Publications by authors named "Martin G Sanda"

144 Publications

Decision regret, adverse outcomes, and treatment choice in men with localized prostate cancer: Results from a multi-site randomized trial.

Urol Oncol 2020 Dec 19. Epub 2020 Dec 19.

Department of Urology, University of Massachusetts Medical Center, Worchester, MA.

Introduction: Men diagnosed with localized prostate cancer must navigate a highly preference-sensitive decision between treatment options with varying adverse outcome profiles. We evaluated whether use of a decision support tool previously shown to decrease decisional conflict also impacted the secondary outcome of post-treatment decision regret.

Methods: Participants were randomized to receive personalized decision support via the Personal Patient Profile-Prostate or usual care prior to a final treatment decision. Symptoms were measured just before randomization and 6 months later; decision regret was measured at 6 months along with records review to ascertain treatment choices. Regression modeling explored associations between baseline variables including race and D`Amico risk, study group, and 6-month variables regret, choice, and symptoms.

Results: At 6 months, 287 of 392 (73%) men returned questionnaires of which 257 (89%) had made a treatment choice. Of that group, 201 of 257 (78%) completely answered the regret scale. Regret was not significantly different between participants randomized to the P3P intervention compared to the control group (P = 0.360). In univariate analyses, we found that Black men, men with hormonal symptoms, and men with bowel symptoms reported significantly higher decision regret (all P < 0.01). Significant interactions were detected between race and study group (intervention vs. usual care) in the multivariable model; use of the Personal Patient Profile-Prostate was associated with significantly decreased decisional regret among Black men (P = 0.037). Interactions between regret, symptoms and treatment revealed that (1) men choosing definitive treatment and reporting no hormonal symptoms reported lower regret compared to all others; and (2) men choosing active surveillance and reporting bowel symptoms had higher regret compared to all others.

Conclusion: The Personal Patient Profile-Prostate decision support tool may be most beneficial in minimizing decisional regret for Black men considering treatment options for newly-diagnosed prostate cancer.

Trial Registration: NCT01844999.
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http://dx.doi.org/10.1016/j.urolonc.2020.11.038DOI Listing
December 2020

Prostate Cancer Biomarker Development: National Cancer Institute's Early Detection Research Network Prostate Cancer Collaborative Group Review.

Cancer Epidemiol Biomarkers Prev 2020 Dec 22;29(12):2454-2462. Epub 2020 Oct 22.

The Leroy T. Canoles Jr. Cancer Research Center, Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia.

Prostate cancer remains the most common non-skin cancer and second leading cause of death among men in the United States. Although progress has been made in diagnosis and risk assessment, many clinical questions remain regarding early identification of prostate cancer and management. The early detection of aggressive disease continues to provide high curative rates if diagnosed in a localized state. Unfortunately, prostate cancer displays significant heterogeneity within the prostate organ and between individual patients making detection and treatment strategies complex. Although prostate cancer is common among men, the majority will not die from prostate cancer, introducing the issue of overtreatment as a major concern in clinical management of the disease. The focus of the future is to identify those at highest risk for aggressive prostate cancer and to develop prevention and screening strategies, as well as discerning the difference in malignant potential of diagnosed tumors. The Prostate Cancer Research Group of the National Cancer Institute's Early Detection Research Network has contributed to the progress in addressing these concerns. This summary is an overview of the activities of the group.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710596PMC
December 2020

In-Bore MRI-guided Prostate Biopsies in Patients with Prior Positive Transrectal US-guided Biopsy Results: Pathologic Outcomes and Predictors of Missed Cancers.

Radiol Imaging Cancer 2020 Sep 25;2(5):e190078. Epub 2020 Sep 25.

Department of Radiology and Imaging Sciences (K.K.E., S.G.N.), Interventional MRI Program (K.K.E., S.G.N.), Department of Urology (C.P.F., M.G.S., A.O.O.), and Department of Pathology (A.O.O.), School of Medicine, and Winship Cancer Institute (C.P.F., M.G.S., A.O.O., S.G.N.), Emory University, 1364 Clifton Rd NE, Room BG-42, Atlanta, GA 30322; Atlanta Veterans Affairs Medical Center, Decatur, Ga (C.P.F., M.G.S.); Department of Pathology, Veterans Affairs Medical Center, Atlanta, Ga (A.O.O.); and Department of Radiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt (K.K.E.).

Purpose: To evaluate the role of confirmatory in-bore MRI-guided biopsy in patients with low- or intermediate-risk disease diagnosed at prior transrectal US-guided biopsy and to evaluate the rate and predictors for missed cancers.

Materials And Methods: A retrospective evaluation of 50 consecutive men who had previously undergone transrectal US-guided biopsy with positive results and who underwent subsequent in-bore MRI-guided biopsy at our university hospital (average time interval, 11 months) between 2012 and 2016 was performed. Ten men were excluded because of a history of treatment after transrectal US-guided biopsy. A total of 40 men (mean age, 63 years; range, 47-84 years) were included in this study. Multiparametric 3-T MRI (T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced) and transrectal in-bore MRI-guided biopsy were performed. Cancer detection, disease-grade changes, and cancers missed at in-bore MRI-guided biopsy were evaluated. Descriptive statistics were used to report different rates. The Fisher exact test was used for categoric variables. The Mann-Whitney test and independent Student test were used for nonparametric and parametric data, respectively. The McNemar test was used for paired data.

Results: The overall cancer detection rate when using in-bore MRI-guided biopsy was 65% (26 of 40). In-bore MRI-guided biopsy detected 14 previously undiscovered cancerous lesions (clinically significant cancers [CSCs], 57.1% [eight of 14]). An overall disease upgrade by in-bore MRI-guided biopsy occurred in 40% (16 of 40) of cases (61.5% [16 of 26] of cases with positive results from in-bore MRI-guided biopsy). One case was downgraded from a Gleason score (GS) of 3 + 4 = 7 to a GS of 3 + 3 = 6. Out of 71 sextant biopsies with positive results detected by transrectal US-guided biopsy (from all 40 patients), 80% (57 of 71) were visible on MR images (in-bore MRI-guided biopsy results were positive in 52.6% [30 of 57]), and 20% (14 of 71) had no image correlates on MR images. In-bore MRI-guided biopsy upgraded 60% (18 of 30) and downgraded 3.3% (one of 30) of detected lesions. The false-negative rate was 35% (14.2% [two of 14] of patients had CSCs; GS ≥ 7), was higher in prostate volumes of greater than 40 mL, and was lower in the anterior gland location ( = .04 and .01, respectively).

Conclusion: Performing confirmatory in-bore MRI-guided biopsy following positive transrectal US-guided biopsy resulted in a high disease-upgrade incidence with subsequently improved disease-risk stratification, particularly when considering patients for active surveillance or focal therapy. © RSNA, 2020See also the commentary by Weiss and Solomon in this issue.
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http://dx.doi.org/10.1148/rycan.2020190078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523503PMC
September 2020

Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy With or Without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer.

J Clin Oncol 2020 09 24;38(26):3042-3050. Epub 2020 Jul 24.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression-free survival (BPFS) over RP alone.

Patients And Methods: Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS).

Results: In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 0.84, respectively; 95% CI for the difference, -0.01 to 0.11; = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone.

Conclusion: The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.
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http://dx.doi.org/10.1200/JCO.20.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479762PMC
September 2020

A prospective study of patient reported urinary incontinence among American, Norwegian and Spanish men 1 year after prostatectomy.

Asian J Urol 2020 Apr 19;7(2):161-169. Epub 2019 Aug 19.

Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.

Objective: To compare pre- and post-radical prostatectomy (RP) responses in the urinary incontinence domain of Expanded Prostate Cancer Index Composite-26 (EPIC-26) in cohorts from the USA, Norway and Spain.

Methods: A prospective study of pre- and 1-year post-treatment responses in American (=537), Norwegian (=520) and Spanish (=111) patients, establishing the prevalence of urinary incontinence defined according to published dichotomization. Thereafter we focused on the response alternatives "occasional dribbling", pad use and problem experience. A multivariate logistic regression analysis (significance level ≤ 0.01) considered risk factors for "not retaining total control".

Results: Compared to the European men, the American patients were younger, healthier and more presented with lower risk tumors. Before RP no inter-country differences emerged the prevalence of urinary incontinence (6%). One-year post-treatment urinary incontinence was described by 30% of the American and 41% of the European patients, occasional dribbling being the most frequent type of urinary leakage. In the multivariate analysis the risk of "not retaining total control" increased almost 3-fold in European compared to American patients, with age and co-morbidity being additional independent risk factor.

Conclusion: After RP patients from Spain and Norway reported more unfavorable outcomes by EPIC-26 than the American patients to most of the urinary incontinence items, the difference between the European and American patients remaining in the multivariate analysis. The most frequent post-RP response alternative "occasional dribbling" needs to be validated with pad weighing as "gold standard".
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http://dx.doi.org/10.1016/j.ajur.2019.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096671PMC
April 2020

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Nature 2019 12 11;576(7787):465-470. Epub 2019 Dec 11.

Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.
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http://dx.doi.org/10.1038/s41586-019-1836-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108171PMC
December 2019

A Four-Group Urine Risk Classifier for Predicting Outcome in Prostate Cancer Patients.

BJU Int 2019 May 20. Epub 2019 May 20.

Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK.

Objectives: To develop a risk classifier using urine-derived extracellular vesicle RNA (UEV-RNA) capable of providing diagnostic information of disease status prior to biopsy, and prognostic information for men on active surveillance (AS).

Patients And Methods: Post-digital rectal examination UEV-RNA expression profiles from urine (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO-based Continuation-Ratio model was built to generate four Prostate-Urine-Risk (PUR) signatures for predicting the probability of normal tissue (PUR-1), D'Amico Low-risk (PUR-2), Intermediate-risk (PUR-3), and High-risk (PUR-4) PCa. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub-cohort (n = 87) for prognostic evaluation.

Results: Each PUR signature was significantly associated with its corresponding clinical category (p<0.001). PUR-4 status predicted the presence of clinically significant Intermediate or High-risk disease, AUC = 0.77 (95% CI: 0.70-0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub-cohort (n=87), groups defined by PUR status and proportion of PUR-4 had a significant association with time to progression (p<0.001; IQR HR = 2.86, 95% CI:1.83-4.47). PUR-4, when utilised continuously, dichotomised patient groups with differential progression rates of 10% and 60% five years post-urine collection (p<0.001, HR = 8.23, 95% CI:3.26-20.81).

Conclusion: UEV-RNA can provide diagnostic information of aggressive PCa prior to biopsy, and prognostic information for men on AS. PUR represents a new & versatile biomarker that could result in substantial alterations to current treatment of PCa patients. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/bju.14811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851983PMC
May 2019

Circulating microRNAs in plasma among men with low-grade and high-grade prostate cancer at prostate biopsy.

Prostate 2019 06 8;79(9):961-968. Epub 2019 Apr 8.

Department of Population Health Science and Policy, Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: MicroRNAs (miRNAs or miR-) have been linked to factors associated with aggressive prostate cancer such as biochemical recurrence and metastasis. We investigated whether circulating miRNAs in plasma could be used as diagnostic biomarkers for more aggressive prostate cancer at prostate biopsy.

Methods: Men, aged 40 years and above, newly diagnosed with prostate cancer were categorized into two risk groups, low-grade (Gleason score, 6 or 7 [3 + 4] and serum prostate-specific antigen [PSA], <20 ng/mL) and high-grade (Gleason score, ≥7 (4 + 3) and serum PSA, ≥20 ng/mL) prostate cancers. The limma R package was used to compare the expression of miRNAs in plasma between the two risk groups, adjusting for age.

Results: There were 66 men, aged 46-86 years, included: 40 men with low-grade and 26 men with high-grade prostate cancers. There were lower expressions of miR-28, miR-100, miR-942, and miR-28-3p, and higher expressions of miR-708, miR-1298, miR-886-3p, miR-374, miR-376c, miR-202, miR-128a, and miR-185 in high-grade compared to low-grade prostate cancer cases at biopsy, after adjusting for age (P < 0.05). These differences were no longer statistically significant after adjusting the P values for multiple comparisons.

Conclusion: There was no circulating miRNA associated with high-grade prostate cancer at biopsy after adjusting for age and multiple comparisons. Nevertheless, relationships between these circulating miRNAs and high-grade prostate cancer were observed, which suggest them as promising prostate cancer biomarkers. Further investigation in a larger cohort may provide insight into their diagnostic potential for aggressive prostate cancer.
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http://dx.doi.org/10.1002/pros.23803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520194PMC
June 2019

Rise in Node-Positive Prostate Cancer Incidence in Context of Evolving Use and Extent of Pelvic Lymphadenectomy.

Clin Genitourin Cancer 2019 06 26;17(3):e494-e504. Epub 2019 Jan 26.

Department of Urology, Emory University School of Medicine, Atlanta, GA; Winship Cancer Institute, Emory Healthcare, Atlanta, GA; Atlanta Veterans Affairs Medical Center, Decatur, GA. Electronic address:

Background: The incidence of node-positive prostate cancer has risen and might be partially explained by evolving use of lymphadenectomy at a population level. We assessed trends of node-positive prostate cancer in context of extent of lymphadenectomy among men treated surgically for prostate cancer.

Patients And Methods: This was a retrospective study using data from a population-based cancer registry to identify men older than 50 years of age diagnosed with prostate cancer from 2010 to 2015 without distant metastases. We considered extent of node dissection as ordinal (1-4, 5-9, 10-14, 15-19, ≥20) and dichotomous (1-14, ≥15) variables. We fit multivariable models to assess trends in receipt of extended lymphadenectomy and then estimated odds of node-positive cancer on the basis of extent of lymphadenectomy.

Results: We identified 280,156 men diagnosed from 2010 to 2015; 5355 men (1.9%) had positive lymph nodes. Incidence of positive nodes increased from 6.4 to 8.4 cases per 100,000 men from 2010 to 2015 (standardized rate ratio, 1.31; 95% confidence interval [CI], 1.20-1.44). Compared with 2010, prostatectomy patients with high-risk (odds ratio [OR], 1.66; 95% CI, 1.42-1.95) and intermediate-risk tumors (OR, 1.66; 95% CI, 1.47-1.88) were more likely to undergo extended lymphadenectomy in 2015. Among high-risk patients, men with ≥20 nodes removed were 7 times more likely to have positive nodes, versus <5 removed (6.1% for 1-4 vs. 32.4% for ≥20; OR, 7.32; 95% CI, 6.16-8.71). After adjusting for extent of dissection, odds of node-positive disease did not increase between 2010 and 2015 (OR, 1.17; 95% CI, 0.98-1.39) among high-risk patients.

Conclusion: Increased incidence of node-positive prostate cancer in the United States is partially explained by more frequent use of extended lymphadenectomy.
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http://dx.doi.org/10.1016/j.clgc.2019.01.012DOI Listing
June 2019

epiCaPture: A Urine DNA Methylation Test for Early Detection of Aggressive Prostate Cancer.

JCO Precis Oncol 2019 14;2019. Epub 2019 Jan 14.

University College Dublin.

Purpose: Liquid biopsies that noninvasively detect molecular correlates of aggressive prostate cancer (PCa) could be used to triage patients, reducing the burdens of unnecessary invasive prostate biopsy and enabling early detection of high-risk disease. DNA hypermethylation is among the earliest and most frequent aberrations in PCa. We investigated the accuracy of a six-gene DNA methylation panel (Epigenetic Cancer of the Prostate Test in Urine [epiCaPture]) at detecting PCa, high-grade (Gleason score greater than or equal to 8) and high-risk (D'Amico and Cancer of the Prostate Risk Assessment] PCa from urine.

Patients And Methods: Prognostic utility of epiCaPture genes was first validated in two independent prostate tissue cohorts. epiCaPture was assessed in a multicenter prospective study of 463 men undergoing prostate biopsy. epiCaPture was performed by quantitative methylation-specific polymerase chain reaction in DNA isolated from prebiopsy urine sediments and evaluated by receiver operating characteristic and decision curves (clinical benefit). The epiCaPture score was developed and validated on a two thirds training set to one third test set.

Results: Higher methylation of epiCaPture genes was significantly associated with increasing aggressiveness in PCa tissues. In urine, area under the receiver operating characteristic curve was 0.64, 0.86, and 0.83 for detecting PCa, high-grade PCa, and high-risk PCa, respectively. Decision curves revealed a net benefit across relevant threshold probabilities. Independent analysis of two epiCaPture genes in the same clinical cohort provided analytical validation. Parallel epiCaPture analysis in urine and matched biopsy cores showed added value of a liquid biopsy.

Conclusion: epiCaPture is a urine DNA methylation test for high-risk PCa. Its tumor specificity out-performs that of prostate-specific antigen (greater than 3 ng/mL). Used as an adjunct to prostate-specific antigen, epiCaPture could aid patient stratification to determine need for biopsy.
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http://dx.doi.org/10.1200/PO.18.00134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383793PMC
January 2019

Expanded Prostate Cancer Index Composite-26 (EPIC-26) Online: Validation of an Internet-Based Instrument for Assessment of Health-Related Quality of Life After Treatment for Localized Prostate Cancer.

Urology 2019 05 18;127:53-60. Epub 2019 Feb 18.

Beth Israel Deaconess Medical Center, Boston, MA. Electronic address:

Objectives: To test the validity of an Internet-based version of Expanded Prostate Cancer Index Composite (EPIC-26) versus the phone-based version. Most men will survive for years after treatment for localized prostate cancer (PCa) and may experience lasting treatment-related toxicities affecting health-related quality of life. The EPIC-26 is a validated instrument that measures health-related quality of life across 5 PCa-specific domains. Previously, EPIC-26 was administered via phone in a large multicenter clinical trial.

Methods: We developed an Internet-based version of EPIC-26. We recruited subjects from two prospective longitudinal study cohorts of PCa patients undergoing local therapy: PROST-QA, and PROSTQA-RP2. Subjects were randomized to either an "Internet-first" or "phone-first" group. Subjects were offered the alternate questionnaire modality 2 weeks after completing the initial modality.

Results: 181 subjects were offered enrollment; 133 agreed to participate. 65 subjects were randomized to the "Internet- first" group and 68 subjects to the "phone-first" group. Of these, 37 and 26 subjects respectively completed both questionnaire versions (response rate: 44.4%). Test-retest analysis showed significant intraclass correlations in all 5 domains of EPIC-26: urinary incontinence (r = 0.96), urinary irritation (r = 0.85), bowel function (r = 0.61), sexual function (r = 0.94), and hormonal function (r = 0.89). There was no effect of order of questionnaire administration.

Conclusion: This study demonstrates excellent correlation of responses between Internet-based and phone-based EPIC-26 administration. All domains demonstrated test-retest reliability between modalities, without ordering effect. This validates the use of internet-based EPIC-26 in international registries as part of the International Consortium for Health Outcomes Measurement effort, and may facilitate its use in clinical practice and quality improvement.
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http://dx.doi.org/10.1016/j.urology.2019.02.004DOI Listing
May 2019

Assigning value to preparation for prostate cancer decision making: a willingness to pay analysis.

BMC Med Inform Decis Mak 2019 01 9;19(1). Epub 2019 Jan 9.

Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

Background: The Personal Patient Profile-Prostate (P3P) is a web-based decision support system for men newly diagnosed with localized prostate cancer that has demonstrated efficacy in reducing decisional conflict. Our objective was to estimate willingness-to-pay (WTP) for men's decisional preparation activities.

Methods: In a multicenter, randomized trial of P3P, usual care group participants received typical preparation for decision making plus referral to publicly-available, educational websites. Intervention group participants received the same, plus online P3P educational media specific to the user's personal preferences and values, and a communication coaching component tailored to race\ethnicity, age and language. WTP data were collected one week after physician consultation. An iterative bidding direct contingent valuation survey format was used, randomly assigning participants to high or low starting values (SV). Tobit models were used to explore associations between SV-adjusted WTP and age, education, marital and work-status, insurance, decision-control preference and decision-making stage.

Results: Of 392 participants enrolled, 141 P3P and 107 usual care (UC) provided a WTP value. Men were willing to pay a median $25 (IQR $10-100) for P3P in addition to usual care preparation materials. In the final multivariable tobit regression model, SV, marital status, stage of decision making and income were significantly associated with WTP for P3P. Decision control preference was considered marginally significant (p = 0.11). Men were WTP a median $30 (IQR $10-$200) for usual care material alone. In the final multivariable model, SV, education, and stage of decision making were significantly associated with WTP in usual care.

Conclusion: WTP was similar for UC and for the addition of P3P to UC decision preparation. The WTP values were associated with demographic and preference variables. Findings can help focus decision support on future patients who would benefit most: those without strong support systems, at earlier stages of decision making, and open to a shared-decision style.

Trial Registration: NCT NCT01844999 . Registered May 3, 2013.
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http://dx.doi.org/10.1186/s12911-018-0725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327504PMC
January 2019

Impact of prebiopsy magnetic resonance imaging of the prostate on cancer detection and treatment patterns.

Urol Oncol 2019 03 1;37(3):181.e15-181.e21. Epub 2018 Dec 1.

Emory University Department of Urology, Emory University School of Medicine, Atlanta, GA; Emory University Winship Cancer Institute, Atlanta, GA; Atlanta Veterans Administration Medical Center, Decatur, GA. Electronic address:

Purpose: Though superior in clinical trial settings, outcomes following magnetic resonance image (MRI)-guided prostate biopsies have not been reported broadly. We compared prostate cancer detection rates for men who did and did not undergo prebiopsy MRI and evaluated treatment patterns based on biopsy approach, year of biopsy, and proximity to early adopters.

Methods: Using private insurance claims (2009-2015), we identified men who underwent prostate biopsy using appropriate procedure codes. Exposure was receipt of prebiopsy MRI within 3 months prior to biopsy. Outcomes included new prostate cancer diagnosis, treatment with prostatectomy/radiation, and receipt of adjunct procedures typically used for higher-risk disease (i.e., lymphadenectomy with prostatectomy, androgen deprivation therapy with radiation). Hierarchical mixed-effects multivariable logistic regression predicted probabilities of each outcome.

Results: We identified 77,350 men (mean age 57.5 ± 5.4 years) who underwent biopsy with 12% having had a prior negative biopsy. Use of prebiopsy MRI was more common among men biopsied from 2014 to 2015 (4.4% vs. 1.3% 2012-2013), in metropolitan statistical areas (2.6% vs. 1.1% not), residing close to early adopters (5.5% vs. 1.5% far), and with prior negative biopsy (7.3% vs. 1.7% biopsy-naïve; all P < 0.001). Compared to patients with a prior negative biopsy and no MRI, men were more likely to be diagnosed with prostate cancer if they had a prior negative biopsy and MRI (24.7% vs. 21.4% prior negative without MRI, odds ratio 1.25, 95% confidence interval 1.04-1.51) or an initial biopsy without prior MRI (40.0% vs. 21.4% prior negative without MRI, odds ratio 2.49, 95% confidence interval 2.36-2.64; P < 0.001). Predicted probability of treatment overall and adjunct treatment did not differ based on receipt of pre-biopsy MRI.

Conclusions: Among privately insured men in the United States, use of prostate MRI prior to prostate biopsy was associated with increased cancer detection among those with prior negative biopsies, but we did not observe significant changes with downstream treatment patterns.
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http://dx.doi.org/10.1016/j.urolonc.2018.11.004DOI Listing
March 2019

Elevated Serum Cytokines and Trichomonas vaginalis Serology at Diagnosis Are Not Associated With Higher Gleason Grade or Lethal Prostate Cancer.

Clin Genitourin Cancer 2019 Feb 4;17(1):32-37. Epub 2018 Oct 4.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address:

Background: Inflammation and infections have been associated with prostate cancer progression. We assessed whether elevated serum cytokines or T. vaginalis seropositivity at the time of diagnosis was associated with higher grade or lethal prostate cancer.

Patients And Methods: Men with localized or metastatic prostate cancer were included in this study. Cytokine serum levels including interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, monocyte chemotactic protein 1 (CCL-2), tumor necrosis factor α, and growth-regulated oncogene α (CXCL-1) using a multiplex enzyme-linked immunosorbent assay and T. vaginalis serology were measured in blood samples at diagnosis.

Results: A total of 324 patients were identified at time of localized disease and 118 at time of metastatic disease. Of the 189 patients with localized disease and clinical follow-up data (median, 73 months), 28 developed lethal disease. There was no association between circulating cytokine levels above median concentrations nor T. vaginalis seropositivity and risk of intermediate- to high-risk or lethal prostate cancer.

Conclusion: Higher levels of serum cytokine levels and T. vaginalis seropositivity at diagnosis are not associated with high-grade or lethal prostate cancer and do not aid risk stratification of localized prostate cancer.
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http://dx.doi.org/10.1016/j.clgc.2018.09.022DOI Listing
February 2019

Predicting erectile function following external beam radiation therapy or brachytherapy for prostate cancer using EPIC-CP.

Pract Radiat Oncol 2018 Nov - Dec;8(6):445-451. Epub 2018 Apr 14.

Harvard Medical School, Boston, Massachusetts; Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.prro.2018.04.007DOI Listing
January 2019

Adoption of Prebiopsy Magnetic Resonance Imaging for Men Undergoing Prostate Biopsy in the United States.

Urology 2018 Jul 18;117:57-63. Epub 2018 Apr 18.

Department of Urology, Emory University School of Medicine, Atlanta, GA; Atlanta Veterans Administration Medical Center, Decatur, GA. Electronic address:

Objective: To assess adoption of prebiopsy prostate magnetic resonance imaging (MRI) in the United States and to evaluate factors associated with magnetic resonance imaging-guided prostate biopsy (MRI-Bx) use. Prior reports have shown improved cancer detection with MRI-Bx vs transrectal ultrasound-guided methods (transrectal ultrasound-guided biopsy [TRUS-Bx]). Population-based trends of their use and outcomes have not been previously characterized.

Materials And Methods: Using private insurance claims (2009-2015), we identified men who underwent prostate biopsy. Exposures were biopsy year and geographic region defined by metropolitan statistical area. Outcomes included biopsy type (MRI-Bx, TRUS-Bx, or transperineal biopsy) based on procedure codes and cancer detection based on a new diagnosis for prostate cancer (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 185). Hierarchical mixed-effects multivariable regression estimated odds of undergoing MRI-Bx.

Results: We identified 241,681 men (mean age 57.5 ± 5.4 years) who underwent biopsy. The use of MRI-Bx rose rapidly (0.2% in 2009 to 6.5% in 2015, P <.001). Overall, 3429 men underwent MRI before biopsy, more commonly in metropolitan statistical areas (odds ratio 1.90, 95% confidence interval 1.66-2.19). In 2015, nearly 18% of men with prior negative biopsy underwent a prebiopsy MRI. Patients with prior negative biopsies were over 4 times more likely to use MRI guidance (vs no prior biopsies, odds ratio 4.63, 95% confidence interval 4.27-5.02) and had a greater chance of cancer detection with MRI-Bx (25.2%) vs TRUS-Bx (19.7%, P = .010).

Conclusion: Among men undergoing prostate biopsy, prebiopsy prostate MRI utilization was concentrated within urban areas and among patients with prior negative biopsies, where its use was associated with superior cancer detection compared with traditional TRUS-Bx.
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http://dx.doi.org/10.1016/j.urology.2018.04.007DOI Listing
July 2018

Incorporation of Urinary Prostate Cancer Antigen 3 and TMPRSS2:ERG into Prostate Cancer Prevention Trial Risk Calculator.

Eur Urol Focus 2019 01 13;5(1):54-61. Epub 2018 Feb 13.

Department of Urology, University of Texas Health at San Antonio, San Antonio, TX, USA. Electronic address:

Background: The Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) is a commonly used risk tool for predicting the outcome on biopsy based on the established risk factors.

Objective: To determine whether incorporation of the novel urinary markers prostate cancer antigen 3 (PCA3) and TMPRSS2:ERG (T2:ERG) into the PCPTRC improves its discrimination, accuracy, and clinical net benefit.

Design, Setting, And Participants: Since PCA3 and T2:ERG were not measured as part of the PCPTRC, a Bayesian modeling approach was used to combine data where the markers were measured in a Michigan cohort with the PCPTRC as prior probabilities to form an updated PCPTRC. This update was compared to the existing PCPTRC on an independent Early Detection Research Network cohort in terms of discrimination, calibration, and decision curve analysis.

Results And Limitations: Among the 1225 Michigan biopsies, 57.7%, 24.0%, and 18.3% were negative, with low- and high-grade (Gleason grade≥7) prostate cancer, respectively. Evaluated on the Early Detection Research Network validation set comprising 854 biopsies, areas under the curve (95% confidence interval) for predicting high-grade cancer in the 854 biopsies comprising the validation set were 70.0% (66.0-74.0%), 76.4% (72.8-80.0%), and 77.1% (73.6-80.6%) for the PCPTRC alone, with PCA3 added, and PCA3 and T2:ERG added, respectively. Net benefit was improved for the updated PCPTRC, while calibration was not. Limitations are that the updated PCPTRC is based on two different cohorts, the PCPT and Michigan, and that 20% of the validation set came from the Michigan center. More validation is required; hence, the updated risk tool is posted online.

Conclusions: Incorporation of PCA3 into the PCPTRC improved validation on an independent cohort, whereas T2:ERG offered negligible utility in addition to PCA3.

Patient Summary: After passing external validation, prostate cancer antigen 3 has been added to the online Prostate Cancer Prevention Trial Risk Calculator for use by patients in deciding whether to proceed to biopsy. TMPRSS2:ERG did not improve prediction on the external validation set, but is included for further validation.
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http://dx.doi.org/10.1016/j.euf.2018.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077104PMC
January 2019

Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part II: Recommended Approaches and Details of Specific Care Options.

J Urol 2018 04 10;199(4):990-997. Epub 2018 Jan 10.

American Urological Association Education and Research, Inc., Linthicum, Maryland; ASTRO, Arlington, Virginia; Society of Urologic Oncology, Schamburg, Illinois.

Purpose: This guideline is structured to provide a clinical framework stratified by cancer severity to facilitate care decisions and guide the specifics of implementing the selected management options. The summary presented herein represents Part II of the two-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline discussing risk stratification and care options by cancer severity. Please refer to Part I for discussion of specific care options and outcome expectations and management.

Materials And Methods: The systematic review utilized in the creation of this guideline was completed by the Agency for Healthcare Research and Quality and through additional supplementation by ECRI Institute. This review included articles published between January 2007 and March 2014 with an update search conducted through August 2016. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. Additional information is provided as Clinical Principles and Expert Opinions (table 2 in supplementary unabridged guideline, http://jurology.com/).

Results: The AUA (American Urological Association), ASTRO, and SUO (Society of Urologic Oncology) formulated an evidence-based guideline based on a risk stratified clinical framework for the management of localized prostate cancer.

Conclusions: This guideline attempts to improve a clinician's ability to treat patients diagnosed with localized prostate cancer, but higher quality evidence in future trials will be essential to improve the level of care for these patients. In all cases, patient preferences should be considered when choosing a management strategy.
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http://dx.doi.org/10.1016/j.juro.2018.01.002DOI Listing
April 2018

In-bore MRI-guided biopsy: can it optimize the need for periodic biopsies in prostate cancer patients undergoing active surveillance? A pilot test-retest reliability study.

Br J Radiol 2018 Apr 13;91(1084):20170603. Epub 2018 Feb 13.

1 Department of Radiology and Imaging Sciences, Emory University School of Medicine , Atlanta, GA , United States.

Objective: To evaluate the test-retest reliability of repeated in-bore MRI-guided prostate biopsy (MRGB).

Methods: 19 lesions in 7 patients who had consecutive MRGBs were retrospectively analysed. Five patients had 2 consecutive MRGBs and two patients had 3 consecutive MRGBs. Both multiparametric MRI and MRGBs were performed using a 3T MRI scanner. Pathology results were categorized into benign, suspicious and malignant. Consistency between first and subsequent biopsy results were analysed as well as the negative predictive value (NPV) for prostate cancer.

Results: 15 lesions (≈79%) had matching second biopsy and 4 (21%) had non-matching second biopsy. Lesions with both Prostate Imaging - Reporting and Data System(PIRADS) categories 1 and 4 were all benign and had matching pathology results. Lesions with non-matching results had PIRADS categories 2, 3 and 5. NPV for prostate cancer in first biopsy was 87.5%. Overall agreement was 78.9% and overall disagreement was 21.1%.κ = 0.55 denoting moderate agreement (p = 0.002). 10/19 lesions had a third biopsy session. 9/10 (90%) had matching pathology results across the three biopsy sessions and all matching lesions were benign.

Conclusion: In-bore MRI-guided prostate biopsy may have a better reliability for repeat biopsies compared to TRUS biopsy. Final conclusion awaits a prospective analysis on a larger cohort of patients. Advances in knowledge: This pilot study showed that repeated prostate in-bore MRI-guided prostate biopsy may have better reliability compared to TRUS biopsy with a suggested high NPV.
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http://dx.doi.org/10.1259/bjr.20170603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965998PMC
April 2018

Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part I: Risk Stratification, Shared Decision Making, and Care Options.

J Urol 2018 03 15;199(3):683-690. Epub 2017 Dec 15.

American Urological Association Education and Research, Inc., Linthicum, Maryland; ASTRO, Arlington, Virginia; Society of Urologic Oncology, Schamburg, Illinois.

Purpose: This guideline is structured to provide a clinical framework stratified by cancer severity to facilitate care decisions and guide the specifics of implementing the selected management options. The summary presented represents Part I of the two-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline discussing risk stratification and care options by cancer severity.

Materials And Methods: The systematic review utilized in the creation of this guideline was completed by the Agency for Healthcare Research and Quality and through additional supplementation by ECRI Institute. This review included articles published between January 2007 and March 2014 with an update search conducted through August 2016. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. Additional information is provided as Clinical Principles and Expert Opinions (table 2 in supplementary unabridged guideline, http://jurology.com/).

Results: The AUA (American Urological Association), ASTRO, and SUO (Society of Urologic Oncology) formulated an evidence-based guideline based on a risk stratified clinical framework for the management of localized prostate cancer.

Conclusions: This guideline attempts to improve a clinician's ability to treat patients diagnosed with localized prostate cancer, but higher quality evidence in future trials will be essential to improve the level of care for these patients. In all cases, patient preferences should be considered when choosing a management strategy.
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http://dx.doi.org/10.1016/j.juro.2017.11.095DOI Listing
March 2018

Patients with Intermediate Risk Prostate Cancer May be Good Candidates for Active Surveillance: Pro.

Authors:
Martin G Sanda

J Urol 2017 11 22;198(5):997-999. Epub 2017 Sep 22.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

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http://dx.doi.org/10.1016/j.juro.2017.08.089DOI Listing
November 2017

Decision Support with the Personal Patient Profile-Prostate: A Multicenter Randomized Trial.

J Urol 2018 01 25;199(1):89-97. Epub 2017 Jul 25.

Private Practice, Niagara Falls, New York.

Purpose: We evaluated the efficacy of the web based P3P (Personal Patient Profile-Prostate) decision aid vs usual care with regard to decisional conflict in men with localized prostate cancer.

Materials And Methods: A randomized (1:1), controlled, parallel group, nonblinded trial was performed in 4 regions of the United States. Eligible men had clinically localized prostate cancer and an upcoming consultation, and they spoke and read English or Spanish. Participants answered questionnaires to report decision making stage, personal characteristics, concerns and preferences plus baseline symptoms and decisional conflict. A randomization algorithm allocated participants to receive tailored education and communication coaching, generic teaching sheets and external websites plus a 1-page summary to clinicians (intervention) or the links plus materials provided in clinic (usual care). Conflict outcomes and the number of consultations were measured at 1 month. Univariate and multivariable models were used to analyze outcomes.

Results: A total of 392 men were randomized, including 198 to intervention and 194 to usual care, of whom 152 and 153, respectively, returned 1-month outcomes. The mean ± SD 1-month decisional conflict scale (score range 0 to 100) was 10.9 ± 16.7 for intervention and 9.9 ± 18.0 for usual care. The multivariable model revealed significantly reduced conflict in the intervention group (-5.00, 95% CI -9.40--0.59). Other predictors of conflict included income, marital or partner status, decision status, number of consultations, clinical site and D'Amico risk classification.

Conclusions: In this multicenter trial the decision aid significantly reduced decisional conflict. Other variables impacted conflict and modified the effect of the decision aid, notably risk classification, consultations and resources. P3P is an effective adjunct for shared decision making in men with localized prostate cancer.
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http://dx.doi.org/10.1016/j.juro.2017.07.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760348PMC
January 2018

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer.

JAMA Oncol 2017 Aug;3(8):1085-1093

New York University School of Medicine, New York.

Importance: Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease.

Objective: To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs.

Design, Setting, And Participants: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort.

Interventions/exposures: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy.

Main Outcomes And Measures: Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes.

Results: Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men.

Conclusions And Relevance: Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.
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http://dx.doi.org/10.1001/jamaoncol.2017.0177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710334PMC
August 2017

External Beam Radiation Therapy or Brachytherapy With or Without Short-course Neoadjuvant Androgen Deprivation Therapy: Results of a Multicenter, Prospective Study of Quality of Life.

Int J Radiat Oncol Biol Phys 2017 06 22;98(2):304-317. Epub 2017 Feb 22.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

Purpose: The long-term effects of neoadjuvant androgen deprivation therapy (NADT) with radiation therapy on participant-reported health-related quality of life (HRQOL) have not been characterized in prospective multicenter studies. We evaluated HRQOL for 2 years among participants undergoing radiation therapy (RT) with or without NADT for newly diagnosed, early-stage prostate cancer.

Methods And Materials: We analyzed longitudinal cohort data from the Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment Consortium to ascertain the HRQOL trajectory of men receiving NADT with external beam RT (EBRT) or brachytherapy. HRQOL was measured using the expanded prostate cancer index composite 26-item questionnaire at 2, 6, 12, and 24 months after the initiation of NADT. We used the χ or Fisher exact test to compare the shift in percentages between groups that did or did not receive NADT. Analyses were conducted at the 2-sided 5% significance level.

Results: For subjects receiving EBRT, questions regarding the ability to have an erection, ability to reach an orgasm, quality of erections, frequency of erections, ability to function sexually, and lack of energy were in a significantly worse dichotomized category for the patients receiving NADT. Comparing the baseline versus 24-month outcomes, 24%, 23%, and 30% of participants receiving EBRT plus NADT shifted to the worse dichotomized category for the ability to reach an orgasm, quality of erections, and ability to function sexually compared with 14%, 13%, and 16% in the EBRT group, respectively.

Conclusions: Compared with baseline, at 2 years, participants receiving NADT plus EBRT compared with EBRT alone had worse HRQOL, as measured by the ability to reach orgasm, quality of erections, and ability to function sexually. However, no difference was found in the ability to have an erection, frequency of erections, overall sexual function, hot flashes, breast tenderness/enlargement, depression, lack of energy, or change in body weight. The improved survival in intermediate- and high-risk patients receiving NADT and EBRT necessitates pretreatment counseling of the HRQOL effect of NADT and EBRT.
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http://dx.doi.org/10.1016/j.ijrobp.2017.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493021PMC
June 2017

Detection of prostate cancer-specific transcripts in extracellular vesicles isolated from post-DRE urine.

Prostate 2017 Jun 17;77(9):990-999. Epub 2017 Apr 17.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

Background: The measurement of gene expression in post-digital rectal examination (DRE) urine specimens provides a non-invasive method to determine a patient's risk of prostate cancer. Many currently available assays use whole urine or cell pellets for the analysis of prostate cancer-associated genes, although the use of extracellular vesicles (EVs) has also recently been of interest. We investigated the expression of prostate-, kidney-, and bladder-specific transcripts and known prostate cancer biomarkers in urine EVs.

Methods: Cell pellets and EVs were recovered from post-DRE urine specimens, with the total RNA yield and quality determined by Bioanalyzer. The levels of prostate, kidney, and bladder-associated transcripts in EVs were assessed by TaqMan qPCR and targeted sequencing.

Results: RNA was more consistently recovered from the urine EV specimens, with over 80% of the patients demonstrating higher RNA yields in the EV fraction as compared to urine cell pellets. The median EV RNA yield of 36.4 ng was significantly higher than the median urine cell pellet RNA yield of 4.8 ng. Analysis of the post-DRE urine EVs indicated that prostate-specific transcripts were more abundant than kidney- or bladder-specific transcripts. Additionally, patients with prostate cancer had significantly higher levels of the prostate cancer-associated genes PCA3 and ERG.

Conclusions: Post-DRE urine EVs are a viable source of prostate-derived RNAs for biomarker discovery and prostate cancer status can be distinguished from analysis of these specimens. Continued analysis of urine EVs offers the potential discovery of novel biomarkers for pre-biopsy prostate cancer detection.
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http://dx.doi.org/10.1002/pros.23355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907935PMC
June 2017

Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.

Clin Cancer Res 2017 Jul 24;23(14):3823-3833. Epub 2017 Jan 24.

Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.

The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511561PMC
July 2017

Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality.

BJU Int 2017 06 11;119(6):961-967. Epub 2017 Feb 11.

Winship Cancer Institute, Atlanta, GA, USA.

Objectives: To determine the prognostic potential of a 24-gene signature, Sig24, for identifying patients with prostate cancer who are at risk of developing metastases or of prostate cancer-specific mortality (PCSM) after radical prostatectomy (RP).

Patients And Methods: Sig24 scores were calculated from previously collected gene expression microarray data from the Cleveland Clinic and Mayo Clinic (I and II). The performance of Sig24 was determined using time-dependent c-index analysis, Cox proportional hazards regression and Kaplan-Meier survival analysis.

Results: Higher Sig24 scores were significantly associated with higher pathological Gleason scores in all three cohorts. Analysis of the Mayo Clinic II cohort, which included time-to-event information, indicated that patients with high Sig24 scores also had a higher risk of developing metastasis (hazard ratio [HR] 3.78, 95% confidence interval [CI]: 1.96-7.29; P < 0.001) or of PCSM (HR 6.54, 95% CI: 2.16-19.83; P < 0.001).

Conclusions: The findings of the present study show the applicability of Sig24 for the prognosis of metastasis or PCSM after RP. Future studies investigating the combination of Sig24 with available prognostic tests may provide new approaches to improve risk stratification for patients with prostate cancer.
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http://dx.doi.org/10.1111/bju.13779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444982PMC
June 2017

Multinational Prospective Study of Patient-Reported Outcomes After Prostate Radiation Therapy: Detailed Assessment of Rectal Bleeding.

Int J Radiat Oncol Biol Phys 2016 11 3;96(4):770-777. Epub 2016 Aug 3.

University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: The new short Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) patient-reported health-related quality of life (HRQOL) tool has removed the rectal bleeding question from the previous much longer version, EPIC-26. Herein, we assess the impact of losing the dedicated rectal bleeding question in 2 independent prospective multicenter cohorts.

Methods And Materials: In a prospective multicenter test cohort (n=865), EPIC-26 patient-reported HRQOL data were collected for 2 years after treatment from patients treated with prostate radiation therapy from 2003 to 2011. A second prospective multicenter cohort (n=442) was used for independent validation. A repeated-effects model was used to predict the change from baseline in bowel summary scores from longer EPIC instruments using the change in EPIC-CP bowel summary scores with and without rectal bleeding scores.

Results: Two years after radiation therapy, 91% of patients were free of bleeding, and only 2.6% reported bothersome bleeding problems. Correlations between EPIC-26 and EPIC-CP bowel scores were very high (r=0.90-0.96) and were statistically improved with the addition of rectal bleeding information (r=0.94-0.98). Considering all patients, only 0.2% of patients in the test cohort and 0.7% in the validation cohort reported bothersome bleeding and had clinically relevant HRQOL changes missed with EPIC-CP. However, of the 2.6% (n=17) of men with bothersome rectal bleeding in the test cohort, EPIC-CP failed to capture 1 patient (6%) as experiencing meaningful declines in bowel HRQOL.

Conclusions: Modern prostate radiation therapy results in exceptionally low rates of bothersome rectal bleeding, and <1% of patients experience bothersome bleeding and are not captured by EPIC-CP as having meaningful HRQOL declines after radiation therapy. However, in the small subset of patients with bothersome rectal bleeding, the longer EPIC-26 should strongly be considered, given its superior performance in this patient subset.
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http://dx.doi.org/10.1016/j.ijrobp.2016.07.038DOI Listing
November 2016

Relief of Urinary Symptom Burden after Primary Prostate Cancer Treatment.

J Urol 2017 02 2;197(2):376-384. Epub 2016 Sep 2.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

Purpose: Harms of prostate cancer treatment on urinary health related quality of life have been thoroughly studied. In this study we evaluated not only the harms but also the potential benefits of prostate cancer treatment in relieving the pretreatment urinary symptom burden.

Materials And Methods: In American (1,021) and Spanish (539) multicenter prospective cohorts of men with localized prostate cancer we evaluated the effects of radical prostatectomy, external radiotherapy or brachytherapy in relieving pretreatment urinary symptoms and in inducing urinary symptoms de novo, measured by changes in urinary medication use and patient reported urinary bother.

Results: Urinary symptom burden improved in 23% and worsened in 28% of subjects after prostate cancer treatment in the American cohort. Urinary medication use rates before treatment and 2 years after treatment were 15% and 6% with radical prostatectomy, 22% and 26% with external radiotherapy, and 19% and 46% with brachytherapy, respectively. Pretreatment urinary medication use (OR 1.4, 95% CI 1.0-2.0, p = 0.04) and pretreatment moderate lower urinary tract symptoms (OR 2.8, 95% CI 2.2-3.6) predicted prostate cancer treatment associated relief of baseline urinary symptom burden. Subjects with pretreatment lower urinary tract symptoms who underwent radical prostatectomy experienced the greatest relief of pretreatment symptoms (OR 4.3, 95% CI 3.0-6.1), despite the development of deleterious de novo urinary incontinence in some men. The magnitude of pretreatment urinary symptom burden and beneficial effect of cancer treatment on those symptoms were verified in the Spanish cohort.

Conclusions: Men with pretreatment lower urinary tract symptoms may experience benefit rather than harm in overall urinary outcome from primary prostate cancer treatment. Practitioners should consider the full spectrum of urinary symptom burden evident before prostate cancer treatment in treatment decisions.
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http://dx.doi.org/10.1016/j.juro.2016.08.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501938PMC
February 2017

Clinical Use of Expanded Prostate Cancer Index Composite for Clinical Practice to Assess Patient Reported Prostate Cancer Quality of Life Following Robot-Assisted Radical Prostatectomy.

J Urol 2017 01 27;197(1):109-114. Epub 2016 Jul 27.

Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address:

Purpose: EPIC-CP (Expanded Prostate Cancer Index Composite for Clinical Practice) is a short questionnaire that comprehensively measures patient reported health related quality of life at the point of care. We evaluated the feasibility of using EPIC-CP in the routine clinical care of patients with prostate cancer without research infrastructure. We compared longitudinal patient and practitioner reported prostate cancer outcomes.

Materials And Methods: We reviewed health related quality of life outcomes in 482 patients who underwent radical prostatectomy at our institution from 2010 to 2014. EPIC-CP was administered and interpreted in routine clinical practice without research personnel. We compared practitioner documented rates of incontinence pad use and functional erections to patient reported rates using EPIC-CP.

Results: A total of 708 EPIC-CP questionnaires were completed. Mean urinary incontinence domain scores were significantly higher (worse) than baseline (mean ± SD 0.6 ± 0.2) 3 and 6 months after treatment (mean 3.1 ± 2.3 and 2.2 ± 2.1, respectively, each p <0.05) but they returned to baseline at 12 months (mean 1.6 ± 1.7, p >0.05). Mean sexual domain scores were significantly worse than baseline (mean 2.4 ± 2.8) at all posttreatment time points (each p <0.05). Practitioners significantly overestimated incontinence pad-free rates at 3 months (48% vs 39%) and functional erection rates at 3 months (18% vs 12%), 6 months (38% vs 23%) and 12 months (45% vs 23%, each p <0.05).

Conclusions: EPIC-CP is feasible to use in the routine clinical care of patients with prostate cancer without requiring a research infrastructure. Using EPIC-CP in clinical practice may help practitioners objectively assess and appropriately manage posttreatment side effects in patients with prostate cancer.
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http://dx.doi.org/10.1016/j.juro.2016.07.080DOI Listing
January 2017