10,224). Progression was defined as metastasis and/or PCa-specific death (JHH) and PCa-specific death (UKB). RPMs of DNA repair genes were annotated using the American College of Medical Genetics recommendations. Known KLK3 variants were genotyped. Associations were tested using a logistic regression model adjusting for genetic background (top ten principal components)., Results: In the JHH, 3.2% (59/1,843) of patients had RPMs in 9 DNA repair genes; odds ratio (OR, 95% confidence interval) for progression was 2.99 (1.6-5.34), P < 0.001. In comparison, KLK3 I179T mutation was more common; 9.7% (189/1,943) carried the mutation, OR = 1.6 (1.05-2.37), P = 0.02. Similar results were found in the UKB. Both types of mutations remained statistically significant in multivariable analyses. In the combined cohort, compared to patients without any mutations (RPMs-/KLK3-), RPMs-/KLK3+ patients had modestly increased risk for progression [OR = 1.54 (1.15-2.02), P = 0.003], and RPMs+/KLK3+ patients had greatly increased risk for progression [OR = 5.41 (2.04-12.99), P < 0.001]. Importantly, associations of mutations with PCa progression were found in patients with clinically defined low- or intermediate risk for disease progression., Conclusions: Two different cohorts consistently demonstrate that KLK3 I179T and RPMs of nine commonly tested DNA repair genes are complementary for predicting PCa progression. These results are highly relevant to PCa germline testing and provide critical information for KLK3 I179T to be considered in guidelines., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: SNP-based polygenic risk scores have recently been adopted in the clinic for risk assessment of some common diseases. Their validity is supported by a consistent trend between their percentile rank and disease risk in populations. However, for clinical use at the individual level, the reliability of score values is necessary considering they are directly used to calculate remaining lifetime risk., Objectives: We assessed the reliability of polygenic score values to estimate prostate cancer (PCa), breast cancer (BCa) and colorectal cancer (CRC) risk in three incident cohorts from the UK Biobank (n>500 000)., Methods: Cancer-specific Genetic Risk Score (GRS), a well-established population-standardised polygenic risk score, was calculated., Results: A systematic bias was found between estimated risks (GRS values) and observed risks; β (95% CI) was 0.67 (0.58-0.76), 0.74 (0.65-0.84) and 0.82 (0.75-0.89), respectively, for PCa, BCa and CRC, all significantly lower than 1.00 (perfect calibration), p<0.001. After applying a correction factor derived from a training data set, the β for corrected GRS values in an independent testing data set were 1.09 (1.05-1.13), 1.00 (0.88-1.12) and 1.08 (0.96-1.21), respectively, for PCa, BCa and CRC., Conclusion: Assessing the calibration of polygenic risk scores is necessary and feasible to ensure their reliability prior to clinical implementation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Familial aggregation is known for both hernia development and recurrence. To date, only one genome-wide association study (GWAS) limited to inguinal hernia has been reported that identified four risk-associated loci. We aim to investigate polygenic architecture of abdominal wall hernia development and recurrence., Methods: A GWAS was performed in 367,394 subjects from the UK Biobank to investigate the polygenic architecture of abdominal wall hernia subtypes (inguinal, femoral, umbilical, ventral) and identify specific single nucleotide polymorphisms (SNPs) that are associated with their risk. Expression quantitative trait loci (eQTL) analysis was performed to identify genes whose expression levels are associated with these SNPs. A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent risk-associated SNPs on hernia development and recurrence in independent subjects (n = 82,064)., Results: Heritability (h 2 ) was 0.12, 0.06, 0.16, and 0.07 for inguinal, femoral, umbilical, and ventral hernias, respectively. A high-level of genetic correlation (r g ) was found among these subtypes of hernia. We confirmed the aforementioned four loci and identified 57 novel loci (P < 5 × 10 -8 ), including 55, 3, 5, and 3 loci for inguinal, femoral, umbilical, and ventral hernias, respectively. Significantly different expression levels between risk/reference alleles of SNPs were found for 145 genes, including TGF-β2 and AIG1 for inguinal hernia risk and CALD1 for umbilical hernia risk. Finally, higher GRS deciles were significantly associated with increased risk for hernia development (P trend  = 3.33 × 10 -38 ) and recurrent hernia repair surgery (P trend  = 3.64 × 10 -14 )., Conclusion: These novel results have potential biological and clinical implications for hernia management in high-risk patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( MAST3 , p = 6.9×10 -7 and GAB2 , p = 2.0×10 -6 ). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS- versus treatment for the initial management of patients with low-risk PC., Competing Interests: Declaration of Interests The authors declare no competing interests.

Background: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis., Methods: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models., Results: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers., Conclusions: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed., (© 2021 Wiley Periodicals LLC.)

Introduction: The AUA guidelines for benign prostatic hyperplasia distinguish treatments based upon prostate volume (PV), particularly for very large prostates (> 150 mL). While the clinical outcomes and benefits of Aquablation have been studied for men with average and large prostates, it is unknown whether this technology can be used for very large prostates., Materials and Methods: Men with PV > 150 mL undergoing Aquablation were identified retrospectively from four North American hospitals. The surgical times and clinical outcomes of men with very large prostates (> 150 mL) were compared to data from men with average PV ≤ 80 mL (WATER study) and large PV 80 mL-150 mL (WATER II study)., Results: The average PV of men who underwent Aquablation with very large prostates was 209 mL ± 56 (n = 34, range 151-362 mL), large PV 107 mL ± 20 (n = 101, range 80-150 mL) and average PV 54 mL ± 16 (n = 116, range 30-80 mL). For men with PV > 150 mL, baseline IPSS was 19 ± 6. With a mean follow up of 7 ± 9 months, the IPSS improved to 7 ± 5 (p < 0.001). Peak urinary flow rate, Qmax, improved from 7 ± 4 mL/s to 19 ± 5 mL/s (p<0.001). Compared to the two other PV groups, there were no differences in terms of improvements in IPSS, quality of life, or uroflowmetry. There were no reports of transfusions (0%) in the cohort of men with very large prostates., Conclusions: In the present study, we demonstrate that Aquablation is effective and safe in prostates greater than 150 mL while showing consistent outcomes compared to average and large prostates sizes.

Purpose: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer., Materials and Methods: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses., Results: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry., Conclusions: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants., Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual., Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0)., Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings., Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer., Competing Interests: Declaration of interests HL holds patents on intact PSA assays and is named on a patent for a statistical method to detect prostate cancer licensed to Arctic Partners and commercialised by OPKO Health, and has stock in Arctic Partners and OPKO Health and receives royalties from sales of the 4Kscore test. RAE has received speaker honoraria from Genitourinary-American Society of Clinical Oncology, The University of Chicago, European Society for Medical Oncology (paid by Bayer and Ipsen), and The Royal Marsden NHS Foundation Trust (with support from Janssen), and is a member of the AstraZeneca UK Limited Prostate Dx Advisory Panel external expert committee. No organisation had any role in the decision to publish or in the writing of the manuscript. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established., Methods: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p < .005 was considered significant based on Bonferroni correction., Results: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p < .005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62-6.69), 3.23 (2.23-4.56), 2.95 (2.01-4.22), 1.94 (1.43-2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%)., Conclusion: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies., (© 2021 Wiley Periodicals LLC.)

Available evidence supports routine implementation of germline genetic testing for many aspects of prostate cancer (PCa) decision making. The purpose of obtaining genetic testing for newly diagnosed men would be focused on identifying mutations that predispose to aggressive PCa. Based on an evidence-based review, the authors review germline rare pathogenic mutations in several genes that are significantly associated with aggressiveness, metastases, and mortality. Then recent studies of these germline mutations in predicting tumor grade reclassification among patients undergoing active surveillance are discussed. Single nucleotide polymorphisms-based polygenic risk scores in differentiating PCa aggressiveness and prognosis are reviewed., Competing Interests: Disclosure Dr B.T. Helfand is an advisor and speaker for Amby Genetics. He is also a consultant for GoPath., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Prostate cancer (PCa) is characterized by its tendency to be multifocal. However, few studies have investigated the endogenous factors that explain the multifocal disease. The primary objective of the current study is to test whether inherited PCa risk is associated with multifocal tumors in PCa patients., Methods: Subjects in this study were PCa patients of European ancestry undergoing active surveillance at Johns Hopkins Hospital (N = 805) and NorthShore University HealthSystem (N = 432). The inherited risk was measured by genetic risk score (GRS), an odds ratio-weighted and population-standardized polygenic risk score based on known risk-associated single nucleotide polymorphisms. PCa multifocality was indirectly measured by the number and laterality of positive tumor cores from a 12-core systematic biopsy., Results: In the combined cohort, 35.7% and 66.3% of patients had ≥2 tumor cores at the initial diagnostic biopsy and on at least one subsequent surveillance biopsy, respectively. For tumor laterality, 7.8% and 47.8% of patients had bilateral tumor cores at diagnostic and surveillance biopsies, respectively. We found, for the first time, that patients with higher numbers of positive cores at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values; p = .01 and p = 5.94E-04. Additionally, patients with bilateral tumors at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values than those with unilateral tumors; p = .04 and p = .01. In contrast, no association was found between GRS and maximum core length of tumor or tumor grade at diagnostic/surveillance biopsies (all p > .05). Finally, we observed a modest trend that patients with higher GRS quartiles had a higher risk for tumor upgrading on surveillance biopsies. The trend, however, was not statistically significant (p > .05)., Conclusions: The associations of GRS with two measurements of PCa multifocality (core numbers and laterality) provide novel and consistent evidence for the link between inherited PCa risk and multifocal tumors., (© 2021 Wiley Periodicals LLC.)

To determine the relationship between popular diets and erectile function we queried the National Health and Nutrition Examination Survey, a cross-sectional dataset, between 2001 and 2004. All men aged 18-85 who answered the prostate and dietary questionnaires were included. Diets were categorized as Mediterranean, low-fat, low-carbohydrate, or nonrestrictive. Multivariable models were created to determine the relationship between erectile function and each diet. Among 4027 men, 649 (16.1%) met criteria for a low-fat diet, 1085 (26.9%) for a Mediterranean diet, and 0 (0%) for a low-carbohydrate diet. 1999 men (49.6%) had some degree of erectile dysfunction. Men with nonrestrictive diets were more likely to endorse normal erectile function compared with those adhering to the Mediterranean or low-fat diets (both p < 0.05) on univariable analysis. Multivariable analysis controlling for age, comorbidities, activity level, and body mass index showed no differences in erectile function among men adhering to a low-fat, Mediterranean diet, or nonrestrictive diet. There was no association between specific diets and erectile function. While additional prospective research is required to corroborate these findings, these data support the notion that individualized diets should be tailored toward goals of weight loss and reduction of comorbidity., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To characterize the epidemiology of male factor infertility and identify which types of providers are treating infertile men in the United States., Materials and Methods: The National Ambulatory Medical Care Survey was queried between 2006 and 2016 for all ambulatory care visits. Men with a diagnosis of infertility were identified by international classification of disease coding. Comorbidities, demographic and visit information were abstracted from the patients' medical record by a combination of trained surveyors and physicians. The survey data was weighted to create nationally representative estimates, and a combination of Chi-squared and Student's t-tests were utilized to determine significance., Result(s): Among the 8.7 billion patient visits between 2006 and 2016, there were 3,422,000 male encounters with a diagnosis of male factor infertility. The most common provider type for male factor infertility encounters was urology (42.12%) followed by primary care (39.79%), gynecology (7.05%) and all other provider types (11.01%). A significant number of men seen for infertility had comorbidities such as cancer (115,000 men, 3.36%) diabetes (267,000 men, 7.81%), depression (301,000 men, 8.8%), and active tobacco use (857,000 men, 30.3%)., Conclusion: In a nationally representative sample, more than 50% of ambulatory care visits for male factor infertility were not seen by urologists. These men also had a significant number of comorbidities for a relatively young cohort, emphasizing the importance of multidisciplinary care for men with a diagnosis of infertility., (Published by Elsevier Inc.)

Sickle cell trait (SCT) carriers inherit one copy of the Glu6Val mutation in the hemoglobin gene and is particularly common in Black individuals (5-10%). Considering the roles of hemoglobin in immune responses and the higher risk for coronavirus disease (COVID-19) among Black individuals, we tested whether Black SCT carriers were at increased risk for COVID-19 infection and mortality according to the United Kingdom Biobank. Among Black individuals who were tested for COVID-19, we found similar infection rates among SCT carriers (14/72; 19.7%) and noncarriers (167/791; 21.1%), but higher COVID-19 mortality rates among SCT carriers (4/14; 28.6%) than among noncarriers (21/167; 12.6%) (odds ratio [OR], 3.04; 95% confidence interval [CI], 0.69-11.82; P = 0.12). Notably, SCT carriers with preexisting diabetes had significantly higher COVID-19 mortality (4/4; 100%) than those without diabetes (0/10; 0%; (OR, 90.71; 95% CI, 5.66-infinite; P = 0.0005). These findings suggest that Black SCT carriers with preexisting diabetes are at disproportionally higher risk for COVID-19 mortality. Confirmation by larger studies is warranted.

The relationship between testosterone and premature mortality has caused recent controversy. While previous studies have demonstrated mixed results, this is partly because of variable patient populations, different testosterone thresholds, and the use of antiquated techniques to measure serum testosterone. Using the National Health and Nutrition Examination Survey we analyzed a cohort representative of men in the USA to explore the relationship between serum testosterone and premature mortality using contemporary guidelines and testosterone measurements. We found that men with low testosterone (<300 ng/dl) were at higher risk (odds ratio 2.07, 95% confidence interval 1.30-3.32; p  < 0.01) of premature death compared to men with normal testosterone. Furthermore, men with low testosterone were also more likely to have treatable comorbid conditions that were independently predictive of premature mortality. Both testosterone and these comorbid conditions are also modulated by lifestyle modifications, rendering this an important therapeutic approach in men with either or both conditions., Patient Summary: We explored the relationship between testosterone levels and premature death in a large US population. We found that low testosterone is associated with both premature death and related disease processes such as obesity, both of which can be initially treated with diet and exercise.

Background: Despite strong evidence of heritability, few studies have attempted to unveil the genetic underpinnings of testosterone levels., Objective: To identify testosterone-associated loci in a large study and assess their biological and clinical implications., Design Setting and Participants: The participants were men from the UK Biobank. A two-stage genome-wide association study (GWAS) was first used to identify/validate loci for low testosterone (LowT, <8 nmol/l) in 80% of men ( N  = 148 902). The cumulative effect of independent LowT risk loci was then evaluated in the remaining 20% of men., Outcome Measurements and Statistical Analysis: Associations of single nucleotide polymorphisms (SNPs) with LowT were tested using an additive model. Analyses of the expression quantitative trait loci (eQTLs) were performed to assess the associations between significant SNPs and expression of nearby genes (within 1 Mbp). A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent SNPs on LowT risk., Results and Limitations: The two-stage GWAS found SNPs in 141 loci of 41 cytobands that were significantly associated with LowT ( p  < 5 × 10 -8 ), including 94 novel loci from 38 cytobands. An eQTL analysis of these 141 loci revealed significant associations with RNA expression of 155 genes, including previously implicated ( SHBG and JMJD1C ) and novel ( LIN28B , LCMT2 , and ZBTB4 ) genes. Among the 141 loci, 42 were independently associated with LowT after a multivariable analysis. The GRS based on these 42 loci was significantly associated with LowT risk in independent individuals ( N  = 37 225, p trend  = 3.16 × 10 -162 ). The risk ratio for LowT between men in the top and those in the bottom GRS deciles was 4.98-fold. Results are limited in generalizability as only Caucasians were studied., Conclusions: Identification of the genetic variants associated with LowT may improve our understanding of its etiology and identify high-risk men for LowT screening., Patient Summary: We identified 141 new genetic loci that can be incorporated into a genetic risk score that can potentially identify men with low testosterone., (© 2021 The Author(s).)

Cystic fibrosis (CF) carriers carrying one defective copy of a CFTR germline mutation are common in the general population. A recent study reported associations of CF carriers with risk for cancers of digestive organs and pancreatic cancer. In the current study, we assessed associations of CFTR F508del carriers with the risk for 54 types of cancers in the UK Biobank, a large population-based study. In Caucasians, compared to the carrier rate of 3.15% (12 357/392274) in noncancer subjects, the rate was significantly higher in cancer patients overall (2621/79619 = 3.29%), especially in patients with colorectal cancer (247/6667 = 3.70%), cancers of gallbladder and biliary tract (21/351 = 5.98%), thyroid cancer (30/665 = 4.51%) and unspecified non-Hodgkin's lymphoma (74/1805 = 4.10%), all P ≤ .05. In contrast, the carrier rate in patients with cancers of lung and bronchus was significantly lower (89/3463 = 2.57%), P = .05. The association of CFTR F508del carriers with these types of cancer remained significant after adjusting for respective cancer-specific risk factors. For pancreatic cancer, although a higher carrier rate (38/1004 = 3.78%) was found in patients with this cancer, the difference was not statistically significant (P = .26). This null association was unlikely due to lack of statistical power; the large sample size of our study had >80% power, at a significance level of .05, to detect an association of >1.5-fold increased risk. In conclusion, the identified associations of CFTR F508del carriers with multiple types of cancer may have potential biological and clinical implications if confirmed in independent study populations., (© 2020 UICC.)

Background: Single nucleotide polymorphism-based genetic risk score (GRS) has been developed and validated for prostate cancer (PCa) risk assessment. As GRS is population standardized, its value can be interpreted as a relative risk to the general population., Objective: To compare the performance of GRS with two guideline-recommended inherited risk measures, family history (FH) and rare pathogenic mutations (RPMs), for predicting PCa incidence and mortality., Design, Setting, and Participants: A prospective cohort was derived from the UK Biobank where 208 685 PCa diagnosis-free participants at recruitment were followed via the UK cancer and death registries., Outcome Measurements and Statistical Analysis: Rate ratios (RRs) of PCa incidence and mortality for FH (positive vs negative), RPMs (carriers vs noncarriers), and GRS (top vs bottom quartile) were measured., Results and Limitations: After a median follow-up of 9.67 yr, 6890 incident PCa cases (419 died of PCa) were identified. Each of the three measures was significantly associated with PCa incidence in univariate analyses; RR (95 % confidence interval [CI]) values were 1.88 (1.75-2.01) for FH, 2.89 (1.89-4.25) for RPMs, and 1.97(1.87-2.07) for GRS (all p < 0.001). The associations were independent in multivariable analyses. While FH and RPMs identified 11 % of men at higher PCa risk, addition of GRS identified an additional 22 % of men at higher PCa risk, and increases in C-statistic from 0.58 to 0.67 for differentiating incidence (p < 0.001) and from 0.65 to 0.71 for differentiating mortality (p = 0.002). Limitations were a small number of minority patients and short mortality follow-up., Conclusions: This population-based prospective study suggests that GRS complements two guideline-recommended inherited risk measures (FH and RPMs) for stratifying the risk of PCa incidence and mortality., Patient Summary: In a large population-based prostate cancer (PCa) prospective study derived from UK Biobank, genetic risk score (GRS) complements two guideline-recommended inherited risk measures (family history and rare pathogenic mutations) in predicting PCa incidence and mortality. These results provide critical data for including GRS in PCa risk assessment., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Direct-to-consumer (DTC) Internet-based prescription and pharmacy platforms offer electronic consultation for evaluation and pharmacologic treatment of erectile dysfunction (ED) without a physical exam or in-person visit, presenting a potentially dramatic shift in care for this condition., Aim: To characterize the extent to which DTC prescribing sites for ED generate traffic and attract individual users., Methods: Using SEMRush, a marketing software platform that provides analytics regarding website traffic, we examined online site visits to 6 major DTC prescribing websites offering ED evaluation and treatment from October 2017 through December 2019., Outcomes: We recorded trends in the number of unique visitors over time, visitor referral patterns, and the proportion of overall visitors to individual sites., Results: During the study period, the total number of unique, quarterly visitors increased by 1,688% from 655,733 in the 4th quarter (Q4) 2017 to over 11 million in Q4 2019. In 2019, there were on average 4,971,674 visits to all sites combined each month. For the 2 largest sites (Hims and Roman), visitors predominantly reached the site via direct web address (27.3%) or search engine referral (27.3%)., Clinical Implications: An increasingly large number of potential patients are utilizing DTC prescribing platforms for the diagnosis and treatment of ED, which do not require physical exams or treatment of other comorbid conditions., Strength & Limitations: Demonstrates high demand for ED DTC prescribing services using independent market research software and characterizes the number of visits for the first time. Limitations include the lack of individual demographics and lack of information regarding what proportion of unique visits lead to evaluation and treatment using the services., Conclusion: The dramatic increase in visits to DTC prescribing sites that treat ED represents a paradigm shift in ED care, and it is imperative that clinicians and researchers work to understand how patients utilize online telemedicine, the safety and efficacy of online management of ED, and the potential downstream implications of its widespread use. Wackerbarth JJ, Fantus RJ, Darves-Bornoz A, et al. Examining Online Traffic Patterns to Popular Direct-To-Consumer Websites for Evaluation and Treatment of Erectile Dysfunction. Sex Med 2021;9:100289., (Published by Elsevier Inc.)

Background: Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention., Methods: This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40-70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups., Results: The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants' reported optimism about their future health neither before nor after receiving GRS results., Conclusions: Genetic risk scores that quantify an individual's risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.

Objectives: To evaluate the extent to which erectile dysfunction (ED) is managed by urologists versus non-urologists. We sought to characterize the epidemiology, diagnosis, and outpatient treatment of ED using a nationally representative cohort., Methods: We examined all male patient visits between 2006 and 2016 in the National Ambulatory Medical Care Survey, a survey designed to provide a nationally representative estimate of ambulatory visits in the United States. Distribution of ED diagnoses among physician specialties was determined. Demographic, clinical, and treatment characteristics of men with ED seeing urologists versus non-urologists were compared using chi-squared tests., Results: Among the 170,499 patient visits analyzed, 1.2% were associated with a diagnosis of ED, which translated into 3,409,244 weighted visits annually. Visits for ED were predominantly seen by urologists (58.0%) and family practitioners (26.2%). Men visiting non-urologists for ED were more likely to be younger than 65 (77.4% vs 52.9%, P < .05). Men seeing urologists for ED more frequently had an active cancer diagnosis (24.2% vs 2.8%, P < .05). Non-urologists more readily ordered or reordered phosphodiesterase-5 inhibitors for men with ED (66.62% vs 50.77%, P < .05). Advanced therapies such as intracavernosal injections and intra-urethral agents were almost exclusively ordered by urologists compared to non-urologists (2.72% vs 0.25%, P < .05)., Conclusion: Almost half of all ED visits were seen by non-urologist providers, who were much less likely than urologists to order advanced pharmacologic therapies. This difference in prescribing patterns presents an opportunity for interdisciplinary collaboration and education to ensure that all patients seeking treatment for ED are receiving guideline-based care., (Published by Elsevier Inc.)

Background: Exercise and weight loss have been shown to improve serum testosterone (T) in obese individuals. However, the association between low T levels and guideline-based exercise thresholds has not been determined., Objective: Using the recently updated Physical Activity Guidelines Advisory Committee (PAGAC) recommendations, we sought to investigate the relationship between recommended activity levels and the prevalence of low T levels., Materials and Methods: The2011-2016 National Health and Nutrition Examination Survey (NHANES) was used to identify men ages 18 to 80 years who answered the physical activity questionnaire and underwent serum T testing. Men were categorized based on PAGAC activity level: less than recommended, recommended and greater than recommended. Multivariable logistic regressions were used to determine the association between low T (<300 ng/dL) and activity level across body mass index (BMI) categories while adjusting for potential confounders., Results: Of the 7372 men who met the inclusion criteria, the majority (4372, 59.3%) exceeded the recommended amount of activity, whereas only 2326 (31.6%) exercised less than the recommended amount. On multivariable analysis, obese men whose activity exceeded the recommended amount were less likely to have low T (OR 0.523, 95% CI 0.409-0.669, P < .001) compared with men who did not meet the recommended activity level., Discussion and Conclusions: Using a large, nationally representative cohort, we demonstrated that obese men whose activity exceeded PAGAC recommendations had a decreased likelihood of having low T levels. Given the numerous benefits of exercise, these data provide a basis for counseling obese patients regarding the association between exercise and decreased prevalence of low T., (© 2020 American Society of Andrology and European Academy of Andrology.)

Background: Genome-wide association studies have identified over 100 single-nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study., Methods: The sample included 1972 PrCa cases and 1919 unaffected controls. Next-generation sequencing was used to assess pathogenic variants in 14 PrCa-susceptibility genes and 72 validated PrCa-associated SNPs. We constructed a population-standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa., Results: The mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P < .0001). Compared with men in the 1st quartile of age-adjusted PRS, those in the 2nd, 3rd, and 4th quartile were 1.58 (95% confidence interval [CI]: 1.31-1.90), 2.36 (95% CI: 1.96-2.84), and 3.98 (95% CI: 3.29-4.82) times as likely to have PrCa (all P < .0001). Adjustment for family history yielded similar results. PRS predictive performance was consistent with prior literature (area under the receiver operating curve = 0.64; 95% CI: 0.62-0.66)., Conclusions: These data suggest that a 72-SNP PRS is predictive of PrCa, supporting its potential use in clinical risk assessment., (© 2020 Ambry Genetics. The Prostate published by Wiley Periodicals LLC.)

Background: To assess the feasibility of a novel DNA-based probe panel to detect copy number alterations (CNAs) in prostate tumor DNA and its performance for predicting clinical progression., Methods: A probe panel was developed and optimized to measure CNAs in trace amounts of tumor DNA (2 ng) isolated from formalin-fixed paraffin-embedded tissues. Ten genes previously associated with aggressive disease were targeted. The panel's feasibility and performance were assessed in 175 prostate cancer (PCa) patients who underwent radical prostatectomy with a median 10-year follow-up, including 42 men who developed disease progression (either metastasis and/or PCa-specific death). Association with disease progression was tested using univariable and multivariable analyses., Results: The probe panel detected CNAs in all 10 genes in tumor DNA isolated from either diagnostic biopsies or surgical specimens. A four-gene model (PTEN/MYC/BRCA2/CDKN1B) had the strongest association with disease progression; 64.3% of progressors and 22.5% of non-progressors had at least one CNA in these four genes, odds ratio (OR) (95% confidence interval) = 6.21 (2.77-13.87), P = 8.48E-06. The association with disease progression remained significant after adjusting for known clinicopathological variables. Among the seven progressors of the 65 patients with clinically low-risk disease, three (42.9%) had at least one CNA in these four genes., Conclusions: The probe panel can detect CNAs in trace amounts of tumor DNA from biopsies or surgical tissues at the time of diagnosis or surgery. CNAs independently predict metastatic/lethal cancer, particularly among men with clinically low-risk disease at diagnosis. If validated, this may improve current abilities to assess tumor aggressiveness., (© 2020 Wiley Periodicals LLC.)

Germline HOXB13 G84E mutation has been consistently associated with prostate cancer (PCa) risk, but its association with other cancers is controversial. We systematically tested its association with the 20 most common cancer types in subjects from the UK Biobank. The G84E mutation was found in 1,545 (0.34%) of 460,224 participants of European ancestry. While mutation status did not associate with cancer risk in females, it was significantly associated with increased risk in males; odds ratio (OR) (95% confidence interval) for overall cancer diagnosis was 2.19 (1.89-2.52), P = 2.5E-19. The association remained after excluding PCa; OR = 1.4 (1.16-1.68), P = 0.003, suggesting association with other cancers. Indeed, suggestive novel associations were found for two other cancer types; rectosigmoid cancer, OR = 2.25 (1.05-4.15), P = 0.05 and non-melanoma skin cancer (NMSC), OR = 1.40 (1.12-1.74), P = 0.01. For NMSC, the association was found only in basal cell carcinoma, OR = 1.37 (1.07-1.74), P = 0.03. These findings have potential clinical utility for genetic counselling regarding HOXB13.

To evaluate whether prostate volume (PV) would provide additional predictive utility to the prostate health index (phi) for predicting prostate cancer (PCa) or clinically significant prostate cancer, we designed a prospective, observational multicenter study in two prostate biopsy cohorts. Cohort 1 included 595 patients from three medical centers from 2012 to 2013, and Cohort 2 included 1025 patients from four medical centers from 2013 to 2014. Area under the receiver operating characteristic curves (AUC) and logistic regression models were used to evaluate the predictive performance of PV-based derivatives and models. Linear regression analysis showed that both total prostate-specific antigen (tPSA) and free PSA (fPSA) were significantly correlated with PV (all P < 0.05). [-2]proPSA (p2PSA) was significantly correlated with PV in Cohort 2 (P< 0.001) but not in Cohort 1 (P= 0.309), while no significant association was observed between phi and PV. When combining phi with PV, phi density (PHID) and another phi derivative (PHIV, calculated as phi/PV 0.5 ) did not outperform phi for predicting PCa or clinically significant PCa in either Cohort 1 or Cohort 2. Logistic regression analysis also showed that phi and PV were independent predictors for both PCa and clinically significant PCa (all P < 0.05); however, PV did not provide additional predictive value to phi when combining these derivatives in a regression model (all models vs phi were not statistically significant, all P > 0.05). In conclusion, PV-based derivatives (both PHIV and PHID) and models incorporating PV did not improve the predictive abilities of phi for either PCa or clinically significant PCa., Competing Interests: None

Purpose: We describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer., Methods: One thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms., Results: A yield of 9.4-12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97-1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37-9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48-3.65); and family history of Lynch syndrome-associated cancers (OR 1.97; 95% CI 1.23-3.15) were predictors of positive results., Conclusion: These results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.

Purpose: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services., Methods: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider)., Results: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM , for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM , and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches., Conclusion: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Background: Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa)., Objective: To compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease., Design, Setting, and Participants: A retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics., Outcome Measurements and Statistical Analysis: Carrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher's exact test., Results and Limitations: Overall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10 -6 ). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10 -5 ), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10 -6 ), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10 -9 ); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10 -13 ); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02)., Conclusions: In men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment., Patient Summary: Prostate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Carcinoma-associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub-populations of human prostate CAF can be identified and functionally characterized., Methods: Single-cell RNA-seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non-tumorigenic, initiated prostate epithelial BPH-1 cells. Resultant grafts were assessed for inflammatory cell recruitment., Results: Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub-renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine-related genes of individual clusters. Migration of THP-1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF-derived chemokine CCL2 may be responsible for CAF-stimulated migration of THP-1 cells, since neutralization of this chemokine abrogates migration capacity., Conclusions: CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued., (© 2019 Wiley Periodicals, Inc.)

Purpose: Lower urinary tract symptoms are common in men and women. Members of the LURN (Lower Urinary Tract Dysfunction Research Network) sought to create a brief, clinically relevant tool to improve existing measurements of lower urinary tract symptoms in men and women., Materials and Methods: Using a modified Delphi methodology during an expert consensus meeting we reduced the LURN CASUS (Comprehensive Assessment of Self-Reported Urinary Symptoms) questionnaire to a brief set of clinically relevant items measuring lower urinary tract symptoms. The sum score of these items was evaluated by comparing it to the AUA SI (American Urological Association Symptom Index), the UDI-6 (Urinary Distress Inventory Short Form) in women only and the CASUS lower urinary tract symptoms screening questions using the Pearson correlation, regression analysis and ROC curves., Results: The LURN SI-10 (10-Item LURN Symptom Index) assesses urinary frequency, nocturia, urgency, incontinence, bladder pain, voiding and post-micturition symptoms (score range 0 to 38). The correlation between LURN SI-10 and AUA SI scores was 0.77 in men and 0.70 in women. The UDI-6 and the LURN SI-10 correlated highly in women (r=0.76). The LURN SI-10 showed good accuracy to predict moderate and severe lower urinary tract symptoms as defined by the AUA SI (ROC AUC range 0.82-0.90). Similar accuracy was shown in predicting different levels of symptom status using the UDI-6 (AUC range 0.84-0.86)., Conclusions: The LURN SI-10 correlates well with the AUA SI and the UDI-6. It includes items related to a broader spectrum of lower urinary tract symptoms, particularly incontinence, bladder pain and post-micturition symptoms, and it applies to men and women.

Background: Several polygenic risk score (PRS) methods are available for measuring the cumulative effect of multiple risk-associated single nucleotide polymorphisms (SNPs). Their performance in predicting risk at the individual level has not been well studied., Methods: We compared the performance of three PRS methods for prostate cancer risk assessment in a clinical trial cohort, including genetic risk score (GRS), pruning and thresholding (P + T), and linkage disequilibrium prediction (LDpred). Performance was evaluated for score deciles (broad-sense validity) and score values (narrow-sense validity)., Results: A training process was required to identify the best P + T model (397 SNPs) and LDpred model (3 011 362 SNPs). In contrast, GRS was directly calculated based on 110 established risk-associated SNPs. For broad-sense validity in the testing population, higher deciles were significantly associated with higher observed risk; P trend was 7.40 × 10 -11 , 7.64 × 10 -13 , and 7.51 × 10 -10 for GRS, P + T, and LDpred, respectively. For narrow-sense validity, the calibration slope (1 is best) was 1.03, 0.77, and 0.87, and mean bias score (0 is best) was 0.09, 0.21, and 0.10 for GRS, P + T, and LDpred, respectively., Conclusions: The performance of GRS was better than P + T and LDpred. Fewer and well-established SNPs of GRS also make it more feasible and interpretable for genetic testing at the individual level., (© 2019 Wiley Periodicals, Inc.)

Importance: Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis., Objectives: To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification., Design, Setting, and Participants: A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019., Interventions: A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk-associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (<0.50), average (0.50-1.49), and high (≥1.50)., Main Outcomes and Measures: Prostate cancer diagnosis-free survival among men of different risk groups., Results: Among 3225 men (median age, 63 years [interquartile range, 58-67 years]) in the study, 683 (21%) were classified as low risk, 1937 (60%) as average risk, and 605 (19%) as high risk based on GRS alone. In comparison, 2789 (86%) were classified as low or average risk and 436 (14%) as high risk based on FH alone. Men in higher GRS risk groups had a PCa diagnosis-free survival rate that was worse than that of those in the lower GRS risk group (χ2 = 53.3; P < .001 for trend) and in participants with a negative FH of PCa (χ2 = 45.5; P < .001 for trend). Combining GRS and FH further stratified overall genetic risk, indicating that 957 men (30%) were at high genetic risk (either high GRS or positive FH), 1667 men (52%) were at average genetic risk (average GRS and negative FH), and 601 men (19%) were at low genetic risk (low GRS and negative FH). The median PCa diagnosis-free survival was 74 years (95% CI, 73-75 years) for men at high genetic risk, 77 years (95% CI, 75 to >80 years) for men at average genetic risk, and more than 80 years (95% CI, >80 to >80 years) for men at low genetic risk. In contrast, the median PCa diagnosis-free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH., Conclusions and Relevance: This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations., Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status., Design, Setting, and Participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy., Outcome Measurements and Statistical Analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians., Results and Limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65)., Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers., Patient Summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Lower urinary tract symptoms are prevalent and burdensome, yet methods to enhance diagnosis and appropriately guide therapies are lacking. We systematically reviewed the literature for human studies of biomarkers associated with lower urinary tract symptoms., Materials and Methods: PubMed®, EMBASE® and Web of Science® were searched from inception to February 13, 2018. Articles were included if they were in English, performed in benign urological populations without neurological disorders or interstitial cystitis/bladder pain syndrome, and assessed a biomarker's association with or ability to predict specific lower urinary tract symptoms or urological conditions. Bioinformatic pathway analyses were conducted to determine whether individual biomarkers associated with symptoms are present in unifying pathways., Results: Of 6,150 citations identified 125 met the inclusion criteria. Most studies (93.6%) assessed biomarkers at 1 time point and were cross-sectional in nature. Few studies adjusted for potentially confounding clinical variables or assessed biomarkers in an individual over time. No individual biomarkers are currently validated as diagnostic tools for lower urinary tract symptoms. Compared to controls, pathway analyses identified multiple immune response pathways that were enriched in overactive bladder syndrome and cell migration/cytoskeleton remodeling pathways that were enriched in female stress incontinence., Conclusions: Major deficiencies in the existing biomarker literature include poor reproducibility of laboratory data, unclear classification of patients with lower urinary tract symptoms and lack of adjustment for clinical covariates. Despite these limitations we identified multiple putative pathways in which panels of biological markers need further research.

Based upon an evidence-based review of recently published manuscripts including our own studies, we first review germline variants that are significantly associated with prostate cancer aggressiveness and progression. We then discuss the clinical implication of germline variants in predicting grade reclassification of prostate cancer patients undergoing active surveillance. Finally, based on currently available evidence, we propose a working recommendation of germline testing and corresponding clinical management for localized prostate cancer patients, including those undergoing active surveillance.

Background: Anxiety is a common patient concern and clinical endpoint in prostate cancer outcomes research. It is measured using different self-report instruments that are not directly comparable, thereby making clinical trials, clinical performance measurement, and comparative effectiveness research challenging when anxiety is the outcome of interest. The objective of the current study was to enable a common reporting metric of anxiety so that scores on commonly used anxiety measures could be converted into Patient-Reported Outcomes Measurement Information System (PROMIS) scores for ease of application, interpretation, and comparability., Methods: Using an internet health panel, a total of 806 men with clinically localized prostate cancer completed items from the National Institutes of Health PROMIS Anxiety Short Form (version 7a) and the 18-item Memorial Anxiety Scale for Prostate Cancer (MAX-PC). A common metric was created using analyses based on item response theory, producing score crosswalk tables. The linking relationships were evaluated by resampling small subsets and estimating confidence intervals for the differences between the observed and linked PROMIS scores., Results: Results of factor analysis and item response theory model fit supported the hypothesis that both scales measure essentially the same concept. Therefore, crosswalk tables appear to be justified and increasingly robust with increasing sample sizes., Conclusions: MAX-PC Anxiety results can be expressed on the PROMIS Anxiety metric for the purposes of clinical performance measurement, clinical trial outcomes, comparative effectiveness research, and other efforts to compare anxiety results across studies that use any one of these measures., (© 2019 American Cancer Society.)

Aims: To develop a representative, self-report assessment of lower urinary tract symptoms (LUTS) for men and women, the symptoms of Lower Urinary Tract Dysfunction Research Network Symptom Index-29 (LURN SI-29)., Methods: Women and men seeking treatment for LUTS at one of six academic medical centers in the US were assessed at baseline, 3-month and 12-month intervals. Twelve-month data on 78 LURN SI-29 items were analyzed among 353 women and 420 men using exploratory factor analysis (EFA), with factor structure confirmed using confirmatory factor analysis (CFA). Internal consistency, reliability, and validity of the five developed scales were evaluated by assessing correlations with the American Urological Association Symptom Index (AUA-SI), the genitourinary pain index (GUPI), and the Pelvic Floor Distress Inventory-20 (PFDI-20), and by examining expected sex differences in scores., Results: EFA results (n = 150 women; 150 men) produced an interpretable eight-factor solution, with three of the factors comprised of dichotomous items addressing LUTS-associated sensations. The remaining five factors, confirmed with CFA in an independent sample of 473 participants, produced five scales: incontinence, urgency, voiding difficulty, bladder pain, and nocturia. Subscales and total LURN SI-29 scores were correlated as expected with AUA-SI, GUPI, and PFDI-20. LURN SI-29 scores also performed as expected in differentiating men from women based upon clinically expected differences, with men reporting more voiding difficulties and nocturia, and women reporting more urgency and incontinence., Conclusions: The LURN SI-29 questionnaire has the potential to improve research and clinical outcome measurement for both men and women with LUTS., (© 2019 Wiley Periodicals, Inc.)

Objectives: To assess the feasibility of a novel proteomics approach to identify biomarkers associated with lower urinary tract symptoms (LUTS) within serum and urine, because many clinical factors contribute to LUTS in men and women. These factors confound clinicians' abilities to reliably evaluate and treat LUTS. Previous studies identified candidate LUTS biomarkers, but none are clinically utilized., Methods: Eighteen male and 18 female symptoms of lower urinary tract dysfunction research network (LURN) observational cohort study participants with LUTS (measured on the LUTS Tool questionnaire) were randomly selected. Twelve male and 12 female controls with minimal or no LUTS were recruited and matched for clinico-demographic characteristics. The SomaScan Assay (SomaLogic) was used to measure the abundance of 1305 proteins contained within urine and serum. Statistical analyses were performed to evaluate reproducibility of assays, compare protein abundances, and estimate effect size., Results: SomaScan assay results were more reproducible in serum than in urine. Within serum, there were many more differentially abundant proteins between cases and controls in males than in females. An enrichment/pathway analysis of the affected proteins in male and female subjects demonstrated that the enriched Gene Ontology processes were related to prostate morphogenesis in men and growth and inflammation in women., Conclusion: The pilot study results support that the etiology and pathophysiologic mechanisms underlying LUTS may be sex-specific. While further studies involving larger numbers of subjects are warranted, our results support the feasibility of a novel proteomic approach to identify biomarkers for diagnostic classification of LUTS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad-sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow-sense validity) are underdeveloped., Methods: We propose two benchmarks for assessing the narrow-sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4-year follow-up., Results: GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10 -3 , P = 1 × 10 -3 , and P = 1.5 × 10 -13 , respectively (broad-sense validity). For narrow-sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3-0.79, 0.8-1.19, 1.2-1.49, 1.5-1.99, 2-2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively., Conclusion: Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment., (© 2019 Wiley Periodicals, Inc.)