Publications by authors named "Bruce J Trock"

173 Publications

A comparative study of PCS and PAM50 prostate cancer classification schemes.

Prostate Cancer Prostatic Dis 2021 Feb 2. Epub 2021 Feb 2.

Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Two prostate cancer (PC) classification methods based on transcriptome profiles, a de novo method referred to as the "Prostate Cancer Classification System" (PCS) and a variation of the established PAM50 breast cancer algorithm, were recently proposed. Both studies concluded that most human PC can be assigned to one of three tumor subtypes, two categorized as luminal and one as basal, suggesting the two methods reflect consistency in underlying biology. Despite the similarity, differences and commonalities between the two classification methods have not yet been reported.

Methods: Here, we describe a comparison of the PCS and PAM50 classification systems. PCS and PAM50 signatures consisting of 37 (PCS37) and 50 genes, respectively, were used to categorize 9,947 PC patients into PCS and PAM50 classes. Enrichment of hallmark gene sets and luminal and basal marker gene expression were assessed in the same datasets. Finally, survival analysis was performed to compare PCS and PAM50 subtypes in terms of clinical outcomes.

Results: PCS and PAM50 subtypes show clear differential expression of PCS37 and PAM50 genes. While only three genes are shared in common between the two systems, there is some consensus between three subtype pairs (PCS1 versus Luminal B, PCS2 versus Luminal A, and PCS3 versus Basal) with respect to gene expression, cellular processes, and clinical outcomes. PCS categories displayed better separation of cellular processes and luminal and basal marker gene expression compared to PAM50. Although both PCS1 and Luminal B tumors exhibited the worst clinical outcomes, outcomes between aggressive and less aggressive subtypes were better defined in the PCS system, based on larger hazard ratios observed.

Conclusion: The PCS and PAM50 classification systems are similar in terms of molecular profiles and clinical outcomes. However, the PCS system exhibits greater separation in multiple clinical outcomes and provides better separation of prostate luminal and basal characteristics.
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http://dx.doi.org/10.1038/s41391-021-00325-4DOI Listing
February 2021

Use of the MyProstateScore Test to Rule Out Clinically Significant Cancer: Validation of a Straightforward Clinical Testing Approach.

J Urol 2021 Mar 20;205(3):732-739. Epub 2020 Oct 20.

Department of Urology, University of Michigan, Ann Arbor, Michigan.

Purpose: The MyProstateScore test was validated for improved detection of clinically significant (grade group ≥2) prostate cancer relative to prostate specific antigen based risk calculators. We sought to validate an optimal MyProstateScore threshold for clinical use in ruling out grade group ≥2 cancer in men referred for biopsy.

Materials And Methods: Biopsy naïve men provided post-digital rectal examination urine prior to biopsy. MyProstateScore was calculated using the validated, locked multivariable model including only serum prostate specific antigen, urinary prostate cancer antigen 3 and urinary TMPRSS2:ERG. The MyProstateScore threshold approximating 95% sensitivity for grade group ≥2 cancer was identified in a training cohort, and performance was measured in 2 external validation cohorts. We assessed the 1) overall biopsy referral population and 2) population meeting guideline based testing criteria (ie, prostate specific antigen 3-10, or <3 with suspicious digital rectal examination).

Results: Validation cohorts were prospectively enrolled from academic (977 patients, median prostate specific antigen 4.5, IQR 3.1-6.0) and community (548, median prostate specific antigen 4.9, IQR 3.7-6.8) settings. In the overall validation population (1,525 patients), 338 men (22%) had grade group ≥2 cancer on biopsy. The MyProstateScore threshold of 10 provided 97% sensitivity and 98% negative predictive value for grade group ≥2 cancer. MyProstateScore testing would have prevented 387 unnecessary biopsies (33%), while missing only 10 grade group ≥2 cancers (3.0%). In 1,242 patients meeting guideline based criteria, MyProstateScore ≤10 provided 96% sensitivity and 97% negative predictive value, and would have prevented 32% of unnecessary biopsies, missing 3.7% of grade group ≥2 cancers.

Conclusions: In a large, clinically pertinent biopsy referral population, MyProstateScore ≤10 provided exceptional sensitivity and negative predictive value for ruling out grade group ≥2 cancer. This straightforward secondary testing approach would reduce the use of more costly and invasive procedures after screening with prostate specific antigen.
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http://dx.doi.org/10.1097/JU.0000000000001430DOI Listing
March 2021

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

Clin Cancer Res 2021 Jan 9;27(1):320-329. Epub 2020 Oct 9.

Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institutes, Tampa, Florida.

Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).

Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.

Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICS) compared with 0 (37.8% vs. 21.9%, = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HR = 2.30; 95% confidence interval (CI), 1.21-4.34; = 0.01] and validation (HR = 2.42; 95% CI, 1.52-3.86; = 0.0001) but not in EAM.

Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2925DOI Listing
January 2021

Natural history of prostate cancer on active surveillance: stratification by MRI using the PRECISE recommendations in a UK cohort.

Eur Radiol 2021 Mar 30;31(3):1644-1655. Epub 2020 Sep 30.

Division of Surgery & Interventional Science, University College London, 3rd Floor, Charles Bell House, 43-45 Foley St., London, W1W 7TS, UK.

Objectives: The PRECISE recommendations for magnetic resonance imaging (MRI) in patients on active surveillance (AS) for prostate cancer (PCa) include repeated measurement of each lesion, and attribution of a PRECISE radiological progression score for the likelihood of clinically significant change over time. We aimed to compare the PRECISE score with clinical progression in patients who are managed using an MRI-led AS protocol.

Methods: A total of 553 patients on AS for low- and intermediate-risk PCa (up to Gleason score 3 + 4) who had two or more MRI scans performed between December 2005 and January 2020 were included. Overall, 2161 scans were retrospectively re-reported by a dedicated radiologist to give a PI-RADS v2 score for each scan and assess the PRECISE score for each follow-up scan. Clinical progression was defined by histological progression to ≥ Gleason score 4 + 3 (Gleason Grade Group 3) and/or initiation of active treatment. Progression-free survival was assessed using Kaplan-Meier curves and log-rank test was used to assess differences between curves.

Results: Overall, 165/553 (30%) patients experienced the primary outcome of clinical progression (median follow-up, 74.5 months; interquartile ranges, 53-98). Of all patients, 313/553 (57%) did not show radiological progression on MRI (PRECISE 1-3), of which 296/313 (95%) had also no clinical progression. Of the remaining 240/553 patients (43%) with radiological progression on MRI (PRECISE 4-5), 146/240 (61%) experienced clinical progression (p < 0.0001). Patients with radiological progression on MRI (PRECISE 4-5) showed a trend to an increase in PSA density.

Conclusions: Patients without radiological progression on MRI (PRECISE 1-3) during AS had a very low likelihood of clinical progression and many could avoid routine re-biopsy.

Key Points: • Patients without radiological progression on MRI (PRECISE 1-3) during AS had a very low likelihood of clinical progression and many could avoid routine re-biopsy. • Clinical progression was almost always detectable in patients with radiological progression on MRI (PRECISE 4-5) during AS. • Patients with radiological progression on MRI (PRECISE 4-5) during AS showed a trend to an increase in PSA density.
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http://dx.doi.org/10.1007/s00330-020-07256-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880925PMC
March 2021

Genomic and Clinicopathologic Characterization of -deficient Prostate Cancer.

Clin Cancer Res 2020 Sep 21;26(18):4869-4881. Epub 2020 Jul 21.

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.

Purpose: The (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized.

Experimental Design: We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes.

Results: ATM protein loss was found in 13% (7/52) of primary Gleason pattern 5 cancers with available sequencing data and was 100% sensitive for biallelic inactivation. In a separate cohort with pathogenic germline mutations, 74% (14/19) had ATM protein loss of which 70% (7/10) of evaluable cases had genomic evidence of biallelic inactivation, compared with zero of four of cases with intact ATM expression. By TMA screening, ATM loss was identified in 3% (25/831) of evaluable primary tumors, more commonly in grade group 5 (17/181; 9%) compared with all other grades (8/650; 1%; < 0.0001). Of those with available sequencing, 80% (4/5) with homogeneous ATM protein loss and 50% (6/12) with heterogeneous ATM protein loss had detectable pathogenic alterations. In surgically treated patients, ATM loss was not significantly associated with clinical outcomes in random-effects Cox models after adjusting for clinicopathologic variables.

Conclusions: ATM loss is enriched among high-grade prostate cancers. Optimal evaluation of ATM status requires both genomic and IHC studies and will guide development of molecularly targeted therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501149PMC
September 2020

Effect of Pharmacologic Prophylaxis on Venous Thromboembolism After Radical Prostatectomy: The PREVENTER Randomized Clinical Trial.

Eur Urol 2020 09 19;78(3):360-368. Epub 2020 May 19.

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

Background: Direct high-quality evidence is lacking evaluating perioperative pharmacologic prophylaxis (PP) after radical prostatectomy (RP) to prevent venous thromboembolism (VTE) leading to significant practice variation.

Objective: To study the impact of in-hospital PP on symptomatic VTE incidence and adverse events after RP at 30 d, with the secondary objective of evaluating overall VTE in a screening subcohort.

Design, Setting, And Participants: A prospective, phase 4, single-center, randomized trial of men with prostate cancer undergoing open or robotic-assisted laparoscopic RP was conducted (July 2017-November 2018).

Intervention: PP (subcutaneous heparin) plus routine care versus routine care alone. The screening subcohort was offered lower extremity duplex ultrasound at 30 d.

Outcomes Measurements And Statistical Analysis: The primary efficacy outcome was symptomatic VTE incidence (pulmonary embolism [PE] or deep venous thrombosis [DVT]). Primary safety outcomes included the incidence of symptomatic lymphocele, hematoma, or bleeding after surgery. Secondary outcomes were overall VTE, estimated blood loss, total surgical drain output, complications, and surveillance imaging bias. Fisher's exact test and modified Poisson regression were performed.

Results And Limitations: A total of 501 patients (75% robotic) were randomized and >99% (500/501) completed follow-up. At second interim analysis (N = 445), the symptomatic VTE rate was 2.3% (four PE + DVT and one DVT) for routine care versus 0.9% (one PE + DVT and one DVT) for PP (relative risk 0.40 [95% confidence interval 0.08-2.03], p = 0.3) meeting a futility threshold for early stopping. In the screening subcohort, the overall VTE rate was 3.3% versus 2.4% (p = 0.7). Results were similar at the final analysis (symptomatic VTE: 2.0% vs 0.8%, p = 0.3; overall VTE: 2.9% vs 2.8%, p = 1). No differences were observed in safety or secondary outcomes. All VTE events (seven symptomatic and three asymptomatic) occurred in patients undergoing pelvic lymph node dissection.

Conclusions: This study was not able to demonstrate a statistically significant reduction in symptomatic VTE associated with PP. There was no increase in the development of symptomatic lymphoceles, bleeding, or other adverse events. Given that the event rate was lower than powered for, further research is needed among high-risk patients (Caprini score ≥8) or patients receiving pelvic lymph node dissection.

Patient Summary: In this report, we randomized patients undergoing radical prostatectomy to perioperative pharmacologic prophylaxis or routine care alone. We found that pharmacologic prophylaxis did not reduce postoperative symptomatic venous thromboembolism significantly for men at routine risk. Importantly, pharmacologic prophylaxis did not increase adverse events, such as formation of lymphoceles or bleeding, and can safely be implemented when indicated for patients with risk factors undergoing radical prostatectomy.
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http://dx.doi.org/10.1016/j.eururo.2020.05.001DOI Listing
September 2020

Performance of clinicopathologic models in men with high risk localized prostate cancer: impact of a 22-gene genomic classifier.

Prostate Cancer Prostatic Dis 2020 12 30;23(4):646-653. Epub 2020 Mar 30.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.

Background: Prostate cancer exhibits biological and clinical heterogeneity even within established clinico-pathologic risk groups. The Decipher genomic classifier (GC) is a validated method to further risk-stratify disease in patients with prostate cancer, but its performance solely within National Comprehensive Cancer Network (NCCN) high-risk disease has not been undertaken to date.

Methods: A multi-institutional retrospective study of 405 men with high-risk prostate cancer who underwent primary treatment with radical prostatectomy (RP) or radiation therapy (RT) with androgen-deprivation therapy (ADT) at 11 centers from 1995 to 2005 was performed. Cox proportional hazards models were used to determine the hazard ratios (HR) for the development of metastatic disease based on clinico-pathologic variables, risk groups, and GC score. The area under the receiver operating characteristic curve (AUC) was determined for regression models without and with the GC score.

Results: Over a median follow-up of 82 months, 104 patients (26%) developed metastatic disease. On univariable analysis, increasing GC score was significantly associated with metastatic disease ([HR]: 1.34 per 0.1 unit increase, 95% confidence interval [CI]: 1.19-1.50, p < 0.001), while age, serum PSA, biopsy GG, and clinical T-stage were not (all p > 0.05). On multivariable analysis, GC score (HR: 1.33 per 0.1 unit increase, 95% CI: 1.19-1.48, p < 0.001) and GC high-risk (vs low-risk, HR: 2.95, 95% CI: 1.79-4.87, p < 0.001) were significantly associated with metastasis. The addition of GC score to regression models based on NCCN risk group improved model AUC from 0.46 to 0.67, and CAPRA from 0.59 to 0.71.

Conclusions: Among men with high-risk prostate cancer, conventional clinico-pathologic data had poor discrimination to risk stratify development of metastatic disease. GC score was a significant and independent predictor of metastasis and may help identify men best suited for treatment intensification/de-escalation.
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http://dx.doi.org/10.1038/s41391-020-0226-2DOI Listing
December 2020

The incidence, predictors, and survival of disappearing small renal masses on active surveillance.

Urol Oncol 2020 02 6;38(2):42.e1-42.e6. Epub 2019 Nov 6.

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

Objective: To evaluate the incidence, predictors, and survival for those small renal masses (SRM, solid mass ≤4 cm suspicious for a clinical T1a renal cell carcinoma) that disappear on imaging while undergoing active surveillance (AS).

Subjects/patients And Methods: The Delayed Intervention and Surveillance for SRM registry prospectively enrolled 739 patients with SRMs. Patients having at least 1 image showing no lesion were considered to have a "disappearing" SRM. Logistic regression assessed predictors of having a disappearing SRM and Kaplan-Meier estimates illustrated relative survival.

Results: Of 374 patients enrolled in AS, 22 (5.9%) experienced a disappearing SRM. Mean time to tumor disappearance was 2.0 years (SD = 1.9) and 50.0% reappeared on subsequent CT imaging. SRM disappearance, most commonly encountered on ultrasound imaging surveillance, was independently associated with tumors <1 cm on multivariable analysis (OR = 10.6 (95% CI: 1.1-100.3), P = 0.04). Furthermore, patients with disappearing SRMs were healthier than other patients on AS with no compromise in overall survival during follow-up (5-year survival = 100% vs. 73.2%, P = 0.06).

Conclusions: Approximately 5% of SRM on AS will disappear during follow-up on surveillance imaging. Most of these represent artifacts of heterogeneous imaging modalities, including ultrasound, and the SRM will reappear on subsequent imaging. Given the indolent nature of these lesions, disappearance events do not require reflex repeat imaging and patients should continue AS with their original surveillance schedule intact. A smaller percentage of patients undergoing AS for a SRM may have a mass the permanently disappears.
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http://dx.doi.org/10.1016/j.urolonc.2019.10.005DOI Listing
February 2020

Prostate cancer mortality and metastasis under different biopsy frequencies in North American active surveillance cohorts.

Cancer 2020 02 22;126(3):583-592. Epub 2019 Oct 22.

Department of Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Active surveillance (AS) is an accepted means of managing low-risk prostate cancer. Because of the rarity of downstream events, data from existing AS cohorts cannot yet address how differences in surveillance intensity affect metastasis and mortality. This study projected the comparative benefits of different AS schedules in men diagnosed with prostate cancer who had Gleason score (GS) ≤6 disease and risk profiles similar to those in North American AS cohorts.

Methods: Times of GS upgrading were simulated based on AS data from the University of Toronto, Johns Hopkins University, the University of California at San Francisco, and the Canary Pass Active Surveillance Cohort. Times to metastasis and prostate cancer death, informed by models from the Scandinavian Prostate Cancer Group 4 trial, were projected under biopsy surveillance schedules ranging from watchful waiting to annual biopsies. Outcomes included the risk of metastasis, the risk of death, remaining life-years (LYs), and quality-adjusted LYs.

Results: Compared with watchful waiting, AS biopsies reduced the risk of prostate cancer metastasis and prostate cancer death at 20 years by 1.4% to 3.3% and 1.0% to 2.4%, respectively; and 5-year biopsies reduced the risk of metastasis and prostate cancer death by 1.0% to 2.4% and 0.6% to 1.6%, respectively. There was little difference between annual and 5-year biopsy schedules in terms of LYs (range of differences, 0.04-0.16 LYs) and quality-adjusted LYs (range of differences, -0.02 to 0.09 quality-adjusted LYs).

Conclusions: Among men diagnosed with GS ≤6 prostate cancer, obtaining a biopsy every 3 or 4 years appears to be an acceptable alternative to more frequent biopsies. Reducing surveillance intensity for those who have a low risk of progression reduces the number of biopsies while preserving the benefit of more frequent schedules.
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http://dx.doi.org/10.1002/cncr.32557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980275PMC
February 2020

A pilot trial of pembrolizumab plus prostatic cryotherapy for men with newly diagnosed oligometastatic hormone-sensitive prostate cancer.

Prostate Cancer Prostatic Dis 2020 03 14;23(1):184-193. Epub 2019 Oct 14.

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

Background: Monotherapy with immune checkpoint inhibitors has generally been unsuccessful in men with advanced prostate cancer. Preclinical data support the notion that cryotherapy may improve immune-mediated and anti-tumor responses. The objective of this study was to assess the safety and feasibility of whole-prostate gland cryotherapy combined with pembrolizumab and androgen deprivation in men with oligometastatic hormone-sensitive prostate cancer.

Methods: This single-institution, pilot trial recruited 12 patients with newly diagnosed oligometastatic prostate cancer between 2015 and 2016. Patients underwent whole-prostate cryoablation combined with short-term androgen deprivation (eight months) and pembrolizumab (6 doses). The primary clinical endpoints were the number of patients with a PSA level of <0.6 ng/mL at one year and the frequency of adverse events. Other outcome measures included progression-free survival and systemic therapy-free survival. Exploratory analyses included PD-L1 protein expression.

Results: Forty two percent (5/12) of patients had a PSAs of <0.6 ng/mL at one year though only 2 of these patients had recovered their testosterone at this time point. Median progression-free survival was 14 months, and median systemic therapy-free survival was 17.5 months. PD-L1 expression was not detectable by IHC in patients with evaluable tissue. All adverse events were grade ≤2, and there were no apparent complications from cryotherapy.

Conclusions: Whole-prostate cryoablation combined with short-term androgen deprivation and pembrolizumab treatment was well tolerated and no safety concerns were observed in men with oligometastatic prostate cancer. Though local disease appeared effectively treated in the majority of men, the regimen only infrequency led to sustained disease control following testosterone recovery.
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http://dx.doi.org/10.1038/s41391-019-0176-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031012PMC
March 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

Prospective Comparison of PET Imaging with PSMA-Targeted F-DCFPyL Versus NaF for Bone Lesion Detection in Patients with Metastatic Prostate Cancer.

J Nucl Med 2020 02 26;61(2):183-188. Epub 2019 Aug 26.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Bone metastases in prostate cancer (PCa) have important prognostic significance, and imaging modalities used for PCa staging should have high sensitivity for detecting such lesions. Prostate-specific membrane antigen (PSMA)-targeted PET radiotracers are promising new agents for imaging PCa. We undertook a head-to-head comparison of PSMA-targeted 2-(3-{1-carboxy-5-[(6-F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (F-DCFPyL) PET to NaF PET to determine which modality was more sensitive for the detection of lesions suggestive of bone metastases in a group of patients with metastatic PCa. Patients with progressive, metastatic PCa were prospectively imaged with both F-DCFPyL and NaF PET/CT, with both scans occurring within 24 h of each other. A consensus 2-reader central review was performed to identify all bone lesions suggestive of sites of PCa involvement on both scans, and maximized SUVs corrected for body weight (SUV) and lean body mass (SUL) were recorded. Soft-tissue lesions were also noted on both scans, and SUV, SUL, and PSMA reporting and data system (RADS) version 1.0 scores were recorded. Data from the 2 scans were compared using a generalized estimating equation. In total, 16 patients meeting all inclusion criteria were enrolled in this study, and 15 of the 16 (93.8%) were imaged with both PET radiotracers. In total, 405 bone lesions suggestive of sites of PCa were identified on at least 1 scan. On F-DCFPyL PET/CT, 391 (96.5%) were definitively positive, 4 (1.0%) were equivocally positive, and 10 (2.5%) were negative. On NaF PET/CT, the corresponding values were 388 (95.8%), 4 (1.0%), and 13 (3.2%). Of the definitively negative lesions on F-DCFPyL PET, 8 of 10 (80.0%) were sclerotic and 2 of 10 (20.0%) were infiltrative or marrow-based. Additionally, 12 of 13 (92.3%) of the definitively negative lesions on NaF PET were infiltrative or marrow-based and 1 of 13 (7.7%) was lytic. Also identified were 78 PSMA-RADS-4, 17 PSMA-RADS-5, and 1 PSMA-RADS-3C soft-tissue lesions. PET/CT imaging using F-DCFPyL and NaF PET had nearly identical sensitivities for the detection of bone lesions in patients with metastatic PCa. As would be expected, PSMA-targeted PET provides more information on soft-tissue disease. There may be little additional value to imaging PCa patients with NaF after a PSMA-targeted PET scan has already been performed.
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http://dx.doi.org/10.2967/jnumed.119.227793DOI Listing
February 2020

Genetic Alterations Detected in Cell-Free DNA Are Associated With Enzalutamide and Abiraterone Resistance in Castration-Resistant Prostate Cancer.

JCO Precis Oncol 2019 3;3. Epub 2019 Apr 3.

Johns Hopkins School of Medicine, Baltimore, MD.

Purpose: Androgen receptor () gene alterations, including ligand-binding domain mutations and copy number (CN) gain, have yet to be fully established as predictive markers of resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). The goal of this study was to validate gene alterations detected in cell-free DNA (cfDNA) as markers of enzalutamide and abiraterone resistance in patients with mCRPC.

Methods: Patients with mCRPC (N = 62) were prospectively enrolled between 2014 and 2018. Blood was collected before therapies-enzalutamide (n = 25), abiraterone (n = 35), or enzalutamide and abiraterone (n -and at disease progression. We used deep next-generation sequencing to analyze cfDNA for sequence variants and CN status in and 45 additional cancer-associated genes. Primary end points were prostate-specific antigen response, progression-free survival (PFS), and overall survival (OS).

Results: Elevated tumor-specific cfDNA (circulating tumor DNA) was associated with a worse prostate-specific antigen response (hazard ratio [HR], 3.17; 95% CI, 1.11 to 9.05; = .031), PFS (HR, 1.76; 95% CI, 1.03 to 3.01; .039), and OS (HR, 2.92; 95% CI, 1.40 to 6.11; .004). ligand-binding domain missense mutations (HR, 2.51; 95% CI, 1.15 to 5.72; = .020) were associated with a shorter PFS in multivariable models. CN gain was associated with a shorter PFS; however, significance was lost in multivariable modeling. Genetic alterations in tumor protein p53 (HR, 2.70; 95% CI, 1.27 to 5.72; .009) and phosphoinositide 3-kinase pathway defects (HR, 2.62; 95% CI, 1.12 to 6.10; .026) were associated with a worse OS in multivariable models.

Conclusion: These findings support the conclusion that high circulating tumor DNA burden is associated with worse outcomes to enzalutamide and abiraterone in men with mCRPC. Tumor protein p53 loss and phosphoinositide 3-kinase pathway defects were associated with worse OS in men with mCRPC. status associations with outcomes were not robust, and additional validation is needed.
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http://dx.doi.org/10.1200/PO.18.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532665PMC
April 2019

The dual-staged pathway for closure in cloacal exstrophy: Successful evolution in collaborative surgical practice.

J Pediatr Surg 2019 Sep 8;54(9):1761-1765. Epub 2019 Apr 8.

Robert D. Jeffs Division of Pediatric Urology, James Buchanan Brady Urological Institutions, Johns Hopkins Hospital, Johns Hopkins Medical Institutions, Charlotte Bloomberg Children's Hospital, Baltimore, MD, USA. Electronic address:

Introduction: A successful abdominal wall and bladder closure is critical in the management of cloacal exstrophy (CE). This study examines closure outcomes and practices over the last 4 decades at the authors' institution. Beginning in 1995, the authors' institution standardized CE closure and management with the Dual-Staged Pathway (DSP). The DSP consists of a staged bladder closure, a staged or concurrent osteotomy, and postoperative immobilization with external fixation. The authors hypothesize that the DSP has provided better outcomes in CE closures.

Methods: A prospective database of 1332 Exstrophy-Epispadias Complex (EEC) patients was reviewed for CE patients closed between 1975 and 2015. The DSP consists of a staged osteotomy and a staged bladder closure in CE patients with a diastasis greater than 4 cm. To evaluate the DSP, outcomes of closure at the authors' institution were compared between two equal, twenty-year periods before and after its implementation. Data on timing of closure, postoperative management, surgical complications, and outcomes were collected.

Results: There are 142 CE patients in the database. In this study, 49 CE patients with 50 closures met inclusion criteria. The overall success rate of closures from 1975 to 1994 was 88% (14 of 16), while the success rate of the DSP was 100% (n = 34), p = 0.098. Twenty-two (65%) primary and 12 (35%) secondary closures were performed using the DSP. Overall complication rates of the DSP remained similar to previous closures, (29% vs 19%, p = 0.508). Since incorporation of the DSP, patients referred for closure have generally had a larger preclosure diastasis (7.2 cm vs 5.1 cm, p = 0.011).

Conclusion: The standardized DSP closure has proven successful in 34 primary and reoperative cloacal closures in the past 20 years. With this approach, the authors feel that the DSP offers greater patient safety and better outcomes.

Level Of Evidence: Level III, retrospective comparative study.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.01.005DOI Listing
September 2019

Meta-analysis of randomized controlled trials that assess the efficacy of low-intensity shockwave therapy for the treatment of erectile dysfunction.

Ther Adv Urol 2019 Jan-Dec;11:1756287219838364. Epub 2019 Mar 29.

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

Background: The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) that evaluate the efficacy of low-intensity extracorporeal shock wave therapy (LiESWT) for the treatment of erectile dysfunction (ED).

Materials And Methods: A comprehensive search of , and databases was performed from November 2005 to July 2018. RCTs evaluating efficacy of LiESWT in the treatment of ED were selected. The primary outcomes were the mean difference between treatment and sham patients in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score 1 month after treatment, and the mean change in IIEF-EF from baseline to 1 month post-treatment. The secondary analysis considered the percentage of men whose erectile hardness score (EHS) changed from <2 at baseline to >3 after treatment. All analyses used a random effects method to pool study-specific results.

Results: A total of seven RCTs provided data for 607 patients. The mean IIEF-EF 1 month post-treatment ranged from 12.8 to 22.0 in the treatment group 8.17-16.43 in the sham group. The mean difference between the treatment and sham groups at the 1 month follow up was a statistically significant increase in IIEF-EF of 4.23 ( = 0.012). Overall, five of the seven trials provided data on the proportion of patients with baseline EHS <2 who improved to EHS >3 at 1 month post-treatment. The proportions ranged from 3.5 to 90% in the treatment group 0-9% in the sham group and the pooled relative risk of EHS improvement for the treated sham group was 6.63 ( = 0.0095). No significant adverse events were reported.

Conclusions: This is the first meta-analysis that evaluates RCTs exploring LiESWT as a treatment modality strictly for ED. This therapeutic strategy appears to be well tolerated with short-term benefits. However further studies exploring specific treatment regimens and long-term outcomes are needed.
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http://dx.doi.org/10.1177/1756287219838364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444401PMC
March 2019

ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer.

Cancer Cell 2019 03 14;35(3):401-413.e6. Epub 2019 Feb 14.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:

Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7.
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http://dx.doi.org/10.1016/j.ccell.2019.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246081PMC
March 2019

ESTIMATING AND COMPARING CANCER PROGRESSION RISKS UNDER VARYING SURVEILLANCE PROTOCOLS.

Ann Appl Stat 2018 Sep 11;12(3):1773-1795. Epub 2018 Sep 11.

Fred Hutchinson Cancer Research Center.

Outcomes after cancer diagnosis and treatment are often observed at discrete times via doctor-patient encounters or specialized diagnostic examinations. Despite their ubiquity as endpoints in cancer studies, such outcomes pose challenges for analysis. In particular, comparisons between studies or patient populations with different surveillance schema may be confounded by differences in visit frequencies. We present a statistical framework based on multistate and hidden Markov models that represents events on a continuous time scale given data with discrete observation times. To demonstrate this framework, we consider the problem of comparing risks of prostate cancer progression across multiple active surveillance cohorts with different surveillance frequencies. We show that the different surveillance schedules partially explain observed differences in the progression risks between cohorts. Our application permits the conclusion that differences in underlying cancer progression risks across cohorts persist after accounting for different surveillance frequencies.
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http://dx.doi.org/10.1214/17-AOAS1130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322848PMC
September 2018

Validation of the Decipher Test for predicting adverse pathology in candidates for prostate cancer active surveillance.

Prostate Cancer Prostatic Dis 2019 09 12;22(3):399-405. Epub 2018 Dec 12.

University of Calgary, Calgary, AB, Canada.

Abstact: BACKGROUND: Many men diagnosed with prostate cancer are active surveillance (AS) candidates. However, AS may be associated with increased risk of disease progression and metastasis due to delayed therapy. Genomic classifiers, e.g., Decipher, may allow better risk-stratify newly diagnosed prostate cancers for AS.

Methods: Decipher was initially assessed in a prospective cohort of prostatectomies to explore the correlation with clinically meaningful biologic characteristics and then assessed in diagnostic biopsies from a retrospective multicenter cohort of 266 men with National Comprehensive Cancer Network (NCCN) very low/low and favorable-intermediate risk prostate cancer. Decipher and Cancer of the Prostate Risk Assessment (CAPRA) were compared as predictors of adverse pathology (AP) for which there is universal agreement that patients with long life-expectancy are not suitable candidates for AS (primary pattern 4 or 5, advanced local stage [pT3b or greater] or lymph node involvement).

Results: Decipher from prostatectomies was significantly associated with adverse pathologic features (p-values < 0.001). Decipher from the 266 diagnostic biopsies (64.7% NCCN-very-low/low and 35.3% favorable-intermediate) was an independent predictor of AP (odds ratio 1.29 per 10% increase, 95% confidence interval [CI] 1.03-1.61, p-value 0.025) when adjusting for CAPRA. CAPRA area under curve (AUC) was 0.57, (95% CI 0.47-0.68). Adding Decipher to CAPRA increased the AUC to 0.65 (95% CI 0.58-0.70). NPV, which determines the degree of confidence in the absence of AP for patients, was 91% (95% CI 87-94%) and 96% (95% CI 90-99%) for Decipher thresholds of 0.45 and 0.2, respectively. Using a threshold of 0.2, Decipher was a significant predictor of AP when adjusting for CAPRA (p-value 0.016).

Conclusion: Decipher can be applied to prostate biopsies from NCCN-very-low/low and favorable-intermediate risk patients to predict absence of adverse pathologic features. These patients are predicted to be good candidates for active surveillance.
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http://dx.doi.org/10.1038/s41391-018-0101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760567PMC
September 2019

Low Tristetraprolin Expression Is Associated with Lethal Prostate Cancer.

Cancer Epidemiol Biomarkers Prev 2019 03 12;28(3):584-590. Epub 2018 Nov 12.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Inflammation is linked to prostate cancer progression and is mediated by NF-κB. Tristetraprolin is a key node of NF-κB activation and we investigated its biological and prognostic role in lethal prostate cancer.

Methods: assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal prostate cancer (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians' Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and Memorial Sloan Kettering Cancer Center. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration-resistant prostate cancer (mCRPC) were assessed in a Cornell University cohort.

Results: tristetraprolin expression was inversely associated with NF-κB-controlled genes, proliferation, and enzalutamide sensitivity. Men with localized prostate cancer and lower quartile of tumor tristetraprolin expression had a significant, nearly two-fold higher risk of lethal prostate cancer after adjusting for known clinical and histologic prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized prostate cancer.

Conclusions: Lower levels of tristetraprolin in human prostate cancer prostatectomy tissue are associated with more aggressive prostate cancer and may serve as an actionable prognostic and predictive biomarker.

Impact: There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized prostate cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494092PMC
March 2019

Distinct transcriptional repertoire of the androgen receptor in ETS fusion-negative prostate cancer.

Prostate Cancer Prostatic Dis 2019 05 26;22(2):292-302. Epub 2018 Oct 26.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Background: Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients. ETS+ PCa express high levels of the androgen receptor (AR), yet PCa tumors lacking ETS fusions (ETS-) also express AR and demonstrate androgen-regulated growth. In this study, we evaluate the differences in the AR-regulated transcriptomes between ETS+ and ETS- PCa tumors.

Methods: 10,608 patient tumors from three independent PCa datasets classified as ETS+ (samples overexpressing ERG or other ETS family members) or ETS- (all other PCa) were analyzed for differential gene expression using false-discovery-rate adjusted methods and gene-set enrichment analysis (GSEA).

Results: Based on the expression of AR-dependent genes and an unsupervised Principal Component Analysis (PCA) model, AR-regulated gene expression alone was able to separate PCa samples into groups based on ETS status in all PCa databases. ETS status distinguished several differentially expressed genes in both TCGA (6.9%) and GRID (6.6%) databases, with 413 genes overlapping in both databases. Importantly, GSEA showed enrichment of distinct androgen-responsive genes in both ETS- and ETS+ tumors, and AR ChIP-seq data identified 131 direct AR-target genes that are regulated in an ETS-specific fashion. Notably, dysregulation of ETS-dependent AR-target genes within the metabolic and non-canonical WNT pathways was associated with clinical outcomes.

Conclusions: ETS status influences the transcriptional repertoire of the AR, and ETS- PCa tumors appear to rely on distinctly different AR-dependent transcriptional programs to drive and sustain tumorigenesis.
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http://dx.doi.org/10.1038/s41391-018-0103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760558PMC
May 2019

Effect of Preanalytic Variables on an Automated PTEN Immunohistochemistry Assay for Prostate Cancer.

Arch Pathol Lab Med 2019 03 8;143(3):338-348. Epub 2018 Oct 8.

From the Departments of Pathology (Drs Guedes, Morais, Fedor, Hicks, Gurel, De Marzo, and Lotan), Oncology (Drs Trock, De Marzo, and Lotan), and Urology (Drs Trock and De Marzo), Johns Hopkins University School of Medicine, Baltimore, Maryland; the Department of Pathology, New York University School of Medicine, New York, New York (Drs Melamed and Lee); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Drs Gopalan and Fine); the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California (Dr Knudsen); the Department of Pathology, University of Washington, Seattle (Dr True); and Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York (Dr Scher).

Context.—: Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predictive biomarker in prostate cancer.

Objective.—: To assess the effects of preanalytic variables on an analytically validated and fully automated PTEN immunohistochemistry assay.

Design.—: PTEN immunohistochemistry was performed on Ventana immunostaining systems. In benign prostate tissues, immunostaining intensity across variable conditions was assessed by digital image analysis. In prostate tumor tissues, immunostaining was scored visually.

Results.—: Delay of fixation for 4 hours or longer at room temperature or 48 hours or longer at 4°C and duration of formalin fixation did not significantly alter immunostaining intensity. Intensity of staining was highest in 10% formalin compared with other fixatives. Tumor tissues with PTEN loss processed using protocols from 11 academic institutions were all evaluable and scored identically. PTEN immunostaining of needle biopsies where tissue blocks had been stored for less than 10 years was more frequently scored as nonevaluable compared with blocks that had been stored for 10 years or longer. This effect was less evident for radical prostatectomy specimens, where low rates of nonevaluable staining were seen for 23 years or more of storage. Storage of unstained slides for 5 years at room temperature prior to immunostaining resulted in equivalent scoring compared with freshly cut slides. Machine-to-machine variability assessed across 3 Ventana platforms and 2 institutions was negligible in 12 tumors, and platform-to-platform variability was also minor comparing Ventana and Leica instruments across 77 tumors (κ = 0.926).

Conclusions.—: Automated PTEN immunostaining is robust to most preanalytic variables in the prostate and may be performed on prostate tumor tissues subjected to a wide range of preanalytic conditions. These data may help guide assay development if PTEN becomes a key predictive biomarker.
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http://dx.doi.org/10.5858/arpa.2018-0068-OADOI Listing
March 2019

PTEN status assessment in the Johns Hopkins active surveillance cohort.

Prostate Cancer Prostatic Dis 2019 03 2;22(1):176-181. Epub 2018 Oct 2.

Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: Up to half of men with Gleason score 6 (GS6) prostate cancers initially managed with active surveillance (AS) will eventually require definitive therapy, usually due to tumor grade reclassification during follow-up. We examined the association between PTEN status on biopsy and subsequent clinicopathologic outcomes in men with GS6 cancers who enrolled in AS.

Methods: We performed a case-control study of men enrolled in the Johns Hopkins AS cohort with diagnostic biopsy tissue available for immunohistochemical (IHC) staining. IHC was performed for PTEN using genetically validated protocols for all patients. Cases included men who underwent grade reclassification to GS ≥ 3 + 4 = 7 on biopsy within 2 years of follow-up (i.e., early reclassification) or reclassification to GS ≥ 4 + 3 = 7 on biopsy or radical prostatectomy during follow-up (i.e., extreme reclassification). Control patients were diagnosed with GS6 cancer and monitored on AS for at least 8 years without undergoing biopsy reclassification.

Results: Among 67 cases with adequate tissue, 31 men underwent early reclassification and 36 men underwent extreme reclassification. Cases were compared to 65 control patients with adequate tissue for assessment. On initial prostate biopsy, cases were older (median age 67 vs. 65, p = 0.024) and were less likely to meet very-low-risk criteria (64 vs 79%, p = 0.042) as compared to controls. Although not statistically significant, PTEN loss was observed in only 1 (1.5%) of 65 controls as compared to 6 (9%) of 67 cases (p = 0.062).

Conclusions: PTEN loss was rare among men with GS6 prostate cancer enrolled in AS at Johns Hopkins. Despite this, PTEN loss was more frequent among men who underwent early or extreme reclassification to higher-grade cancer as compared to controls. Additional studies in larger low-risk cohorts may better elucidate a potential role for PTEN in selecting patients for AS.
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http://dx.doi.org/10.1038/s41391-018-0093-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372343PMC
March 2019

Older Age Predicts Biopsy and Radical Prostatectomy Grade Reclassification to Aggressive Prostate Cancer in Men on Active Surveillance.

J Urol 2019 01;201(1):98-104

Purpose: Age at prostate cancer diagnosis has been positively associated with prostate cancer specific mortality and in men on active surveillance with a higher risk of biopsy grade reclassification to Gleason score 3 + 4 or greater (Grade Group 2 or greater). However, to our knowledge the association between age and biopsy grade reclassification to an aggressive phenotype (Gleason score 4 + 3 or greater [Grade Group 3 or greater]) has not been explored.

Materials And Methods: From 1995 to 2016 we followed 1,625 men 41 to 81 years old with NCCN® (National Comprehensive Cancer Network®) very low (68%) or low (32%) risk prostate cancer on active surveillance. We determined the rate of biopsy grade reclassification to Grade Group 3 or greater. Competing risk analysis was applied to evaluate the association between age at enrollment and the risk of biopsy grade reclassification. Additionally, in men who underwent radical prostatectomy after biopsy grade reclassification we assessed the rate of radical prostatectomy grade reclassification (ie radical prostatectomy Grade Group greater than biopsy Grade Group).

Results: The 5-year incidence of biopsy grade reclassification to Grade Group 3 or greater was 4%, 7% and 14% in men younger than 60, 60 to 69 and 70 years old or older, respectively (p <0.001). On univariate analysis older age was associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.43, p <0.001). On multivariable analysis adjusting for year of diagnosis, race, prostate specific antigen density and cancer volume at diagnosis older age remained associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.19, p <0.001). In men who underwent radical prostatectomy after biopsy grade reclassification those who were older had a higher rate of radical prostatectomy grade reclassification (p <0.05).

Conclusions: In men on active surveillance older age at diagnosis was positively associated with biopsy grade reclassification to Grade Group 3 or greater and radical prostatectomy grade reclassification. These observations imply that for many older men, active surveillance as opposed to watchful waiting remains a more appropriate management strategy.
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http://dx.doi.org/10.1016/j.juro.2018.08.023DOI Listing
January 2019

Clinical utility of assessing PTEN and ERG protein expression in prostate cancer patients: a proposed method for risk stratification.

J Cancer Res Clin Oncol 2018 Nov 12;144(11):2117-2125. Epub 2018 Aug 12.

Brady Urological Institute, John Hopkins School of Medicine, Baltimore, MD, USA.

Objectives: To assess the prognostic value of ERG and PTEN protein expression as two of the most common genetic aberration in men with prostate cancer managed non-surgically by androgen deprivation therapy (ADT).

Materials And Methods: 463 tumor samples were assessed by double immunohistochemistry stains for ERG and PTEN and data correlated with clinical pathological features including, Gleason score, patients' outcome and ADT.

Results: ERG expression and PTEN protein loss were present in 28.2% and 38% of total patients respectively. There was a significant interplay between ERG and PTEN expression with 21.8% PTEN negative tumors being ERG positive (p < 0.001). Both ERG and PTEN showed significant association with lethal disease in all patients and those treated with prior ADT representing castrate-resistant disease. However, only PTEN remained significant in multivariable proportional hazards regression analysis, when including Gleason score and patients' age. Depending on patient's subgroup, intact positive PTEN intensity showed better cancer-specific survival with HR ranging from 0.25 to 0.4 compared to tumors with loss of PTEN expression. Assessing combined marker status, patients with decreased PTEN intensity without ERG positivity showed the worst clinical outcome compared to those with no PTEN loss and no ERG expression, where they had best clinical outcome. Patients with ERG expression with or without PTEN loss showed intermediate risk in relation to lethal disease.

Conclusion: This study confirms a significant prognostic role for assessing ERG and PTEN in men with prostate cancer. It supports a role for utilizing combined ERG/PTEN status clinically and prospectively for stratifying PCa patients into different prognostic groups.
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http://dx.doi.org/10.1007/s00432-018-2730-5DOI Listing
November 2018

Predictors of a successful primary bladder closure in cloacal exstrophy: A multivariable analysis.

J Pediatr Surg 2019 Mar 6;54(3):491-494. Epub 2018 Jul 6.

Robert D. Jeffs Division of Pediatric Urology, James Buchanan Brady Urological Institutions, Johns Hopkins Hospital, Johns Hopkins Medical Institutions, Charlotte Bloomberg Children's Hospital, Baltimore, MD, USA. Electronic address:

Purpose: To investigate the factors affecting primary bladder closure in cloacal exstrophy (CE). A successful primary closure is important for optimizing reconstructive outcomes, and it is a critical first-step in the reconstruction of CE. The authors' hypothesize that a smaller diastasis and use of an osteotomy are independent predictors of a successful closure.

Methods: A prospectively maintained database of 1332 exstrophy-epispadias complex (EEC) patients was reviewed for CE patients closed between 1975 and 2015. Univariate and multivariable analyses were performed to identify significant factors associated with CE primary bladder closure.

Results: Of 143 CE patients identified, 99 patients met inclusion criteria. Median follow-up time was 8.82 [IQR 5.43-14.26] years. In the multivariable model, the odds of having a successful closure are about 4 times greater for the staged cloacal approach compared to the 1-stage approach (OR, 3.7; 95% CI 1.2-11.5; p-value = 0.023). Also, having an osteotomy increases the chance of a successful closure by almost six-fold (OR, 5.8; 95% CI 1.7-19.6; p-value = 0.004).

Conclusions: Using the staged approach with a pelvic osteotomy is paramount to a successful primary closure in CE. The authors strongly recommend using the staged approach and osteotomy as these factors independently increase the chance for a successful primary bladder closure.

Study Type: Therapeutic study.

Level Of Evidence: Level III, Retrospective comparative study.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.06.030DOI Listing
March 2019

Comparative effectiveness of management options for patients with small renal masses: a prospective cohort study.

BJU Int 2019 01 9;123(1):42-50. Epub 2018 Aug 9.

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

Objectives: To explore the comparative effectiveness of partial nephrectomy (PN), radical nephrectomy (RN), ablative therapies (ablation) and active surveillance (AS) for small renal masses (SRMs; tumour diameter ≤4.0 cm) in the domains of survival, renal function and quality of life (QoL) using the prospectively maintained Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry.

Patients And Methods: Estimated glomerular filtration rate (eGFR) was calculated from creatinine values to determine renal function. QoL was measured using the Short Form 12 (SF-12) questionnaire. The Kaplan-Meier method and Cox proportional hazards regression were used for survival analysis. The mixed-effects model was used for renal function and QoL analysis.

Results: Of 638 patients, 231 (36.2%) chose PN, 41 (6.4%) RN, 27 (4.2%) ablation and 339 (53.1%) AS. Cancer-specific survival at 7 years was 98.8% in PN patients and 100% in all other groups. Overall survival (OS) at 7 years was 87.9%, 90.2%, 83.5% and 66.1% in PN, RN, ablation and AS patients, respectively. The OS rate was significantly worse in the AS group than other groups and likely attributable to older age and increased comorbidities. The eGFR was lowest in RN patients but comparable in all other groups. QoL was lowest in AS patients due to lower physical health scores, but mental health scores were similar in all groups.

Conclusions: With excellent oncological outcomes in all groups, nephron-sparing approaches, like PN and ablation, are preferred over RN when intervention is indicated for SRMs. AS is a reasonable option for select patients, given the comparable oncological and mental health outcomes.
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http://dx.doi.org/10.1111/bju.14490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301094PMC
January 2019

Comparative Analysis of Biopsy Upgrading in Four Prostate Cancer Active Surveillance Cohorts.

Ann Intern Med 2018 01 28;168(1):1-9. Epub 2017 Nov 28.

From University of Washington, Seattle, Washington; Fred Hutchinson Cancer Research Center, Seattle, Washington; Technical University of Munich, Garching, Germany; The James Buchanan Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland; University of California, San Francisco, San Francisco, California; University of Toronto, Toronto, Ontario, Canada; and Vanderbilt University, Nashville, Tennessee.

Background: Active surveillance (AS) is increasingly accepted for managing low-risk prostate cancer, yet there is no consensus about implementation. This lack of consensus is due in part to uncertainty about risks for disease progression, which have not been systematically compared or integrated across AS studies with variable surveillance protocols and dropout to active treatment.

Objective: To compare risks for upgrading from a Gleason score (GS) of 6 or less to 7 or more across AS studies after accounting for differences in surveillance intervals and competing treatments and to evaluate tradeoffs of more versus less frequent biopsies.

Design: Joint statistical model of longitudinal prostate-specific antigen (PSA) levels and risks for biopsy upgrading.

Setting: Johns Hopkins University (JHU); Canary Prostate Active Surveillance Study (PASS); University of California, San Francisco (UCSF); and University of Toronto (UT) AS studies.

Patients: 2576 men aged 40 to 80 years with a GS between 2 and 6 and clinical stage T1 or T2 prostate cancer enrolled between 1995 and 2014.

Measurements: PSA levels and biopsy GSs.

Results: After variable surveillance intervals and competing treatments were accounted for, estimated risks for biopsy upgrading were similar in the PASS and UT studies but higher in UCSF and lower in JHU studies. All cohorts had a delay of 3 to 5 months in detecting upgrading with biennial biopsies starting after a first confirmatory biopsy versus annual biopsies.

Limitation: The model does not account for possible misclassification of biopsy GS.

Conclusion: Men in different AS studies have different risks for biopsy upgrading after variable surveillance protocols and competing treatments are accounted for. Despite these differences, the consequences of more versus less frequent biopsies seem to be similar across cohorts. Biennial biopsies seem to be an acceptable alternative to annual biopsies.

Primary Funding Source: National Cancer Institute.
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http://dx.doi.org/10.7326/M17-0548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752581PMC
January 2018

Rapid Loss of RNA Detection by In Situ Hybridization in Stored Tissue Blocks and Preservation by Cold Storage of Unstained Slides.

Am J Clin Pathol 2017 Nov;148(5):398-415

Department of Pathology.

Objectives: Recent commercialization of methods for in situ hybridization using Z-pair probe/branched DNA amplification has led to increasing adoption of this technology for interrogating RNA expression in formalin-fixed, paraffin-embedded (FFPE) tissues. Current practice for FFPE block storage is to maintain them at room temperature, often for many years.

Methods: To examine the effects of block storage time on FFPE tissues using a number of RNA in situ probes with the Advanced Cellular Diagnostic's RNAscope assay.

Results: We report marked reductions in signals after 5 years and significant reductions often after 1 year. Furthermore, storing unstained slides cut from recent cases (<1 year old) at -20°C can preserve hybridization signals significantly better than storing the blocks at room temperature and cutting the slides fresh when needed.

Conclusions: We submit that the standard practice of storing FFPE tissue blocks at room temperature should be reevaluated to better preserve RNA for in situ hybridization.
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http://dx.doi.org/10.1093/ajcp/aqx094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848261PMC
November 2017

Growth Kinetics of Small Renal Masses on Active Surveillance: Variability and Results from the DISSRM Registry.

J Urol 2018 03 23;199(3):641-648. Epub 2017 Sep 23.

The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital (ACU, HDP, RA, MAG, MHJ, HG, MFR, BJT, MEA, PMP), Baltimore, Maryland; Division of Urology, Beth Israel Deaconess Medical Center (PC, AAW), Boston, Massachusetts; Department of Urology, Columbia University Medical Center (JMM), New York, New York.

Purpose: Active surveillance is emerging as a safe and effective strategy for the management of small renal masses (4 cm or less). We characterized the growth rate and its pertinence to clinical outcomes in a prospective multi-institutional study of patients with small renal masses.

Materials And Methods: Since 2009, the DISSRM (Delayed Intervention and Surveillance for Small Renal Masses) prospective, multi-institutional registry of patients with small renal masses has enrolled patients who elect primary intervention or active surveillance. Patients who elect active surveillance received regularly scheduled imaging and those with 3 or more followup images were included in the current study to evaluate growth rates.

Results: We evaluated 318 patients who elected active surveillance, of whom 271 (85.2%) had 3 or more followup images available with a median imaging followup of 1.83 years. The overall mean ± SD small renal mass growth rate was 0.09 ± 1.51 cm per year (median 0.09) with no variables demonstrating statistically significant associations. The growth rate and variability decreased with longer followup (0.54 and 0.07 cm per year at less than 6 months and greater than 1 year, respectively). No patients had metastatic disease or died of kidney cancer. No statistically significant difference was noted in the growth rate in patients with biopsy demonstrated renal cell carcinoma or in those who died.

Conclusions: Small renal mass growth kinetics are highly variable early on active surveillance with growth rates and variability decreasing with time. Early in active surveillance, especially during the initial 6 to 12 months, the growth rate is variable and does not reliably predict death or adverse pathological features in the patient subset with available pathology findings. An elevated growth rate may indicate the need for further assessment with imaging or consideration of biopsy prior to progressing to treatment. Additional followup will inform the best clinical pathway for elevated growth rates.
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http://dx.doi.org/10.1016/j.juro.2017.09.087DOI Listing
March 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