Publications by authors named "Patrick C Walsh"

354 Publications

Association of prostate cancer polygenic risk score with number and laterality of tumor cores in active surveillance patients.

Prostate 2021 May 6. Epub 2021 May 6.

The Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

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.
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http://dx.doi.org/10.1002/pros.24140DOI Listing
May 2021

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
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http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer.

Eur Urol Oncol 2020 04 14;3(2):224-230. Epub 2020 Jan 14.

Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA. Electronic address:

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). 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), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10), 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); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10); 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.
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http://dx.doi.org/10.1016/j.euo.2019.12.003DOI Listing
April 2020

PSA Doubling Time and Absolute PSA Predict Metastasis-free Survival in Men With Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.

Clin Genitourin Cancer 2019 12 21;17(6):470-475.e1. Epub 2019 Aug 21.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Introduction: The aim of this study was to investigate the association of prostate-specific antigen (PSA) values on metastasis-free survival (MFS) in men with biochemically recurrent prostate cancer (BRPC) and PSA doubling time (PSADT) < 12 months. This dataset also reflects an update with longer follow-up of our prior publications on the natural history of BRPC in the absence of treatment.

Materials And Methods: In this report, we combined databases from the Center for Prostate Disease Research and Johns Hopkins University (CPDR/JHU). In the CPDR/JHU radical prostatectomy database (30,936 total patients), 656 men with BRPC (> 0.2 ng/mL) after prostatectomy and PSADT < 12 months, who received no adjuvant/salvage androgen deprivation and/or radiation therapy, were prospectively followed until radiologic evidence of metastasis and are included in this analysis.

Results: Metastasis occurred in 250 of 656 patients with BRPC (median follow-up, 5 years). PSADT < 7.5 months and Gleason score were independent risk factors for distant metastasis in multivariable analysis. Risk of metastasis increased for PSADT 6.01 to 7.50, 4.51 to 6.0, 3.01 to 4.50, and ≤ 3.0 months, after adjusting for Gleason score. A PSA value ≥ 0.5 ng/mL significantly and independently increased risk of metastasis in patients with PSADT < 12 months (hazard ratio, 2.79; 95% confidence interval, 1.47-5.29; P = .001).

Conclusions: In men with PSADT < 12 months, PSADT ≤ 7.5 months, PSA ≥ 0.5 ng/mL, and Gleason score are independent predictors of MFS on multivariable analysis.
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http://dx.doi.org/10.1016/j.clgc.2019.08.002DOI Listing
December 2019

Radiation Therapy in the Definitive Management of Oligometastatic Prostate Cancer: The Johns Hopkins Experience.

Int J Radiat Oncol Biol Phys 2019 12 13;105(5):948-956. Epub 2019 Aug 13.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: The use of radiation therapy (RT) in consolidating oligometastatic prostate cancer (OPCa) is a rapidly evolving treatment paradigm. We review our institutional experience using metastasis-directed therapy in the definitive management of men with OPCa.

Methods And Materials: Patients with OPCa treated with definitive RT were included. The Kaplan-Meier method and multivariable Cox regression analysis were performed to assess biochemical progression-free survival (bPFS) and time to next intervention. Cumulative incidence functions were used to calculate rates of local failure. Toxicity was assessed using Common Terminology Criteria for Adverse Events (version 4).

Results: This study analyzed 156 patients with OPCa and 354 metastatic lesions with median follow-up of 24.6 months. Of 150 patients with toxicity data, 53 (35%) experienced acute grade 1 toxicity, 8 (5%) had grade 2, and none had grade 3 toxicity. Only 13 patients (9%) had late toxicities. At 24 months, the cumulative incidence of local failure was 7.4%. Median bPFS for the entire cohort was 12.9 months and 52% at 1 year. On multivariable analysis, factors associated with prolonged bPFS were peri-RT androgen deprivation therapy (ADT), lower gross tumor volume, and hormone-sensitive (HS) OPCa. Median time to next intervention, including repeat RT, was 21.6 months. Median bPFS for men with HS prostate cancer was 17.2 months compared with 7.2 months in men with castrate-resistant OPCa (P < .0001), and cumulative incidence of local failure at 24 months was lower with HS OPCa (4.8% vs 12.1%; P = .034). We analyzed 28 men with HS OPCa treated with a course of peri-RT ADT (median, 4.3 months) with recovery of testosterone. At a median follow-up of 33.5 months, 20 patients had not developed bPFS, median bPFS had not been reached, and 24-month bPFS was 77%.

Conclusions: Metastasis-directed therapy can be effective across a wide range of OPCa subtypes, but with differential efficacy. Further study is warranted to investigate the use of RT across the wide range of patients with OPCa.
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http://dx.doi.org/10.1016/j.ijrobp.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050213PMC
December 2019

Re: Association of Treatment with 5α-Reductase inhibitors with Time to Diagnosis and Mortality in Prostate Cancer.

Authors:
Patrick C Walsh

Eur Urol 2019 11 23;76(5):704. Epub 2019 Jul 23.

James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2019.07.022DOI Listing
November 2019

RE: Risk of Prostate Cancer in Men Treated With 5α-Reductase Inhibitors-A Large Population-Based Prospective Study.

Authors:
Patrick C Walsh

J Natl Cancer Inst 2019 07;111(7):747

Brady Urological Institute, Johns Hopkins Hospital, Baltimore, MD.

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http://dx.doi.org/10.1093/jnci/djy186DOI Listing
July 2019

Stereotactic ablative radiation therapy for oligometastatic prostate cancer delays time-to-next systemic treatment.

World J Urol 2019 Dec 6;37(12):2623-2629. Epub 2018 Sep 6.

Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Rm 406, Baltimore, MD, 21231, USA.

Purpose: Local ablative treatment to oligometastatic patients can result in long-term disease-free survival in some cancer patients. The importance of this treatment paradigm in prostate cancer is a rapidly evolving field. Herein, we report on the safety and preliminary clinical outcomes of a modern cohort of oligometastatic prostate cancer (OPC) patients treated with consolidative stereotactic ablative radiation (SABR).

Methods: Records of men with OPC who underwent consolidative SABR at our institution were reviewed. SABR was delivered in 1-5 fractions of 5-18 Gray. Kaplan-Meier estimates of local progression-free survival (LPFS), biochemical progression-free survival (bPFS; PSA nadir + 2), distant progression-free survival (DPFS), and time-to-next intervention (TTNI) were calculated.

Results: In total, 66 OPC patients were identified with consolidative SABR delivered to 134 metastases: 89 bone, 40 nodal, and 5 viscera. The majority of men (49/66) had hormone-sensitive prostate cancer (HSPC). Crude grade 1 and 2 acute toxicities were 36% and 11%, respectively, with no ≥ grade 3 toxicity. At 1 year, LPFS was 92% and bPFS and DPFS were 69%. Of the 18 men with HSPC who had deferred hormone therapy , 11 (56%) remain disease free following SABR (1-year ADT-FS was 78%). In 17 castration-resistant men, 11 had > 50% prostate-specific antigen (PSA) declines with 1-year TTNI of 30%.

Conclusions: Consolidative SABR in OPC is feasible and well tolerated. The heterogeneity and small size of our series limit extrapolation of clinically meaningful outcomes following consolidative SABR in OPC, but our preliminary data suggest that this approach warrants continued prospective study.
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http://dx.doi.org/10.1007/s00345-018-2477-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401357PMC
December 2019

Germline mutations in PPFIBP2 are associated with lethal prostate cancer.

Prostate 2018 12 24;78(16):1222-1228. Epub 2018 Jul 24.

Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa.

Methods: A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis.

Results: In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034).

Conclusions: While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.
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http://dx.doi.org/10.1002/pros.23697DOI Listing
December 2018

Differences in inherited risk among relatives of hereditary prostate cancer patients using genetic risk score.

Prostate 2018 Jun 19. Epub 2018 Jun 19.

Division of Urology, John and Carol Walter for Urologic Health, NorthShore University HealthSystem, Evanston, Illinois.

Purpose: Family history assigns equivalent risk to all relatives based upon the degree of relationship. Recent genetic studies have identified single nucleotide polymorphisms (SNPs) that can be used to calculate a genetic risk score (GRS) to determine prostate cancer (PCa) risk. We sought to determine whether GRS can stratify PCa risk among individuals in families considered to be at higher risk due their family history of PCa.

Materials And Methods: Family members with hereditary PCa were recruited and genotyped for 17 SNPs associated with PCa. A GRS was calculated for all subjects. Analyses compared the distribution of GRS values among affected and unaffected family members of varying relationship degrees.

Results: Data was available for 789 family members of probands including 552 affected and 237 unaffected relatives. Median GRSs were higher among first-degree relatives compared to second- and third-degree relatives. In addition, GRS values among affected first- and second-degree relatives were significantly higher than unaffected relatives (P = 0.042 and P = 0.016, respectively). Multivariate analysis including GRS and degree of relationship demonstrated that GRS was a significant and independent predictor of PCa (OR 1.52, 95%CI 1.15-2.01).

Conclusion: GRS is an easy-to-interpret, objective measure that can be used to assess differences in PCa risk among family members of affected men. GRS allows for further differentiation among family members, providing better risk assessment. While prospective validation studies are required, this information can help guide relatives in regards to the time of initiation and frequency of PCa screening.
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http://dx.doi.org/10.1002/pros.23664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773522PMC
June 2018

Magnetic Resonance Imaging Prior to First Prostate Biopsy-Are we there yet?

Eur Urol 2018 10 14;74(4):409-410. Epub 2018 Jun 14.

The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1016/j.eururo.2018.05.018DOI Listing
October 2018

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

J Clin Oncol 2018 02 13;36(4):414-424. Epub 2017 Dec 13.

Veda N. Giri, Karen E. Knudsen, William K. Kelly, Robert B. Den, Adam P. Dicker, Jean Hoffman-Censits, Mark D. Hurwitz, Colette Hyatt, Grace Lu-Yao, Mark J. Mann, James R. Mark, Peter A. McCue, Ronald E. Myers, Stephen C. Peiper, Edouard J. Trabulsi, and Leonard G. Gomella, Jefferson Sidney Kimmel Cancer Center; Justin E. Bekelman, University of Pennsylvania Perelman School of Medicine; S. Bruce Malkowicz, University of Pennsylvania; Elias Obeid and Robert Uzzo, Fox Chase Cancer Center; Gordon F. Schwartz, Foundation for Breast and Prostate Health, Philadelphia; Mark S. Shahin, Hanjani Institute for Gynecologic Oncology, Abington Hospital-Jefferson Health, Abington, PA; Wassim Abida, Philip Kantoff, and Mark E. Robson, Memorial Sloan Kettering Cancer Center; Mitchell C. Benson, Columbia University, New York, NY; Gerald L. Andriole, Washington University School of Medicine, St Louis, MO; Chris H. Bangma, Erasmus Medical Center, Rotterdam, the Netherlands; Amie Blanco, and Matthew Cooperberg, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco; Christopher J. Kane, University of California San Diego, San Diego; Howard Sandler, Cedars-Sinai Medical Center, Los Angeles; Howard R. Soule, Prostate Cancer Foundation, Santa Monica, CA; Arthur Burnett, William B. Isaacs, Christian P. Pavlovich, and Patrick C. Walsh, Johns Hopkins Medical Institutions, Baltimore; Peter A. Pinto and Carol J. Weil, National Cancer Institute, Bethesda, MD; William J. Catalona and Edward Schaeffer, Northwestern University Feinberg School of Medicine; Scott Eggener, Sarah M. Nielsen, and Donald J. Vander Griend, University of Chicago, Chicago, IL; Kathleen A. Cooney, University of Utah School of Medicine, Salt Lake City, UT; David E. Crawford, University of Colorado, Aurora; Lawrence I. Karsh, The Urology Center of Colorado, Denver; Wendy Poage, Prostate Conditions Education Council, Elizabeth, CO; Neil Fleshner, University of Toronto Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Matthew L. Freedman, Kevin R. Loughlin, and Timothy R. Rebbeck, Dana Farber Cancer Institute, and Harvard TH Chan School of Public Health, Boston, MA; Freddie C. Hamdy, University of Oxford, Oxford, England; R. Jeffrey Karnes, Mayo Clinic, Rochester, MN; Eric A. Klein, Cleveland Clinic, Cleveland; Robert Pilarski, The Ohio State University, Columbus, OH; Daniel W. Lin, University of Washington, Seattle, WA; Martin M. Miner, Brown University, Providence, RI; Todd Morgan and Scott A. Tomlins, University of Michigan, Ann Arbor; Matt T. Rosenberg, Mid-Michigan Health Center, Jackson, MI; Judd W. Moul, Duke University, Duke Cancer Institute, Durham, NC; David F. Penson, Vanderbilt University Medical Center, Nashville, TN; Daniel Petrylak and Brian Shuch, Yale University, New Haven, CT; Curtis A. Pettaway, The University of Texas MD Anderson Cancer Center, Houston; Ganesh V. Raj, University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Oliver Sartor, Tulane University Medical School, New Orleans, LA; Neal D. Shore, Atlantic Urology Clinics/Carolina Urologic Research Center, Myrtle Beach, SC; and Richard Wender, American Cancer Society, Atlanta, GA.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.
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http://dx.doi.org/10.1200/JCO.2017.74.1173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075860PMC
February 2018

Prostate Specific Antigen Testing after Radical Prostatectomy-Can We Stop at 20 Years?

J Urol 2018 01 14;199(1):114-119. Epub 2017 Aug 14.

The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: We examined the clinical features and outcomes associated with delayed biochemical recurrence after radical prostatectomy, specifically among men with more than 20 years of followup.

Materials And Methods: A total of 16,720 men underwent radical prostatectomy and 2,699 experienced biochemical recurrence. We determined predictors of delayed biochemical recurrence as well as metastasis-free and cancer specific survival rates for recurrence at various time points after radical prostatectomy. We performed subset analysis of the 732 men with 20 or more years of recurrence-free followup. Cumulative incidence curves for metastasis and prostate cancer death were calculated and stratified by biochemical recurrence time points.

Results: Predictors of delayed biochemical recurrence included elevated prostate specific antigen at radical prostatectomy, higher clinical and pathological stage, and positive surgical margins. Delayed biochemical recurrence was associated with favorable cumulative incidence curves for metastasis and prostate cancer death compared to early biochemical recurrence. Among the 732 men with undetectable prostate specific antigen at 20 years biochemical recurrence developed in 17 (2.3%), metastatic disease developed in a single patient and none died of prostate cancer. The actuarial probability of biochemical recurrence among men with undetectable prostate specific antigen at 20 years increased with adverse pathological features.

Conclusions: Men with delayed biochemical recurrence have favorable clinical features and improved survival. Men with undetectable prostate specific antigen 20 years after radical prostatectomy had a low rate of recurrence and no deaths from prostate cancer. This suggests that 20 years is a reasonable time to discontinue prostate specific antigen testing.
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http://dx.doi.org/10.1016/j.juro.2017.08.041DOI Listing
January 2018

A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).

Prostate 2017 Aug 28;77(11):1213-1220. Epub 2017 Jun 28.

Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.

Background: Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common conditions. Little is known about their etiologies except that studies have suggested a substantial heritable component. Our objective is to provide a comprehensive, genome-wide evaluation of inherited risks and possible mechanisms of etiology in BPH.

Methods: We performed a three-stage, genome-wide association study (GWAS) of men from three independent populations, the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, the CLUE II cohort, and a Finnish hospital-based population. DNA samples were genotyped using the Illumina HumanOmniExpress BeadChip in REDUCE and CLUE II, and using the Sequenom iPLEX system for the confirmation stage in the Finnish population. A logistic regression model was used to evaluate the association between each SNP and BPH/LUTS.

Results: Fourteen SNPs reached P < 5.0 × 10 in the meta-analysis of the two GWASs (CLUE II and REDUCE). A total of 773 SNPs were chosen for the confirmation step in the Finish cohort. Only one SNP (rs17144046) located ∼489 kb downstream of GATA3 remained significant after correction for multiple testing (P < 6.5 × 10 ). This SNP marginally reached the GWAS significance level after performing a meta-analysis of the three stages (P  = 8.89 × 10 ). Expression quantitative trait loci (eQTL) analyses showed that the risk allele (G) of rs17144046 was significantly associated with increased expression of GATA3 (P = 0.017). Reported studies indicated a close correlation between GATA3 and BPH pathogenesis and progression.

Conclusions: Rs17144046 located near GATA3 was significantly associated with BPH/LUTS in three independent populations, but did not reach a stringent GWAS significance level. Genetic variants of GATA3 may play a role in the inherited susceptibility and etiology of BPH/LUTS. Further research in this area is needed.
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http://dx.doi.org/10.1002/pros.23380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565164PMC
August 2017

Prostate Cancer Screening.

Authors:
Patrick C Walsh

N Engl J Med 2017 06;376(24):2401-2

Johns Hopkins Hospital, Baltimore, MD

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http://dx.doi.org/10.1056/NEJMc1705480DOI Listing
June 2017

If You Want to Make an Important Discovery, Listen to Your Patients.

Authors:
Patrick C Walsh

Eur Urol 2017 10 22;72(4):482. Epub 2017 Apr 22.

James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, MD, USA. Electronic address:

No one knows more about certain aspects of a disease than the patient who has it. So, listen to your patients and they may lead you in a direction in which no one else is going.
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http://dx.doi.org/10.1016/j.eururo.2017.04.001DOI Listing
October 2017

The Search for the Missing Heritability of Prostate Cancer.

Authors:
Patrick C Walsh

Eur Urol 2017 11 22;72(5):657-659. Epub 2017 Apr 22.

James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, MD, USA. Electronic address:

Scientists and clinicians at Johns Hopkins have been working since 1987 to uncover the genetic pathogenesis of prostate cancer. A patient query about the hereditary nature of the disease led to data collection on family history, followed by segregation and linkage analyses. Collaborative investigations using next-generation sequencing to identify genetic variants associated with prostate cancer risk have revealed the significance of HOXB13, BRCA 1/2, and DNA repair mutations.
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http://dx.doi.org/10.1016/j.eururo.2017.04.003DOI Listing
November 2017

Impotence Following Radical Prostatectomy: Insight into Etiology and Prevention.

J Urol 2017 02 21;197(2S):S165-S170. Epub 2016 Dec 21.

James Buchanan Brady Urological Institute, The Johns Hopkins Hospital and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, and Departments of Anatomy and Embryology, and Urology, University of Leiden, Leiden, The Netherlands.

This study was undertaken to identify the cause of impotence in men undergoing radical prostatectomy, with the hope that this information may provide insight into the possible prevention of this complication. The autonomic innervation of the corpora cavernosa in the male fetus and newborn was traced to determine the topographical relationship between the pelvic nerve plexus, and the prostate, urethra and urogenital diaphragm. We have demonstrated that the branches of the pelvic plexus that innervate the corpora cavernosa are situated between the rectum and urethra, and penetrate the urogenital diaphragm near or in the muscular wall of the urethra. Injuries to the pelvic plexus can occur in 2 ways: 1) during division of the lateral pedicle and 2) at the time of apical dissection with transection of the urethra. Thirty-one men who underwent radical retropubic prostatectomy were evaluated to determine risk factors that correlated with postoperative impotence: 5 (16 per cent) were fully potent, 7 (23 per cent) had partial erections that were inadequate for sexual intercourse and 19 (61 per cent) had total erectile impotence. The 2 factors that had a favorable influence on postoperative potency were age and pathologic stage of the lesion: 31 per cent of the patients less than 60 years old were potent versus only 6 per cent of the patients more than 60 years, while 33 per cent of the patients with tumor microscopically confined to the prostatic capsule were potent versus only 5 per cent of those with capsular penetration. When the factors of age and capsular penetration were combined 60 per cent of the men less than 60 years old who had an intact prostatic capsule were potent. Arterial insufficiency and psychogenic factors were excluded as major contributing factors by the finding of normal penile blood flow and absence of nocturnal penile tumescence in the impotent patients. We conclude that impotence after radical prostatectomy results from injury to the pelvic nerve plexus that provides autonomic innervation to the corpora cavernosa. Further studies will be necessary to determine whether refinements in surgical technique, especially during ligation of the lateral pedicle and apical dissection, can prevent this complication.
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http://dx.doi.org/10.1016/j.juro.2016.10.105DOI Listing
February 2017

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.

Eur Urol 2017 05 15;71(5):740-747. Epub 2016 Dec 15.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Background: Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk.

Objective: To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death.

Design, Setting, And Participants: A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes.

Outcome Measurements And Statistical Analysis: Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively.

Results And Limitations: The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed.

Conclusions: Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time.

Patient Summary: Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.
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http://dx.doi.org/10.1016/j.eururo.2016.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535082PMC
May 2017

Technique and outcomes of bladder neck intussusception during robot-assisted laparoscopic prostatectomy: A parallel comparative trial.

Urol Oncol 2016 12 12;34(12):529.e1-529.e7. Epub 2016 Oct 12.

Department of Urology, University of California, Los Angeles, CA; Brady Department of Urology, Weill Cornell Medicine New York, New York. Electronic address:

Introduction: Postprostatectomy incontinence significantly impairs quality of life. Although bladder neck intussusception has been reported to accelerate urinary recovery after open radical retropubic prostatectomy, its adaption to robotic surgery has not been assessed. Accordingly, we describe our technique and compare outcomes between men treated with and without bladder neck intussusception during robot-assisted laparoscopic prostatectomy.

Materials And Methods: We performed a comparative trial of 48 men undergoing robot-assisted laparoscopic prostatectomy alternating between bladder neck intussusception (n = 24) and nonintussusception (n = 24). Intussusception was completed using 3-0 polyglycolic acid horizontal mattress sutures anterior and posterior to the bladder neck. We assessed baseline characteristics and clinicopathologic outcomes. Adjusting for age, body mass index, race, and D׳Amico risk classification, we prospectively compared urinary function at 2 days, 2 weeks, 2 months, and last follow-up using the urinary domain of the Expanded Prostate Cancer Index-Short Form.

Results: Baseline patient characteristics and clinicopathologic outcomes were similar between treatment groups (P>0.05). Median catheter duration (8 vs. 8d, P = 0.125) and rates of major postoperative complications (4.2% vs. 4.2%, P = 1.000) did not differ. In adjusted analyses, Expanded Prostate Cancer Index-Short Form urinary scores were significantly higher for the intussusception arm at 2 weeks (65.4 vs. 46.6, P = 0.019) before converging at 2 months (69.1 vs. 68.3, P = 0.929) after catheter removal and at last follow-up (median = 7mo, 80.5 vs. 77.0; P = 0.665).

Conclusions: Bladder neck intussusception during robot-assisted laparoscopic prostatectomy is feasible and safe. Although the long-term effects appear limited, intussusception may improve urinary function during the early recovery period.
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http://dx.doi.org/10.1016/j.urolonc.2015.01.012DOI Listing
December 2016

Pathological analysis of the prostatic anterior fat pad at radical prostatectomy: insights from a prospective series.

BJU Int 2017 03 30;119(3):444-448. Epub 2016 Sep 30.

Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Objective: To assess factors associated with lymphatic drainage and lymph node (LN) metastasis to the prostatic anterior fat pad (PAFP) in men with prostate cancer and the utility of routine PAFP analysis at the time of radical prostatectomy (RP).

Patients And Methods: Our institution began to prospectively collect PAFP tissue in 2010. The PAFP was removed at the time of RP and sent as a pathological specimen separate from the pelvic LNs and prostate. Consecutive RPs performed at our institution in which the PAFP was removed were reviewed to determine the rate of LNs in the PAFP, the rate of metastatic LNs in the PAFP, and the association of metastatic PAFP LN with clinical and pathological features. The impact on biochemical recurrence (BCR) was assessed with a Cox's proportional hazard model.

Results: In all, 2 413 PAFP specimens were available for analysis. LNs were found in the PAFP in 255 (10.6%) cases and metastatic LNs in the PAFPs were found in 14 (0.6%) cases. Metastatic PAFP LNs were associated with anterior tumours in 11 of the 14 cases (P = 0.01), and were present only in preoperative D'Amico intermediate- (six of 14) and high- (eight of 14) risk patients (P < 0.001). Metastatic PAFP LNs were associated with extraprostatic disease in 13 of the 14 cases, although concomitant pelvic LN involvement was present in only four of the 14 cases. With a mean follow-up of 1.5 years, three of the 14 patients with metastatic PAFP LN developed BCR. Positive LN involvement in either the pelvic LN or PAFP had worse BCR than LN-negative patients (P < 0.001); however, there was no difference in BCR between patients with positive pelvic LN and positive PAFP LN (P = 0.5).

Conclusion: Metastatic PAFP LNs are rare and always occur in the presence of other adverse pathological features. The routine pathological analysis of PAFP as a separate specimen, especially in low-risk disease, may not be warranted.
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http://dx.doi.org/10.1111/bju.13654DOI Listing
March 2017

Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.

Hum Genet 2016 08 4;135(8):923-38. Epub 2016 Jun 4.

Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA.

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.
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http://dx.doi.org/10.1007/s00439-016-1690-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020907PMC
August 2016

Infectious mononucleosis, other infections and prostate-specific antigen concentration as a marker of prostate involvement during infection.

Int J Cancer 2016 May 21;138(9):2221-30. Epub 2016 Jan 21.

Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD.

Although Epstein-Barr virus has been detected in prostate tissue, no associations have been observed with prostate cancer in the few studies conducted to date. One possible reason for these null findings may be use of cumulative exposure measures that do not inform the timing of infection, i.e., childhood versus adolescence/early adulthood when infection is more likely to manifest as infectious mononucleosis (IM). We sought to determine the influence of young adult-onset IM on the prostate by measuring prostate-specific antigen (PSA) as a marker of prostate inflammation/damage among U.S. military members. We defined IM cases as men diagnosed with IM from 1998 to 2003 (n = 55) and controls as men without an IM diagnosis (n = 255). We selected two archived serum specimens for each participant, the first collected after diagnosis for cases and one randomly selected from 1998 to 2003 for controls (index), as well as the preceding specimen (preindex). PSA was measured in each specimen. To explore the specificity of our findings for prostate as opposed to systemic inflammation, we performed a post hoc comparison of other infectious disease cases without genitourinary involvement (n = 90) and controls (n = 220). We found that IM cases were more likely to have a large PSA rise than controls (≥ 20 ng/mL: 19.7% versus 8.8%, p = 0.027; ≥ 40% rise: 25.7% versus 9.4%, p = 0.0021), as were other infectious disease cases (25.7% versus 14.0%, p = 0.020; 27.7% versus 18.0%, p = 0.092). These findings suggest that, in addition to rising because of prostate infection, PSA may also rise because of systemic inflammation, which could have implications for PSA interpretation in older men.
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http://dx.doi.org/10.1002/ijc.29966DOI Listing
May 2016

Immediate Adjuvant Radiation Therapy Following Radical Prostatectomy Should Not Be Advised for Men with Extraprostatic Extension Who Have Negative Surgical Margins.

Eur Urol 2016 Feb 23;69(2):191-2. Epub 2015 Oct 23.

University of Melbourne, Department of Surgery and Olivia Newton-John Cancer Research Institute, Austin Hospital and Peter MacCallum Cancer Centre, Melbourne, Australia.

Although three large randomized prospective clinical trials have demonstrated that postoperative radiotherapy in patients with adverse pathological features reduces prostate-specific antigen recurrence and may decrease clinical failure, this approach has not gained widespread acceptance, likely because the data strongly support such an approach only in men with Gleason ≥7 with positive surgical margins.
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http://dx.doi.org/10.1016/j.eururo.2015.09.045DOI Listing
February 2016

Do Ultrasensitive Prostate Specific Antigen Measurements Have a Role in Predicting Long-Term Biochemical Recurrence-Free Survival in Men after Radical Prostatectomy?

J Urol 2016 Feb 22;195(2):330-6. Epub 2015 Aug 22.

James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Purpose: In this study we evaluate an ultrasensitive prostate specific antigen assay in patients with prostate cancer after radical prostatectomy to predict long-term biochemical recurrence-free survival.

Materials And Methods: A total of 754 men who underwent radical prostatectomy and had an undetectable prostate specific antigen after surgery (less than 0.1 ng/ml) were studied. Prostate specific antigen was measured in banked serum specimens with an ultrasensitive assay (Hybritech® PSA, Beckman Coulter Access® 2) using a cutoff of 0.01 ng/ml. Prostate specific antigen was also measured in 44 men after cystoprostatectomy who had no pathological evidence of prostate cancer with the Hybritech assay and with the Quanterix AccuPSA™ assay.

Results: Of the 754 men 17% (131) experienced biochemical recurrence (median 4.0 years). Those men without biochemical recurrence (83%, 623) had a minimum of 5 years of followup (median 11). Prostate specific antigen was less than 0.01 ng/ml in 93.4% of men with no biochemical recurrence, whereas 30.5% of men with biochemical recurrence had a prostate specific antigen of 0.01 ng/ml or greater. On multivariate analysis postoperative prostate specific antigen at a 0.01 ng/ml cutoff, pathological stage and Gleason score, and surgical margins were significant independent predictors of biochemical recurrence risk. Kaplan-Meier estimates for mean biochemical recurrence-free survival were 15.2 years (95% CI 14.9-15.6) for prostate specific antigen less than 0.01 ng/ml and 10.0 years (95% CI 8.4-11.5) for prostate specific antigen 0.01 ng/ml or greater (p <0.0001). Biochemical recurrence-free rates 11 years after surgery were 86.1% (95% CI 83.2-89.0) for prostate specific antigen less than 0.01 ng/ml and 48.9% (95% CI 37.5-60.3) for prostate specific antigen 0.01 ng/ml or greater (p <0.0001). Prostate specific antigen concentrations in 44 men after cystoprostatectomy were all less than 0.03 ng/ml, with 95.4% less than 0.01 ng/ml.

Conclusions: In men with a serum prostate specific antigen less than 0.1 ng/ml after radical prostatectomy a tenfold lower cutoff (0.01 ng/ml) stratified biochemical recurrence-free survival and was a significant independent predictor of biochemical recurrence, as were pathological features. Prostate specific antigen concentrations in men without pathological evidence of prostate cancer suggest that a higher prostate specific antigen concentration (0.03 ng/ml) in the ultrasensitive range may be needed to define the detection threshold.
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http://dx.doi.org/10.1016/j.juro.2015.08.080DOI Listing
February 2016

Utility of Risk Models in Decision Making After Radical Prostatectomy: Lessons from a Natural History Cohort of Intermediate- and High-Risk Men.

Eur Urol 2016 Mar 25;69(3):496-504. Epub 2015 Apr 25.

James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Background: Current guidelines suggest adjuvant radiation therapy for men with adverse pathologic features (APFs) at radical prostatectomy (RP). We examine at-risk men treated only with RP until the time of metastasis.

Objective: To evaluate whether clinicopathologic risk models can help guide postoperative therapeutic decision making.

Design, Setting, And Participants: Men with National Comprehensive Cancer Network intermediate- or high-risk localized prostate cancer undergoing RP in the prostate-specific antigen (PSA) era were identified (n=3089). Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis were included. APFs were defined as pT3 disease or positive surgical margins.

Outcome Measurements And Statistical Analysis: Area under the receiver operating characteristic curve (AUC) for time to event data was used to measure the discrimination performance of the risk factors. Cumulative incidence curves were constructed using Fine and Gray competing risks analysis to estimate the risk of biochemical recurrence (BCR) or metastasis, taking censoring and death due to other causes into consideration.

Results And Limitations: Overall, 43% of the cohort (n=1327) had APFs at RP. Median follow-up for censored patients was 5 yr. Cumulative incidence of metastasis was 6% at 10 yr after RP for all patients. Cumulative incidence of metastasis among men with APFs was 7.5% at 10 yr after RP. Among men with BCR, the incidence of metastasis was 38% 5 yr after BCR. At 10 yr after RP, time-dependent AUC for predicting metastasis by Cancer of the Prostate Risk Assessment Postsurgical or Eggener risk models was 0.81 (95% confidence interval [CI], 0.72-0.97) and 0.78 (95% CI, 0.67-0.97) in the APF population, respectively. At 5 yr after BCR, these values were lower (0.58 [95% CI, 0.50-0.66] and 0.70 [95% CI, 0.63-0.76]) among those who developed BCR. Use of risk model cut points could substantially reduce overtreatment while minimally increasing undertreatment (ie, use of an Eggener cut point of 2.5% for treatment of men with APFs would spare 46% from treatment while only allowing for metastatic events in 1% at 10 yr after RP).

Conclusions: Use of risk models reduces overtreatment and should be a routine part of patient counseling when considering adjuvant therapy. Risk model performance is significantly reduced among men with BCR.

Patient Summary: Use of current risk models can help guide decision making regarding therapy after surgery and reduce overtreatment.
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http://dx.doi.org/10.1016/j.eururo.2015.04.016DOI Listing
March 2016

Joseph J. Kaufman: renaissance man.

Urology 2015 Mar;85(3):487-90

Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

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http://dx.doi.org/10.1016/j.urology.2014.10.039DOI Listing
March 2015

The relationship between the extent of extraprostatic extension and survival following radical prostatectomy.

Eur Urol 2015 Feb 23;67(2):342-6. Epub 2014 Jun 23.

Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address:

Background: Subclassification of the extent of extraprostatic extension (EPE) in radical prostatectomy (RP) specimens may enhance prognostication for prostate cancer (PCa) patients. Yet optimal criteria for staging, validation within a large cohort, and long-term follow-up are lacking.

Objective: To compare biochemical recurrence-free survival (BRFS), PCa-specific survival (PCSS), and overall survival (OS) for focal EPE (pT3aF) and nonfocal EPE (pT3aNF) in a large tertiary-referral center with the Epstein criteria for EPE extent.

Design, Setting, And Participants: Between 1982 and 2012, 20 434 men underwent RP, and 15 565 men (76.2%) had available pathologic and survival data. A total of 4216 men with isolated EPE were subclassified into pT3aF (1869 men, 44%) and pT3aNF (2347 men, 56%).

Outcome Measurements And Statistical Analysis: Predictors of BRFS, PCSS, and OS were identified with multivariate Cox proportional hazard models. Covariates included age, preoperative prostate-specific antigen, body mass index, surgery year, Gleason score, and surgical margin status.

Results And Limitations: With a median follow-up of 9.0 yr (range: 1-27), 314 men died of PCa, with 1300 deaths from any cause. In a multivariate model, pT3aNF compared with pT3aF was an independent predictor of BRFS (hazard ratio [HR]: 1.39; 95% confidence interval [CI], 1.18-1.62; p<0.001), but not of PCSS (HR: 1.38; 95% CI, 0.89-2.11; p=0.146) or OS (HR: 1.13; 95% CI, 0.94-1.36; p=0.197). Ten-year BRFS, PCSS, and OS for pT3aF and pT3aNF were 76% versus 59%, 98% versus 96%, and 95% versus 90%, respectively.

Conclusions: In a large RP cohort, subclassification of EPE extent with the Epstein criteria improves correlation with BRFS. PCSS and OS in men with isolated EPE (pT3a) are excellent and are not significantly different between pT3aF and pT3aNF. The EPE extent should be subclassified to identify a subgroup of men with a higher risk of recurrence (pT3aNF) and to consider them for additional therapy.

Patient Summary: Subclassification of extraprostatic extension (EPE) with the Epstein criteria improves correlation with biochemical recurrence-free survival. Prostate cancer-specific survival and overall survival in men with isolated EPE (pT3a) are excellent and are not significantly different between pT3aF and pT3aNF.
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http://dx.doi.org/10.1016/j.eururo.2014.06.015DOI Listing
February 2015

Obesity and long-term survival after radical prostatectomy.

J Urol 2014 Oct 21;192(4):1100-4. Epub 2014 Apr 21.

James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, Seoul National University Boramae Hospital (SBL), Seoul, South Korea; Sungkyunkwan University Samsung Medical Center (BCJ), Seoul, South Korea; Duke University Medical Center, Durham, North Carolina (SJF). Electronic address:

Purpose: Obesity is a modifiable risk factor associated with worse outcomes for many cancers, yet implications for prostate cancer are not well understood. Notably the impact of body mass index on long-term survival after treatment is unclear. We performed a retrospective cohort study on a large series of men who underwent radical prostatectomy to assess the impact of obesity on long-term biochemical recurrence-free survival, prostate cancer specific survival and overall survival.

Materials And Methods: Between 1982 and 2012, 11,152 men underwent radical prostatectomy at a single tertiary referral center. Patients were stratified according to body mass index as normal weight (body mass index less than 25 kg/m(2)), overweight (body mass index 25 to less than 30 kg/m(2)), mild obesity (body mass index 30 to less than 35 kg/m(2)) and moderate/severe obesity (body mass index 35 kg/m(2) or greater), comprising 27.6%, 56.0%, 14.1% and 2.3% of the cohort, respectively. Covariates included age, preoperative prostate specific antigen, surgery year, Gleason score, pathological stage, surgical margin and race. Predictors of biochemical recurrence-free survival, prostate cancer specific survival and overall survival were identified using Cox proportional hazard models.

Results: Median followup was 5 years (range 1 to 27). Actuarial 20-year biochemical recurrence-free survival for mild and moderate/severe obesity was 65% and 51%, respectively, compared to 76% for normal weight men (p ≤0.001). In a multivariate model obesity was a significant predictor of biochemical recurrence-free survival (mild HR 1.30, p = 0.002; moderate/severe HR 1.45, p = 0.028) and overall survival (mild HR 1.41, p = 0.003; moderate/severe HR 1.81, p = 0.033). However, only mild obesity was significantly associated with prostate cancer specific survival (HR 1.51, p = 0.040), whereas moderate/severe obesity was not (HR 1.58, p = 0.356).

Conclusions: Obese men have higher rates of biochemical recurrence than normal weight patients during long-term followup. Obesity at the time of surgery independently predicts overall survival and biochemical recurrence-free survival but not prostate cancer specific survival.
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http://dx.doi.org/10.1016/j.juro.2014.04.086DOI Listing
October 2014