R. Jeffrey Karnes

Clinicopathologic features and biochemical recurrence are sensitive, but not specific, predictors of metastatic disease and lethal prostate cancer. We hypothesize that a genomic expression signature detected in the primary tumor represents true biological potential of aggressive disease and provides improved prediction of early prostate cancer metastasis.A nested case-control design was used to select 639 patients from the Mayo Clinic tumor registry who underwent radical prostatectomy between 1987 and 2001. A genomic classifier (GC) was developed by modeling differential RNA expression using 1.4 million feature high-density expression arrays of men enriched for rising PSA after prostatectomy, including 213 who experienced early clinical metastasis after biochemical recurrence. A training set was used to develop a random forest classifier of 22 markers to predict for cases--men with early clinical metastasis after rising PSA. Performance of GC was compared to prognostic factors such as Gleason score and previous gene expression signatures in a withheld validation set.Expression profiles were generated from 545 unique patient samples, with median follow-up of 16.9 years. GC achieved an area under the receiver operating characteristic curve of 0.75 (0.67-0.83) in validation, outperforming clinical variables and gene signatures. GC was the only significant prognostic factor in multivariable analyses. Within Gleason score groups, cases with high GC scores experienced earlier death from prostate cancer and reduced overall survival. The markers in the classifier were found to be associated with a number of key biological processes in prostate cancer metastatic disease progression.A genomic classifier was developed and validated in a large patient cohort enriched with prostate cancer metastasis patients and a rising PSA that went on to experience metastatic disease. This early metastasis prediction model based on genomic expression in the primary tumor may be useful for identification of aggressive prostate cancer.

The introduction of novel imaging modalities has increased the detection of oligometastatic prostate cancer (PCa) recurrence, potentially justifying the use of a metastasis-directed therapy (MDT) with surgery or radiotherapy (RT) rather than a systemic approach.To perform a systematic review of MDT for oligometastatic PCa recurrence.This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. We searched the Medline and Embase databases from 1946 to February 2014 for studies reporting on biochemical or clinical progression and/or toxicity or complications of MDT (RT or surgery). Reports were excluded if these end points could not be ascertained or separately analysed, or if insufficient details were provided. Methodological quality was assessed using an 18-item validated quality appraisal tool for case series.Fifteen single-arm case series reporting on a total of 450 patients met the inclusion criteria. Seven studies were considered of acceptable quality. Oligometastatic PCa recurrence was diagnosed with positron emission tomography with coregistered computed tomography in most of the patients (98%). Nodal, bone, and visceral metastases were treated in 78%, 21%, and 1%, respectively. Patients were treated with either RT (66%) or lymph node dissection (LND) (34%). Adjuvant androgen deprivation was given in 61% of patients (n=275). In the case of nodal metastases, prophylactic nodal irradiation was administered in 49% of patients (n=172). Overall, 51% of patients were progression free 1-3 yr after salvage MDT, with most of them receiving adjuvant treatment. For RT, grade 2 toxicity was observed in 8.5% of patients, with one case of grade 3 toxicity. In the case of LND, 11% and 12% of grade 2 and grade 3 complications, respectively, were reported.MDT is a promising approach for oligometastatic PCa recurrence, but the low level of evidence generated by small case series does not allow extrapolation to a standard of care.We performed a systematic review to assess complications and outcomes of treating oligometastatic prostate cancer recurrence with surgery or radiotherapy. We concluded that although this approach is promising, it requires validation in randomised controlled trials.

No AccessJournal of UrologyAdult Urology1 Dec 2013Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population R. Jeffrey Karnes, Eric J. Bergstralh, Elai Davicioni, Mercedeh Ghadessi, Christine Buerki, Anirban P. Mitra, Anamaria Crisan, Nicholas Erho, Ismael A. Vergara, Lucia L. Lam, Rachel Carlson, Darby J.S. Thompson, Zaid Haddad, Benedikt Zimmermann, Thomas Sierocinski, Timothy J. Triche, Thomas Kollmeyer, Karla V. Ballman, Peter C. Black, George G. Klee, and Robert B. Jenkins R. Jeffrey KarnesR. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author , Eric J. BergstralhEric J. Bergstralh Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota More articles by this author , Elai DavicioniElai Davicioni GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Mercedeh GhadessiMercedeh Ghadessi GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Christine BuerkiChristine Buerki GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Anirban P. MitraAnirban P. Mitra Department of Pathology, University of Southern California, Los Angeles, California More articles by this author , Anamaria CrisanAnamaria Crisan GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Nicholas ErhoNicholas Erho GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Ismael A. VergaraIsmael A. Vergara GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Lucia L. LamLucia L. Lam GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Rachel CarlsonRachel Carlson Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota More articles by this author , Darby J.S. ThompsonDarby J.S. Thompson EMMES Canada, Burnaby, British Columbia, Canada More articles by this author , Zaid HaddadZaid Haddad GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Benedikt ZimmermannBenedikt Zimmermann GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Thomas SierocinskiThomas Sierocinski GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , Timothy J. TricheTimothy J. Triche GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Department of Pathology, University of Southern California, Los Angeles, California Current address: Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Department of Pathology and Pediatrics, Keck School of Medicine at University of Southern California, Los Angeles, California. More articles by this author , Thomas KollmeyerThomas Kollmeyer Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota More articles by this author , Karla V. BallmanKarla V. Ballman Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Journal of Clinical Oncology. More articles by this author , Peter C. BlackPeter C. Black Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author , George G. KleeGeorge G. Klee Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota More articles by this author , and Robert B. JenkinsRobert B. Jenkins Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.06.017AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Patients with locally advanced prostate cancer after radical prostatectomy are candidates for secondary therapy. However, this higher risk population is heterogeneous. Many cases do not metastasize even when conservatively managed. Given the limited specificity of pathological features to predict metastasis, newer risk prediction models are needed. We report a validation study of a genomic classifier that predicts metastasis after radical prostatectomy in a high risk population. Materials and Methods: A case-cohort design was used to sample 1,010 patients after radical prostatectomy at high risk for recurrence who were treated from 2000 to 2006. Patients had preoperative prostate specific antigen greater than 20 ng/ml, Gleason 8 or greater, pT3b or a Mayo Clinic nomogram score of 10 or greater. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded from analysis. A 20% random sampling created a subcohort that included all patients with metastasis. We generated 22-marker genomic classifier scores for 219 patients with available genomic data. ROC and decision curves, competing risk and weighted regression models were used to assess genomic classifier performance. Results: The genomic classifier AUC was 0.79 for predicting 5-year metastasis after radical prostatectomy. Decision curves showed that the genomic classifier net benefit exceeded that of clinical only models. The genomic classifier was the predominant predictor of metastasis on multivariable analysis. The cumulative incidence of metastasis 5 years after radical prostatectomy was 2.4%, 6.0% and 22.5% in patients with low (60%), intermediate (21%) and high (19%) genomic classifier scores, respectively (p <0.001). Conclusions: Results indicate that genomic information from the primary tumor can identify patients with adverse pathological features who are most at risk for metastasis and potentially lethal prostate cancer. References 1 : International variation in prostate cancer incidence and mortality rates. Eur Urol2012; 61: 1079. Google Scholar 2 : Prostate cancer epidemiology in the United States. World J Urol2012; 30: 195. Google Scholar 3 : Cancer statistics, 2012. CA Cancer J Clin2012; 62: 10. Google Scholar 4 : Prognostic factors for failure after prostatectomy. J Cancer2011; 2: 1. Google Scholar 5 : Impact of biochemical recurrence in prostate cancer among US veterans. Arch Intern Med2010; 170: 1390. 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Google Scholar 27 : Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol2011; 29: 742. Google Scholar 28 : Reverse stage shift at a tertiary care center: escalating risk in men undergoing radical prostatectomy. Cancer2011; 117: 4855. Google Scholar 29 : Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med2012; 157: 120. Google Scholar 30 : Initial Report of RTOG 9601: A phase III trial in prostate cancer: anti-androgen therapy (AAT) with bicalutamide during and after radiation therapy (RT) improves freedom from progression and reduces the incidence of metastatic disease in patients following radical prostatectomy (RP) with pT2-3, N0 disease and elevated PSA levels. Int J Radiat Oncol Biol Physics2010; 78: S27. Google Scholar © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byAtala A (2019) Re: Large-Scale Transcriptome-Wide Association Study Identifies New Prostate Cancer Risk RegionsJournal of Urology, VOL. 201, NO. 3, (447-447), Online publication date: 1-Mar-2019.Taneja S (2018) Re: Development and Validation of a Novel Integrated Clinical-Genomic Risk Group Classification for Localized Prostate CancerJournal of Urology, VOL. 200, NO. 3, (498-499), Online publication date: 1-Sep-2018.Taneja S (2018) Re: Development and Validation of a 24-Gene Predictor of Response to Postoperative Radiotherapy in Prostate Cancer: A Matched, Retrospective AnalysisJournal of Urology, VOL. 197, NO. 5, (1264-1266), Online publication date: 1-May-2017.Gild P and Abdollah F (2018) Editorial CommentJournal of Urology, VOL. 198, NO. 2, (361-361), Online publication date: 1-Aug-2017.Glass A, Leo M, Haddad Z, Yousefi K, du Plessis M, Chen C, Choeurng V, Abdollah F, Robbins B, Ra S, Richert-Boe K, Buerki C, Pearson K, Davicioni E and Weinmann S (2018) Validation of a Genomic Classifier for Predicting Post-Prostatectomy Recurrence in a Community Based Health Care SettingJournal of Urology, VOL. 195, NO. 6, (1748-1753), Online publication date: 1-Jun-2016.Taneja S (2018) Re: Impact of a Genomic Classifier of Metastatic Risk on Postprostatectomy Treatment Recommendations by Radiation Oncologists and UrologistsJournal of Urology, VOL. 195, NO. 5, (1472-1472), Online publication date: 1-May-2016.Johnson M, Ross A, Alshalalfa M, Erho N, Yousefi K, Glavaris S, Fedor H, Han M, Faraj S, Bezerra S, Netto G, Partin A, Trock B, Davicioni E and Schaeffer E (2018) SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy CohortJournal of Urology, VOL. 196, NO. 5, (1436-1444), Online publication date: 1-Nov-2016. Volume 190Issue 6December 2013Page: 2047-2053Supplementary Materials Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Keywordsprostatic neoplasmsprostateneoplasm metastasisprognosistranscriptomeAcknowledgmentsStephanie Fink assisted with experiments.MetricsAuthor Information R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Eric J. Bergstralh Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota More articles by this author Elai Davicioni GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Mercedeh Ghadessi GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Christine Buerki GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Anirban P. Mitra Department of Pathology, University of Southern California, Los Angeles, California More articles by this author Anamaria Crisan GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Nicholas Erho GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Ismael A. Vergara GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Lucia L. Lam GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Rachel Carlson Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota More articles by this author Darby J.S. Thompson EMMES Canada, Burnaby, British Columbia, Canada More articles by this author Zaid Haddad GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Benedikt Zimmermann GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Thomas Sierocinski GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author Timothy J. Triche GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada Department of Pathology, University of Southern California, Los Angeles, California Current address: Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Department of Pathology and Pediatrics, Keck School of Medicine at University of Southern California, Los Angeles, California. More articles by this author Thomas Kollmeyer Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota More articles by this author Karla V. Ballman Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Journal of Clinical Oncology. More articles by this author Peter C. Black Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada Financial interest and/or other relationship with GenomeDx Biosciences. More articles by this author George G. Klee Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota More articles by this author Robert B. Jenkins Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota More articles by this author Expand All Advertisement PDF downloadLoading ...

The natural history of biochemical recurrence (BCR) after radical retropubic prostatectomy (RRP) is variable and does not always translate into systemic progression or prostate cancer (PCa) death. To evaluate long-term clinical outcomes of patients with BCR and to determine predictors of disease progression and mortality in these men. We reviewed our institutional registry of 14 632 patients who underwent RRP between 1990 and 2006 to identify 2426 men with BCR (prostate-specific antigen [PSA] levels ≥0.4 ng/ml) who did not receive neoadjuvant or adjuvant therapy. Median follow-up was 11.5 yr after RRP and 6.6 yr after BCR. RRP. Patients were grouped into quartiles according to time from RRP to BCR. Survival after BCR was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard regression models were used to analyze clinicopathologic variables associated with systemic progression and death from PCa. Median systemic progression-free survival (PFS) and cancer-specific survival (CSS) had not been reached after 15 yr of follow-up after BCR. Cancer-specific mortality 10 yr after BCR was 9.9%, 9.3%, 7.8%, and 4.7% for patients who experienced BCR <1.2 yr, 1.2–3.1 yr, 3.1–5.9 yr, and >5.9 yr after RRP, respectively (p = 0.10). On multivariate analysis, time from RRP to BCR was not significantly associated with the risk of systemic progression (p = 0.50) or cancer-specific mortality (p = 0.81). Older patient age, increased pathologic Gleason score, advanced tumor stage, and rapid PSA doubling time (DT) predicted systemic progression and death from PCa. Limitations included retrospective design, varied utilization of salvage therapies, and the inclusion of few patients with positive lymph nodes. Only a minority of men experience systemic progression and death from PCa following BCR. The decision to institute secondary therapies must balance the risk of disease progression with the cost and morbidity of treatment, independent of time from RRP to BCR.

While the incidence of lymph node positive prostate cancer has decreased during the prostate specific antigen era, the optimal treatment of these patients remains in question. We examined the impact of lymph node metastases on the outcome of patients following radical prostatectomy and investigated prognostic factors that affect survival.We identified 507 men treated with radical prostatectomy between 1988 and 2001 who had lymph node positive disease. Of the 507 patients 455 (89.7%) were treated with adjuvant hormonal therapy. Median followup was 10.3 years (IQR 6.1-13.5). Postoperative survival rates were estimated using the Kaplan-Meier method and the impact of various clinicopathological factors on outcome was analyzed using Cox proportional hazard regression models.Ten-year cancer specific survival for patients with positive lymph nodes was 85.8% with 56% of the men free from biochemical recurrence at last followup. On multivariate analysis pathological Gleason score 8-10 (p = 0.004), positive surgical margins (p = 0.016), nondiploid tumor ploidy (p = 0.023) and 2 or greater positive nodes (p = 0.001) were adverse predictors of cancer specific survival. Tumor stage, year of surgery and total number of nodes removed did not significantly affect outcome. Adjuvant hormonal therapy decreased the risk of biochemical recurrence (p <0.001) and local recurrence (p = 0.004) but it was not associated with systemic progression (p = 0.4) or cancer specific survival (p = 0.4).Radical prostatectomy may offer long-term survival to patients with lymph node positive prostate cancer. Gleason score, margin status, tumor ploidy and the number of involved nodes predict survival, while the role of adjuvant hormonal therapy continues to be defined.

Prostate cancer (PCa) recurrence following definitive radiation therapy (RT) remains a vexing challenge for the practicing physician. Salvage radical prostatectomy (SRP) has not been recognized yet as a valuable therapeutic option. We critically analyzed the currently available evidence on SRP as to patient selection, predictive oncologic factors, surgical technique, cancer control, surgical complications, functional outcomes, and comparison to other salvage therapies. A systematic review of the literature was performed in June 2011 using the Medline, Embase, and Web of Science databases, limiting the review to English-language articles published between January 1980 and June 2011. All authors reviewed the list of references and added papers relevant to the topic of the review prior to the analysis. The panel selected 40 articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Positive surgical margins in SRP varied from 43% to 70% in earlier publications versus 0–36% in recent publications, and pathologic organ-confined disease (OCD) was found in 22–53% versus 44–73% in earlier versus recent publications. Biochemical recurrence–free probability after SRP ranged from 47% to 82% at 5 yr and from 28% to 53% at 10 yr. Cancer-specific survival (CSS) and overall survival varied from 70% to 83% and 54% to 89% at 10 yr. Pre-SRP prostate-specific antigen value and prostate biopsy Gleason score were the strongest prognostic risk factors for progression-free survival, OCD, and CSS. Open, laparoscopic, and robotic techniques were shown to be feasible in the hands of experienced surgeons. The most frequent complications included anastomotic stricture (7–41%) followed by rectal injury (0–28%). Major complications (modified Clavien classification grade 3–5) varied from 0% to 25%. Most complications were less frequent in more recent series, except for anastomotic stricture. The majority of patients had erectile dysfunction prior to SRP (50–91%) and 80–100% after SRP. Urinary continence ranged from 21% to 90% after surgery. Limitations of this review include the absence of prospective studies and lack of comparative analyses between SRP and other therapies. In selected patients with confirmed, localized, radiation-recurrent PCa, SRP may effectively promote durable cancer control with acceptable associated surgical morbidity and variable functional recovery.

Abstract BACKGROUND: The long‐term survival of patients with high‐risk prostate cancer was compared after radical prostatectomy (RRP) and after external beam radiation therapy (EBRT) with or without adjuvant androgen‐deprivation therapy (ADT). METHODS: In total, 1238 patients underwent RRP, and 609 patients received with EBRT (344 received EBRT plus ADT, and 265 received EBRT alone) between 1988 and 2004 who had a pretreatment prostate‐specific antigen (PSA) level ≥ 20 ng/mL, a biopsy Gleason score between 8 and 10, or clinical tumor classification ≥ T3. The median follow‐up was 10.2 years, 6.0 years, and 7.2 years after RRP, EBRT plus ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer‐specific survival, and overall survival was evaluated using multivariate Cox proportional hazard regression analysis and a competing risk‐regression model. RESULTS: The 10‐year cancer‐specific survival rate was 92%, 92%, and 88% after RRP, EBRT plus ADT, and EBRT alone, respectively ( P = .06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.51‐1.18; P = .23) or prostate cancer death (HR, 1.14; 95% CI, 0.68‐1.91; P = .61) were observed between patients who received EBRT plus ADT and patients who underwent RRP. The risk of all‐cause mortality, however, was greater after EBRT plus ADT than after RRP (HR, 1.60; 95% CI, 1.25‐2.05; P = .0002). CONCLUSIONS: RRP alone and EBRT plus ADT provided similar long‐term cancer control for patients with high‐risk prostate cancer. The authors concluded that continued investigation into the differing impact of treatments on quality‐of‐life and noncancer mortality will be necessary to determine the optimal management approach for these patients. Cancer 2011. © 2011 American Cancer Society.

The role of adjuvant radiotherapy (aRT) in treating patients with pN1 prostate cancer is controversial. We tested the hypothesis that the impact of aRT on cancer-specific mortality (CSM) in these individuals is related to tumor characteristics.We evaluated 1,107 patients with pN1 prostate cancer treated with radical prostatectomy and anatomically extended pelvic lymph node dissection between 1988 and 2010 at two tertiary care centers. All patients received adjuvant hormonal therapy with or without aRT. Regression tree analysis stratified patients into risk groups on the basis of their tumor characteristics and the corresponding CSM rate. Cox regression analysis tested the relationship between aRT and CSM rate, as well as overall mortality (OM) rate in each risk group separately.Overall, 35% of patients received aRT. At multivariable analysis, aRT was associated with more favorable CSM rate (hazard ratio [HR], 0.37; P < .001). However, when patients were stratified into risk groups, only two groups of men benefited from aRT: (1) patients with positive lymph node (PLN) count ≤ 2, Gleason score 7 to 10, pT3b/pT4 stage, or positive surgical margins (HR, 0.30; P = .002); and (2) patients with PLN count of 3 to 4 (HR, 0.21; P = .02), regardless of other tumor characteristics. These results were confirmed when OM was examined as an end point.The beneficial impact of aRT on survival in patients with pN1 prostate cancer is highly influenced by tumor characteristics. Men with low-volume nodal disease (≤ two PLNs) in the presence of intermediate- to high-grade, non-specimen-confined disease and those with intermediate-volume nodal disease (three to four PLNs) represent the ideal candidates for aRT after surgery.

Improved clinical predictors for disease progression are needed for localised prostate cancer, since only a subset of patients develop recurrent or refractory disease after first-line treatment. Therefore, we undertook an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy.Prostate cancer samples from patients treated with radical prostatectomy at three academic institutions were analysed for gene expression by a high-density Affymetrix GeneChip platform, encompassing more than 1 million genomic loci. In a discovery cohort, all protein-coding genes and known long non-coding RNAs were ranked by fold change in expression between tumours that subsequently metastasised versus those that did not. The top ranked gene was then validated for its prognostic value for metastatic progression in three additional independent cohorts. 95% of the gene expression assays were done in a Clinical Laboratory Improvements Amendments certified laboratory facility. All genes were assessed for their ability to predict metastatic progression by receiver-operating-curve area-under-the-curve analyses. Multivariate analyses were done for the primary endpoint of metastatic progression, with variables including Gleason score, preoperative prostate-specific antigen concentration, seminal vesicle invasion, surgical margin status, extracapsular extension, lymph node invasion, and expression of the highest ranked gene.1008 patients were included in the study: 545 in the discovery cohort and 463 in the validation cohorts. The long non-coding RNA SChLAP1 was identified as the highest-ranked overexpressed gene in cancers with metastatic progression. Validation in three independent cohorts confirmed the prognostic value of SChLAP1 for metastatic progression. On multivariate modelling, SChLAP1 expression (high vs low) independently predicted metastasis within 10 years (odds ratio [OR] 2·45, 95% CI 1·70-3·53; p<0·0001). The only other variable that independently predicted metastasis within 10 years was Gleason score (8-10 vs 5-7; OR 2·14, 95% CI 1·77-2·58; p<0·0001).We identified and validated high SChLAP1 expression as significantly prognostic for metastatic disease progression of prostate cancer. Our findings suggest that further development of SChLAP1 as a potential biomarker, for treatment intensification in aggressive prostate cancer, warrants future study.Prostate Cancer Foundation, National Institutes of Health, Department of Defense, Early Detection Research Network, Doris Duke Charitable Foundation, and Howard Hughes Medical Institute.

<h3>Importance</h3> There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. <h3>Objectives</h3> To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. <h3>Design, Setting, and Participants</h3> The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes. <h3>Main Outcomes and Measures</h3> Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. <h3>Results</h3> Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as<i>NKX3.1</i>and<i>KRT18</i>, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%;<i>P</i> = .006 for interaction). <h3>Conclusions and Relevance</h3> Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.

The optimal management strategy for men with newly diagnosed clinically localized prostate cancer remains a matter of debate. Numerous series have reported cancer control and quality-of-life (QoL) outcomes following treatment with radical prostatectomy (RP). Critically review published oncologic and functional outcomes after RP, and evaluate factors associated with these outcome measures. A review of the literature was performed using the Medline and Web of Sciences databases. Relevant reports published between 1980 and 2011 identified using the keywords prostate cancer, radical prostatectomy, prostate-specific antigen, biochemical recurrence, incontinence, and erectile dysfunction were reviewed and summarized. Cancer control rates following RP largely depend on the definition of treatment efficacy. While up to 40% of men have been reported to experience postoperative biochemical recurrence on long-term follow-up, death from prostate cancer has been noted in <10% of men at 15 yr after surgery in contemporary series. For men with high-risk disease, surgery affords pathologic staging, thereby facilitating the selective application of secondary therapies, and has been associated with decreased mortality risk versus radiation in retrospective series. Reported functional outcomes after surgery, particularly urinary continence and erectile dysfunction, have varied greatly to date. These assessments have been limited by nonstandardized reporting methodology. The use of robot-assisted radical prostatectomy has increased in recent years, and while follow-up is thus far short, available data do not suggest the superiority of either approach in terms of functional or oncologic outcomes. RP is associated with excellent long-term cancer control. Continued efforts to conduct prospective assessments of postoperative functional outcomes are necessary using validated QoL instruments. The importance of surgical approach will also require further study, incorporating comparative oncologic, functional, and economic data.

Telemedicine in an ambulatory surgical population remains incompletely evaluated.To investigate patient encounters in the outpatient setting using video visit (VV) technology compared to traditional office visits (OVs).From June 2013 to March 2014, 55 prescreened men with a history of prostate cancer were prospectively randomized. VVs, with the patient at home or at work, were included in the outpatient clinic calendar of urologists.Remote VV versus traditional OV.An equivalence analysis was used to assess the primary outcome, visit efficiency as measured by time studies. Secondary outcomes were patient/provider satisfaction and costs.There were 28 VVs and 27 OVs. VVs were equivalent in efficiency to relative to OVs, as measured by patient-provider face time (mean 14.5 vs 14.3min; p=0.96), patient wait time (18.4 vs 13.0min; p=0.20), and total time devoted to care (17.9 vs 17.8min; p=0.97). There were no significant differences in patient perception of visit confidentiality, efficiency, education quality, or overall satisfaction. VVs incurred lower costs, including distance traveled (median 0 vs 95 miles), travel time (0 vs 95min), missed work (0 vs 1 d), and money spent on travel ($0 vs $48; all p<0.0001). There was a high level of urologist satisfaction for both VVs (88%) and OVs (90%). The major limitation was sample size.VV in the ambulatory postprostatectomy setting may have a future role in health care delivery models. We found equivalent efficiency, similar satisfaction, but significantly reduced patient costs for VV compared to OV. Further prospective analyses are warranted.Among men with surgically treated prostate cancer, we evaluated the utility of remote video visits compared to office visits for outpatient consultation with a urologist. Video visits were associated with equivalent efficiency, similar satisfaction, and significantly lower patient costs when compared to office visits. We conclude that video visits may have a future role in health care delivery models.

The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making.To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment.Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011.Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS).With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥ 70 yr, size ≥ 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥ 70 yr with tumor size ≥ 3 cm and 13% otherwise.T1G3 patients ≥ 70 yr with tumors ≥ 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression.Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥ 70 yr, tumor size ≥ 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

The optimal timing of postoperative radiotherapy (RT) after radical prostatectomy (RP) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into the development of clinical metastases in men receiving post-RP RT and inform decision making.GC scores were calculated from 188 patients with pT3 or margin-positive prostate cancer, who received post-RP RT at Thomas Jefferson University and Mayo Clinic between 1990 and 2009. The primary end point was clinical metastasis. Prognostic accuracy of the models was tested using the concordance index for censored data and decision curve analysis. Cox regression analysis tested the relationship between GC and metastasis.The cumulative incidence of metastasis at 5 years after RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (P = .002). In multivariable analysis, GC and pre-RP prostate-specific antigen were independent predictors of metastasis (both P < .01). Within the low GC score (< 0.4), there were no differences in the cumulative incidence of metastasis comparing patients who received adjuvant or salvage RT (P = .79). However, for patients with higher GC scores (≥ 0.4), cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared with 23% for patients treated with salvage RT (P < .01).In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical and pathologic features. Although preliminary, patients with low GC scores are best treated with salvage RT, whereas those with high GC scores benefit from adjuvant therapy. These findings provide the first rational selection of timing for post-RP RT.

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

Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS).To assess the efficacy of alvimopan to accelerate GI recovery after RC.We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics.Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo.The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed.Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy.Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo.This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety.ClinicalTrials.gov identifier NCT00708201.

Postoperative radiotherapy has an important role in the treatment of prostate cancer, but personalised patient selection could improve outcomes and spare unnecessary toxicity. We aimed to develop and validate a gene expression signature to predict which patients would benefit most from postoperative radiotherapy.Patients were eligible for this matched, retrospective study if they were included in one of five published US studies (cohort, case-cohort, and case-control studies) of patients with prostate adenocarcinoma who had radical prostatectomy (with or without postoperative radiotherapy) and had gene expression analysis of the tumour, with long-term follow-up and complete clinicopathological data. Additional treatment after surgery was at the treating physician's discretion. In each cohort, patients who had postoperative radiotherapy were matched with patients who had not had radiotherapy using Gleason score, prostate-specific antigen concentration, surgical margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion, and androgen deprivation therapy. We constructed a matched training cohort using patients from one study in which we developed a 24-gene Post-Operative Radiation Therapy Outcomes Score (PORTOS). We generated a pooled matched validation cohort using patients from the remaining four studies. The primary endpoint was the development of distant metastasis.In the training cohort (n=196), among patients with a high PORTOS (n=39), those who had radiotherapy had a lower incidence of distant metastasis than did patients who did not have radiotherapy, with a 10-year metastasis rate of 5% (95% CI 0-14) in patients who had radiotherapy (n=20) and 63% (34-80) in patients who did not have radiotherapy (n=19; hazard ratio [HR] 0·12 [95% CI 0·03-0·41], p<0·0001), whereas among patients with a low PORTOS (n=157), those who had postoperative radiotherapy (n=78) had a greater incidence of distant metastasis at 10 years than did their untreated counterparts (n=79; 57% [44-67] vs 31% [20-41]; HR 2·5 [1·6-4·1], p<0·0001), with a significant treatment interaction (pinteraction<0·0001). The finding that PORTOS could predict outcome due to radiotherapy treatment was confirmed in the validation cohort (n=330), which showed that patients who had radiotherapy had a lower incidence of distant metastasis compared with those who did not have radiotherapy, but only in the high PORTOS group (high PORTOS [n=82]: 4% [95% CI 0-10] in the radiotherapy group [n=57] vs 35% [95% CI 7-54] in the no radiotherapy group [n=25] had metastasis at 10 years; HR 0·15 [95% CI 0·04-0·60], p=0·0020; low PORTOS [n=248]: 32% [95% CI 19-43] in the radiotherapy group [n=108] vs 32% [95% CI 22-40] in the no radiotherapy group [n=140]; HR 0·92 [95% CI 0·56-1·51], p=0·76), with a significant interaction (pinteraction=0·016). The conventional prognostic tools Decipher, CAPRA-S, and microarray version of the cell cycle progression signature did not predict response to radiotherapy (pinteraction>0·05 for all).Patients with a high PORTOS who had postoperative radiotherapy were less likely to have metastasis at 10 years than those who did not have radiotherapy, suggesting that treatment with postoperative radiotherapy should be considered in this subgroup. PORTOS should be investigated further in additional independent cohorts.None.

High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory.To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high-risk PCa based on combinations of unfavorable risk factors.We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high-volume centers.Retropubic radical prostatectomy with pelvic lymphadenectomy.Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (< cT3 vs cT3-4), Gleason score (GS) (2-7 vs 8-10), and prostate-specific antigen (PSA; ≤ 20 ng/ml vs > 20 ng/ml). The first "extended" model includes all seven possible combinations; the second "simplified" model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3-4); and a poor prognosis subgroup (GS 8-10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups.The simplified model yielded an R(2) of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R(2): 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period.This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting.

Purpose To perform the first meta-analysis of the performance of the genomic classifier test, Decipher, in men with prostate cancer postprostatectomy. Methods MEDLINE, EMBASE, and the Decipher genomic resource information database were searched for published reports between 2011 and 2016 of men treated by prostatectomy that assessed the benefit of the Decipher test. Multivariable Cox proportional hazards models fit to individual patient data were performed; meta-analyses were conducted by pooling the study-specific hazard ratios (HRs) using random-effects modeling. Extent of heterogeneity between studies was determined with the I2 test. Results Five studies (975 total patients, and 855 patients with individual patient-level data) were eligible for analysis, with a median follow-up of 8 years. Of the total cohort, 60.9%, 22.6%, and 16.5% of patients were classified by Decipher as low, intermediate, and high risk, respectively. The 10-year cumulative incidence metastases rates were 5.5%, 15.0%, and 26.7% ( P < .001), respectively, for the three risk classifications. Pooling the study-specific Decipher HRs across the five studies resulted in an HR of 1.52 (95% CI, 1.39 to 1.67; I2 = 0%) per 0.1 unit. In multivariable analysis of individual patient data, adjusting for clinicopathologic variables, Decipher remained a statistically significant predictor of metastasis (HR, 1.30; 95% CI, 1.14 to 1.47; P < .001) per 0.1 unit. The C-index for 10-year distant metastasis of the clinical model alone was 0.76; this increased to 0.81 with inclusion of Decipher. Conclusion The genomic classifier test, Decipher, can independently improve prognostication of patients postprostatectomy, as well as within nearly all clinicopathologic, demographic, and treatment subgroups. Future study of how to best incorporate genomic testing in clinical decision-making and subsequent treatment recommendations is warranted.

Risk prediction models that incorporate biomarkers and clinicopathologic variables may be used to improve decision making after radical prostatectomy (RP). We compared two previously validated post-RP classifiers-the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) and the Decipher genomic classifier (GC)-to predict prostate cancer-specific mortality (CSM) in a contemporary cohort of RP patients.To evaluate the combined prognostic ability of CAPRA-S and GC to predict CSM.A cohort of 1010 patients at high risk of recurrence after RP were treated at the Mayo Clinic between 2000 and 2006. High risk was defined by any of the following: preoperative prostate-specific antigen >20 ng/ml, pathologic Gleason score ≥8, or stage pT3b. A case-cohort random sample identified 225 patients (with cases defined as patients who experienced CSM), among whom CAPRA-S and GC could be determined for 185 patients.The scores were evaluated individually and in combination using concordance index (c-index), decision curve analysis, reclassification, cumulative incidence, and Cox regression for the prediction of CSM.Among 185 men, 28 experienced CSM. The c-indices for CAPRA-S and GC were 0.75 (95% confidence interval [CI], 0.55-0.84) and 0.78 (95% CI, 0.68-0.87), respectively. GC showed higher net benefit on decision curve analysis, but a score combining CAPRA-S and GC did not improve the area under the receiver-operating characteristic curve after optimism-adjusted bootstrapping. In 82 patients stratified to high risk based on CAPRA-S score ≥6, GC scores were likewise high risk for 33 patients, among whom 17 had CSM events. GC reclassified the remaining 49 men as low to intermediate risk; among these men, three CSM events were observed. In multivariable analysis, GC and CAPRA-S as continuous variables were independently prognostic of CSM, with hazard ratios (HRs) of 1.81 (p<0.001 per 0.1-unit change in score) and 1.36 (p=0.01 per 1-unit change in score). When categorized into risk groups, the multivariable HR for high CAPRA-S scores (≥6) was 2.36 (p=0.04) and was 11.26 (p<0.001) for high GC scores (≥0.6). For patients with both high GC and high CAPRA-S scores, the cumulative incidence of CSM was 45% at 10 yr. The study is limited by its retrospective design.Both GC and CAPRA-S were significant independent predictors of CSM. GC was shown to reclassify many men stratified to high risk based on CAPRA-S ≥6 alone. Patients with both high GC and high CAPRA-S risk scores were at markedly elevated post-RP risk for lethal prostate cancer. If validated prospectively, these findings suggest that integration of a genomic-clinical classifier may enable better identification of those post-RP patients who should be considered for more aggressive secondary therapies and clinical trials.The Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) and the Decipher genomic classifier (GC) were significant independent predictors of prostate cancer-specific mortality. These findings suggest that integration of a genomic-clinical classifier may enable better identification of those post-radical prostatectomy patients who should be considered for more aggressive secondary therapies and clinical trials.

Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low- to very-high-risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.

Pretreatment neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been associated with adverse survival in a variety of malignancies. However, the relationship between NLR and oncologic outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) has not been well studied.To evaluate the association of preoperative NLR with clinicopathologic outcomes following RC.We identified 899 patients who underwent RC without neoadjuvant therapy at our institution between 1994 and 2005 and who had a pretreatment NLR.Preoperative NLR (within 90 d prior to RC) was recorded. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox proportional hazard and logistic regression models were used to analyze the association of NLR with clinicopathologic outcomes.Median postoperative follow-up was 10.9 yr (interquartile range: 8.3-13.9 yr). Higher preoperative NLR was associated with significantly increased risks of pathologic, extravesical tumor extension (odds ratio [OR]: 1.07; p=0.03) and lymph node involvement (OR: 1.09; p=0.02). Univariately, 10-yr cancer-specific survival was significantly worse among patients with a preoperative NLR (≥2.7 [51%] vs. <2.7 [64%]; p<0.001). Moreover, on multivariate analysis, increased preoperative NLR was independently associated with greater risks of disease recurrence (hazard ratio [HR]: 1.04; p=0.02), death from bladder cancer (HR: 1.04; p=0.01), and all-cause mortality (HR: 1.03; p=0.01).Elevated preoperative NLR among patients undergoing RC is associated with significantly increased risk for locally advanced disease as well as subsequent disease recurrence, and cancer-specific and all-cause mortality. These data suggest that serum NLR may be a useful prognostic marker for preoperative patient risk stratification, including consideration for neoadjuvant therapy and clinical trial enrollment.

Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets. We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013–2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided. Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03). In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.

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.

The coronavirus disease 2019 (COVID-19) pandemic is leading to delays in the treatment of many urologic cancers.To provide a contemporary picture of the risks from delayed treatment for urologic cancers to assist with triage.A collaborative review using literature published as of April 2, 2020.Patients with low-grade non-muscle-invasive bladder cancer are unlikely to suffer from a 3-6-month delay. Patients with muscle-invasive bladder cancer are at risk of disease progression, with radical cystectomy delays beyond 12 wk from diagnosis or completion of neoadjuvant chemotherapy. Prioritization of these patients for surgery or management with radiochemotherapy is encouraged. Active surveillance should be used for low-risk prostate cancer (PCa). Treatment of most patients with intermediate- and high-risk PCa can be deferred 3-6 mo without change in outcomes. The same may be true for cancers with the highest risk of progression. With radiotherapy, neoadjuvant androgen deprivation therapy (ADT) is the standard of care. For surgery, although the added value of neoadjuvant ADT is questionable, it may be considered if a patient is interested in such an approach. Intervention may be safely deferred for T1/T2 renal masses, while locally advanced renal tumors (≥T3) should be treated expeditiously. Patients with metastatic renal cancer may consider vascular endothelial growth factor targeted therapy over immunotherapy. Risks for delay in the treatment of upper tract urothelial cancer depend on grade and stage. For patients with high-grade disease, delays of 12 wk in nephroureterectomy are not associated with adverse survival outcomes. Expert guidance recommends expedient local treatment of testis cancer. In penile cancer, adverse outcomes have been observed with delays of ≥3 mo before inguinal lymphadenectomy. Limitations include a paucity of data and methodologic variations for many cancers.Patients and clinicians should consider the oncologic risk of delayed cancer intervention versus the risks of COVID-19 to the patient, treating health care professionals, and the health care system.The coronavirus disease 2019 pandemic has led to delays in the treatment of patients with urologic malignancies. Based on a review of the literature, patients with high-grade urothelial carcinoma, advanced kidney cancer, testicular cancer, and penile cancer should be prioritized for treatment during these challenging times.

Molecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use. To perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC). The review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446–52) and American Urology Association (AUA) criteria. In total, 42 studies and 30 407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n = 12 141), prospective registries (n = 17 053), and prospective and post hoc randomized trial analyses (n = 1213). In 32 studies (n = 12 600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n = 8543). GC use changed the management in active surveillance (number needed to test [NNT] = 9) and postprostatectomy (NNT = 1.5–4) settings in five studies (n = 4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state. Consistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making. In this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making.

Abstract c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

No AccessJournal of UrologyAdult Urology1 Apr 2008Mayo Clinic Validation of the D’Amico Risk Group Classification for Predicting Survival Following Radical Prostatectomyis accompanied byEarly Postoperative Plasma Transforming Growth Factor-β1 is a Strong Predictor of Biochemical Progression After Radical Prostatectomy Stephen A. Boorjian, R. Jeffrey Karnes, Laureano J. Rangel, Eric J. Bergstralh, and Michael L. Blute Stephen A. BoorjianStephen A. Boorjian , R. Jeffrey KarnesR. Jeffrey Karnes , Laureano J. RangelLaureano J. Rangel , Eric J. BergstralhEric J. Bergstralh , and Michael L. BluteMichael L. Blute View All Author Informationhttps://doi.org/10.1016/j.juro.2007.11.061AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: The D’Amico risk group classification was originally developed to estimate the risk of biochemical recurrence following treatment for localized prostate cancer. We externally validated the ability of the risk groups to predict clinical progression, and cancer specific and overall survival following radical prostatectomy, and identify predictors of outcome in patients with high risk disease. Materials and Methods: We evaluated the records of 7,591 consecutive patients who underwent radical prostatectomy at our institution between 1987 and 2003. Postoperative survival was estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to analyze the ability of the risk groups to predict survival and to evaluate the impact of clinicopathological factors on outcome in patients at high risk. Results: Preoperative risk group stratification predicted the patient risk of biochemical and local recurrence, systemic progression, and cancer specific and overall survival (each p <0.001). The HR of death from prostate cancer after surgery in patients with high or intermediate risk disease was 11.5 (95% CI 5.9 to 22.3, p <0.0001) and 6.3 (95% CI 3.3 to 12.3, p <0.0001), respectively, compared to patients at low risk. In patients in the high risk group biopsy Gleason score (p = 0.006), pathological Gleason score (p = 0.006), pathological tumor stage (p = 0.04), positive lymph nodes (p = 0.02) and positive surgical margins (p = 0.008) predicted death from prostate cancer. Conclusions: We validated the ability of the risk group stratification to predict disease progression and patient survival following radical prostatectomy. Additional prognostic information from surgical staging may assist in individualized postoperative management, particularly for patients at high risk. References 1 : Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA1998; 280: 969. Crossref, Medline, Google Scholar 2 : A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst1998; 90: 766. Crossref, Medline, Google Scholar 3 : Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. J Urol2001; 165: 119. Link, Google Scholar 4 : Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol2005; 23: 7005. Google Scholar 5 : Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol2004; 172: 910. Link, Google Scholar 6 : The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol2003; 170: 1872. Link, Google Scholar 7 : Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA2005; 294: 433. Google Scholar 8 : Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA1998; 280: 975. Google Scholar 9 : Determinants of prostate cancer-specific survival after radiation therapy for patients with clinically localized prostate cancer. J Clin Oncol2002; 20: 4567. Google Scholar 10 : Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol2003; 21: 2163. Google Scholar 11 : Ability of 2 pretreatment risk assessment methods to predict prostate cancer recurrence after radical prostatectomy: data from CaPSURE. J Urol2005; 173: 1126. Link, Google Scholar 12 : Is the GPSM scoring algorithm for prostate cancer patients valid in the contemporary era?. J Urol2007; 178: 459. Link, Google Scholar 13 : Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol2003; 170: S21. Link, Google Scholar 14 : Changing nature of high risk patients undergoing radical prostatectomy. J Urol2007; 177: 113. Link, Google Scholar 15 : Treatment of patients with high risk localized prostate cancer: results form Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE). J Urol2005; 173: 1557. Link, Google Scholar 16 : Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol2006; 7: 472. Google Scholar 17 : Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol2006; 24: 4448. Google Scholar 18 : Outcome after radical prostatectomy with a pretreatment prostate biopsy Gleason score of ≥8. BJU Int2003; 92: 539. Google Scholar 19 : Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int2005; 95: 751. Google Scholar Department of Urology and Division of Biostatistics (LJR, EJB), Mayo Medical School and Mayo Clinic, Rochester, Minnesota© 2008 by American Urological AssociationFiguresReferencesRelatedDetailsCited byMaganty A, Sabik L, Sun Z, Eom K, Li J, Davies B and Jacobs B (2019) Under Treatment of Prostate Cancer in Rural LocationsJournal of Urology, VOL. 203, NO. 1, (108-114), Online publication date: 1-Jan-2020.Bhindi B, Karnes R, Rangel L, Mason R, Gettman M, Frank I, Tollefson M, Lin D, Thompson R and Boorjian S (2017) Independent Validation of the American Joint Committee on Cancer 8th Edition Prostate Cancer Staging ClassificationJournal of Urology, VOL. 198, NO. 6, (1286-1294), Online publication date: 1-Dec-2017.Baskin A, Kwan L, Zavala M and Chamie K (2016) The Impact of Partnership Status and Social Support on Health Related Quality of Life Outcomes in Men with Prostate CancerUrology Practice, VOL. 4, NO. 3, (225-231), Online publication date: 1-May-2017.Tollefson M, Karnes R, Rangel L, Bergstralh E and Boorjian S (2012) The Impact of Clinical Stage on Prostate Cancer Survival Following Radical ProstatectomyJournal of Urology, VOL. 189, NO. 5, (1707-1712), Online publication date: 1-May-2013.Mullins J, Feng Z, Trock B, Epstein J, Walsh P and Loeb S (2012) The Impact of Anatomical Radical Retropubic Prostatectomy on Cancer Control: The 30-Year AnniversaryJournal of Urology, VOL. 188, NO. 6, (2219-2224), Online publication date: 1-Dec-2012.Elliott S, Johnson D, Jarosek S, Konety B, Adejoro O and Virnig B (2012) Bias Due to Missing SEER Data in D'Amico Risk Stratification of Prostate CancerJournal of Urology, VOL. 187, NO. 6, (2026-2031), Online publication date: 1-Jun-2012.Holmes J, Carpenter W, Wu Y, Hendrix L, Peacock S, Massing M, Schenck A, Meyer A, Diao K, Wheeler S, Godley P, Stitzenberg K and Chen R (2012) Impact of Distance to a Urologist on Early Diagnosis of Prostate Cancer Among Black and White PatientsJournal of Urology, VOL. 187, NO. 3, (883-888), Online publication date: 1-Mar-2012.Daskivich T, Chamie K, Kwan L, Labo J, Dash A, Greenfield S and Litwin M (2011) Improved Prediction of Long-Term, Other Cause Mortality in Men With Prostate CancerJournal of Urology, VOL. 186, NO. 5, (1868-1873), Online publication date: 1-Nov-2011.Related articlesJournal of Urology22 Feb 2008Early Postoperative Plasma Transforming Growth Factor-β1 is a Strong Predictor of Biochemical Progression After Radical Prostatectomy Volume 179Issue 4April 2008Page: 1354-1361 Advertisement Copyright & Permissions© 2008 by American Urological AssociationKeywordsprostatectomyprostateprostate-specific antigenriskprostatic neoplasmsAcknowledgmentsDr. Anthony D’Amico provided suggestions on the manuscript.MetricsAuthor Information Stephen A. Boorjian More articles by this author R. Jeffrey Karnes More articles by this author Laureano J. Rangel More articles by this author Eric J. Bergstralh More articles by this author Michael L. Blute More articles by this author Expand All Advertisement PDF downloadLoading ...

Previous prospective randomised trials have shown a positive impact of adjuvant radiation therapy (RT) in patients with locally advanced prostate cancer. However, none of these trials included patients with lymph node invasion (LNI). The aim of this study was to assess the impact of combination adjuvant hormonal therapy (HT) and RT on the survival of patients with prostate cancer and histologically documented lymph node metastases (pN+). Data on 703 consecutive patients with LNI treated with radical prostatectomy, pelvic lymph node dissection, and adjuvant treatments between September 1986 and November 2002 at two large academic institutions were reviewed. For study purposes, patients treated with adjuvant HT plus RT and patients treated with adjuvant HT alone were matched for age at surgery, pathologic T stage and Gleason score, number of nodes removed, surgical margin status, and length of follow-up. Differences in cancer-specific survival (CSS) and overall survival (OS) were compared using the Kaplan-Meier method and life table analyses. Following the matching process, 117 pT2–4 pN1 patients of 171 (68.4%) treated with adjuvant HT plus RT (group 1) were compared with 247 pT2–4 pN1 patients of 532 (46.4%) receiving adjuvant HT alone (group 2). After matching, the two groups of patients were comparable in terms of pre- and postoperative characteristics (all p ≥ 0.07). Mean follow-up was 100.8 mo (median: 95.1 mo; range: 3.5–229.3 mo). Overall, prostate CSS and OS rates at 5, 8, and 10 yr were 90%, 82%, and 75%, and 85%, 70%, and 60%, respectively. Patients treated with adjuvant RT plus HT had significantly higher CSS and OS rates compared with patients treated with HT alone at 5, 8, and 10 yr after surgery (95%, 91%, and 86% vs 88%, 78%, and 70%, and 90%, 84%, and 74% vs 82%, 65%, and 55%, respectively; p = 0.004 and p < 0.001, respectively). Similarly, higher survival rates associated with the combination of HT plus RT were found when patients were stratified according to the extent of nodal invasion (namely, two or fewer vs more than two positive nodes; all p ≤ 0.006). Lack of standardised HT and RT protocols represents the main limitations of our retrospective study. Adjuvant RT plus HT significantly improved CSS and OS of pT2–4 pN1 patients, regardless of the extent of nodal invasion. These results reinforce the need for a multimodal approach in the treatment of node-positive prostate cancer.

Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined.To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP.This is a retrospective, international, multi-institutional cohort analysis. There was a median follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers.Open SRP.BCR after SRP was defined as a serum prostate-specific antigen (PSA) ≥ 0.1 or ≥ 0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancer-specific death.Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31-43), 77% (95% CI, 71-82), and 83% (95% CI, 76-88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period.In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in >75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP.

SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests.To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping.We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non-ERG ETS gene rearrangements (ETS(+)) or SPINK1 overexpression (SPINK1(+)).Associations with clinical features and outcomes by multivariate logistic regression analysis and receiver operating curves.The m-ERG classifier showed 95% accuracy in an independent validation subset (155 samples). Across cohorts, 45% of PCas were classified as m-ERG(+), 9% as m-ETS(+), 8% as m-SPINK1(+), and 38% as triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Gene expression profiling supports three underlying molecularly defined groups: m-ERG(+), m-ETS(+), and m-SPINK1(+)/triple negative. On multivariate analysis, m-ERG(+) tumors were associated with lower preoperative serum prostate-specific antigen and Gleason scores, but greater extraprostatic extension (p<0.001). m-ETS(+) tumors were associated with seminal vesicle invasion (p=0.01), while m-SPINK1(+)/triple negative tumors had higher Gleason scores and were more frequent in Black/African American patients (p<0.001). Clinical outcomes were not significantly different among subtypes.A clinically available prognostic test (Decipher) can also assess PCa molecular subtypes, obviating the need for additional testing. Clinicopathologic differences were found among subtypes based on global expression patterns.Molecular subtyping of prostate cancer can be achieved using extra data generated from a clinical-grade, genome-wide expression-profiling prognostic assay (Decipher). Transcriptomic and clinical analysis support three distinct molecular subtypes: (1) m-ERG(+), (2) m-ETS(+), and (3) m-SPINK1(+)/triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Incorporation of subtyping into a clinically available assay may facilitate additional applications beyond routine prognosis.

Due to their varied outcomes, men with biochemical recurrence (BCR) following radical prostatectomy (RP) present a management dilemma. Here, we evaluate Decipher, a genomic classifier (GC), for its ability to predict metastasis following BCR.The study population included 85 clinically high-risk patients who developed BCR after RP. Time-dependent receiver operating characteristic (ROC) curves, weighted Cox proportional hazard models and decision curves were used to compare GC scores to Gleason score (GS), PSA doubling time (PSAdT), time to BCR (ttBCR), the Stephenson nomogram and CAPRA-S for predicting metastatic disease progression. All tests were two-sided with a type I error probability of 5%.GC scores stratified men with BCR into those who would or would not develop metastasis (8% of patients with low versus 40% with high scores developed metastasis, P<0.001). The area under the curve for predicting metastasis after BCR was 0.82 (95% CI, 0.76-0.86) for GC, compared to GS 0.64 (0.58-0.70), PSAdT 0.69 (0.61-0.77) and ttBCR 0.52 (0.46-0.59). Decision curve analysis showed that GC scores had a higher overall net benefit compared to models based solely on clinicopathologic features. In multivariable modeling with clinicopathologic variables, GC score was the only significant predictor of metastasis (P=0.003).When compared to clinicopathologic variables, GC better predicted metastatic progression among this cohort of men with BCR following RP. While confirmatory studies are needed, these results suggest that use of GC may allow for better selection of men requiring earlier initiation of treatment at the time of BCR.

The presence of a positive surgical margin at radical prostatectomy has been linked to an increased risk of postoperative biochemical recurrence. We evaluated the impact of margin status on subsequent clinical progression and mortality.We reviewed the records of 11,729 patients who underwent prostatectomy between 1990 and 2006. Survival was estimated for patients with vs without a positive margin and compared using the log rank test. Cox proportional hazards regression models were used to analyze the impact of margin status on survival.Overall 3,651 (31.1%) men were identified with a positive margin. Median postoperative followup was 8.2 years (IQR 4.4, 12.1). The 10-year biochemical recurrence-free rate for patients with and without a positive margin was 56% and 77%, respectively (p <0.001), while 10-year local recurrence-free survival was 89% vs 95% (p <0.001). Margin status also stratified systemic progression-free survival (93% vs 97%, p <0.001), cancer specific survival (96% vs 99%, p <0.001) and overall survival (83% vs 88%, p <0.001). On multivariate analysis the presence of a positive margin was associated with increased risk of biochemical recurrence (HR 1.63, 95% CI 1.47-1.80, p <0.0001), local recurrence (HR 1.78, 95% CI 1.45-2.19, p <0.0001) and receipt of salvage therapy (HR 1.79, 95% CI 1.58-2.02, p <0.0001) but was not a significant predictor of systemic progression (p = 0.95), cancer specific death (p = 0.15) or overall mortality (p = 0.16).The presence of a positive margin increased the risk of biochemical recurrence, local recurrence and the need for salvage treatment but was not independently associated with systemic progression, cancer specific death or overall mortality. These results should be considered when evaluating patients for adjuvant therapy.

The current role of radical prostatectomy (RP) in patients with high-risk disease remains controversial.To identify which high-risk prostate cancer (PCa) patients might have favorable pathologic outcomes when surgically treated.We evaluated 1366 patients with high-risk PCa (ie, at least one of the following risk factors: prostate-specific antigen [PSA]>20 ng/ml, cT3, biopsy Gleason 8-10) treated with RP and pelvic lymph node dissection (PLND) at eight European centers between 1987 and 2009. A favorable pathologic outcome was defined as specimen-confined (SC) disease-namely, pT2-pT3a, node negative PCa with negative surgical margins.All patients underwent radical retropubic prostatectomy and PLND.Univariable and multivariable logistic regression models tested the association between predictors and SC disease. A logistic regression coefficient-based nomogram was developed and internally validated using 200 bootstrap resamples. The Kaplan-Meier method was used to depict biochemical recurrence (BCR) and cancer-specific survival (CSS) rates.Overall, 505 of 1366 patients (37%) had SC disease at RP. All preoperative variables (ie, age and PSA at surgery, clinical stage, and biopsy Gleason sum) were independent predictors of SC PCa at RP (all p≤0.04). Patients with SC disease had significantly higher 10-yr BCR-free survival and CSS rates than patients without SC disease at RP (66% vs 47% and 98 vs 88%, respectively; all p<0.001). A nomogram including PSA, age, clinical stage, and biopsy Gleason sum demonstrated 72% accuracy in predicting SC PCa. This study is limited by its retrospective design and by the lack of an external validation of the nomogram.Roughly 40% of patients with high-risk PCa have SC disease at final pathology. These patients showed excellent long-term outcomes when surgically treated, thus representing the ideal candidates for RP as the primary treatment for PCa. Prediction of such patients is possible using a nomogram based on routinely available clinical parameters.

Early salvage radiotherapy (eSRT) represents the only curative option for prostate cancer patients experiencing biochemical recurrence (BCR) for local recurrence after radical prostatectomy (RP). To develop and internally validate a novel nomogram predicting BCR after eSRT in patients treated with RP. Using a multi-institutional cohort, 472 node-negative patients who experienced BCR after RP were identified. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at prostate-specific antigen (PSA) ≤0.5 ng/ml. BCR after eSRT was defined as two consecutive PSA values ≥0.2 ng/ml. Uni- and multivariable Cox regression models predicting BCR after eSRT were fitted. Regression-based coefficients were used to develop a nomogram predicting the risk of 5-yr BCR after eSRT. The discrimination of the nomogram was quantified with the Harrell concordance index and the calibration plot method. Two hundred bootstrap resamples were used for internal validation. Mean follow-up was 58 mo (median: 48 mo). Overall, 5-yr BCR-free survival rate after eSRT was 73.4%. In univariable analyses, pathologic stage, Gleason score, and positive surgical margins were associated with the risk of BCR after eSRT (all p ≤ 0.04). These results were confirmed in multivariable analysis, where all the previously mentioned covariates as well as pre-RT PSA were significantly associated with BCR after eSRT (all p ≤ 0.04). A coefficient-based nomogram demonstrated a bootstrap-corrected discrimination of 0.74. Our study is limited by its retrospective nature and use of BCR as an end point. eSRT leads to excellent cancer control in patients with BCR for presumed local failure after RP. We developed the first nomogram to predict outcome after eSRT. Our model facilitates risk stratification and patient counselling regarding the use of secondary therapy for individuals experiencing BCR after RP. Salvage radiotherapy leads to optimal cancer control in patients who experience recurrence after radical prostatectomy. We developed a novel tool to identify the best candidates for salvage treatment and to allow selection of patients to be considered for additional forms of therapy.

To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette-Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups.Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints.Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR.

HSD3B1 (1245A>C) has been mechanistically linked to castration-resistant prostate cancer because it encodes an altered enzyme that augments dihydrotestosterone synthesis from non-gonadal precursors. We postulated that men inheriting the HSD3B1 (1245C) allele would exhibit resistance to androgen-deprivation therapy (ADT).In this multicohort study, we determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. We used data and samples from prospectively maintained prostate cancer registries at the Cleveland Clinic (Cleveland, OH, USA; primary study cohort) and the Mayo Clinic (Rochester, MN, USA; post-prostatectomy and metastatic validation cohorts). In the post-prostatectomy cohorts, patients of any age were eligible if they underwent prostatectomy between Jan 1, 1996, and Dec 31, 2009 (at the Cleveland Clinic; primary cohort), or between Jan 1, 1987, and Dec 31, 2011 (at the Mayo Clinic; post-prostatectomy cohort) and were treated with ADT for biochemical failure or for non-metastatic clinical failure. In the metastatic validation cohort, patients of any age were eligible if they were enrolled at Mayo Clinic between Sept 1, 2009, and July 31, 2013, with metastatic castration-resistant prostate cancer. The primary endpoint was progression-free survival according to HSD3B1 genotype. We did prespecified multivariable analyses to assess the independent predictive value of HSD3B1 genotype on outcomes.We included and genotyped 443 patients: 118 in the primary cohort (who underwent prostatectomy), 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median progression-free survival diminished as a function of the number of variant alleles inherited: 6·6 years (95% CI 3·8-not reached) in men with homozygous wild-type genotype, 4·1 years (3·0-5·5) in men with heterozygous variant genotype, and 2·5 years (0·7 to not reached) in men with homozygous variant genotype (p=0·011). Relative to the homozygous wild-type genotype, inheritance of two copies of the variant allele was predictive of decreased progression-free survival (hazard ratio [HR] 2·4 [95% CI 1·1-5·3], p=0·029), as was inheritance of one copy of the variant allele (HR 1·7 [1·0-2·9], p=0·041). Findings were similar for distant metastasis-free survival and overall survival. The effect of the HSD3B1 genotype was independently confirmed in the validation cohorts.Inheritance of the HSD3B1 (1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. HSD3B1 could therefore potentially be a powerful genetic biomarker capable of distinguishing men who are a priori likely to fare favourably with ADT from those who harbour disease liable to behave more aggressively, and who therefore might warrant early escalated therapy.Prostate Cancer Foundation, National Institutes of Health, US Department of Defense, Howard Hughes Medical Institute, American Cancer Society, Conquer Cancer Foundation of the American Society of Clinical Oncology, Cleveland Clinic Research Programs Committee and Department of Radiation Oncology, Gail and Joseph Gassner Development Funds.

The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

Because pelvic lymph node (LN)-positive prostate cancer (PCa) is generally considered a regionally metastatic disease, surgery needs to be better defined.To review the impact of radical prostatectomy (RP) and pelvic lymph node dissection (PLND), possibly in conjunction with a multimodal approach using local radiotherapy and/or androgen-deprivation therapy (ADT), in LN-positive PCa.A systematic Medline search for studies reporting on treatment regimens and outcomes in patients with LN-positive PCa undergoing RP between 1993 and 2012 was performed.RP can improve progression-free and overall survival in LN-positive PCa, although there is a lack of high-level evidence. Therefore, the former practice of aborting surgery in the presence of positive nodes might no longer be supported by current evidence, especially in those patients with a limited LN tumor burden. Current data demonstrate that the lymphatic spread takes an ascending pathway from the pelvis to the retroperitoneum, in which the internal and the common iliac nodes represent critical landmarks in the metastatic distribution. Sophisticated imaging technologies are still under investigation to improve the prediction of LN-positive PCa. Nonetheless, extended PLND including the common iliac arteries should be offered to intermediate- and high-risk patients to improve nodal staging with a possible benefit in prostate-specific antigen progression-free survival by removing significant metastatic load. Adjuvant ADT has the potential to improve overall survival after RP; the therapeutic role of a trimodal approach with adjuvant local radiotherapy awaits further elucidation. Age is a critical parameter for survival because cancer-specific mortality exceeds overall mortality in younger patients (<60 yr) with high-risk PCa and should be an impetus to treat as thoroughly as possible.Increasing evidence suggests that RP and extended PLND improve survival in LN-positive PCa. Our understanding of surgery of the primary tumor in LN-positive PCa needs a conceptual change from a palliative option to the first step in a multimodal approach with a significant improvement of long-term survival and cure in selected patients.

No data exist on the patterns of biochemical recurrence (BCR) and their effect on survival in patients with high-risk prostate cancer (PCa) treated with surgery. The aim of our investigation was to evaluate the natural history of PCa in patients treated with radical prostatectomy (RP) alone.Overall, 2,065 patients with high-risk PCa treated with RP at 7 tertiary referral centers between 1991 and 2011 were identified. First, we calculated the probability of experiencing BCR after surgery. Particularly, we relied on conditional survival estimates for BCR after RP. Competing-risks regression analyses were then used to evaluate the effect of time to BCR on the risk of cancer-specific mortality (CSM).Median follow-up was 70 months. Overall, the 5-year BCR-free survival rate was 55.2%. Given the BCR-free survivorship at 1, 2, 3, 4, and 5 years, the BCR-free survival rates improved by+7.6%,+4.1%,+4.8%,+3.2%, and+3.7%, respectively. Overall, the 10-year CSM rate was 14.8%. When patients were stratified according to time to BCR, patients experiencing BCR within 36 months from surgery had higher 10-year CSM rates compared with those experiencing late BCR (19.1% vs. 4.4%; P<0.001). At multivariate analyses, time to BCR represented an independent predictor of CSM (P<0.001).Increasing time from surgery is associated with a reduction of the risk of subsequent BCR. Additionally, time to BCR represents a predictor of CSM in these patients. These results might help provide clinicians with better follow-up strategies and more aggressive treatments for early BCR.

Survival after surgical treatment using competing-risk analysis has been previously examined in patients with prostate cancer (PCa). However, the combined effect of age and comorbidities has not been assessed in patients with high-risk PCa who might have heterogeneous rates of competing mortality despite the presence of aggressive disease.To examine the risk of 10-yr cancer-specific mortality (CSM) and other-cause mortality (OCM) according to clinical and pathologic characteristics of patients treated with radical prostatectomy (RP) for high-risk PCa.Within a multi-institutional cohort, 3828 men treated with RP for high-risk PCa (defined as the presence of at least one of these risk factors: prostate-specific antigen >20 ng/ml, biopsy Gleason score 8-10, clinical stage ≥ T3) were identified.All patients underwent RP and pelvic lymph node dissection.Competing-risk Poisson regression analyses were performed to simultaneously assess the 10-yr CSM and OCM rates after RP. The same analyses were also conducted after stratification of patients according to age at surgery, comorbidity status assessed by the Charlson Comorbidity Index (CCI), and number of risk factors (one vs two or more).Overall, 229 patients (5.9%) died from PCa; 549 (14.3%) died from other causes. The 10-yr CSM and OCM rates ranged from 5.1% to 12.8% and from 4.3% to 37.4%, respectively. Age and CCI were the major determinants of OCM; their impact on CSM was minimal. OCM was the leading cause of death in all patient groups except in young men (≤ 59 yr) with no comorbidities, regardless of the number of risk factors (10-yr CSM and OCM 6.9-12.8% and 5.5-6.3%, respectively). The main limitation was the lack of patients managed conservatively.Even in the context of high-risk PCa, long-term CSM after RP is modest and represents the leading cause of death only in young, healthy patients. Conversely, older and sicker patients with multiple risk factors are at the highest risk of dying from OCM while sharing very low CSM rates.

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Early salvage radiation therapy (eSRT) represents a treatment option for patients who experience a prostate-specific antigen (PSA) rise after radical prostatectomy (RP); however, the optimal PSA level for eSRT administration is still unclear. To test the impact of PSA level on cancer control after eSRT according to pathologic tumour characteristics. The study included 716 node-negative patients with undetectable postoperative PSA who experienced a PSA rise after RP. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at PSA ≤0.5 ng/ml. Biochemical recurrence (BCR) after eSRT was defined as two consecutive PSA values ≥0.2 ng/ml. Multivariable Cox regression analysis tested the association between pre-eSRT PSA level and BCR after eSRT. Covariates consisted of pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). We tested an interaction with PSA level and baseline pathologic risk for the hypothesis that BCR-free survival differed by pre-eSRT PSA level. Three pathologic risk factors were identified: pathologic stage pT3b or higher, pathologic Gleason score ≥8, and negative surgical margins. Median follow-up among patients who did not experience BCR after eSRT was 57 mo (interquartile range: 27–105). At 5 yr after eSRT, BCR-free survival rate was 82% (95% confidence interval [CI], 78–85). At multivariable Cox regression analysis, pre-eSRT PSA level was significantly associated with BCR after eSRT (hazard ratio: 4.89; 95% CI, 1.40–22.9; p < 0.0001). When patients were stratified according to the number of risk factors at final pathology, patients with at least two pathologic risk factors showed an increased risk of 5-yr BCR as high as 10% per 0.1 ng/ml of PSA level compared with only 1.5% in patients with one or no pathologic risk factors. In this retrospective study, cancer control after eSRT greatly depended on pretreatment PSA. The absolute PSA level had a different prognostic value depending on the pathologic characteristics of the tumour. In patients with more adverse pathologic features, eSRT conferred better cancer control when administered at the very first sign of PSA rise. Conversely, the benefit of eSRT was less evident in men with favourable disease at RP. In this retrospective study, cancer control after early salvage radiation therapy (eSRT) was influenced by pretreatment prostate-specific antigen (PSA) level. This effect was highest in men with at least two of the following pathologic features: pT3b/pT4 disease, pathologic Gleason score ≥8, and negative surgical margins. In these patients, eSRT conferred better cancer control when administered at the very first sign of PSA rise.

No AccessJournal of UrologyAdult Urology1 Apr 2013Operational Characteristics of 11C-Choline Positron Emission Tomography/Computerized Tomography for Prostate Cancer with Biochemical Recurrence After Initial Treatment Christopher R. Mitchell, Val J. Lowe, Laureano J. Rangel, Joseph C. Hung, Eugene D. Kwon, and R. Jeffrey Karnes Christopher R. MitchellChristopher R. Mitchell Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author , Val J. LoweVal J. Lowe Department of Nuclear Medicine, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Bayer Schering Pharma, GE Healthcare, Siemens Molecular Imaging and Avid Pharmaceuticals. More articles by this author , Laureano J. RangelLaureano J. Rangel Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota More articles by this author , Joseph C. HungJoseph C. Hung Department of Nuclear Medicine, Mayo Clinic, Rochester, Minnesota More articles by this author , Eugene D. KwonEugene D. Kwon Department of Urology, Mayo Clinic, Rochester, Minnesota Equal study contribution. More articles by this author , and R. Jeffrey KarnesR. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota Equal study contribution. More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.10.069AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We examined the performance of 11C-choline positron emission tomography/computerized tomography for its ability to delineate prostate cancer distribution and extent after initial therapy. Materials and Methods: A consecutive series retrospective review was performed of all patients with prostate cancer who were evaluated using 11C-choline positron emission tomography/computerized tomography from September 2007 to November 2010 at the Mayo Clinic. Statistical analysis was performed to determine the sensitivity, specificity, positive predictive value, negative predictive value and prostate specific antigen threshold for the detection of recurrent lesions. Results: In the study period 176 patients with biochemical recurrence after primary treatment failure underwent 11C-choline positron emission tomography/computerized tomography. Using patient based analysis 11C-choline positron emission tomography yielded a sensitivity, specificity, positive predictive value and negative predictive value of 93%, 76%, 91% and 81%, respectively. Of the 176 positron emission tomography/computerized tomography scans performed 56 (32%) were deemed clinically useful as defined by the ability to identify lesions not delineated using conventional imaging, thereby prompting changes in clinical management. The optimal prostate specific antigen for lesion detection was 2.0 ng/ml. On multivariate analysis prostate specific antigen at positron emission tomography (HR 1.37, p = 0.04) and clinical stage at initial diagnosis of prostate cancer (HR 5.19, p = 0.0035) were significant predictors of positive 11C-choline positron emission tomography/computerized tomography. Conclusions: 11C-choline positron emission tomography/computerized tomography performs well in men with biochemical recurrence after primary treatment failure. The optimal prostate specific antigen value for lesion detection is approximately 2.0 ng/ml. We found that 11C-choline positron emission tomography/computerized tomography substantially enhances the rate of prostate cancer lesion detection by approximately 32% beyond what can be garnered using conventional imaging techniques and at a lower prostate specific antigen value. References 1 : Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol2004; 172: 910. Link, Google Scholar 2 : The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol2003; 170: 1872. Link, Google Scholar 3 : Overall survival after prostate-specific-antigen-detected recurrence following conformal radiation therapy. Int J Radiat Oncol Biol Phys2000; 48: 629. Google Scholar 4 : Biochemical disease-free survival in men younger than 60 years with prostate cancer treated with external beam radiation. J Urol2002; 168: 536. Link, Google Scholar 5 : Recurrence-free survival rates after external-beam radiotherapy for patients with clinical T1–T3 prostate carcinoma in the prostate-specific antigen era: what should we expect?. Cancer2004; 100: 1283. Google Scholar 6 : Radionuclide bone scintigraphy in patients with biochemical recurrence after radical prostatectomy: when is it indicated?. BJU Int2004; 94: 299. Google Scholar 7 : Predictors of metastatic disease in men with biochemical failure following radical prostatectomy. J Urol2004; 171: 2260. Link, Google Scholar 8 : A model that predicts the probability of positive imaging in prostate cancer cases with biochemical failure after initial definitive local therapy. J Urol2008; 179: 906. Link, Google Scholar 9 : Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res2001; 61: 3599. 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Eur J Nucl Med Mol Imaging2008; 35: 253. Google Scholar 16 : Clinical impact of 18F-choline PET/CT in patients with recurrent prostate cancer. Eur J Nucl Med Mol Imaging2012; 39: 936. Google Scholar 17 : Influence of trigger PSA and PSA kinetics on 11C-Choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy. J Nucl Med2009; 50: 1394. Google Scholar 18 : Is there a role for 11C-choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase <1.5 ng/ml?. Eur J Nucl Med Mol Imaging2011; 38: 55. Google Scholar 19 : The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging2008; 35: 18. 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Google Scholar © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byFossati N, Scarcella S, Gandaglia G, Suardi N, Robesti D, Boeri L, Karnes R, Heidenreich A, Pfister D, Kretschmer A, Buchner A, Stief C, Battaglia A, Joniau S, Van Poppel H, Osmonov D, Juenemann K, Shariat S, Hiester A, Nini A, Albers P, Tilki D, Graefen M, Gill I, Mottrie A, Galosi A, Montorsi F and Briganti A (2020) Underestimation of Positron Emission Tomography/Computerized Tomography in Assessing Tumor Burden in Prostate Cancer Nodal Recurrence: Head-to-Head Comparison of 68Ga-PSMA and 11C-Choline in a Large, Multi-Institutional Series of Extended Salvage Lymph Node DissectionsJournal of Urology, VOL. 204, NO. 2, (296-302), Online publication date: 1-Aug-2020.Nehra A, Parker W, Haloi R, Park S, Mynderse L, Lowe V, Davis B, Quevedo J, Johnson G, Kwon E and Karnes R (2017) Identification of Recurrence Sites Following Post-Prostatectomy Treatment for Prostate Cancer Using 11C-Choline Positron Emission Tomography and Multiparametric Pelvic Magnetic Resonance ImagingJournal of Urology, VOL. 199, NO. 3, (726-733), Online publication date: 1-Mar-2018.Sobol I, Zaid H, Haloi R, Mynderse L, Froemming A, Lowe V, Davis B, Kwon E and Karnes R (2016) Contemporary Mapping of Post-Prostatectomy Prostate Cancer Relapse with 11C-Choline Positron Emission Tomography and Multiparametric Magnetic Resonance ImagingJournal of Urology, VOL. 197, NO. 1, (129-134), Online publication date: 1-Jan-2017.Zargar-Shoshtari K, Sharma P and Pow-Sang J (2015) Salvage Therapies for Radiorecurrent Prostate CancerUrology Practice, VOL. 2, NO. 3, (126-132), Online publication date: 1-May-2015.Karnes R, Murphy C, Bergstralh E, DiMonte G, Cheville J, Lowe V, Mynderse L and Kwon E (2014) Salvage Lymph Node Dissection for Prostate Cancer Nodal Recurrence Detected by 11C-Choline Positron Emission Tomography/Computerized TomographyJournal of Urology, VOL. 193, NO. 1, (111-116), Online publication date: 1-Jan-2015.Schuster D, Nieh P, Jani A, Amzat R, Bowman F, Halkar R, Master V, Nye J, Odewole O, Osunkoya A, Savir-Baruch B, Alaei-Taleghani P and Goodman M (2013) Anti-3-[18F]FACBC Positron Emission Tomography-Computerized Tomography and 111In-Capromab Pendetide Single Photon Emission Computerized Tomography-Computerized Tomography for Recurrent Prostate Carcinoma: Results of a Prospective Clinical TrialJournal of Urology, VOL. 191, NO. 5, (1446-1453), Online publication date: 1-May-2014.Steers W (2013) This Month in Adult UrologyJournal of Urology, VOL. 189, NO. 4, (1181-1182), Online publication date: 1-Apr-2013. Volume 189Issue 4April 2013Page: 1308-1313 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Keywordscholinepositron-emission tomography and computed tomographyrecurrenceprostatic neoplasmsMetrics Author Information Christopher R. Mitchell Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Val J. Lowe Department of Nuclear Medicine, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Bayer Schering Pharma, GE Healthcare, Siemens Molecular Imaging and Avid Pharmaceuticals. More articles by this author Laureano J. Rangel Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota More articles by this author Joseph C. Hung Department of Nuclear Medicine, Mayo Clinic, Rochester, Minnesota More articles by this author Eugene D. Kwon Department of Urology, Mayo Clinic, Rochester, Minnesota Equal study contribution. More articles by this author R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota Equal study contribution. More articles by this author Expand All Advertisement PDF downloadLoading ...

In the present report we aimed to analyze the incremental value of preoperative magnetic resonance imaging (MRI), in addition to clinical variables and clinically-derived nomograms, in predicting outcomes radical prostatectomy (RP). All Mayo Clinic RP patients who underwent preoperative 1.5-Tesla MRI with endo-rectal coil from 2003 to 2013 were identified. Clinical and histopathological variables were used to calculate Partin estimates and Cancer of the Prostate Risk Assessment (CAPRA) score. MRI results in terms of extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymph-node invasion (N+) were recorded. Using RP pathology as gold standard, we developed multivariate logistic regression models based on clinical variables, Partin Tables, and CAPRA score, and assessed their predictive accuracy before and after the addition of MRI results. Five hundred and one patients were included. MRI + clinical models outperformed clinical-based models alone for all outcomes. Comparing Partin and Partin + MRI predictive models, the areas under the curve were 0.61 versus 0.73 for ECE, 0.75 versus 0.82 for SVI, and 0.82 versus 0.85 for N+. Comparing CAPRA and CAPRA + MRI models, the areas under the curve were 0.69 versus 0.77 for ECE, 0.75 versus 0.83 for SVI, and 0.82 versus 0.85 for N+. Our data show that MRI can improve clinical-based models in prediction of nonorgan confined disease, particularly for ECE and SVI. Magnetic resonance imaging, together with clinical information, can be useful in preoperative assessment before radical prostatectomy.

Serum levels of miR-194 have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion, and epithelial-mesenchymal transition in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts. Conversely, inhibition of miR-194 activity suppressed the invasive capacity of prostate cancer cell lines in vitro and in vivo Mechanistic investigations identified the ubiquitin ligase suppressor of cytokine signaling 2 (SOCS2) as a direct, biologically relevant target of miR-194 in prostate cancer. Low levels of SOCS2 correlated strongly with disease recurrence and metastasis in clinical specimens. SOCS2 downregulation recapitulated miR-194-driven metastatic phenotypes, whereas overexpression of a nontargetable SOCS2 reduced miR-194-stimulated invasion. Targeting of SOCS2 by miR-194 resulted in derepression of the oncogenic kinases FLT3 and JAK2, leading to enhanced ERK and STAT3 signaling. Pharmacologic inhibition of ERK and JAK/STAT pathways reversed miR-194-driven phenotypes. The GATA2 transcription factor was identified as an upstream regulator of miR-194, consistent with a strong concordance between GATA2 and miR-194 levels in clinical specimens. Overall, these results offer new insights into the molecular mechanisms of metastatic progression in prostate cancer. Cancer Res; 77(4); 1021-34. ©2016 AACR.

Salvage lymph node dissection (SLND) represents a possible treatment option for prostate cancer patients affected by nodal recurrence after local treatment. However, SLND may be associated with intra- and postoperative complications, and the oncological benefit may be limited to specific groups of patients. To identify the optimal candidates for SLND based on preoperative characteristics. The study included 654 patients who experienced prostate-specific antigen (PSA) rise and nodal recurrence after radical prostatectomy (RP) and underwent SLND at nine tertiary referral centers. Lymph node recurrence was documented by positron emission tomography/computed tomography (PET/CT) scan using either 11C-choline or 68Ga-labeled prostate-specific membrane antigen ligand. SLND. The study outcome was early clinical recurrence (eCR) developed within 1 yr after SLND. Multivariable Cox regression analysis was used to develop a predictive model. Multivariable-derived coefficients were used to develop a novel risk calculator. Decision-curve analysis was used to evaluate the net benefit of the predictive model. Median follow-up was 30 (interquartile range, 16–50) mo among patients without clinical recurrence (CR), and 334 patients developed CR after SLND. In particular, eCR at 1 yr after SLND was observed in 150 patients, with a Kaplan-Meier probability of eCR equal to 25%. The development of eCR was significantly associated with an increased risk of cancer-specific mortality at 3 yr, being 20% versus 1.4% in patients with and without eCR, respectively (p < 0.0001). At multivariable analysis, Gleason grade group 5 (hazard ratio [HR]: 2.04; p < 0.0001), time from RP to PSA rising (HR: 0.99; p = 0.025), hormonal therapy administration at PSA rising after RP (HR: 1.47; p = 0.0005), retroperitoneal uptake at PET/CT scan (HR: 1.24; p = 0.038), three or more positive spots at PET/CT scan (HR: 1.26; p = 0.019), and PSA level at SLND (HR: 1.05; p < 0.0001) were significant predictors of CR after SLND. The coefficients of the predictive model were used to develop a risk calculator for eCR at 1 yr after SLND. The discrimination of the model (Harrel's C index) was 0.75. At decision-curve analysis, the net benefit of the model was higher than the “treat-all” option at all the threshold probabilities. We reported the largest available series of patients treated with SLND. Roughly 25% of men developed eCR after surgery. We developed the first risk stratification tool to identify the optimal candidate to SLND based on routinely available preoperative characteristics. This tool can be useful to avoid use of SLND in men more likely to progress despite any imaging-guided approach. The risk of early recurrence after salvage lymph node dissection (SLND) was approximately 25%. In this study, we developed a novel tool to predict the risk of early failure after SLND. This tool will be useful to identify patients who would benefit the most from SLND from other patients who should be spared from surgery.

According to the TNM staging system, patients with prostate cancer (PCa) with lymph node invasion (LNI) are considered a single-risk group. However, not all LNI patients share the same cancer control outcomes. To develop and internally validate novel nomograms predicting cancer-specific mortality (CSM)–free rate in pN1 patients. We evaluated 1107 patients with pN1 PCa treated with radical prostatectomy, pelvic lymph node dissection, and adjuvant therapy at two tertiary care centers between 1988 and 2010. Univariable and multivariable Cox regression models tested the relationship between CSM and patient clinical and pathologic characteristics, which consisted of prostate-specific antigen (PSA) value, pathologic Gleason score, pathologic tumor stage, status of surgical margins, number of positive lymph nodes, and status of adjuvant therapy. A Cox regression coefficient-based nomogram was developed and internally validated. All 1107 patients received adjuvant hormonal therapy (aHT). Additionally, 35% of patients received adjuvant radiotherapy (aRT). The 10-yr CSM-free rate was 84% in the entire cohort and 87% in patients treated with aRT plus aHT versus 82% in patients treated with aHT alone (p = 0.08). At multivariable analyses, PSA value, pathologic Gleason score, pathologic tumor stage, surgical margin status, number of positive lymph nodes, and aRT status were statistically significant predictors of CSM (all p ≤ 0.04). Based on these predictors, nomograms were developed to predict the 10-yr CSM-free rate in the overall patient population and in men with biochemical recurrence. These models showed high discrimination accuracy (79.5–83.3%) and favorable calibration characteristics. These results are limited by their retrospective nature. Some patients with pN1 PCa have favorable CSM-free rates at 10 yr. We developed and internally validated the first nomograms that allow an accurate prediction of the CSM-free rate in these patients at an individual level.

Randomized clinical trials have recently examined the benefit of adding docetaxel or abiraterone to androgen deprivation therapy (ADT) in hormone-naïve advanced prostate cancer (PCa).To perform a systematic review and network meta-analysis of randomized clinical trials, indirectly evaluating overall survival (OS) for men treated with abiraterone acetate plus prednisone/prednisolone with ADT (Abi-ADT) versus docetaxel with ADT (Doce-ADT) in hormone-naïve high-risk and metastatic PCa.Medline, Embase, Web of Science, Scopus, and Clinicaltrials.gov databases were searched in August 2017. We pooled results using the inverse variance technique and random-effects models. The Bucher technique for indirect treatment comparison was used to compare Abi-ADT with Doce-ADT. A priori subgroup and sensitivity analyses were performed.Overall, 6067 patients from five trials were included: 1181 (19.5%) patients who received Doce-ADT, 1557 (25.7%) patients who received Abi-ADT, and 3329 (54.9%) patients who received ADT-alone. There was a total of 1921 deaths: 391 in the Doce-ADT group, 353 in the Abi-ADT group, and 1177 in the ADT-only group. The pooled hazard ratio (HR) for OS was 0.75 (95% confidence interval [CI]: 0.63-0.91, I2=51%, 3 trials, 2951 patients) for Doce-ADT versus ADT-alone and 0.63 (95% CI: 0.55-0.72, I2=0%, 2 trials, 3116 patients) for Abi-ADT versus ADT-alone. The indirect comparison of Abi-ADT to Doce-ADT demonstrated no statistically significant difference in OS between these approaches (HR: 0.84, 95% CI: 0.67-1.06). Findings were similar in various a priori subset analyses, including patients with metastatic disease. Bayesian analyses demonstrated comparable results (HR: 0.83, 95% CI: 0.63-1.16). Despite the lack of statistical significance, Surface Under the Cumulative Ranking Analysis demonstrated an 89% probability that Abi-ADT was preferred.We did not identify a significant difference in OS between Abi-ADT and Doce-ADT for men with hormone-naïve high-risk or metastatic PCa, although Bayesian analysis demonstrates a high likelihood that Abi-ADT was preferred.We synthesized the evidence available from studies examining the administration of docetaxel or abiraterone in combination with hormonal therapy for patients with newly diagnosed, advanced prostate cancer. While these studies did not directly compare these agents, we used methodological techniques to indirectly compare them and found no significant difference in overall survival.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease.Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived murine cell lines.Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy.Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072-83. ©2017 AACR.

No AccessJournal of UrologyAdult Urology1 Jan 2015Salvage Lymph Node Dissection for Prostate Cancer Nodal Recurrence Detected by 11C-Choline Positron Emission Tomography/Computerized Tomography R. Jeffrey Karnes, Christopher R. Murphy, Eric J. Bergstralh, Guy DiMonte, John C. Cheville, Val J. Lowe, Lance A. Mynderse, and Eugene D. Kwon R. Jeffrey KarnesR. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota , Christopher R. MurphyChristopher R. Murphy Department of Urology, Mayo Clinic, Rochester, Minnesota , Eric J. BergstralhEric J. Bergstralh Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota , Guy DiMonteGuy DiMonte Department of Urology, Mayo Clinic, Rochester, Minnesota , John C. ChevilleJohn C. Cheville Department of Pathology, Mayo Clinic, Rochester, Minnesota , Val J. LoweVal J. Lowe Department of Radiology, Mayo Clinic, Rochester, Minnesota , Lance A. MynderseLance A. Mynderse Department of Urology, Mayo Clinic, Rochester, Minnesota , and Eugene D. KwonEugene D. Kwon Department of Urology, Mayo Clinic, Rochester, Minnesota View All Author Informationhttps://doi.org/10.1016/j.juro.2014.08.082AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We report salvage lymph node dissections for prostate cancer nodal recurrence detected by 11C-choline positron emission tomography/computerized tomography in the setting of increasing prostate specific antigen after radical prostatectomy. Materials and Methods: Retrospective chart review was performed for all patients who underwent salvage lymph node dissection for prostate cancer nodal recurrence. Only patients previously treated with radical prostatectomy were included in the study and those with evidence of local recurrence were excluded from analysis. Primary end points included biochemical recurrence, systemic progression and cancer specific mortality. Results: From 2009 to 2013, 52 men underwent salvage lymph node dissection. Before salvage lymph node dissection 78.8% (41 of 52) had some form of therapy after radical prostatectomy. Median age at salvage lymph node dissection was 60 years and median prostate specific antigen was 2.2 ng/ml (IQR 1.4–3.7). The median number of lymph nodes dissected was 21.5 (IQR 16–30) and the median number of positive nodes was 3.5 (IQR 1.2–6.5). Since salvage lymph node dissection 46.2% of the men (24 of 52) have had no further treatment, 34.6% (18 of 52) are on hormonal therapy and 19.2% (10 of 52) have received multiple different treatments. At the last followup at a median of 20 months (IQR 8–33), 57.7% (30 of 52) had prostate specific antigen remain less than 0.2 ng/ml, 75% (39 of 52) remained free of systemic progression and 96.2% of the men (50 of 52) were alive. Two patients died of prostate cancer. Three-year biochemical recurrence-free, systemic progression-free and cancer specific survival was 45.5%, 46.9% and 92.5%, respectively. Conclusions: This represents the largest U.S. series of salvage lymph node dissection in the setting of lymph node metastatic prostate cancer after radical prostatectomy. Although followup was short and the study lacked a randomized control group, salvage lymph node dissection may represent a valid treatment option. References 1 : Cancer statistics, 2013. CA Cancer J Clin2013; 63: 11. Google Scholar 2 : Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol2003; 169: 517. Link, Google Scholar 3 : Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy. Eur J Nucl Med Mol Imaging2010; 37: 301. 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Google Scholar 8 : Utility of [11C]choline PET/CT in guiding lesion-targeted salvage therapies in patients with prostate cancer recurrence localized to a single lymph node at imaging: results from a pathologically validated series. Urol Oncol2014; 32: 38. Google Scholar 9 : Pelvic lymph node dissection in prostate cancer. Eur Urol2009; 55: 1251. Google Scholar 10 : NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw2010; 8: 162. Google Scholar 11 : Anatomical extent of pelvic lymphadenectomy in patients undergoing radical prostatectomy. Eur Urol2007; 52: 29. Google Scholar 12 : Debulking surgery in the setting of very high-risk prostate cancer scenarios. BJU Int2012; 110: E192. Google Scholar 13 : Androgen deprivation therapy for prostate cancer. JAMA2005; 294: 238. Google Scholar 14 : Salvage lymphadenectomy in postprostatectomy patients with prostate-specific antigen recurrence. Curr Opin Urol2011; 21: 237. Google Scholar 15 : Value of lymphadenectomy for limited nodal recurrence of prostate cancer after local therapy with curative intent. Urologe A2008; 47: 1436. Google Scholar 16 : [11C]Choline PET/CT for targeted salvage lymph node dissection in patients with biochemical recurrence after primary curative therapy for prostate cancer. Preliminary results of a prospective study. Urol Int2008; 81: 191. Google Scholar 17 : Pelvic/retroperitoneal salvage lymph node dissection for patients treated with radical prostatectomy with biochemical recurrence and nodal recurrence detected by [11C]choline positron emission tomography/computed tomography. Eur Urol2011; 60: 935. Google Scholar 18 : Salvage lymph node dissection with adjuvant radiotherapy for nodal recurrence of prostate cancer. J Urol2012; 188: 2190. Link, Google Scholar 19 : Long-term outcomes of salvage lymph node dissection for clinically recurrent prostate cancer: results of a single-institution series with a minimum follow-up of 5 years. Eur Urol2014; . Epub ahead of print. Google Scholar 20 : Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure?. J Urol2003; 169: 849. Link, Google Scholar 21 : Prognosis of patients with lymph node positive prostate cancer following radical prostatectomy: long-term results. J Urol2004; 172: 2252. Link, Google Scholar 22 : Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol2007; 178: 864. Link, Google Scholar 23 : Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol2014; 65: 20. Google Scholar 24 : Two positive nodes represent a significant cut-off value for cancer specific survival in patients with node positive prostate cancer. A new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. Eur Urol2009; 55: 261. Google Scholar 25 : Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy. Eur Urol2008; 54: 344. Google Scholar © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byAndrews J, Ahmed M, Sharma V, Britton C, Stish B, Phillips R, Kendi A, Joshi V, Sood A, Tollefson M, Boorjian S, Karnes R and Kwon E (2022) Metastasis-directed Therapy Without Androgen Deprivation Therapy in Solitary Oligorecurrent Prostate CancerJournal of Urology, VOL. 208, NO. 6, (1240-1249), Online publication date: 1-Dec-2022.Taneja S (2019) Re: Metastasis-Directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-Institutional Analysis Comparing the Outcome and Toxicity of Stereotactic Body Radiotherapy and Elective Nodal RadiotherapyJournal of Urology, VOL. 203, NO. 3, (463-463), Online publication date: 1-Mar-2020.Ploussard G, Almeras C, Briganti A, Giannarini G, Hennequin C, Ost P, Renard-Penna R, Salin A, Lebret T, Villers A, Soulié M, de la Taille A and Flamand V (2015) Management of Node Only Recurrence after Primary Local Treatment for Prostate Cancer: A Systematic Review of the LiteratureJournal of Urology, VOL. 194, NO. 4, (983-988), Online publication date: 1-Oct-2015.Steers W (2014) This Month in Adult UrologyJournal of Urology, VOL. 193, NO. 1, (1-3), Online publication date: 1-Jan-2015. Volume 193Issue 1January 2015Page: 111-116Supplementary Materials Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.Keywordsrecurrencecholinelymph node excisionlymphatic metastasisprostatic neoplasmsMetrics Author Information R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Christopher R. Murphy Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Eric J. Bergstralh Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with GenomeDx. More articles by this author Guy DiMonte Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author John C. Cheville Department of Pathology, Mayo Clinic, Rochester, Minnesota More articles by this author Val J. Lowe Department of Radiology, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with GE Healthcare, Siemens Molecular Imaging and AVID Pharmaceuticals. More articles by this author Lance A. Mynderse Department of Urology, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Watermark Research Partners. More articles by this author Eugene D. Kwon Department of Urology, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Mayo Clinic. More articles by this author Expand All Advertisement PDF downloadLoading ...

While it has been demonstrated that receipt of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) improves survival compared to RC alone, the driving factor for this benefit may be from patients with ypT0 status at surgery. Meanwhile, the implications of having residual urothelial carcinoma of the bladder (rUCB) at RC after NAC are less clear. We therefore evaluated whether survival differed between patients with rUCB at RC after NAC and stage-matched controls who underwent RC alone. Patients who underwent NAC + RC (n = 180) were matched to controls who underwent RC alone (n=324) on the basis of pT and pN stage, margin status, and year of RC. The 5-yr recurrence-free survival (RFS; 90% vs 94%; p=1), cancer-specific survival (CSS; 82% vs 93%; p=0.4), and overall survival (OS; 82% vs 82%; p=0.5) were not significantly different between the NAC and control groups for patients with ypT0N0/pT0N0 disease (n=103). Conversely, among patients with rUCB at RC (n=401), patients who received NAC had significantly worse 5-yr RFS (50% vs 63%; p=0.01), CSS (40% vs 59%; p=0.003), and OS (33% vs 48%; p=0.02). On multivariable analysis for patients with rUCB, NAC receipt remained independently associated with worse RFS (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.28-2.66; p=0.001), CSS (HR 1.81, 95% CI 1.30-2.52; p<0.001), and OS (HR 1.57, 95% CI 1.18-2.08; p=0.002). Limitations include potential for selection bias owing to the retrospective observational design. Thus, while patients who achieve a complete response to NAC have excellent survival outcomes, those with rUCB after NAC have a worse prognosis compared to stage-matched controls undergoing RC alone. It may be worthwhile considering these patients for clinical trials evaluating the role of additional treatments after RC using newer agents while we await further research on predicting which patients achieve ypT0 status from NAC before RC.On surgical removal of the bladder, patients without residual bladder cancer after neoadjuvant chemotherapy have excellent survival outcomes. However, patients with residual cancer after neoadjuvant chemotherapy and surgery have worse outcomes compared to patients undergoing surgery alone. These patients should therefore be considered for additional treatments after surgery using newer agents while we await further research on predicting which patients will benefit from neoadjuvant chemotherapy before bladder removal for cancer.

Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes.To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT).PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis.The SOC cohort (n=1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort (n=263) received either salvage lymph node dissection (n=166) or stereotactic body radiotherapy (n=97) at PSA progression to a positron emission tomography-detected nodal recurrence.The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses.At a median follow-up of 70 (interquartile range: 48-98) mo, MDT was associated with an improved CSS on univariate (p=0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17-0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3-99.6) and 95.7% (95% CI: 93.2-97.3) for MDT and SOC, respectively (p=0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort.MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis-generating and inform future randomized trials in this setting.Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes.

Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT).To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT.Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml.We compared aRT versus observation followed by esRT.The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis).Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population.At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.At long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.

Prostate cancer (PCa) patients found to have adverse pathologic features following radical prostatectomy (RP) are less likely to be cured with surgery alone.To analyze the role of postoperative radiotherapy (RT) in patients with aggressive PCa.We performed a systematic literature review of the Medline and EMBASE databases. The search strategy included the terms radical prostatectomy, adjuvant radiotherapy, and salvage radiotherapy, alone or in combination. We limited our search to studies published between January 2009 and August 2016.Three randomized trials demonstrated that immediate RT after RP reduces the risk of recurrence in patients with aggressive PCa. However, immediate postoperative RT is associated with an increased risk of acute and late side effects ranging from 15% to 35% and 2% to 8%, respectively. Retrospective studies support the oncologic efficacy of initial observation followed by salvage RT administered at the first sign of recurrence; however, the impact of this delay on long-term control remains uncertain. Hopefully, ongoing randomized trials will shed light on the role of adjuvant RT versus observation±salvage RT in individuals with adverse features at RP. Accurate patient selection based on clinical characteristics and molecular profile is crucial. Dose escalation, whole-pelvis RT, novel techniques, and the use of hormonal therapy might improve the outcomes of postoperative RT.Immediate RT reduces the risk of recurrence after RP in patients with aggressive disease. However, this approach is associated with an increase in the incidence of short- and long-term side effects. Observation followed by salvage RT administered at the first sign of recurrence might be associated with durable cancer control, but prospective randomized comparison with adjuvant RT is still awaited. Dose escalation, refinements in the technique, and the concomitant use of hormonal therapies might improve outcomes of patients undergoing postoperative RT.Postoperative radiotherapy has an impact on oncologic outcomes in patients with aggressive disease characteristics. Salvage radiotherapy administered at the first sign of recurrence might be associated with durable cancer control in selected patients but might compromise cure in others.

Purpose Despite documented oncologic benefit, use of postoperative adjuvant radiotherapy (aRT) in patients with prostate cancer is still limited in the United States. We aimed to develop and internally validate a risk-stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Patient and Methods Our cohort included 512 patients with prostate cancer treated with radical prostatectomy at one of four US academic centers between 1990 and 2010. All patients had ≥ pT3a disease, positive surgical margins, and/or pathologic lymph node invasion. Multivariable Cox regression analysis tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk-stratification tool. Our study adhered to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for development of prognostic models. Results Overall, 21.9% of patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT versus initial observation ( P < .001). Pathologic T3b/T4 stage, Gleason score 8-10, lymph node invasion, and Decipher score > 0.6 were independent predictors of CR (all P < .01). The cumulative number of risk factors was 0, 1, 2, and 3 to 4 in 46.5%, 28.9%, 17.2%, and 7.4% of patients, respectively. aRT was associated with decreased CR rate in patients with two or more risk factors (10-year CR rate 10.1% in aRT v 42.1% in initial observation; P = .012), but not in those with fewer than two risk factors ( P = .18). Conclusion Using the new model to indicate aRT might reduce overtreatment, decrease unnecessary adverse effects, and reduce risk of CR in the subset of patients (approximately 25% of all patients with aggressive pathologic disease in our cohort) who benefit from this therapy.

Long-term outcomes of patients treated with salvage lymph node dissection (sLND) for nodal recurrence of prostate cancer (PCa) remain unknown.To investigate long-term oncological outcomes after sLND in a large multi-institutional series.The study included 189 patients who experienced prostate-specific antigen (PSA) rise and nodal-only recurrence after radical prostatectomy (RP) and underwent sLND at 11 tertiary referral centers between 2002 and 2011. Lymph node recurrence was documented by positron emission tomography/computed tomography (PET/CT) scan using either 11C-choline or 68Ga prostate-specific membrane antigen ligand.The primary outcome of the study was cancer-specific mortality (CSM). The secondary outcomes were overall mortality, clinical recurrence (CR), biochemical recurrence (BCR), and androgen deprivation therapy (ADT)-free survival after sLND. The probability of freedom from each outcome was calculated using Kaplan-Meier analyses. Cox regression analysis was used to predict the risk of prostate CSM after accounting for several parameters, including the use of additional treatments after sLND.At long term, 110 and 163 patients experienced CR and BCR, respectively, with CR-free and BCR-free survival at 10 yr of 31% and 11%, respectively. After sLND, a total of 145 patients received ADT, with a median time to ADT of 41 mo. At a median (interquartile range) follow-up for survivors of 87 (51, 104) mo, 48 patients died. Of them, 45 died from PCa. The probabilities of freedom from cancer-specific and all-cause death at 10 yr were 66% and 64%, respectively. Similar results were obtained in sensitivity analyses in patients with pelvic-only positive PET/CT scan, as well as after excluding men on ADT at PET/CT scan and patients with PSA level at sLND higher than the 75th percentile. At multivariable analyses, patients who had PSA response after sLND (hazard ratio [HR]: 0.45; p = 0.001), and those receiving ADT within 6 mo from sLND (HR: 0.51; p = 0.010) had lower risk of death from PCa.A third of men treated with sLND for PET-detected nodal recurrence of PCa died at long term, with PCa being the main cause of death. Salvage LND alone was associated with durable long-term outcomes in a minority of men who significantly benefited from additional treatments after surgery. Taken together, all these data argue against the use of metastasis-directed therapy alone for patients with node-only recurrent PCa. These men should instead be considered at high risk of systemic dissemination already at the time of sLND.We assessed long-term outcomes of patients treated with salvage lymph node dissection (sLND) for node-recurrent prostate cancer (PCa). In contrast with prior evidence, we found that the majority of these men recurred after sLND and eventually died from PCa. A significant survival benefit associated with the administration of androgen deprivation therapy after sLND suggests that sLND should be considered part of a multimodal approach rather than an exclusive treatment strategy.

Abstract Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.

Salvage radical prostatectomy has historically yielded a poor functional outcome and a high complication rate. However, recent reports of robotic salvage radical prostatectomy have demonstrated improved results. In this study we assessed salvage radical prostatectomy functional outcomes and complications when comparing robotic and open approaches.We retrospectively collected data on salvage radical prostatectomy for recurrent prostate cancer after local nonsurgical treatment at 18 tertiary referral centers from 2000 to 2016. The Clavien-Dindo classification was applied to classify complications. Complications and functional outcomes were evaluated by univariable and multivariable analysis.We included 395 salvage radical prostatectomies, of which 186 were open and 209 were robotic. Robotic salvage radical prostatectomy yielded lower blood loss and a shorter hospital stay (each p <0.0001). No significant difference emerged in the incidence of major and overall complications (10.1%, p=0.16, and 34.9%, p=0.67), including an overall low risk of rectal injury and fistula (1.58% and 2.02%, respectively). However, anastomotic stricture was more frequent for open salvage radical prostatectomy (16.57% vs 7.66%, p <0.01). Overall 24.6% of patients had had severe incontinence, defined as 3 or more pads per day, for 12 or 6 months. On multivariable analysis robotic salvage radical prostatectomy was an independent predictor of continence preservation (OR 0.411, 95% CI 0.232-0.727, p=0.022). Limitations include the retrospective nature of the study and the absence of a standardized surgical technique.In this contemporary series to our knowledge salvage radical prostatectomy showed a low risk of major complications and better functional outcomes than previously reported. Robotic salvage radical prostatectomy may reduce anastomotic stricture, blood loss and hospital stay, and improve continence outcomes.

Pelvic lymph node dissection (PLND) yields the most accurate staging in patients undergoing radical prostatectomy (RP) for prostate cancer (PCa), although it can be associated with morbidity. To systematically evaluate the impact of PLND extent on perioperative morbidity in patients undergoing RP. A new PLND-related complication assessment tool is proposed. A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was conducted. MEDLINE/PubMed, Scopus, Embase and Web of Science databases were searched to yield studies discussing perioperative complications following RP and PLND. The extent of PLND was classified according to the European Association of Urology PCa guidelines. Studies were categorized according to the extent of PLND. Intra- and postoperative complications were classified as “strongly,” “likely,” or “unlikely” related to PLND. Anatomical site of perioperative complications was recorded. A cumulative meta-analysis of comparative studies was conducted using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). Our search generated 3645 papers, with 176 studies meeting the inclusion criteria. Details of 77 303 patients were analyzed. Of these studies, 84 (47.7%), combining data on 28 428 patients, described intraoperative complications as an outcome of interest. Overall, 534 (1.8%) patients reported one or more intraoperative complications. Postoperative complications were reported in 151 (85.7%) studies, combining data on 73 629 patients. Overall, 10 401 (14.1%) patients reported one or more postoperative complication. The most reported postoperative complication strongly related to PLND was lymphocele (90.6%). The pooled meta-analysis revealed that RP + limited PLND/standard PLND had a significantly decreased risk of experiencing any intraoperative complication (risk ratio [RR]: 0.55; p = 0.01) and postoperative complication strongly related to PLND (RR: 0.46; p = <0.00001), particularly for lymphocele formation (RR: 0.52; p = 0.0003) and thromboembolic events (RR: 0.59; p = 0.008), when compared with extended/superextended PLND. The extent of PLND was confirmed to be an independent predictor of lymphocele formation (RR: 1.77; p < 0.00001). The perioperative morbidity of PLND in patients undergoing RP and PLND for PCa significantly correlates with the extent of PLND. More standardized reporting of intra- and postoperative complications is needed to better estimate the direct impact of PLND extent on perioperative morbidity. Pelvic lymph node dissection (PLND) is the most accurate method for staging in patients undergoing radical prostatectomy for prostate cancer, although it can be associated with complications. This study aims to systematically evaluate the impact of PLND extent on perioperative complications in these patients. We found that intra- and postoperative complications correlate significantly with the extent of PLND. A more rigorous assessment and thorough reporting of perioperative complications are recommended.

Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPKEYFP mice (for Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-G12D/+; R26R-CAG-LSL-EYFP/+) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Transcriptomic and whole-exome analyses of bone metastasis from these mice revealed distinct molecular profiles conserved between human and mouse and specific patterns of subclonal branching from the primary tumor. Integrating bulk and single-cell transcriptomic data from mouse and human datasets with functional studies in vivo unravels a unique MYC/RAS co-activation signature associated with prostate cancer metastasis. Finally, we identify a gene signature with prognostic value for time to metastasis and predictive of treatment response in human patients undergoing androgen receptor therapy across clinical cohorts, thus uncovering conserved mechanisms of metastasis with potential translational significance. Using lineage tracing and molecular profiling, Abate-Shen and colleagues identify a Ras and Myc co-activation signature that predicts metastasis and castration resistance in localized prostate cancer.

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).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.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 (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (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 [HRAAM = 2.30; 95% confidence interval (CI), 1.21-4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52-3.86; P = 0.0001) but not in EAM.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.

Abstract Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.

Although secondary radiation therapy decreases the risk of biochemical progression after radical prostatectomy, its impact on metastasis and survival is less well established. We evaluated the impact of adjuvant and salvage radiotherapy on clinical progression and mortality.A total of 361 patients who received adjuvant radiation were matched based on clinicopathological features to patients who did not receive adjuvant radiation in a 2:1 case-control ratio. Postoperative survival was estimated using the Kaplan-Meier method and compared using the log rank test. A second cohort of 2,657 men who experienced biochemical recurrence after prostatectomy was separately evaluated. Cox proportional hazard regression models were used to analyze the impact of salvage radiotherapy on disease progression and survival.Adjuvant radiotherapy was associated with significantly improved 10-year biochemical recurrence-free survival (63% vs 45%, p <0.001), local recurrence-free survival (97% vs 82%, p <0.001) and a decreased need for late hormone therapy (17% vs 28%, p = 0.002) but did not impact systemic progression and overall survival (p = 0.94 and 0.27, respectively). Of the 2,657 patients who experienced biochemical recurrence after surgery 856 (32.3%) received salvage radiation. On multivariate analysis salvage radiotherapy decreased the risk of local recurrence (HR 0.13, 95% CI 0.06-0.28, p <0.0001) and delayed hormonal therapy (HR 0.81, 95% CI 0.71-0.93, p = 0.003) and systemic progression (HR 0.24, 95% CI 0.13-0.45, p <0.0001) but did not significantly impact mortality (p = 0.48).Adjuvant and salvage radiation provide long-term local control and decrease the need for delayed hormonal therapy but neither improves survival. These results must be weighed against the potential morbidity of postoperative radiation when counseling patients.

No AccessJournal of UrologyAdult Urology1 Jun 2012The Implications of Hospital Acquired Adverse Events on Mortality, Length of Stay and Costs for Patients Undergoing Radical Cystectomy for Bladder Cancer Simon P. Kim, Nilay D. Shah, R. Jeffrey Karnes, Christopher J. Weight, Igor Frank, James P. Moriarty, Leona C. Han, Bijan Borah, Matthew K. Tollefson, and Stephen A. Boorjian Simon P. KimSimon P. Kim Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , Nilay D. ShahNilay D. Shah Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , R. Jeffrey KarnesR. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , Christopher J. WeightChristopher J. Weight Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , Igor FrankIgor Frank Department of Urology, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Rochester Medical Company. More articles by this author , James P. MoriartyJames P. Moriarty Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , Leona C. HanLeona C. Han Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , Bijan BorahBijan Borah Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , Matthew K. TollefsonMatthew K. Tollefson Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author , and Stephen A. BoorjianStephen A. Boorjian Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.01.077AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: The incidence of hospital acquired adverse events in radical cystectomy and their implications for hospital outcomes and costs remain poorly described. We describe the incidence of hospital acquired adverse events in radical cystectomy, and characterize its relationship with in-hospital mortality, length of stay and hospitalization costs. Materials and Methods: We identified 10,856 patients who underwent radical cystectomy for bladder cancer at 1,175 hospitals in the Nationwide Inpatient Sample from 2001 to 2008. We used hospital claims to identify adverse events for accidental puncture, decubitus ulcer, deep vein thrombosis/pulmonary embolus, methicillin-resistant Staphylococcus aureus, Clostridium difficile, surgical site infection and sepsis. Logistic regression and generalized estimating equation models were used to test the associations of hospital acquired adverse events with mortality, predicted prolonged length of stay and total hospitalization costs. Results: Hospital acquired adverse events occurred in 11.3% of all patients undergoing radical cystectomy (1,228). Adverse events were associated with a higher odds of in-hospital death (OR 8.07, p <0.001), adjusted prolonged length of stay (41.3%) and total costs ($54,242 vs $26,306; p <0.001) compared to no adverse events on multivariate analysis. The incremental total costs attributable to hospital acquired adverse events were $43.8 million. Postoperative sepsis was associated with the highest risk of mortality (OR 17.56, p <0.001), predicted prolonged length of stay (62.22%) and adjusted total cost ($79,613). Conclusions: With hospital acquired adverse events occurring in approximately 11% of radical cystectomy cases, they pose a significant risk of in-hospital mortality and higher hospitalization costs. Therefore, increased attention is needed to reduce adverse events by improving patient safety, while understanding the economic implications for tertiary referral centers with possible policy changes such as denial of payment for hospital acquired adverse events. References 1 : Adverse outcomes in surgery: redefinition of postoperative complications. Am J Surg2009; 197: 479. Google Scholar 2 : Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA2003; 290: 1868. Google Scholar 3 : The $17.1 billion problem: the annual cost of measurable medical errors. Health Aff (Millwood)2011; 30: 596. Google Scholar 4 : Medicare payment for selected adverse events: building the business case for investing in patient safety. 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Accessed July 1, 2011. Google Scholar 20 : Estimating log models: to transform or not transform?. J Health Econ2001; 20: 461. Google Scholar 21 : Effect of postcystectomy infectious complications on cost, length of stay, and mortality. Urology2009; 73: 598. Google Scholar 22 : Analysis of early complications after radical cystectomy: results of a collaborative care pathway. J Urol2002; 167: 2012. Link, Google Scholar 23 : Clinical and economic outcomes attributable to health care-associated sepsis and pneumonia. Arch Intern Med2010; 170: 347. Google Scholar 24 : Hospital costs associated with surgical complications: a report from the private-sector National Surgical Quality Improvement Program. J Am Coll Surg2004; 199: 531. Google Scholar 25 : Limitations of claims and registry data in surgical oncology research. Ann Surg Oncol2008; 15: 415. Google Scholar 26 : Centers for Medicare and Medicaid Services' “never events”: an analysis and recommendations to hospitals. Health Care Manag (Frederick)2008; 27: 338. Google Scholar 27 : The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics2003; 21: 1315. Google Scholar 28 : Association of procedure volume with radical cystectomy outcomes in a nationwide database. J Urol2007; 178: 1418. Link, Google Scholar 29 : Volume-based referral for cancer surgery: informing the debate. J Clin Oncol2007; 25: 91. Google Scholar 30 : Contemporary trends of in-hospital complications and mortality for radical cystectomy from a population-based analysis. BJU IntMarch 22, 2012; . Epub ahead of print. Google Scholar © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byGinsburg K, Curtis G, Timar R, George A and Cher M (2020) Delayed Radical Prostatectomy is Not Associated with Adverse Oncologic Outcomes: Implications for Men Experiencing Surgical Delay Due to the COVID-19 PandemicJournal of Urology, VOL. 204, NO. 4, (720-725), Online publication date: 1-Oct-2020.Calaway A, Jacob J, Tong Y, Shumaker L, Kitley W, Boris R, Cary C, Kaimakliotis H, Masterson T, Bihrle R and Koch M (2019) A Prospective Program to Reduce the Clinical Incidence of Clostridium difficile Colitis Infection after CystectomyJournal of Urology, VOL. 201, NO. 2, (342-349), Online publication date: 1-Feb-2019.Shah P, Thompson R, Boorjian S, Lohse C, Lyon T, Shields R, Froehling D, Leibovich B and Viers B (2018) Symptomatic Venous Thromboembolism is Associated with Inferior Survival among Patients Undergoing Nephrectomy with Inferior Vena Cava Tumor Thrombectomy for Renal Cell CarcinomaJournal of Urology, VOL. 200, NO. 3, (520-527), Online publication date: 1-Sep-2018.Zaid H, Yang D, Tollefson M, Frank I, Parker W, Thompson R, Karnes R and Boorjian S (2016) Safety and Efficacy of Extended Duration of Thromboembolic Prophylaxis Following Radical Cystectomy: An Initial Institutional ExperienceUrology Practice, VOL. 3, NO. 6, (462-467), Online publication date: 1-Nov-2016.Xu W, Daneshmand S, Bazargani S, Cai J, Miranda G, Schuckman A and Djaladat H (2015) Postoperative Pain Management after Radical Cystectomy: Comparing Traditional versus Enhanced Recovery Protocol PathwayJournal of Urology, VOL. 194, NO. 5, (1209-1213), Online publication date: 1-Nov-2015.Sun A, Djaladat H, Schuckman A, Miranda G, Cai J and Daneshmand S (2014) Venous Thromboembolism Following Radical Cystectomy: Significant Predictors, Comparison of Different Anticoagulants and Timing of EventsJournal of Urology, VOL. 193, NO. 2, (565-569), Online publication date: 1-Feb-2015.Daneshmand S, Ahmadi H, Schuckman A, Mitra A, Cai J, Miranda G and Djaladat H (2014) Enhanced Recovery Protocol after Radical Cystectomy for Bladder CancerJournal of Urology, VOL. 192, NO. 1, (50-56), Online publication date: 1-Jul-2014. Volume 187Issue 6June 2012Page: 2011-2017Supplementary Materials Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.Keywordscomplicationstreatment outcomeurinary bladder neoplasmscosts and cost analysiscystectomyMetricsAuthor Information Simon P. Kim Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Nilay D. Shah Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Christopher J. Weight Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Igor Frank Department of Urology, Mayo Clinic, Rochester, Minnesota Financial interest and/or other relationship with Rochester Medical Company. More articles by this author James P. Moriarty Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Leona C. Han Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Bijan Borah Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Matthew K. Tollefson Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Stephen A. Boorjian Department of Urology, Mayo Clinic, Rochester, Minnesota Nothing to disclose. More articles by this author Expand All Advertisement PDF downloadLoading ...

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.

Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Despite a lack of randomised controlled trials, most men with locally advanced prostate cancer are recommended to undergo external beam radiotherapy (EBRT), often combined with long-term androgen-deprivation therapy (ADT). Many of these men are not offered radical prostatectomy (RP) by their treating urologist. Additionally, it is know that EBRT with long-term ADT does provide good cancer control (88% at 10 years). We have previously published intermediate-term follow-up of a large series of men treatment with RP for cT3 prostate cancer. We report long-term follow-up of a large series of men treated with RP as primary treatment for cT3 prostate cancer. Our study shows that with long-term follow-up RP provides excellent oncological outcomes even at 20 years. While most men do require a multimodal treatment approach, many men can be managed successfully with RP alone.• To present long-term survival outcomes after radical prostatectomy (RP) for patients with cT3 prostate cancer, as the optimal treatment for patients with clinical T3 prostate cancer is debated.• We identified 843 men who underwent RP for cT3 tumours between 1987 and 1997. • Survival was estimated using the Kaplan-Meier method. • Cox proportional hazards regression models were used to evaluate the association of clinicopathological features with outcome• The median (range) postoperative follow-up was 14.3 (0.1-23.5) years. • Down-staging to pT2 disease occurred in 26% (223/843) at surgery. • Local recurrence-free, systemic progression-free and cancer-specific survival for men with cT3 prostate cancer after RP was 76%, 72%, and 81%, respectively, at 20 years. • On multivariate analysis, increasing RP Gleason score (hazard ratio [HR] 1.8; P = 0.01), non-diploid chromatin content (HR 1.8; P = 0.01), positive surgical margins (HR 2.1; P = 0.007), and seminal vesicle invasion (HR 2.1; P = 0.005) were associated with a significant risk of prostate cancer death, while a more recent year of surgery was associated with a decreased risk of cancer-specific mortality (HR 0.88; P = 0.01)• RP affords accurate pathological staging and may be associated with durable cancer control for cT3 prostate cancer, with 20 years of follow-up presented here. • RP as part of a multimodal treatment strategy therefore remains a viable treatment option for patients with cT3 tumours.

Despite salvage radiation therapy (SRT) for recurrent prostate cancer (PCa) after radical prostatectomy (RP), some patients still progress to metastases. Identifying these men would allow them to undergo systemic therapy including testing novel therapies to reduce metastases risk.To test whether the genomic classifier (GC) predicts development of metastatic disease.Retrospective multi-center and multi-ethnic cohort study from two academic centers and one Veterans Affairs Medical Center in the United States involving 170 men receiving SRT for recurrent PCa post-RP.Time from SRT to development of metastatic disease tested using Cox regression, survival c-index, and decision curve analysis. Performance of GC was compared to the Cancer of the Prostate Risk Assessment Score and Briganti risk models based on these metrics.With a median 5.7 yr follow-up after SRT, 20 patients (12%) developed metastases. On multivariable analysis, for each 0.1 unit increase in GC (scaled from 0 to 1), the hazard ratio for metastasis was 1.58 (95% confidence interval 1.16-2.17; p=0.002). Adjusting for androgen deprivation therapy did not materially change the results. The c-index for GC was 0.85 (95% confidence interval 0.73-0.88) versus 0.63-0.65 for published clinico-pathologic risk models. The 5-yr cumulative incidence of metastasis post-SRT in patients with low, intermediate, and high GC scores was 2.7%, 8.4%, and 33.1%, respectively (p<0.001).While validation in larger, prospectively collected cohorts is required, these data suggest GC is a strong predictor of metastases among men receiving SRT for recurrent PCa post-RP, accurately identifying men who are excellent candidates for systemic therapy due to their very high-risk of metastases.Genomic classifier and two clinico-pathologic risk models were evaluated on their ability to predict metastases among men receiving salvage radiation therapy for recurrent prostate cancer. Genomic classifier was able to identify candidates for further therapies due to their very high-risk of metastases.

Determining clinicopathologic features that stratify the risk of disease progression in patients with seminal vesicle invasion at radical prostatectomy remains critical for patient counseling, clinical trial enrollment, and the judicious application of secondary therapies. Then, we evaluated the prognostic significance of concomitant extracapsular extension (ECE) in patients with seminal vesicle invasion and negative lymph nodes at radical prostatectomy.We identified 1,132 patients who underwent prostatectomy between 1987 and 2009 and were found to have pT3bN0 disease. Median postoperative follow-up was 10.6 years (interquartile range, 5.9-15.3). Survival was estimated using the Kaplan-Meier method and compared for patients with and without ECE with the log-rank test. The association of ECE with outcome was evaluated using Cox proportional hazards regression models.A total of 693 (61%) patients were noted to have ECE. Compared with pT3bN0 patients without ECE, patients with pT3bN0 tumors and ECE had a significantly worse 15-year biochemical recurrence-free survival (29% vs. 39%; P<0.001), systemic progression-free survival (71% vs. 81%; P<0.001), cancer-specific survival (80% vs. 89%; P<0.001), and overall survival (50% vs. 63%; P<0.001). On multivariate analysis, the presence of ECE was associated with significantly increased risks of systemic progression (hazard ratio [HR], 1.56; P=0.006), death from prostate cancer (HR, 1.71; P=0.01), and all-cause mortality (HR, 1.35; P=0.007). Meanwhile, adjuvant hormonal therapy, which was received by 334 patients (29.5%), was associated with significantly decreased risks of systemic progression (HR, 0.50; P=0.0004) and cancer death (HR, 0.57; P=0.03), but not all-cause mortality (HR, 0.81; P=0.09). Limitations included retrospective design and nonstandardized application of secondary treatments.The presence of ECE in patients with pT3bN0 prostate cancer is associated with increased risks of systemic progression and cancer death. Pending validation, ECE may be incorporated into risk stratification or staging classification or both. Meanwhile, these patients continue to represent ideal candidates for adjuvant therapy trials.

To determine the role of cellular proliferation and other biopsy-based features in the prediction of prostate cancer mortality.Between 1993 and 2012, our institution has performed quantitation of prostate cancer DNA ploidy and Ki-67 (MIB-1) on most prostate cancer needle biopsy specimens. The outcomes of 451 consecutive patients with biopsy-proven cancer treated by radical prostatectomy between January 24, 1995, and December 29, 1998, without neoadjuvant hormonal therapy were assessed. Clinical and biopsy information obtained before radical prostatectomy was placed in multivariate Cox proportional hazards regression models to predict local or systemic progression and cancer-specific death. Predictive ability was evaluated using a concordance index.With a median follow-up of 12.9 years, 46 patients experienced local or systemic progression, and 18 patients died of prostate cancer. On multivariate analysis, the biopsy features of Ki-67 expression, perineural invasion, and Gleason score were associated with local or systemic progression. Ki-67 expression, perineural invasion, and Gleason score were associated with cancer-specific death with a concordance index of 0.892. After adjusting for perineural invasion and Gleason score, each 1% increase in Ki-67 expression was associated with a 12% increased risk of cancer-specific death (P<.001). Ki-67 expression alone was a strong predictor of cancer-specific outcomes and improved the predictive ability of currently used algorithms.This study documents that long-term prostate cancer outcomes are best estimated with a combination of Gleason score, perineural invasion, and Ki-67 expression. Given its low cost, rapid assessment, and strong predictive power, we believe that adding Ki-67 expression to perineural invasion and Gleason score at biopsy should be considered a standard by which all new biomarkers are compared before introducing them into clinical practice.

Salvage radiation therapy (SRT) is a recommended treatment option for biochemical recurrence after radical prostatectomy (RP). However, its effectiveness may be limited to specific categories of patients. We aimed to identify the optimal candidates for early SRT after RP. The study included 925 node-negative patients treated with SRT after RP at seven institutions. Patients received SRT for either prostate-specific antigen (PSA) rising, or PSA persistence after RP that was defined as PSA level ≥0.1 ng/ml at 1 mo after surgery. All patients received local radiation to the prostate and seminal vesicle bed. The primary outcome measured was distant metastasis after SRT. Regression tree analysis was used to develop a risk-stratification tool. Multivariable Cox regression analysis and nonparametric curve fitting methods were used to explore the relationship between PSA level at SRT and the probability of metastasis-free survival at 8 yr. At a median follow-up of 8.0 yr, 130 patients developed distant metastasis. At multivariable analysis, pre-SRT PSA level was significantly associated with distant metastasis (hazard ratio: 1.06, p < 0.0001). However, when patients were stratified into five risk groups using regression tree analysis (area under the curve: 85%), early SRT administration provided better metastasis-free survival in three groups only: (1) low risk: undetectable PSA after RP, Gleason score ≤7, and tumour stage ≥pT3b, (2) intermediate risk: undetectable PSA after RP with Gleason score ≥8, (3) high risk: PSA persistence after RP with Gleason score ≤7. We developed an accurate risk stratification tool to facilitate the individualised recommendation for early SRT based on prostate cancer characteristics. Early SRT proved to be beneficial only in selected groups of patients who are more likely to be affected by clinically significant but not yet systemic recurrence at the time of salvage treatment administration. In patients affected by prostate cancer recurrence after radical prostatectomy, the early administration of salvage radiation therapy is beneficial only for selected subgroups of patients. In this study, these groups of patients were identified.

Patients with lymph node (LN)-positive prostate cancer (PCa) at radical prostatectomy (RP) face a high risk of cancer recurrence. Nevertheless, recurrence patterns of LN-positive PCa and their prognostic significance remain understudied in the literature.To analyze a large single-institution series with long-term follow-up to elucidate the various clinical recurrence patterns of LN-positive PCa and their association with oncologic outcomes.Years 1987-2012 of a prospectively maintained institutional RP registry were queried for men with LN-positive PCa at RP. Clinical recurrences were categorized as local, nodal, skeletal, or visceral.In addition to descriptive statistics and Kaplan-Meier analysis, univariable and multivariable Cox proportional hazards models were constructed to predict recurrence and to quantify the impact of recurrence patterns on cancer-specific mortality (CSM).Data from 1011 men with LN-positive PCa at RP were analyzed with 17.6 yr of median follow-up. The 15-yr clinical recurrence rate was 33% (95% confidence interval [CI], 31-35%) for all patients and 52.2% (95% CI, 47.3-57.1%) for patients with biochemical recurrence. The solitary locations were skeletal (n=94, 55%), nodal (n=59, 34%), local soft tissue (n=29, 17%), and visceral (n=8, 5%). Significant multivariable predictors of recurrence were Gleason score 8-10, number of positive nodes, pathologic Gleason score, and more recent year of surgery. The 15-yr CSM after clinical recurrence was 80%, with a mean overall survival of 30 mo after recurrence. On multivariable analysis, recurrences after 5 yr from RP (hazard ratio [HR]: 0.05), multiple recurrences (HR: 1.97), skeletal (HR: 3.13), and visceral metastases (HR: 7.43) were independently associated with CSM (all p<0.05).Recurrences after RP for LN-positive PCa are heterogeneous in terms of time from RP, location, and number of concomitant lesions.We found that impact of recurrence patterns on cancer-specific mortality varies significantly and allows these patients to be stratified for purposes of prognostication, follow-up, and therapy.

Clinical grading systems using clinical features alongside nomograms lack precision in guiding treatment decisions in prostate cancer (PCa). There is a critical need for identification of biomarkers that can more accurately stratify patients with primary PCa. To identify a robust prognostic signature to better distinguish indolent from aggressive prostate cancer (PCa). To develop the signature, whole-genome and whole-transcriptome sequencing was conducted on five PCa patient-derived xenograft (PDX) models collected from independent foci of a single primary tumor and exhibiting variable metastatic phenotypes. Multiple independent clinical cohorts including an intermediate-risk cohort were used to validate the biomarkers. The outcome measurement defining aggressive PCa was metastasis following radical prostatectomy. A generalized linear model with lasso regularization was used to build a 93-gene stroma-derived metastasis signature (SDMS). The SDMS association with metastasis was assessed using a Wilcoxon rank-sum test. Performance was evaluated using the area under the curve (AUC) for the receiver operating characteristic, and Kaplan-Meier curves. Univariable and multivariable regression models were used to compare the SDMS alongside clinicopathological variables and reported signatures. AUC was assessed to determine if SDMS is additive or synergistic to previously reported signatures. A close association between stromal gene expression and metastatic phenotype was observed. Accordingly, the SDMS was modeled and validated in multiple independent clinical cohorts. Patients with higher SDMS scores were found to have worse prognosis. Furthermore, SDMS was an independent prognostic factor, can stratify risk in intermediate-risk PCa, and can improve the performance of other previously reported signatures. Profiling of stromal gene expression led to development of an SDMS that was validated as independently prognostic for the metastatic potential of prostate tumors. Our stroma-derived metastasis signature can predict the metastatic potential of early stage disease and will strengthen decisions regarding selection of active surveillance versus surgery and/or radiation therapy for prostate cancer patients. Furthermore, profiling of stroma cells should be more consistent than profiling of diverse cellular populations of heterogeneous tumors.

Disease-specific registries that enroll a considerable number of patients play a major role in prostate cancer (PCa) research.To evaluate available registries, describe their strengths and limitations, and discuss the potential future role of PCa registries in outcomes research.We performed a literature review of the Medline, Embase, and Web of Science databases. The search strategy included the terms prostate cancer, outcomes, statistical approaches, population-based cohorts, registries of outcomes, and epidemiological studies, alone or in combination. We limited our search to studies published between January 2005 and January 2015.Several population-based and prospective disease-specific registries are currently available for prostate cancer. Studies performed using these data sources provide important information on incidence and mortality, disease characteristics at presentation, risk factors, trends in utilization of health care services, disparities in access to treatment, quality of care, long-term oncologic and health-related quality of life outcomes, and costs associated with management of the disease. Although data from these registries have some limitations, statistical methods are available that can address certain biases and increase the internal and external validity of such analyses. In the future, improvements in data quality, collection of tissue samples, and the availability of data feedback to health care providers will increase the relevance of studies built on population-based and disease-specific registries.The strengths and limitations of PCa registries should be carefully considered when planning studies using these databases. Although randomized controlled trials still provide the highest level of evidence, large registries play an important and growing role in advancing PCa research and care.Several population-based and prospective disease-specific registries for prostate cancer are currently available. Analyses of data from these registries yield information that is clinically relevant for the management of patients with prostate cancer.

Long noncoding RNAs (lncRNAs) are an emerging class of relatively underexplored oncogenic molecules with biological and clinical significance. Current inadequacies for stratifying patients with aggressive disease presents a strong rationale to systematically identify lncRNAs as clinical predictors in localized prostate cancer. To identify RNA biomarkers associated with aggressive prostate cancer. Radical prostatectomy microarray and clinical data was obtained from 910 patients in three published institutional cohorts: Mayo Clinic I (N = 545, median follow-up 13.8 yr), Mayo Clinic II (N = 235, median follow-up 6.7 yr), and Thomas Jefferson University (N = 130, median follow-up 9.6 yr). The primary clinical endpoint was distant metastasis-free survival. Secondary endpoints include prostate cancer-specific survival and overall survival. Univariate and multivariate Cox regression were used to evaluate the association of lncRNA expression and these endpoints. An integrative analysis revealed Prostate Cancer Associated Transcript-14 (PCAT-14) as the most prevalent lncRNA that is aberrantly expressed in prostate cancer patients. Down-regulation of PCAT-14 expression significantly associated with Gleason score and a greater probability of metastatic progression, overall survival, and prostate cancer-specific mortality across multiple independent datasets and ethnicities. Low PCAT-14 expression was implicated with genes involved in biological processes promoting aggressive disease. In-vitro analysis confirmed that low PCAT-14 expression increased migration while overexpressing PCAT-14 reduced cellular growth, migration, and invasion. We discovered that androgen-regulated PCAT-14 is overexpressed in prostate cancer, suppresses invasive phenotypes, and lower expression is significantly prognostic for multiple clinical endpoints supporting its significance for predicting metastatic disease that could be used to improve patient management. We discovered that aberrant prostate cancer associated transcript-14 expression during prostate cancer progression is prevalent across cancer patients. Prostate cancer associated transcript-14 is also prognostic for metastatic disease and survival highlighting its importance for stratifying patients that could benefit from treatment intensification.

No AccessJournal of UrologyAdult Urology1 Jul 2017Redefining and Contextualizing the Hospital Volume-Outcome Relationship for Robot-Assisted Radical Prostatectomy: Implications for Centralization of Care Boris Gershman, Sarah K. Meier, Molly M. Jeffery, Daniel M. Moreira, Matthew K. Tollefson, Simon P. Kim, R. Jeffrey Karnes, and Nilay D. Shah Boris GershmanBoris Gershman Division of Urology, Rhode Island Hospital and Miriam Hospital, Providence, Rhode Island More articles by this author , Sarah K. MeierSarah K. Meier Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota More articles by this author , Molly M. JefferyMolly M. Jeffery Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota More articles by this author , Daniel M. MoreiraDaniel M. Moreira Department of Urology, University of Illinois at Chicago, Chicago, Illinois More articles by this author , Matthew K. TollefsonMatthew K. Tollefson Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author , Simon P. KimSimon P. Kim Department of Urology, Urology Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio More articles by this author , R. Jeffrey KarnesR. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author , and Nilay D. ShahNilay D. Shah Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota OptumLabs, Cambridge, Massachusetts More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.01.067AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Robot-assisted radical prostatectomy has undergone rapid dissemination driven in part by market forces to become the most frequently used surgical approach in the management of prostate cancer. Accordingly, a critical analysis of its volume-outcome relationship has important health policy implications. Therefore, we evaluated the association of hospital robot-assisted radical prostatectomy volume with perioperative outcomes, and examined the distribution of hospital procedure volume to contextualize the volume-outcome relationship. Materials and Methods: We identified 140,671 men who underwent robot-assisted radical prostatectomy from 2009 to 2011 in NIS (Nationwide Inpatient Sample). The associations of hospital volume with perioperative outcomes and total hospital costs were evaluated using multivariable logistic regression and generalized linear models. Results: In 2011, 70% of hospitals averaged 1 robot-assisted radical prostatectomy per week or less, accounting for 28% of surgeries. Compared to patients treated at the lowest quartile hospitals, those treated at the highest quartile hospitals had significantly lower rates of intraoperative complications (0.6% vs 1.4%), postoperative complications (4.8% vs 13.9%), perioperative blood transfusion (1.5% vs 4.0%), prolonged hospitalization (4.3% vs 13.8%) and mean total hospital costs ($12,647 vs $15,394, all ptrend <0.001). When modeled as a nonlinear continuous variable, increasing hospital volume was independently associated with improved rates of each perioperative end point up to approximately 100 robot-assisted radical prostatectomies per year, beyond which there appeared to be marginal improvement. Conclusions: Increasing hospital robot-assisted radical prostatectomy volume was associated with improved perioperative outcomes up to approximately 100 surgeries per year, beyond which there appeared to be marginal improvement. A substantial proportion of these procedures is performed at low volume hospitals. References 1 : Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol2010; 28: 1117. Google Scholar 2 : Prostate cancer, version 2.2014. J Natl Compr Canc Netw2014; 12: 686. Google Scholar 3 : Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. J Clin Oncol2014; 32: 1419. Google Scholar 4 : Direct-to-consumer Internet promotion of robotic prostatectomy exhibits varying quality of information. Health Aff (Millwood)2012; 31: 760. Google Scholar 5 : Robot-assisted versus open radical prostatectomy: a contemporary analysis of an all-payer discharge database. Eur Urol2016; 70: 837. Google Scholar 6 : Adverse effects of robotic-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of Medicare-age men. J Clin Oncol2012; 30: 513. Google Scholar 7 : Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA2009; 302: 1557. Google Scholar 8 : Hospitalization costs for radical prostatectomy attributable to robotic surgery. Eur Urol2013; 64: 11. Google Scholar 9 : Searching robotic prostatectomy online: what information is available?. Urology2011; 77: 941. Google Scholar 10 : Factors associated with adoption of robotic surgical technology in US hospitals and relationship to radical prostatectomy procedure volume. Ann Surg2014; 259: 1. Google Scholar 11 : The association of robotic surgical technology and hospital prostatectomy volumes: increasing market share through the adoption of technology. Cancer2012; 118: 371. Google Scholar 12 : Trends in radical prostatectomy: centralization, robotics, and access to urologic cancer care. Cancer2012; 118: 54. Google Scholar 13 : Blood transfusions in radical prostatectomy: a contemporary population-based analysis. Urology2012; 79: 332. Google Scholar 14 : Variations in morbidity after radical prostatectomy. N Engl J Med2002; 346: 1138. Crossref, Medline, Google Scholar 15 : The surgical learning curve for prostate cancer control after radical prostatectomy. J Natl Cancer Inst2007; 99: 1171. Google Scholar 16 : Cancer control and functional outcomes after radical prostatectomy as markers of surgical quality: analysis of heterogeneity between surgeons at a single cancer center. Eur Urol2011; 59: 317. Google Scholar 17 : A systematic review of the volume-outcome relationship for radical prostatectomy. Eur Urol2013; 64: 786. Google Scholar 18 : A new frontier in patient safety. JAMA2011; 305: 2221. Google Scholar 19 : Comorbidity measures for use with administrative data. Med Care1998; 36: 8. Google Scholar 20 : Utilization and outcomes of minimally invasive radical prostatectomy. J Clin Oncol2008; 26: 2278. Google Scholar 21 : Dose-response analyses using restricted cubic spline functions in public health research. Stat Med2010; 29: 1037. Google Scholar 22 : Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. New York: Springer2001. Google Scholar 23 : A Wilcoxon-type test for trend. Stat Med1985; 4: 87. Google Scholar 24 : Centralization of radical prostatectomy in the United States. J Urol2013; 189: 500. Link, Google Scholar 25 : Hospital volume, utilization, costs and outcomes of robot-assisted laparoscopic radical prostatectomy. J Urol2012; 187: 1632. Link, Google Scholar 26 : Robot-assisted versus open radical prostatectomy: the differential effect of regionalization, procedure volume and operative approach. J Urol2013; 189: 1289. Link, Google Scholar 27 : The diminishing returns of robotic diffusion: complications following robot-assisted radical prostatectomy. BJU Int2016; 117: 211. Google Scholar 28 : Should we regionalize major surgery? Potential benefits and policy considerations. J Am Coll Surg2000; 190: 341. Google Scholar 29 Guidance on Cancer Services: Improving Outcomes in Urological Cancers. London, United Kingdom: National Institute for Health and Care Excellence2002. Google Scholar 30 : Achieving quality assurance of prostate cancer surgery during reorganisation of cancer services. Eur Urol2015; 68: 22. Google Scholar © 2017 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byXia L, Sperling C, Taylor B, Talwar R, Chelluri R, Raman J, Lee D, Lee D and Guzzo T (2019) Associations between Hospital Volume and Outcomes of Robot-Assisted Radical ProstatectomyJournal of Urology, VOL. 203, NO. 5, (926-932), Online publication date: 1-May-2020.Cadeddu J (2018) Re: Hospital Volume and Outcomes of Robot-Assisted Partial NephrectomyJournal of Urology, VOL. 201, NO. 1, (12-12), Online publication date: 1-Jan-2019.Smith J (2017) This Month in Adult UrologyJournal of Urology, VOL. 198, NO. 1, (1-2), Online publication date: 1-Jul-2017. Volume 198Issue 1July 2017Page: 92-99Supplementary Materials Advertisement Copyright & Permissions© 2017 by American Urological Association Education and Research, Inc.Keywordshospitalslow-volumeprostatic neoplasmstreatment outcomeroboticsprostatectomyMetricsAuthor Information Boris Gershman Division of Urology, Rhode Island Hospital and Miriam Hospital, Providence, Rhode Island More articles by this author Sarah K. Meier Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota More articles by this author Molly M. Jeffery Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota More articles by this author Daniel M. Moreira Department of Urology, University of Illinois at Chicago, Chicago, Illinois More articles by this author Matthew K. Tollefson Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Simon P. Kim Department of Urology, Urology Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio More articles by this author R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Nilay D. Shah Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota OptumLabs, Cambridge, Massachusetts More articles by this author Expand All Advertisement PDF downloadLoading ...

Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n = 150) or undetectable (n = 327) based on post-RP PSA nadir ≥0.1 ng/ml. Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02–19.41, p = 0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p = 0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p = 0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p < 0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p = 0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.

Objectives To evaluate oncological outcomes after combination intravesical therapy with gemcitabine ( GC ) and mitomycin C ( MMC ) in the setting of recurrent non‐muscle‐invasive bladder cancer ( NMIBC ) after failure of previous intravesical therapy. Patients and Methods We retrospectively identified patients with recurrent NMIBC after previous intravesical therapy, who refused or were not candidates for cystectomy, between 2005 and 2011. GC and MMC were sequentially instilled weekly for 6–8 weeks. Data were collected regarding patient demographics, bladder cancer history, and number and type of intravesical therapies before GC / MMC . Outcomes evaluated included time to recurrence and/or progression after GC / MMC . Recurrence‐free outcomes were estimated using the Kaplan–Meier method, and Cox proportional hazards regression models were used to test the association of clinicopathological features with outcomes. Results In all, 27 patients were identified, 23 with high‐risk disease (high‐grade or carcinoma in situ ) and four with intermediate‐risk disease (multifocal or recurrent low‐grade). All patients received prior intravesical therapy, and 17 patients (63%) received multiple courses. Twenty‐four patients were treated with BCG . The median (range) disease‐free survival of all patients was 15.2 (1.7–39.3) months. Seventeen patients (63%) developed recurrent bladder cancer, a median of 15.2 months after therapy. One patient progressed to muscle‐invasive disease 5 months after treatment, and one developed metastatic disease 22 months after treatment. Three patients went on to cystectomy. Ten patients (37%) had no evidence of disease at last follow‐up, with a median follow‐up of 22.1 months. Conclusion The combination of intravesical GC and MMC could offer durable recurrence‐free survival to some patients with recurrent NMIBC who are not candidates for, or refuse, cystectomy.

Potential differences in efficacy of different bacillus Calmette-Guérin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non–muscle-invasive bladder cancer patients. Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011. Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival. Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20–1.82; P<0.001). With maintenance, TICE was more effective than Connaught for the time to first recurrence (HR = 0.66; 95% CI: 0.47–0.93; P = 0.019) with a trend for cancer specific survival (HR = 0.36; 95% CI: 0.14–0.92; P = 0.033). For time to progression and overall survival, Connaught and TICE had a similar efficacy. Compared to no maintenance therapy, maintenance BCG significantly reduced the risk of recurrence, progression and death, both overall, and disease specific, for TICE, but not for Connaught. We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used. However, the opposite is true when maintenance is given. As there is currently a BCG shortage, information on the efficacy of different BCG strains is important. In this nonrandomized retrospective comparison in over 2,000 patients, we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used, but the opposite is true when maintenance is given.

Small-cell neuroendocrine differentiation in prostatic carcinoma is an increasingly common resistance mechanism to potent androgen deprivation therapy (ADT), but can be difficult to identify morphologically. We investigated whether cyclin D1 and p16 expression can inform on Rb functional status and distinguish small-cell carcinoma from adenocarcinoma.We used gene expression data and immunohistochemistry to examine cyclin D1 and p16 levels in patient-derived xenografts (PDX), and prostatic small-cell carcinoma and adenocarcinoma specimens.Using PDX, we show proof-of-concept that a high ratio of p16 to cyclin D1 gene expression reflects underlying Rb functional loss and distinguishes morphologically identified small-cell carcinoma from prostatic adenocarcinoma in patient specimens (n = 13 and 9, respectively). At the protein level, cyclin D1, but not p16, was useful to distinguish small-cell carcinoma from adenocarcinoma. Overall, 88% (36/41) of small-cell carcinomas showed cyclin D1 loss by immunostaining compared with 2% (2/94) of Gleason score 7-10 primary adenocarcinomas at radical prostatectomy, 9% (4/44) of Gleason score 9-10 primary adenocarcinomas at needle biopsy, and 7% (8/115) of individual metastases from 39 patients at autopsy. Though rare adenocarcinomas showed cyclin D1 loss, many of these were associated with clinical features of small-cell carcinoma, and in a cohort of men treated with adjuvant ADT who developed metastasis, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death.Cyclin D1 loss identifies prostate tumors with small-cell differentiation and may identify a small subset of adenocarcinomas with poor prognosis. Clin Cancer Res; 21(24); 5619-29. ©2015 AACR.

Androgen deprivation therapy (ADT) represents the standard treatment for hormone-naïve prostate cancer with systemic metastases (mPCA). The role of radical prostatectomy (RP) in this setting is unclear. To evaluate the oncological and functional outcomes of men with mPCA who underwent cytoreductive RP (CRP). Retrospective, multi-institutional study of 113 patients with biopsy-proven mPCA who fulfilled the following selection criteria: (1) completely resectable PCA; (2) osseous metastases; (3) absence of gross retroperitoneal lymph node metastases; (4) absence of bulky pelvic lymph node metastases >3 cm; (5) no or minimal visceral metastases; (6) Eastern Cooperative Oncology Group performance status of 0–1; and (7) written informed consent. CRP with extended pelvic lymphadenectomy. Eighty patients (70.8%) received neoadjuvant ADT and 91 (86.5%) adjuvant ADT and/or radiation therapy. Cancer-specific survival, overall survival (OS), biochemical relapse-free survival (BRFS), and clinical relapse-free survival (CRFS) were evaluated using descriptive statistical analyses, the Kaplan-Meier method, and univariate and multivariate analyses. Treatment-associated complications were analysed according to the Clavien-Dindo classification. The mean patient age was 61 yr (range 42–69). The mean follow-up was 53.6 mo (range 13–96, median 45.7). The 3-yr and 5-yr OS was 99 (87.6%) and 90 (79.6%), respectively, and the mean CRFS was 72.3 mo. Preoperative prostate-specific antigen (PSA) < 1.0 ng/ml and PSA below the median of 8.0 ng/ml were significantly associated with BRFS (p < 0.0004). Pathohistology revealed viable PCA in all cases: 16 (14.2%) had pT4a, 21 (18.6%) had pT2a–c, and 76 (67.3%) had pT3a/b PCA. Positive lymph nodes were identified in 61.6% and positive surgical margins in 36.8% of the patients. Eleven men (9.7%) experienced Clavien Dindo grade IIIa–b complications. Low-volume disease, neoadjuvant ADT, and preoperative PSA were significantly associated with a lower risk of surgery-related complications (p < 0.05). No, mild (1–2 pads/d), and severe incontinence (>2 pads/d) was observed in 68.1%, 17.7%, and 14.1%, respectively. Limitations of the study are the retrospective nature and potential patient selection bias. CRP results in 5-yr OS of 80%, a low rate of significant complications, and good functional outcome in well-selected patients. CRP might be an individualised treatment option in the multimodal management of mPCA. We assessed oncological and functional outcomes associated with cytoreductive radical prostatectomy (CRP) in select men with prostate cancer and osseous metastases. We found that CRP might be associated with long overall and relapse-free survival in well-selected patients. CRP could become an additional treatment option in the multimodal therapy of metastatic prostate cancer; it should be performed in a clinical protocol setting and does not represent a standard therapeutic option.

Localized prostate cancer (PCa) is a clinically heterogeneous disease, which presents with variability in patient outcomes within the same risk stratification (low, intermediate or high) and even within the same Gleason scores. Genomic tools have been developed with the purpose of stratifying patients affected by this disease to help physicians personalize therapies and follow-up schemes. This review focuses on these tissue-based tools. At present, four genomic tools are commercially available: Decipher™, Oncotype DX®, Prolaris® and ProMark®. Decipher™ is a tool based on 22 genes and evaluates the risk of adverse outcomes (metastasis) after radical prostatectomy (RP). Oncotype DX® is based on 17 genes and focuses on the ability to predict outcomes (adverse pathology) in very low-low and low-intermediate PCa patients, while Prolaris® is built on a panel of 46 genes and is validated to evaluate outcomes for patients at low risk as well as patients who are affected by high risk PCa and post-RP. Finally, ProMark® is based on a multiplexed proteomics assay and predicts PCa aggressiveness in patients found with similar features to Oncotype DX®. These biomarkers can be helpful for post-biopsy decision-making in low risk patients and post-radical prostatectomy in selected risk groups. Further studies are needed to investigate the clinical benefit of these new technologies, the financial ramifications and how they should be utilized in clinics.

Management of recurrent prostate cancer (CaP) after radiotherapy (RT) is dependent on accurate localization of the site of recurrent disease. To describe the anatomic patterns and clinical features associated with CaP recurrence following RT identified on advanced imaging. Retrospective review of 184 patients with a rising prostate-specific antigen (PSA) after RT for CaP. C-11 choline positron emission tomography/computed tomography (CholPET). Recurrence patterns were classified as pelvic soft tissue only (as a surrogate for potentially salvageable disease) versus any extrapelvic disease, and clinical features were compared between patterns. Multivariable logistic regression was used to generate a predictive nomogram for extrapelvic recurrence. Discrimination was assessed with a c-index. Recurrence site was identified in 161 (87%) patients, with 95 (59%) sites histologically confirmed. Factors associated with the detection of recurrence included the difference between PSA nadir and PSA at CholPET (odds ratio: 1.30, p < 0.01) and National Comprehensive Cancer Network high-risk classification (odds ratio: 10.83, p = 0.03). One hundred (54.3%) patients recurred in the pelvic soft tissue only, while 61 (33%) had extrapelvic recurrence. Of 21 patients who underwent CholPET prior to meeting the Phoenix criteria of biochemical failure, 15 (71%) had recurrence identified on CholPET with 11 localized to the pelvis. On multivariable analysis, the difference between PSA nadir and PSA at CholPET, time from RT, and National Comprehensive Cancer Network risk group were predictive of recurrence outside of the pelvis, and a nomogram was generated with a c-index of 0.79. CholPET identified the site of recurrence in 87% of patients with a rising PSA after RT; most commonly within the pelvis in potentially salvageable locations. A predictive nomogram was generated, and pending external validation, this may aid in assessing the risk of disease beyond the pelvis. These findings underscore the importance of advanced imaging when considering management strategies for patients with a rising PSA following primary RT. We identified anatomic patterns of recurrence in patients with a rising prostate-specific antigen after radiotherapy using C-11 choline positron emission tomography/computed tomography. Most recurrences were localized to the pelvis and we were able to generate a tool to aid in disease localization prior to evaluation with advanced imaging.

Risk of prostate cancer-specific mortality (PCSM) is highly variable for men with adverse pathologic features at radical prostatectomy (RP); a majority will die of other causes. Accurately stratifying PCSM risk can improve therapy decisions. Validate the 22 gene Decipher genomic classifier (GC) to predict PCSM in men with adverse pathologic features after RP. Men with adverse pathologic features: pT3, pN1, positive margins, or Gleason score > 7 who underwent RP in 1987–2010 at Johns Hopkins, Cleveland Clinic, Mayo Clinic, and Durham Veteran's Affairs Hospital. We also analyzed subgroups at high risk (prostate-specific antigen > 20 ng/ml, RP Gleason score 8–10, or stage > pT3b), or very high risk of PCSM (biochemical recurrence in < 2 yr [BCR2], or men who developed metastasis after RP [MET]). Logistic regression evaluated the association of GC with PCSM within 10 yr of RP (PCSM10), adjusted for the Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S). GC performance was evaluated with area under the receiver operating characteristic curve (AUC) and decision curves. Five hundred and sixty-one men (112 with PCSM10), median follow-up 13.0 yr (patients without PCSM10). For high GC score (> 0.6) versus low-intermediate (≤ 0.6), the odds ratio for PCSM10 adjusted for CAPRA-S was 3.91 (95% confidence interval: 2.43–6.29), with AUC = 0.77, an increase of 0.04 compared with CAPRA-S. Subgroup odds ratios were 3.96, 3.06, and 1.95 for high risk, BCR2, or MET, respectively (all p < 0.05), with AUCs 0.64–0.72. GC stratified cumulative PCSM10 incidence from 2.8% to 30%. Combined use of case-control and cohort data is a potential limitation. In a large cohort with the longest follow-up to date, Decipher GC demonstrated clinically important prediction of PCSM at 10 yr, independent of CAPRA-S, in men with adverse pathologic features, BCR2, or MET after RP. Decipher genomic classifier may improve treatment decision-making for men with adverse or high risk pathology after radical prostatectomy.

Optimal management of prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy and pelvic lymph node dissection still remains unclear. To assess the effectiveness of postoperative treatment strategies for pathologically node-positive PCa patients. The secondary aim was to identify the most relevant prognostic factors to guide the management of pN1 patients. A systematic review was performed in January 2020 using Medline, Embase, and other databases. A total of 5063 articles were screened, and 26 studies including 12 537 men were selected for data synthesis and included in the current review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations. Ten-year biochemical recurrence (BCR)-free, clinical recurrence–free, cancer-specific (CSS), and overall (OS) survival rates ranged from 28% to 56%, 70% to 92%, 72% to 98%, and 60% to 87.6%, respectively. A total of seven, five, and six studies assessed the oncological outcomes of observation, adjuvant radiotherapy (aRT), or adjuvant androgen deprivation therapy (ADT), respectively. Initial observation followed by salvage therapies at the time of recurrence represents a safe option in selected patients with a low disease burden. The use of aRT with or without ADT might improve survival in men with locally advanced disease and a higher number of positive nodes. Risk stratification according to pathological Gleason score, number of positive nodes, pathological stage, and surgical margins status is the key to risk stratification and selection of the optimal postoperative therapy. Limitations of this systematic review are the retrospective design of the studies included and the lack of data on adverse events. While the majority of men with pN1 disease would experience BCR after surgery, long-term disease-free survival has been reported in selected patients. Management options to improve oncological outcomes include observation versus adjuvant therapies such as aRT and/or ADT. Disease characteristics should be used to select the optimal postoperative management for pN1 PCa patients. Finding node-positive prostate cancer after a radical prostatectomy often leads to high postoperative prostate-specific antigen levels and is overall a poor prognostic factor. However, this does not necessarily translate into poor survival for all men. Management can be tailored to the severity of disease and options include observation, androgen deprivation therapy, and/or radiotherapy.

In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus.To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer.This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019.Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy.Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts.Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782).Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

Delaying radical cystectomy (RC) after a diagnosis of muscle-invasive bladder cancer (MIBC) has been associated with adverse survival. However, data are lacking regarding the impact of RC delay in patients receiving neoadjuvant chemotherapy (NAC).To assess whether the time from last cycle of NAC to RC (time to cystectomy, TTC) is associated with survival among MIBC patients.The study cohort comprised 226 patients treated with NAC and RC between 1999 and 2015 for cT2-T4N0M0 bladder cancer.Descriptive statistics were used to test the association between TTC and clinicopathologic variables. Overall mortality (OM) and cancer-specific mortality (CSM) were analyzed via Kaplan-Meier estimation according to TTC. We assessed factors associated with OM and CSM using multivariable Cox regression analyses.The median TTC was 7.57wk (interquartile range 5.2-10.8). Patients with a Charlson comorbidity index (CCI) ≥1 had a longer TTC than those with a score of <1 (p=0.027). The group with TTC >10wk had significantly lower OM-free (p=0.003) and CSM-free rates (p<0.001) than the group with TTC ≤10wk. TTC was independently associated with higher risk of OM (p=0.027) and CSM (p=0.004) after accounting for age, gender, pathologic extravesical disease, and nodal status.TTC of >10wk after NAC was associated with adverse survival among patients with MIBC. Patients with a higher CCI were more likely to have prolonged TTC.The impact of delaying radical cystectomy in patients who have received neoadjuvant chemotherapy (NAC) is unknown. In this study we assessed whether prolonged time to cystectomy (TTC) after NAC affects survival outcomes in patients with muscle-invasive bladder cancer. We found that TTC of >10wk was associated with adverse overall survival and cancer-specific survival, and attempts should be made to shorten TTC after preoperative chemotherapy.

<h2>Abstract</h2><h3>Context</h3> Neoadjuvant chemotherapy (NAC) is recommended prior to radical cystectomy in the setting of muscle-invasive bladder cancer. Despite a 5–10% survival benefit, some patients do not respond to NAC. Identification of the nonresponders could avoid side effects and delay in surgery. <h3>Objective</h3> The objective of this review is to summarize the latest evidence regarding predictors of NAC response. <h3>Evidence acquisition</h3> MEDLINE, Embase, and the Cochrane Library databases were searched for published studies including clinical, pathological, molecular, and imaging tests or factors that can be applied before or during NAC to predict its results. <h3>Evidence synthesis</h3> Patient characteristics and imaging techniques seem to have minimal utility to predict NAC response. Only advanced magnetic resonance imaging techniques seem to have a potential role. There is insufficient evidence to suggest a change in NAC paradigm for variant histology, whereas the most promising results come from molecular characterization of tumors. <h3>Conclusions</h3> No validated instrument currently exists to predict NAC response. While awaiting further evidence, no strong recommendation can be made toward a shift in paradigm. <h3>Patient summary</h3> The most effective and aggressive treatment for muscle-invasive bladder cancer is radical cystectomy preceded by effective neoadjuvant chemotherapy. In this paper, we reviewed the current literature and published evidence to identify predictors of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer. To date, no instrument exists to predict which patients will respond to neoadjuvant chemotherapy.

Whether or not adding systematic biopsies (transrectal ultrasound-guided biopsy [TRUS-Bx]) to targeted cores in patients with a lesion detected at multiparametric magnetic resonance imaging (mpMRI) is still a debated topic.To identify patients who can avoid TRUS-Bx at the time of mpMRI targeted biopsy (MRI-TBx) relying on individual patient probability to harbour clinically significant prostate cancer (csPCa) outside the index lesion (IL).A total of 339 European and 441 North American patients underwent fusion MRI-TBx and concomitant TRUS-Bx at two tertiary care referral centres between 2013 and 2017.The study outcome was csPCa, defined as a Gleason score at biopsy of ≥7, outside the IL. Multivariable logistic regression analyses (MVAs) were performed to develop a predictive model for the study outcome. Multivariable-derived coefficients were used to develop a novel risk calculator in each cohort. The models were evaluated using the area under the curve (AUC), calibration plot, and decision-curve analyses.In the European cohort, csPCa detection rate was 55%. The csPCa detection rate for TRUS-Bx was 41%. At MVAs, prostate volume, previous negative biopsy, and Prostate Imaging Reporting and Data System versions 4 and 5 were independent predictors for the presence of csPCa outside the IL. The multivariable model had an AUC of 0.78. Omitting TRUS-Bx in patients with a calculated risk of <15% would have spared 16% of TRUS-Bx at the cost of missing 7% of csPCa. Similar findings were obtained when the same analyses were performed in the North American cohort. No net benefit was observed for low-threshold probabilities (<15%) of the each model relative to the standard of care (performing TRUS-Bx in addition to MRI-TBx to all patients) in both cohorts. The study is limited by its retrospective design.We failed to identify those patients who might safely benefit from MRI-TBx alone. The combination of MRI-TBx and TRUS-Bx should strongly be considered the best available approach.In the presence of positive multiparametric magnetic resonance imaging (mpMRI) of the prostate, physicians should always perform systematic sampling of the prostate in addition to mpMRI targeted biopsy.

Magnetic resonance imaging (MRI) of the prostate (MRI-prostate) facilitates better detection of clinically significant prostate cancer (PCa). Yet, the national trends of MRI at the time of prostate biopsy and its ability to increase the detection of PCa in a biopsy-naïve population remain unknown.To elucidate the contemporary trends of MRI and prostate biopsy, and whether it improved PCa diagnosis among privately insured patients.This was a retrospective cohort study of a large private health insurance database in the USA-the OptumLabs Data Warehouse. We identified all men ≥40 yr of age who underwent index prostate biopsies from 2010 through 2016.MRI-prostate at the time of index biopsy.Utilization of the MRI at the time of biopsy and incident PCa diagnosis constituted the primary outcomes. We enumerated unadjusted and age-specific annual rates of MRI over time to elucidate trends using regression models (trend analysis). Bivariate and multivariable regression analyses identified patient characteristics associated with MRI-prostate, and the association between the use of MRI and PCa diagnosis.Overall, 119 202 men underwent index prostate biopsies. Unadjusted annual rates of MRI at the time of biopsy significantly increased from 7 per 1000 biopsies in 2010 to 83 per 1000 biopsies in 2016 (p < 0.001 for trend). Age-specific rates increased across all age groups (40-49, 50-59, 60-65, 66-74, and 75+ yr; all p < 0.001). On multivariable analysis, black patients had a lower likelihood of MRI compared with white patients (odds ratio [OR]: 0.6; p < 0.01). MRI at the time of biopsy was not associated with a higher likelihood of incident PCa compared with traditional systematic biopsy (OR: 1.0; p = 0.7). The retrospective design and the inability to detect clinically significant PCa (Gleason 7+) constitute the limitations of this study.While the use of MRI at the time of biopsy rose markedly, it was not associated with a higher detection rate of PCa. Further research is needed to address effective dissemination of MRI and targeted biopsies, and racial disparities.From 2010 to 2016, our study found a significant rise in the utilization of magnetic resonance imaging of the prostate (MRI-prostate) at the time of index biopsy, although only a minority of patients undergo MRI-prostate. The use of MRI-prostate was not associated with a higher likelihood of diagnosing incident prostate cancer.

Purpose of review Metastatic prostate cancer (PCa) continues to be an invariably fatal condition. While historically, de-novo metastatic PCa was primarily treated with androgen deprivation therapy (ADT) and systemic therapy, there is a growing trend toward incorporating local treatments in the early management of the disease. This is particularly applicable to men with oligometastatic PCa (OMPC), which represents an ‘intermediate phase’ between localized and disseminated metastatic disease. Local treatment offers an opportunity for disease control before it progresses to a more advanced stage. This review discussed the current evidence for local treatment options for OMPC. Recent findings Currently, it has been suggested that men with OMPC may have a more indolent course and, therefore, favorable outcomes may be observed with metastasis-directed therapy (MDT). This review will not address the role of MDT to patients with OMPC but will focus on local treatments of the primary disease. The three main forms of local therapy employed for OMPC are cryotherapy, radiation therapy, and cytoreductive prostatectomy (CRP). Whole gland cryotherapy, either with ADT or with ADT and systemic chemotherapy, has shown some limited promising results. Radiation therapy combined with ADT has also demonstrated improvements in progression-free survival in clinical trials (primarily STAMPEDE Arm G and HORRAD). CRP often combined with ADT has emerged as a potential strategy for managing OMPC, with promising findings primarily from retrospective studies. Currently, several randomized controlled trials are underway to further investigate the role of CRP in the oligometastatic setting. Summary OMPC has become a unique category of disease with specific therapeutic implications. Lack of robust clinical data renders treatment selection controversial. Further studies with long follow up are necessary to identify men with oligometastatic disease who will benefit from local treatment.

In men who are at high-risk of prostate cancer, progression and death from cancer after radical retropubic prostatectomy (RRP), limited prognostic information is provided by established prognostic features. The objective of this study was to develop a model predictive of outcome in this group of patients.Candidate genes were identified from microarray expression data from 102 laser capture microdissected prostate tissue samples. Candidates were overexpressed in tumor compared with normal prostate and more frequently in Gleason patterns 4 and 5 than in 3. A case control study of 157 high-risk patients, matched on Gleason score and stage with systemic progression or death of prostate cancer as the end point, was used to evaluate the expression of candidate genes and build a multivariate model. Tumor was collected from the highest Gleason score in paraffin-embedded blocks and the gene expression was quantified by real-time reverse transcription polymerase chain reaction. Validation of the final model was performed on a separate case-control study of 57 high-risk patients who underwent RRP.A model incorporating gene expression of topoisomerase-2a, cadherin-10, the fusion status based on ERG, ETV1, and ETV4 expression, and the aneuploidy status resulted in a 0.81 area under the curve (AUC) in receiver operating characteristic statistical analysis for the identification of men with systemic progression and death from high grade prostate cancer. The AUC was 0.79 in the independent validation study.The model can identify men with high-risk prostate cancer who may benefit from more intensive postoperative follow-up and adjuvant therapies.

Study Type – Therapy (trend analysis) Level of Evidence 2b What's known on the subject? and What does the study add? Radical cystectomy (RC) carries significant risks of morbidity and mortality. Little is known whether in‐hospital outcomes are improving for RC. Using a contemporary population‐based cohort, the present study suggests minimal improvement in postoperative complications and mortality overall or by hospital‐volume category from 2001 to 2008. About 29% and 2% of patients undergoing RC will experience a postoperative complication or die during hospitalisation, respectively. OBJECTIVE To characterise the contemporary trends of in‐hospital complications and mortality for radical cystectomy (RC) from a contemporary population‐based cohort, as patients undergoing RC for bladder cancer are at significant risk for complications and mortality and the degree to which in‐hospital outcomes have changed over time is unknown. PATIENTS AND METHODS We identified 50 625 individuals who underwent RC for bladder cancer between 2001 and 2008 from the Nationwide Inpatient Sample. Multivariable regression models were used to identify hospital and patient covariates associated with in‐hospital complications and mortality and to estimate predicted probabilities of each outcome. Temporal trends of in‐hospital mortality and complications were assessed by Wilcoxon rank‐sum test. RESULTS The proportion of patients with in‐hospital complications remained stable at 28.3% in 2001–2002 compared with 28.0% in 2007–2008 ( P = 0.81 for trend). In‐hospital mortality was also unchanged from 2.4% in 2001–2002 compared with 2.3% in 2007–2008 ( P = 0.87 for trend). While high‐volume hospitals were associated with lower odds of in‐hospital complications (odds ratio [OR] 0.77, P = 0.01) and mortality (OR 0.60, P = 0.02) compared with low‐volume hospitals, the predicted probabilities of in‐hospital complications or mortality were unchanged within each volume category between 2001 and 2008. CONCLUSIONS In‐hospital complications and mortality for RC remain unchanged from 2001 to 2008. While high‐volume hospitals continue to have better outcomes, there is little evidence that postoperative mortality and morbidity are improving among low‐, medium‐ and high‐volume hospitals. Increased attention is needed to identify the modifiable aspects of postoperative care to improve in‐hospital outcomes and safety for patients undergoing RC.

No AccessJournal of UrologyAdult Urology1 Feb 2013Disparities in Access to Hospitals with Robotic Surgery for Patients with Prostate Cancer Undergoing Radical Prostatectomy Simon P. Kim, Stephen A. Boorjian, Nilay D. Shah, Christopher J. Weight, Jon C. Tilburt, Leona C. Han, R. Houston Thompson, Quoc-Dien Trinh, Maxine Sun, James P. Moriarty, and R. Jeffrey Karnes Simon P. KimSimon P. Kim Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author , Stephen A. BoorjianStephen A. Boorjian Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author , Nilay D. ShahNilay D. Shah Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota Division of Health Care Policy & Research, Mayo Clinic, Rochester, Minnesota More articles by this author , Christopher J. WeightChristopher J. Weight Department of Urology, University of Minnesota, Minneapolis, Minnesota More articles by this author , Jon C. TilburtJon C. Tilburt Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota Biomedical Ethics Research Unit, Mayo Clinic, Rochester, Minnesota More articles by this author , Leona C. HanLeona C. Han Biomedical Ethics Research Unit, Mayo Clinic, Rochester, Minnesota More articles by this author , R. Houston ThompsonR. Houston Thompson Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author , Quoc-Dien TrinhQuoc-Dien Trinh Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada More articles by this author , Maxine SunMaxine Sun Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada Department of Public Health, Faculty of Medicine, University of Montreal Health Center, Montreal, Canada More articles by this author , James P. MoriartyJames P. Moriarty Division of Health Care Policy & Research, Mayo Clinic, Rochester, Minnesota More articles by this author , and R. Jeffrey KarnesR. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.09.033AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We described population level trends in radical prostatectomy for patients with prostate cancer by hospitals with robotic surgery, and assessed whether socioeconomic disparities exist in access to such hospitals. Materials and Methods: After merging the NIS (Nationwide Inpatient Sample) and the AHA (American Hospital Association) survey from 2006 to 2008, we identified 29,837 patients with prostate cancer who underwent radical prostatectomy. The primary outcome was treatment with radical prostatectomy at hospitals that have adopted robotic surgery. Multivariate logistic regression was used to identify patient and hospital characteristics associated with radical prostatectomy performed at hospitals with robotic surgery. Results: Overall 20,424 (68.5%) patients were surgically treated with radical prostatectomy at hospitals with robotic surgery, while 9,413 (31.5%) underwent radical prostatectomy at hospitals without robotic surgery. There was a marked increase in radical prostatectomy at hospital adopters from 55.8% in 2006 and 70.7% in 2007 to 76.1% in 2008 (p <0.001 for trend). After adjusting for patient and hospital features, lower odds of undergoing radical prostatectomy at hospitals with robotic surgery were seen in black patients (OR 0.81, p <0.001) and Hispanic patients (OR 0.77, p <0.001) vs white patients. Compared to having private health insurance, being primarily insured with Medicaid (OR 0.70, p <0.001) was also associated with lower odds of being treated at hospitals with robotic surgery. Conclusions: Although there was a rapid shift of patients who underwent radical prostatectomy to hospitals with robotic surgery from 2006 to 2008, black and Hispanic patients or those primarily insured by Medicaid were less likely to undergo radical prostatectomy at such hospitals. References 1 : Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin2011; 61: 212. Google Scholar 2 : Racial differences in clinical progression among Medicare recipients after treatment for localized prostate cancer (United States). Cancer Causes Control2006; 17: 803. Google Scholar 3 : Racial differences in mortality among Medicare recipients after treatment for localized prostate cancer. J Natl Cancer Inst2003; 95: 1702. 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Cancer2011; 117: 5569. Google Scholar 23 : New technology and health care costs–the case of robot-assisted surgery. N Engl J Med2010; 363: 701. Google Scholar 24 : The effect of the approach to radical prostatectomy on the profitability of hospitals and surgeons. BJU Int2010; 105: 1531. Google Scholar 25 : Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med2008; 148: 435. Google Scholar 26 : Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA2012; 307: 1611. Google Scholar 27 : The implications of the 2010 Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act on cancer care delivery. Cancer2011; 117: 1564. Google Scholar 28 : The new economics of radical prostatectomy: cost comparison of open, laparoscopic and robot assisted techniques. J Urol2004; 172: 1431. Link, Google Scholar 29 : Costs of medical care after open or minimally invasive prostate cancer surgery: a population-based analysis. Cancer2012; 118: 3079. Google Scholar 30 : Local cost structures and the economics of robot assisted radical prostatectomy. J Urol2005; 174: 2323. Link, Google Scholar © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited by (2018) Reply by AuthorsJournal of Urology, VOL. 191, NO. 4, (912-913), Online publication date: 1-Apr-2014. Volume 189Issue 2February 2013Page: 514-520 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Keywordshealthcare disparitiesprostatectomyprostatic neoplasmsroboticsMetrics Author Information Simon P. Kim Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Stephen A. Boorjian Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Nilay D. Shah Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota Division of Health Care Policy & Research, Mayo Clinic, Rochester, Minnesota More articles by this author Christopher J. Weight Department of Urology, University of Minnesota, Minneapolis, Minnesota More articles by this author Jon C. Tilburt Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota Biomedical Ethics Research Unit, Mayo Clinic, Rochester, Minnesota More articles by this author Leona C. Han Biomedical Ethics Research Unit, Mayo Clinic, Rochester, Minnesota More articles by this author R. Houston Thompson Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Quoc-Dien Trinh Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada More articles by this author Maxine Sun Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada Department of Public Health, Faculty of Medicine, University of Montreal Health Center, Montreal, Canada More articles by this author James P. Moriarty Division of Health Care Policy & Research, Mayo Clinic, Rochester, Minnesota More articles by this author R. Jeffrey Karnes Department of Urology, Mayo Clinic, Rochester, Minnesota More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract The objective of this study was to assess the relationship of the tumor protein levels of TOP2A and MIB-1 and ERG status with cancer-specific outcomes in men with high-risk prostate cancer treated by radical prostatectomy (RP). A 150-pair case-control study was designed from RP patients who developed systemic progression (SP) within 6 years of RP (cases) and men who were free of disease at least 8 years after RP (controls). The cases and controls were matched on conventional prognostic clinical parameters. TOP2A and MIB-1 levels were assessed by immunohistochemical methods, and ERG status was assessed by quantitative reverse transcription-PCR. The prognostic abilities of TOP2A and MIB-1 were significantly better in ERG(−) patients, and TOP2A was superior to MIB-1. In receiver operating characteristic analysis, the TOP2A and MIB-1 scores exhibited AUCs of 0.81 and 0.78 for ERG(−) patients, versus 0.67 and 0.68 for ERG(+) patients, respectively. Clinical parameters attained an AUC of 0.65 in ERG(−) patients and 0.54 in ERG(+) patients. When both markers were incorporated into a model for ERG(−) patients, the AUC increased to 0.83, with TOP2A showing a stronger association with SP than MIB-1. The time to SP was significantly associated with TOP2A; higher 5-year SP rates were observed in patients with higher TOP2A protein levels. In addition, although patient numbers are small, the response to adjuvant androgen deprivation therapy is associated with ERG status, showing more significant treatment effect in ERG(+) patients. Cancer Res; 70(22); 8994–9002. ©2010 AACR.

What's known on the subject? and What does the study add? Variations in the type of urinary diversion exist for patients undergoing radical cystectomy. Although its use has been increasing from 2001 to 2008, patients who are older, female, and primary insured by Medicaid are less likely to receive continent diversions. Furthermore, patients treated surgically at high‐volume and teaching hospitals are more likely to receive continent diversions. Objective To describe the contemporary trends in urinary diversion among patients undergoing radical cystectomy ( RC ) for bladder cancer; and elucidate whether socioeconomic disparities persist in the type of diversion performed in the USA from a population‐based cohort. Patients and Methods Using the Nationwide Inpatient Sample, we identified patients who underwent RC for bladder cancer between 2001 and 2008. Multivariable regression models were used to identify patient and hospital covariates associated with continent urinary diversion and enumerate predicted probabilities for statistically significant variables over time. Results Overall, 55 635 (92%) patients undergoing RC for bladder cancer received incontinent urinary diversion, while 4552 (8%) patients received continent diversion from 2001 to 2008. Receipt of continent urinary diversion increased from 6.6% in 2001–2002 to 9.4% in 2007–2008 ( P &lt; 0.001 for trend). Patients who were older (odds ratio [ OR ] 0.93; P &lt; 0.001), female ( OR 0.52; P &lt; 0.001) and insured by Medicaid ( OR 0.54; P = 0.002) were less likely to receive continent urinary diversion. However, patients treated at teaching ( OR 2.14; P &lt; 0.001) and high‐volume hospitals ( OR 2.39; P = 0.04) had higher odds of continent urinary diversion. Predicted probabilities of continent diversion remained lower for female patients, Medicaid insurance status, and non‐teaching and medium/low‐volume hospitals over time. Conclusions In this nationally representative sample of hospitals from 2001 to 2008, the use of continent diversion in RC gradually increased. Although variations in urinary diversion exist by hospital teaching status, case volume, patient gender and primary health insurance, increased attention in expanding the use of continent diversions may help reduce these disparities for patients undergoing RC for bladder cancer.

Objective To establish the feasibility of magnetic resonance imaging (MRI)–guided cryoablation in patients with previous radical prostatectomy and MRI visualized biopsy-proven local recurrence of prostate adenocarcinoma. Materials and Methods Eighteen postprostatectomy patients (mean 67, 57-78 years) were treated with MRI-guided cryoablation for recurrent prostate carcinoma. Patients were found to have a hyperenhancing nodule using multiparametric MRI with endorectal coil followed by a positive transrectal ultrasound–guided biopsy. Of 18 postsurgical patients, 6 had additional salvage external beam radiation with subsequent recurrence. Under general anesthesia and MRI guidance (wide-bore 1.5T MRI), 2-5 cryotherapy probes were placed in or around the recurrence by transperineal approach and cryoablation performed. The patients were stratified into 2 groups: the initial 9 consecutive patients had cryoprobes placed 1 cm apart with 2 freeze-thaw cycles (group 1), and the subsequent 9 patients had cryoprobes placed 0.5 cm apart with 3 freeze-thaw cycles (group 2). Results In group I, the average preprocedure prostate-specific antigen (PSA) was 1.21 ± 1.12 ng/mL, and 1-3 months postprocedure PSA was 0.14 ± 0.11 ng/mL (P <.01). Sixty-seven percent of patients had PSA ≤0.2 ng/mL at 1-3 months follow-up, but only 25% at 4-6 months. No change in impotence or incontinence occurred. In group II, average preprocedure PSA was 2.24 ± 2.71 ng/mL, and 1-3 month postprocedure PSA was 0.08 ± 0.10 ng/mL (P <.05). Eighty-nine percent of patients had PSA ≤0.2 ng/mL at 1-3 months follow-up and at 4-6 months. Complications in group 2 included worsening incontinence in 3 patients. Conclusion MRI-guided salvage cryoablation of postradical prostatectomy prostate cancer recurrence is safe and feasible. Both techniques produce early PSA decrease with more lasting PSA results in the more aggressive group II methodology. To establish the feasibility of magnetic resonance imaging (MRI)–guided cryoablation in patients with previous radical prostatectomy and MRI visualized biopsy-proven local recurrence of prostate adenocarcinoma. Eighteen postprostatectomy patients (mean 67, 57-78 years) were treated with MRI-guided cryoablation for recurrent prostate carcinoma. Patients were found to have a hyperenhancing nodule using multiparametric MRI with endorectal coil followed by a positive transrectal ultrasound–guided biopsy. Of 18 postsurgical patients, 6 had additional salvage external beam radiation with subsequent recurrence. Under general anesthesia and MRI guidance (wide-bore 1.5T MRI), 2-5 cryotherapy probes were placed in or around the recurrence by transperineal approach and cryoablation performed. The patients were stratified into 2 groups: the initial 9 consecutive patients had cryoprobes placed 1 cm apart with 2 freeze-thaw cycles (group 1), and the subsequent 9 patients had cryoprobes placed 0.5 cm apart with 3 freeze-thaw cycles (group 2). In group I, the average preprocedure prostate-specific antigen (PSA) was 1.21 ± 1.12 ng/mL, and 1-3 months postprocedure PSA was 0.14 ± 0.11 ng/mL (P <.01). Sixty-seven percent of patients had PSA ≤0.2 ng/mL at 1-3 months follow-up, but only 25% at 4-6 months. No change in impotence or incontinence occurred. In group II, average preprocedure PSA was 2.24 ± 2.71 ng/mL, and 1-3 month postprocedure PSA was 0.08 ± 0.10 ng/mL (P <.05). Eighty-nine percent of patients had PSA ≤0.2 ng/mL at 1-3 months follow-up and at 4-6 months. Complications in group 2 included worsening incontinence in 3 patients. MRI-guided salvage cryoablation of postradical prostatectomy prostate cancer recurrence is safe and feasible. Both techniques produce early PSA decrease with more lasting PSA results in the more aggressive group II methodology.

No AccessJournal of UrologyAdult Urology1 Jun 2014Alvimopan, a Peripherally Acting μ-Opioid Receptor Antagonist, is Associated with Reduced Costs after Radical Cystectomy: Economic Analysis of a Phase 4 Randomized, Controlled Trial Teresa L. Kauf, Robert S. Svatek, Gilad Amiel, Timothy L. Beard, Sam S. Chang, Amr Fergany, R. Jeffrey Karnes, Michael Koch, Jerome O'Hara, Cheryl T. Lee, Wade J. Sexton, Joel W. Slaton, Gary D. Steinberg, Shandra S. Wilson, Lee Techner, Carolyn Martin, Jessica Moreno, and Ashish M. Kamat Teresa L. KaufTeresa L. Kauf Cubist Pharmaceuticals, Lexington, Massachusetts Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author , Robert S. SvatekRobert S. Svatek University of Texas Health Science Center at San Antonio, San Antonio, Texas Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author , Gilad AmielGilad Amiel Baylor University, Baylor College of Medicine, Houston, Texas More articles by this author , Timothy L. BeardTimothy L. Beard Bend Memorial Clinic, Bend, Oregon Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author , Sam S. ChangSam S. Chang Vanderbilt University Medical Center, Nashville, Tennessee More articles by this author , Amr FerganyAmr Fergany Cleveland Clinic Foundation, Cleveland, Ohio More articles by this author , R. Jeffrey KarnesR. Jeffrey Karnes Mayo Clinic, Rochester, Minnesota More articles by this author , Michael KochMichael Koch Indiana University Medical Center, Indianapolis, Indiana Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author , Jerome O'HaraJerome O'Hara Cleveland Clinic Foundation, Cleveland, Ohio More articles by this author , Cheryl T. LeeCheryl T. Lee University of Michigan, Ann Arbor, Michigan Financial interest and/or other relationship with Adolor. More articles by this author , Wade J. SextonWade J. Sexton H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida Financial interest and/or other relationship with Endo Pharmaceuticals. More articles by this author , Joel W. SlatonJoel W. Slaton University of Oklahoma College of Medicine, Oklahoma City, Oklahoma Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author , Gary D. SteinbergGary D. Steinberg University of Chicago Medical Center, Chicago, Illinois More articles by this author , Shandra S. WilsonShandra S. Wilson University of Colorado Health Science Center, Aurora, Colorado More articles by this author , Lee TechnerLee Techner Cubist Pharmaceuticals, Lexington, Massachusetts Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author , Carolyn MartinCarolyn Martin Optum, Eden Prairie, Minnesota Financial interest and/or other relationship with Optum. More articles by this author , Jessica MorenoJessica Moreno Cubist Pharmaceuticals, Lexington, Massachusetts Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author , and Ashish M. KamatAshish M. Kamat University of Texas M.D. Anderson Cancer Center, Houston, Texas Financial interest and/or other relationship with PhotoCure, Abbot, Cubist and FKD Therapies. More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.12.015AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial. Materials and Methods: Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach. Results: Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean ± SD 8.44 ± 3.05 vs 11.07 ± 8.23 days, p = 0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p = 0.001). Postoperative ileus related health care costs were $2,340 lower for alvimopan and mean total combined costs were decreased by $2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p = 0.04) but not total combined costs (p = 0.068) was significantly lower for alvimopan than for placebo. Conclusions: In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with postoperative ileus and decreasing the hospital stay. References 1 : Causes of increased hospital stay after radical cystectomy in a clinical pathway setting. J Urol2002; 167: 208. Link, Google Scholar 2 : Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol2009; 55: 177. 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Volume 191Issue 6June 2014Page: 1721-1727Supplementary Materials Advertisement Copyright & Permissions© 2014 by American Urological Association Education and Research, Inc.Keywordscost-benefit analysisgastrointestinal tractileusurinary bladderpostoperative complicationsAcknowledgmentsDrs. Fang Liu and John Mbagwu, and Michael Maschio and Valery Walker, Optum, assisted with economic analysis. Dr. Amy Rachfal, Cubist Pharmaceuticals, assisted with economic analysis and the manuscript. Dr. Andrea Kurz, Cleveland Clinic Foundation, provided comments. Dr. Kyoko Kelly, ProEd Communications, provided medical editorial assistance.Metrics Author Information Teresa L. Kauf Cubist Pharmaceuticals, Lexington, Massachusetts Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author Robert S. Svatek University of Texas Health Science Center at San Antonio, San Antonio, Texas Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author Gilad Amiel Baylor University, Baylor College of Medicine, Houston, Texas More articles by this author Timothy L. Beard Bend Memorial Clinic, Bend, Oregon Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author Sam S. Chang Vanderbilt University Medical Center, Nashville, Tennessee More articles by this author Amr Fergany Cleveland Clinic Foundation, Cleveland, Ohio More articles by this author R. Jeffrey Karnes Mayo Clinic, Rochester, Minnesota More articles by this author Michael Koch Indiana University Medical Center, Indianapolis, Indiana Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author Jerome O'Hara Cleveland Clinic Foundation, Cleveland, Ohio More articles by this author Cheryl T. Lee University of Michigan, Ann Arbor, Michigan Financial interest and/or other relationship with Adolor. More articles by this author Wade J. Sexton H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida Financial interest and/or other relationship with Endo Pharmaceuticals. More articles by this author Joel W. Slaton University of Oklahoma College of Medicine, Oklahoma City, Oklahoma Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author Gary D. Steinberg University of Chicago Medical Center, Chicago, Illinois More articles by this author Shandra S. Wilson University of Colorado Health Science Center, Aurora, Colorado More articles by this author Lee Techner Cubist Pharmaceuticals, Lexington, Massachusetts Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author Carolyn Martin Optum, Eden Prairie, Minnesota Financial interest and/or other relationship with Optum. More articles by this author Jessica Moreno Cubist Pharmaceuticals, Lexington, Massachusetts Financial interest and/or other relationship with Cubist Pharmaceuticals. More articles by this author Ashish M. Kamat University of Texas M.D. Anderson Cancer Center, Houston, Texas Financial interest and/or other relationship with PhotoCure, Abbot, Cubist and FKD Therapies. More articles by this author Expand All Advertisement PDF downloadLoading ...