Background Methyl Methanesulfonate-Sensitivity Protein 22-Like (MMS22L) plays a key role in homology-directed DNA repair, and experimental models have shown that its loss confers sensitivity to Poly (ADP-ribose) polymerase inhibitors (PARPi). A rare germline loss-of-function founder mutation in MMS22L, F722fs (c.2164_2168del), was recently identified as a prostate cancer risk factor among individuals of Ashkenazi Jewish ancestry. The impact of this mutation on the disease course following prostate cancer diagnosis remains unclear. Here, we report the longitudinal outcomes of seven MMS22L F722fs carriers diagnosed with different stages of prostate cancer identified at the Brady Urological Institute at Johns Hopkins University.Methods We investigated the longitudinal outcomes of seven MMS22L F722fs carriers diagnosed with different stages of prostate cancer identified at the Brady Urological Institute.Results With a follow-up time ranging from 5 to 27 years, five of the seven patients who were initially treated with radical prostatectomy remain alive and disease-free, including two patients who had adjuvant and salvage therapies, and one patient who was cured after developing metastatic disease post-surgery. For the remaining two patients with metastatic prostate cancer at diagnosis, one patient responded to ADT for 11 years, and the other died of unknown causes 5 years after diagnosis. None of these patients received PARPi.Conclusions Although limited by its retrospective design and small cohort size, this series suggests the potential for exceptional outcomes in F722fs mutation carriers diagnosed with prostate cancer, despite the aggressive disease features and lack of treatment with PARPi. The findings also suggest that prostate cancer patients with this mutation may respond well to standard systemic treatments.

BACKGROUND AND OBJECTIVE:Most of the genes for which an association with susceptibility to prostate cancer (PCa) has been established (eg, BRCA2) are involved in DNA repair, with a subset involved in sensitivity to PARP inhibitor (PARPi) therapy. We systematically tested the association with PCa risk for 65 newly reported genes involved in these pathways. METHODS:Ancestry-specific association between loss-of-function (LoF) germline variants in these 65 genes and PCa risk was first tested between a cohort of PCa patients from Johns Hopkins University (Hopkins; n = 3,716) and population controls from the Genome Aggregation Database (gnomAD; n = 103,221). Results were confirmed in three additional PCa patient cohorts and the UK Biobank (UKB). KEY FINDINGS AND LIMITATIONS:Among men of Ashkenazi Jewish ancestry (ASJ), the carrier rate of LoF MMS22L mutations was significantly higher in the Hopkins PCa cohort than in the gnomAD control cohort. The association was confirmed in the UKB. Combined analysis of all cohorts revealed that the carrier rate for F722fs, an ASJ founder mutation, was 1.5% for PCa cases versus 0.31% for controls (odds ratio [OR] 4.9, 95% confidence interval [CI] 2.1-10.6; p = 1.44 × 10-4, Fisher's test). The proportion of patients with aggressive disease was also significantly higher in the carrier group than in the noncarrier group (83% vs 27%; OR 12.3, 95% CI 2.2-132.5; p = 0.003, Firth test). Another founder mutation in the non-Finnish European population, c.340+1G>A, was significantly associated with PCa risk in the UKB (OR 7.7, 95% CI 2.6-21.0; p =5.10 × 10-4, Firth test). Somatic DNA analysis and assessment of the response to PARPi therapy are needed. CONCLUSIONS AND CLINICAL IMPLICATIONS:Our results suggest that MMS22L is a novel major gene associated with PCa susceptibility. Its carrier rate and effect size are similar to those for BRCA2. If these results are validated, MMS22L could be used for stratification of PCa risk and aggressiveness.

Background and objective: High-intensity focused ultrasound (HIFU) has emerged as an interesting ablative alternative to radical prostatectomy (RP) and radiation therapy (RT) for localized prostate cancer (PC). However, no prospective comparative data have been published for HIFU. Methods: We performed a prospective nonrandomized nationwide trial in 46 centers in France comparing RP versus HIFU. The main inclusion criterion was low-to intermediate-risk PC. The primary endpoint was salvage therapy-free survival (STFS). Secondary endpoints were metastasis-free survival, PC-specific survival, overall survival, and functional outcomes. Key findings and limitations: From 2015 to 2019, 3328 patients were included (1967 HIFU and 1361 RP). Median age was 74.7 versus 65.1 yr (p < 0.001) and median PSA was 7.1 versus 6.9 ng/ml (p = 0.5) in the HIFU and RP groups, respectively. Intermediate-risk PC was diagnosed in 61% of patients in the HIFU group and 64% in the RP group (p = 0.10). The 30-mo STFS was not inferior in the HIFU group (hazard ratio 0.71, 95% confidence interval 0.52-0.97; p = 0.008). Some 10% of patients experienced urinary retention after HIFU. Grade >IIIa complications occurred in 54/1967 cases in the HIFU group and 29/1361 cases in the RP group (p = 0.3). In the HIFU group, fewer patients experienced a deterioration in 12-mo urinary continence (29% vs 44%) and the decrease in median International Index of Erectile Function-5 score was lower (difference 7 vs 13) in comparison to RP. Internal Prostate Symptom Scores and quality-of-life scores were comparable in the two groups. The main limitations are the lack of randomization and the age difference between the groups. Conclusions and clinical implications: This large prospective trial demonstrates that whole-gland or subtotal HIFU provides comparable medium-term STFS outcomes to RP. Urinary continence and erectile function were less impaired after HIFU. These results should be interpreted with caution owing to the lack of randomization and the age difference between the groups. Future research should consider longer follow-up and evaluate focal treatments. (c) 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:Approximately 50% of prostate cancer (PCa) patients meet the National Comprehensive Cancer Network (NCCN) guidelines for germline testing at diagnosis. However, the selection of genes for testing, their supporting evidence, and clinical interpretation remain poorly understood. METHODS:An evidence-based evaluation of the recommended genes was conducted using data from the UK Biobank and Johns Hopkins School of Medicine, including 22,052 PCa patients and 191,055 unaffected controls. Association of germline pathogenic/likely pathogenic (P/LP) variants in each gene was tested using logistic regression, adjusting for age and genetic background. RESULTS:Among the 11 NCCN-recommended PCa-related genes, significant associations (p < 0.0045) were identified between germline P/LP variants of five genes (HOXB13, BRCA2, ATM, CHEK2, and MSH2) and PCa risk. Additionally, BRCA2 and ATM variants were significantly associated with PCa aggressiveness. Of the 19 NCCN-recommended genes related to PARPi sensitivity, consistent evidence supported an enhanced response to PARPi therapy in patients with BRCA2 alterations, with weaker evidence for BRCA1, and limited supporting evidence for the remaining genes. Germline P/LP variants in BRCA2 and BRCA1 were observed in 0.77% and 0.14% of unselected PCa patients, respectively. Notably, no published study specifically assessed the efficacy of germline alterations, which were considerably rarer than somatic mutations. CONCLUSION:Supporting statistical evidence is available for only a subset of the NCCN-recommended genes for germline testing. This evidence-based analysis may aid urologists-particularly those without specialized genetics training-in understanding germline testing for PCa risk assessment, prognosis, and treatment decision-making in clinical practice.

Background To independently assess data for recently reported genes-BIK, SAMHD1, FAM111A, and AOX1-in which rare variants have been associated with prostate cancer (PCa) risk and aggressiveness.Methods The study included 4448 PCa cases from Johns Hopkins School of Medicine and 103,221 population-based controls from the Genome Aggregation Database (gnomAD). Gene-based and variant-based association tests were performed within each major ancestry group using Fisher's exact test and Firth logistic regression. Bonferroni-corrected significance thresholds were applied to account for multiple testing.Results and Conclusion In the NFE population, suggestive statistical evidence of association with PCa risk was found for two of the four genes, BIK and SAMHD1. The evidence was primarily driven by missense variants: BIK S87G and SAMHD1 Q465K and V112I. The effect sizes of these variants were stronger than, or comparable to, those of well-established PCa risk variants such as HOXB13 G84E and CHEK2 T367fs. A weak association signal was observed between AOX1 and PCa aggressiveness. Statistical power was limited for analyses in other ancestry groups, particularly for tests of PCa aggressiveness. Implication of BIK and SAMHD1 as PCa susceptibility genes represents a major breakthrough since the discovery of HOXB13 in 2012 and may have clinical utility for risk stratification and contribute to our understanding of the molecular etiology of PCa.

You have accessJournal of UrologyHistory of Urology Forum II (HF02)1 May 2024HF02-03 GREAT EXPECTATIONS: A BRIEF HISTORY OF WOMEN RESIDENTS AT THE BRADY UROLOGICAL INSTITUTE AT JOHNS HOPKINS MEDICINE, 1980-2022 Aurora J. Grutman, Nathaniel C. Comfort, Marisa M. Clifton, and Patrick C. Walsh Aurora J. GrutmanAurora J. Grutman , Nathaniel C. ComfortNathaniel C. Comfort , Marisa M. CliftonMarisa M. Clifton , and Patrick C. WalshPatrick C. Walsh View All Author Informationhttps://doi.org/10.1097/01.JU.0001008760.25751.09.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In 1985, there were 22 female urologists in the United States. The same year, the first female resident at the Brady Urological Institute began her final year of training. Over thirty-five years later, despite women's increasing participation in medicine, women still represent a small fraction of all practicing urologists. This project therefore sought to understand the complexities and nuances of navigating the field of urology as a woman, through oral histories conducted with eight out of the sixteen women who trained at the Brady Urological Institute at Johns Hopkins University from 1980 to 2022. As the first residency in urology in the United States and a leader in urological treatment and research, the Brady Urological Institute at Johns Hopkins has been at the forefront of many developments in the field. By understanding the experiences of women urologists both at the Brady and more generally, it is possible to identify strategies for promoting greater gender equity and inclusion in urology specifically. METHODS: Interviews with women who are former residents of the Brady Urological Institute at Johns Hopkins were completed and qualitatively coded using NVivo. Archival research at the Alan Mason Chesney Archives at Johns Hopkins provided context for these oral histories. RESULTS: The experience of a female resident at the Brady Urological Institute is defined by demands of greatness. With the support of exceptional mentors at the Brady Urological Institute, women residents are motivated to reach a high professional potential. However, family life, which is another key aspect of "greatness" for many women, often complicates their professional development. For the majority of the study participants, the demands of childbearing and family life resulted in tension between these competing visions of greatness. Indeed, while the field of urology has been increasingly accepting of women, findings suggest that patients and other members of the medical profession may not be as accepting of practicing female urologists. Nevertheless, the Brady is a continuing leader in encouraging women to become the next generation of urological leaders. CONCLUSIONS: This project made a record of the experiences of women who have been residents at the Brady Urological Institute. Archival research situated interviews within a broader historical context, providing insights which amplify, complicate, and enrich the stories collected. Highlighted common themes allow for suggested future areas of growth within the field of urology. Source of Funding: This project was supported by the Persky Summer Research Award and the Hugh Hawkins Research Fellowship for the Study of Hopkins History © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e273 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Aurora J. Grutman More articles by this author Nathaniel C. Comfort More articles by this author Marisa M. Clifton More articles by this author Patrick C. Walsh More articles by this author Expand All Advertisement PDF downloadLoading ...

You have accessJournal of UrologyCME1 Apr 2023MP01-13 E-CIGARETTE VAPOR EXPOSURE NEGATIVELY AFFECTS SPERMATOGENESIS IN MICE Daniel Pelzman, Patrick Walsh, Tatum Tarin, Miguel Brieño-Enriquez, and Kathleen Hwang Daniel PelzmanDaniel Pelzman More articles by this author , Patrick WalshPatrick Walsh More articles by this author , Tatum TarinTatum Tarin More articles by this author , Miguel Brieño-EnriquezMiguel Brieño-Enriquez More articles by this author , and Kathleen HwangKathleen Hwang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003212.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Vaping, or e-cigarette usage, has grown drastically in popularity over the past decade, particularly among teenagers and young adults. The impact of vaping on spermatogenesis has not been established. The primary aim of our study was to assess the effects of e-cigarette vapor exposure on semen parameters, patterns of testicular apoptosis, and meiotic function in mice. METHODS: Outbred CD-1 mice were divided into five cohorts: 5-week experimental, 10-week experimental, 5-week control, 10-week control, and wild-type. Experimental groups were subjected to 200 puffs of e-cigarette vapor over 100 minutes 5 times per week for 5 and 10 weeks. Control groups underwent the same protocol but with 100% glycerol as the aerosolized vapor. Wild type mice were not exposed to either protocol. After completing the protocol, the mice were sacrificed and testes/epididymides were harvested. Epididymal sperm concentration was calculated, TUNEL assay was performed on testicular sections, and meiotic spreads were performed on testicular tissue. The expression and localization of MLH1, RPA, MEIOB, SYCP1, and H2AX were assessed using immunohistochemical staining with >50 cells analyzed per mouse. RESULTS: Epididymal sperm concentration was decreased in both control and experimental groups when compared to wild-type (Figure 1). There were higher numbers of apoptotic cells per seminiferous tubule in the control and experimental groups compared to wild-type (Figure 2). Fewer MLH1 foci per cell and increased autosomal H2AX localization were seen in experimental and control groups compared to wild-type, indicating abnormal DNA repair. CONCLUSIONS: Exposure to both aerosolized e-cigarette fluid and 100% glycerol negatively impacted spermatogenesis in mice, possibly via abnormal apoptotic pathways or DNA repair mechanisms. Source of Funding: Funding was provided internally by the UPMC Department of Urology. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e7 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Pelzman More articles by this author Patrick Walsh More articles by this author Tatum Tarin More articles by this author Miguel Brieño-Enriquez More articles by this author Kathleen Hwang More articles by this author Expand All Advertisement PDF downloadLoading ...

Supplementary Table 3 from A Novel Prostate Cancer Susceptibility Locus at 19q13

PurposeBladder cancer is a complex disease with a wide range of outcomes. Clinicopathological factors only partially explain the variability between patients in prognosis and treatment response. There is a need for large cohorts collecting extensive data and biological samples to: (1) investigate gene-environment interactions, pathological/molecular classification and biomarker discovery; and (2) describe treatment patterns, outcomes, resource use and quality of life in a real-world setting.ParticipantsCOBLAnCE (COhort to study BLAdder CancEr) is a French national prospective cohort of patients with bladder cancer recruited between 2012 and 2018 and followed for 6 years. Data on patient and tumour characteristics, treatments, outcomes and biological samples are collected at enrolment and during the follow-up.Findings to dateWe describe the cohort at enrolment according to baseline surgery and tumour type. In total, 1800 patients were included: 1114 patients with non-muscle-invasive bladder cancer (NMIBC) and 76 patients with muscle-invasive bladder cancer (MIBC) had transurethral resection of a bladder tumour without cystectomy, and 610 patients with NMIBC or MIBC underwent cystectomy. Most patients had a solitary lesion (56.3%) without basement membrane invasion (71.7% of Ta and/or Tis). Half of the patients with cystectomy were stage <= T2 and 60% had non-continent diversion. Surgery included local (n=298) or super-extended lymph node dissections (n=11) and prostate removal (n=492). Among women, 16.5% underwent cystectomy and 81.4% anterior pelvectomy.Future plansCOBLAnCE will be used for long-term studies of bladder cancer with focus on clinicopathological factors and molecular markers. It will lead to a much-needed improvement in the understanding of the disease. The cohort provides valuable real-world data, enabling researchers to study various research questions, assess routine medical practices and guide medical decision-making.

Supplementary Figure 1 from Germ-Line Mutation of <i>NKX3.1</i> Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function

BackgroundAlthough men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men. MethodsWhole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N=960) and Wayne State University (N=747) was performed. All nonsynonymous variants present in both case cohorts, with a carrier rate between 0.5% and 1%, were identified. Their carrier rates were compared with rates from 8128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher's exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value <= 0.05, were further evaluated in AA PCa cases (N=132) and controls (N=1184) from the UK Biobank (UKB). ResultsTwo variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95% confidence interval CI 4.68-299.72), p(exact)=7.01E-06, FDR-adjusted p-value=0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65-99.76), p(exact)=5.51E-06, FDR-adjusted p-value=0.05. The mean percentage of African ancestry was similar between variant carriers and noncarriers of each variant, p>0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), p(exact)=0.19. However, IGF1R R511Q was not found in cases or controls. ConclusionsThis WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.

Individual monitoring of radiation workers is essential to ensure compliance with legal dose limits and to ensure that doses are As Low As Reasonably Achievable. However, large uncertainties still exist in personal dosimetry and there are issues with compliance and incorrect wearing of dosimeters. The objective of the PODIUM (Personal Online Dosimetry Using Computational Methods) project was to improve personal dosimetry by an innovative approach: the development of an online dosimetry application based on computer simulations without the use of physical dosimeters. Occupational doses were calculated based on the use of camera tracking devices, flexible individualised phantoms and data from the radiation source. When combined with fast Monte Carlo simulation codes, the aim was to perform personal dosimetry in real-time. A key component of the PODIUM project was to assess and validate the methodology in interventional radiology workplaces where improvements in dosimetry are needed. This paper describes the feasibility of implementing the PODIUM approach in a clinical setting. Validation was carried out using dosimeters worn by Vascular Surgeons and Interventional Cardiologists during patient procedures at a hospital in Ireland. Our preliminary results from this feasibility study show acceptable differences of the order of 40% between calculated and measured staff doses, in terms of the personal dose equivalent quantity H p (10), however there is a greater deviation for more complex cases and improvements are needed. The challenges of using the system in busy interventional rooms have informed the future needs and applicability of PODIUM. The availability of an online personal dosimetry application has the potential to overcome problems that arise from the use of current dosimeters. In addition, it should increase awareness of radiation protection among staff. Some limitations remain and a second phase of development would be required to bring the PODIUM method into operation in a hospital setting. However, an early prototype system has been tested in a clinical setting and the results from this two-year proof-of-concept PODIUM project are very promising for future development.

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 x 10(-4)), with greater risk observed for more aggressive and advanced disease (Gleason >= 8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 x 10(-5); stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 x 10(-4); metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. Patient summary: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry. (C) 2022 Published by Elsevier B.V. on behalf of European Association of Urology.