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Background and Objective: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility., Methods: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, 6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%,

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: Scott Delacroix, Jared Foster, Francesca Khani, Joseph Liao, Abdul Tawab-Amiri Pamela West, Alex Wyatt: No conflicts. David McConkey: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Grants and contracts – Department of Defense, Mark Foundation, Commonwealth Foundation. Brian Baumann: Consulting fees – Boston Scientific, Varian, Novartis, Blue Earth; leadership or fiduciary role – Board of Directors, National Association for Proton Therapy. Stephanie Cooper Greenberg: Patient advocate, Johns Hopkins Greenberg Bladder Cancer Institute and NCI’s Bladder Cancer Task Force. David DeGraff: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review Grants and contracts – Bristol Myers Squibb, Department of Defense; receipt of material – Astra-Zeneca. Jason Efstathiou: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review Consulting fees – Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Astellas/Pfizer, Lantheus; payment or honoraria – IBA, Elekta, UpToDate; advisory boards – Merck, Roivant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Astellas, Gilead, Lantheus, Blue Earth Diagnostics, Angiodynamics; committee leadership – Vice-Chair, GU Committee, NRG; Board member (unpaid) – Massachusetts Prostate Cancer Coalition (MPCC) American College of Radiation Oncology (ACRO), Radiation Oncology Institute (ROI). Susan Groshen: Financial support from NCI/GUSC for attending a 2-day workshop that led to the CTPM. Edward Kadel: Patent, “PD-L1 PROMOTER METHYLATION IN CANCER”; stock or stock options, 89bio, Apple, Amazon, Alphabet, Eli Lilly & Co, Inspire Medical Systems, Merck & Co, Roche, SPDR S&P Biotech ETF, Teladoc; employee of Genentech/Roche. William Kim: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Grants or contracts – NIH R01-CA241810, Merck; consulting fees – Focal Medical (spouse); advisory board – OncoRev; stock or stock options – Abbvie, Amgen, Apellis, BeiGene, BMS, Lilly, ImmunityBio, Moderna, Natera, NovoNordisk, Revolution Medicines, Tango Therapeutics, Zentalis; other financial or non-financial interests – Focal Medical, ownership interest (spouse). Seth Lerner: Co-Editor-in-Chief of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Advisory board – FerGene, Pfizer. BMS, Incyte; consultant – Vaxiion, Verity, Protara, C2i Genomics, Ferring, Aura Bioscience, Surge Therapeutics; clinical trials – Genentech (SWOG), Vaxiion, Endo, FKD, JBL (SWOG), Merck (Alliance), Aura Bioscience, Surge Therapeutics, QED Therapeutics; honoraria – UroToday, co-editor bladder cancer section UpToDate, Grand Rounds Urology; compensated editorial responsibilities – IOS Press. Trevor Levin: Grants or contracts – NCI SBIR 5R44CA200174-05; patents issued or pending – WO/2017/056451, WO/2020/023630, WO/2020/243587, WO/2022/216865A1; leadership or fiduciary role – Convergent Genomics (Executive and Board roles); stock or stock options – Convergent Genomics. Matthew Milowski: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consulting: Loxo/Lilly; payments or honoraria, Medscape, Research to Practice; other financial or non-financial interests: Co-Editor in Chief, Clinical Genitourinary Cancer, Elsevier. Joshua Meeks: grants or contracts, VA, NIH, Department of Defense; consulting fees, Merck, AstraZeneca, Incyte, Janssen, BMS, UroGen, Prokarium, Imvax, Pfizer, Seagen/Astellas, Ferring; payments, Olympus, AUA, UroToday, OncLive; advisory boards, Astra-Zeneca, Medscape. David Miyamoto: grant support from NIH and the Radiation Oncology Institute. Kent Mouw: consulting fees, EMD Serono, Pfizer, UroGen, Riva Therapeutics. Eugene Pietzak: participation in a Data Safety Monitoring Committee or Advisory Board, QED Pharmaceuticals, Merck, Janssen, Urogen; society leadership, Chair of the Program Committtee, 2024 BCAN Think Tank. David Solit: consulting fees from Pfizer, Fog Pharma, PaigeAI, BridgeBio, Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, and Elsie Biotechnologies, Inc.; participation on a Data Safety Monitoring Board for Rain Therapeutics; stock or stock options from Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, Elsie Biotechnologies, Inc. Debashish Sundi: grants or contracts from Janssen, consulting fees from Janssen. Sara Wobker: royalties – Wolters Kluwer; honoraria – College of American Pathologists, American Society of Clinical Pathology, USCAP; travel reimbursement – Kidney Cancer Society. Andrea Apolo: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Peter Black: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consulting fees – AbbVie, AstraZeneca, Astellas, Bayer, BMS, Combat, EMD-Serono, Ferring, Janssen, Merck, Nonagen, Nanobot, NanOlogy, Pfizer, Photocure, Prokarium, Sumitomo, TerSera, Tolmar, Verity; payments – Janssen, TerSera, Bayer, Pfizer; patents issued or pending – Veracyte.

Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area.

Urothelial cancer is an immune-responsive cancer, but only a subset of patients benefits from immune checkpoint inhibition. Currently, single-agent immune checkpoint inhibitors (ICIs) and the combination of pembrolizumab with the antibody-drug conjugate enfortumab vedotin are approved to treat patients with metastatic UC (mUC). Approval of first-line nivolumab in combination with gemcitabine and cisplatin is expected imminently. Many treatment approaches are being investigated to better harness the immune system to fight mUC. In this review, we summarize the landmark clinical trials of ICIs that led to their incorporation into the current standard of care for mUC. We further discuss recent and ongoing clinical trials in mUC, which are investigating ICIs in combination with other agents, including chemotherapy, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Lastly, we review novel approaches utilizing bispecific antibodies, cellular therapies, and vaccines. The landscape of immunotherapy for mUC is rapidly evolving and will hopefully lead to better outcomes for patients.

The Melanoma Antigen Gene (MAGE) is a large family of highly conserved proteins that share a common MAGE homology domain. Interestingly, many MAGE family members exhibit restricted expression in reproductive tissues but are abnormally expressed in various human malignancies, including bladder cancer, which is a common urinary malignancy associated with high morbidity and mortality rates. The recent literature suggests a more prominent role for MAGEA family members in driving bladder tumorigenesis. This review highlights the role of MAGEA proteins, the potential for them to serve as diagnostic or prognostic biomarker(s), and as therapeutic targets for bladder cancer.

Myeloid-derived suppressor cells (MDSC) have been linked to loss of immune effector cell function through a variety of mechanisms such as the generation of reactive oxygen and nitrogen species and the production of inhibitory cytokines. Our group has shown that signaling through Bruton's tyrosine kinase (BTK) is important for MDSC function. Ibrutinib is an orally administered targeted agent that inhibits BTK activation and is currently used for the treatment of B cell malignancies. Using a syngeneic murine model of melanoma, the effect of BTK inhibition with ibrutinib on the therapeutic response to systemic PD-L1 blockade was studied. BTK was expressed by murine MDSC and their activation was inhibited by ibrutinib. Ibrutinib was not directly cytotoxic to cancer cells in vitro, but it inhibited BTK activation in MDSC and reduced expression of inducible nitric oxide synthase (NOS2) and production of nitric oxide. Ibrutinib treatments decreased the levels of circulating MDSC in vivo and increased the therapeutic efficacy of anti-PD-L1 antibody treatment. Gene expression profiling showed that ibrutinib decreased Cybb (NOX2) signaling, and increased IL-17 signaling (upregulating downstream targets Mmp9, Ptgs2, and S100a8). These results suggest that further exploration of MDSC inhibition could enhance the immunotherapy of advanced melanoma.PrécisInhibition of Bruton's tyrosine kinase, a key enzyme in myeloid cellular function, improves therapeutic response to an anti-PD-L1 antibody in an otherwise fairly resistant murine melanoma model., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk., Experimental Design: This is a multicenter case-control study using banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or urothelial carcinoma surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmp platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting urothelial carcinoma tumor presence, grade, and recurrence risk were compared with cytology, cystoscopy, and pathology., Results: uCGP algorithms had a validation sensitivity/specificity of 95%/90% for initial cancer diagnosis in patients with hematuria and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary urothelial carcinoma classification demonstrated an NPV of 91%. uCGP recurrence-risk prediction significantly prognosticated future recurrence (hazard ratio, 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable with cytology (45% vs. 42%) with much higher sensitivity (79% vs. 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%., Conclusions: uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: Effective therapies for patients with nonmuscle invasive bladder cancer that recurs or progresses after Bacille Calmette-Guérin (BCG) are lacking. This unmet need is the focus of many drug development efforts, reflected in many completed/ongoing/planned clinical trials for patients with BCG unresponsive bladder cancer. Though BCG unresponsive criteria are well defined, enrollment criteria are variable such that, even at centers with several open trials in this space, a given patient with BCG unresponsive bladder cancer might not qualify for any. To understand the scope of this dilemma, we systematically analyzed enrollment criteria for all BCG unresponsive protocols registered on ClinicalTrials.gov to quantify heterogeneity in enrollment criteria and to determine what proportion of trials were inclusive to patients meeting U.S. Food and Drug Administration (FDA) BCG unresponsive criteria., Methods: The ClinicalTrials.gov search tool was queried for relevant trials using the terms "bladder cancer" "nonmuscle invasive bladder cancer" and "BCG". Previously published review articles were cross-referenced to ensure that search results were comprehensive. Inclusion and exclusion criteria for the resulting 31 protocols pertaining to distinct categories such as performance status, laboratory parameters, co-morbidities, active medications, and prior therapies were recorded. Based on enrollment criteria, the trial was assessed as fully inclusive or not to patients considered to be BCG unresponsive by the 2018 FDA criteria., Results: Of 31 trials, 15 (48%) had inclusion/exclusion criteria that were fully consistent with (inclusive of patients that met) the BCG unresponsive bladder cancer definition. 18 (58%) of trials excluded patients with a history of prior pelvic radiation therapy. 14 (45%) of trials excluded patients with ECOG performance status >2 (or Karnofsky Performance Status equivalent). The most common disease specific exclusion for patients with BCG unresponsive bladder cancer was a requirement for stage Tis (carcinoma in situ, CIS), which pertained to 7 (23%) of trials., Conclusions: Enrollment criteria for patients with BCG unresponsive bladder cancer are highly variable. Over half of trials evaluated do not meet stringent criteria for this disease state based upon treatment history and cancer staging requirements. For patients who desire to enroll in clinical trials, this restricts access to novel agents. For bladder cancer treating physicians and regulatory bodies, this also hinders comparisons across agents., Competing Interests: Conflicts of interest disclosure Michael Chandra: no relationships to disclose. Roger Li: stock and other ownership interests - crispr therapeutics; Guardant Health. Consulting or Advisory Role - Arquer Diagnostics; Bristol-Myers Squibb; FerGene; Ferring. Research Funding - CG Oncology. Expert Testimony - CG Oncology. Other Relationship – Predicine Anil Parwani: No Relationships to Disclose. William Edgar Carson: No Relationships to Disclose. Kamal S. Pohar: Consulting or Advisory Role - Photocure. Debasish Sundi: Consulting or Advisory Role - Janssen, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking., Methods: We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method., Results: The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance., Conclusions: LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kwok, Khorasanchi, Psutka, Hinkley, Dason, Sundi, Yang, Yang, Verschraegen, Gross, Orcutt and Yin.)

The use of advanced preclinical models has become increasingly important in drug development. This is particularly relevant in bladder cancer, where the global burden of disease is quite high based on prevalence and a relatively high rate of lethality. Predictive tools to select patients who will be responsive to invasive or morbid therapies (chemotherapy, radiotherapy, immunotherapy, and/or surgery) are largely absent. Patient-derived and clinically relevant models including patient-derived xenografts (PDX), organoids, and conditional reprogramming (CR) of cell cultures efficiently generate numerous models and are being used in both basic and translational cancer biology. These CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and reproduce the genomic and histological characteristics of the parental tissue. Therefore, CR technology may be a clinically relevant model to test and predict drug sensitivity, conduct gene profile analysis and xenograft research, and undertake personalized medicine. This review discusses studies that have utilized CR technology to conduct bladder cancer research.

The cancer research field is finally starting to unravel the mystery behind why males have a higher incidence and mortality rate than females for nearly all cancer types of the non-reproductive systems. Here, we explain how sex - specifically sex chromosomes and sex hormones - drives differential adaptive immunity across immune-related disease states including cancer, and why males are consequently more predisposed to tumor development. We highlight emerging data on the roles of cell-intrinsic androgen receptors in driving CD8 + T cell dysfunction or exhaustion in the tumor microenvironment and summarize ongoing clinical efforts to determine the impact of androgen blockade on cancer immunotherapy. Finally, we outline a framework for future research in cancer biology and immuno-oncology, underscoring the importance of a holistic research approach to understanding the mechanisms of sex dimorphisms in cancer, so sex will be considered as an imperative factor for guiding treatment decisions in the future., Competing Interests: Z.L. serves as a member of the scientific advisory board for Heat Biologics, Alphamab, Hengenix, and Ikonisys. Other authors declare no competing interests., (© 2022.)

Sex bias exists in the development and progression of nonreproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8 + T cell-dependent antitumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7 /TCF1 + progenitor exhausted CD8 + T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8 + T cells and a pertinent contribution from AR as a direct transcriptional transactivator of Tcf7 /TCF1. The T cell-intrinsic function of AR in promoting CD8 + T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8 + T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

Purpose: Neoadjuvant chemotherapy (NAC) is the standard of care for eligible patients with cT2-4a N0 M0 bladder cancer undergoing surgical resection. The extent to which (and if) NAC increases patient survival is not clear as clinical trials and meta-analyses have generated both negative and "borderline" positive results. The novel method of calculating restricted mean survival times (RMST) may provide a more meaningful way to quantify treatment efficacy due to inherent statistical limitations of conventional hazard ratios. In this study we analyzed the survival benefit attributable to NAC in bladder cancer by calculating RMST of previously published clinical trials., Materials and Methods: All published randomized controlled clinical trials of bladder cancer with available survival data comparing NAC plus radical cystectomy with cystectomy alone were included. RMSTs were calculated for each cohort at the 5-year and total follow-up time periods, comparing the NAC and radical cystectomy groups. Fixed effect meta-analysis of the 5-year RMSTs was then performed to calculate the net impact of NAC on overall survival., Results: For 2 among 7 included trails, RMST analysis changed the statistical significance. The SWOG 8,710 trial that had previously suggested a survival benefit associated with NAC (P = 0.06) was found to have a clearer beneficial association by 5-year RMST (6.5 month benefit; P = 0.01) and total follow-up RMST (13.6 month benefit over 168 months; P = 0.04). The International Collaboration of Trialists trial that had previously suggested a survival benefit with NAC (P = 0.04) was found to have a beneficial association by total follow-up RMST (6.7 months benefit over 120 months; P = 0.04) but not 5-year RMST (P = 0.10). The interpretation of other trials did not change.  Fixed effect meta-analysis suggested a clinically significant overall survival benefit associated with NAC (3.2 months benefit over 60 months; P < 0.01)., Conclusions: Evaluation of published randomized controlled trials using RMSTs strengthens the association of neoadjuvant chemotherapy with survival benefit in bladder cancer. As RMST may enable improved detection of clinical benefit when compared to conventional statistical methods, consideration should be given to RMST-based endpoints in future clinical trial design., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy., Methods: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men., Results: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis., Conclusions: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy., (© 2021 American Cancer Society.)

The robotic approach to radical cystectomy is compelling because of its oncologic equivalence to open radical cystectomy (ORC), its association with lower surgical blood loss, its potential association with shorter hospital stay after surgery. These factors suggest that the robotic approach to radical cystectomy may be an important component of enhanced recovery programs aimed at reducing surgical morbidity. This paper describes the importance of the cranial placement of robotic trocars, the use of Cadiere forceps for atraumatic bowel grasping, pelvic lymph node dissection (PLND), and utero-enteric anastomoses. Also discussed are steps that are critical for the successful outcome of RARC. In spite of the increased operating times and associated costs and the costs of robotic surgical platforms and equipment, adoption of the robotic technique by bladder cancer surgeons has increased. This paper describes a systematic and reproducible method that details robotic extended pelvic lymph node dissection, cystectomy/cystoprostatectomy, and intracorporeal ileal conduit urinary diversion.

High-risk prostate cancer is a heterogeneous disease that lacks clear consensus on its ideal management. Historically, non-surgical treatment was the preferred strategy, and several studies demonstrated improved survival among men with high-risk disease managed with the combination of radiotherapy and androgen deprivation therapy (ADT) compared with ADT alone. However, practice trends in the past 10-15 years have shown increased use of radical prostatectomy with pelvic lymph node dissection for primary management of high-risk, localized disease. Radical prostatectomy, as a primary monotherapy, offers the potential benefits of avoiding ADT, reducing rates of symptomatic local recurrence, enabling full pathological tumour staging and potentially reducing late adverse effects such as secondary malignancy compared with radiation therapy. Retrospective studies have reported wide variability in short-term (pathological) and long-term (oncological) outcomes of radical prostatectomy. Surgical monotherapy continues to be appropriate for selected patients, whereas in others the best treatment strategy probably involves a multimodal approach. Appropriate risk stratification utilizing clinical, pathological and potentially also genomic risk data is imperative in the initial management of men with prostate cancer. However, data from ongoing and planned prospective trials are needed to identify the optimal management strategy for men with high-risk, localized prostate cancer.

Purpose: We examined rates of Grade Group 4 downgrading at radical prostatectomy among men diagnosed with high and very high risk prostate cancer at biopsy., Materials and Methods: A pooled cohort of 1,776 patients from 3 tertiary referral centers who underwent radical prostatectomy for National Comprehensive Cancer Network® high risk (prostate specific antigen greater than 20 ng/ml, or Grade Group 4-5, or clinical stage T3 or greater) or very high risk (primary Gleason pattern 5, or more than 4 biopsy cores with Grade Group 4-5, or 2 or more high risk features) disease from 2005 to 2015 were reviewed. Overall 893 patients with Grade Group 4 disease at biopsy were identified and 726 patients were available for analysis. Multivariable logistic regression models were fit to determine factors associated with downgrading to Grade Group 3 or less at radical prostatectomy., Results: Overall 333 (45%) cases were downgraded to Grade Group 3 or less at radical prostatectomy. Of these cases 198 (27%) had concordant Grade Group 4 biopsy and radical prostatectomy pathology and 195 (27%) were upgraded at radical prostatectomy to Grade Group 5. Of high risk cases with biopsy Grade Group 4 disease 49% had any downgrading vs 29% of very high risk cases (p <0.0001). Downgrading to Grade Group 2 or less occurred in 16% (98 of 604) of high risk and 7% (8 of 122) of very high risk cases (p <0.01). Downgraded cases had a lower prostate specific antigen, fewer positive biopsy cores and lower clinical stage (p <0.01). On multivariable analysis fewer positive biopsy cores were significantly associated with downgrading at radical prostatectomy (p <0.01)., Conclusions: In this cohort of patients with high risk/very high risk prostate cancer, downgrading from biopsy Grade Group 4 at radical prostatectomy occurred less frequently than in other published reports. Any downgrading was significantly less common in very high risk compared to high risk patients, and downgrading to Grade Group 2 or less occurred in a minority of cases in high risk and very high risk patients.

Context: There is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR., Objective: To elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results., Evidence Acquisition: We performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis., Evidence Synthesis: Median CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities., Conclusions: We demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space., Patient Summary: In this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The optimal treatment for unfavorable intermediate-risk prostate cancer is unknown. Given the lack of randomized evidence, large comparative studies may be useful in guiding clinical decision-making., Methods: We queried the National Cancer Database for patients with unfavorable intermediate-risk prostate cancer, as defined by the National Comprehensive Cancer Network. We compared overall survival between patients treated with radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy, and EBRT plus brachytherapy (EBRT+BT) using Cox proportional hazards models and propensity score matching., Results: A total of 10,439 patients were analyzed. There was no statistically significant difference in overall survival between RP and EBRT+BT (hazard ratio [HR] = 1.24; 95% confidence interval [CI] 0.58-2.65). RP was associated with higher survival when compared to EBRT (HR = 2.30, 95% CI 1.70-3.20) and brachytherapy (HR = 2.90, 95% CI 1.40-6.20). When accounting for androgen deprivation therapy (ADT), there was no statistically significant difference in survival between RP and brachytherapy with ADT (HR = 3.08; 95% CI 0.62-15.27) or EBRT to a dose of ≥7920 cGy with ADT (HR = 2.6, 95% CI 0.50-13.20)., Conclusion: We found no statistically significant difference in survival between RP and EBRT+BT. EBRT and brachytherapy had higher mortality, respectively, compared to RP. When including only radiotherapy patients who received ADT and, in the case of EBRT, a total dose ≥ 7920 cGy, there was no statistically significant difference in survival when comparing RP to EBRT or brachytherapy. These findings should be prospectively studied., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To determine whether time from diagnosis to treatment impacted outcomes in a multicentre cohort of high- and very-high-risk (VHR) patients with prostate cancer undergoing radical prostatectomy (RP)., Patients and Methods: In all, 1392 patients from three tertiary centres who underwent RP for either high-risk or VHR disease, from 2005 to 2015, were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer-specific mortality (PCSM) were calculated for each tertile. The Kaplan-Meier method was used to evaluate for differences in all-cause mortality (ACM) amongst tertiles. Competing risks regression models, as well as Cox proportional hazards regression models, were fitted to assess the association between time-to-event outcomes and patient characteristics., Results: The median (interquartile range [IQR]) time from biopsy to RP was 68 (50-94) days. The median (IQR) follow-up was 31 (12.1-55.7) months. The cumulative incidence of BCR (P = 0.14), metastasis (P = 0.15), and PCSM (P = 0.69) did not differ amongst time-to-treatment tertiles of VHR patients. Also, Kaplan-Meier estimates of ACM (P = 0.53) did not differ amongst time-to-treatment tertiles. Similarly, BCR, metastasis, PCSM, and ACM did not significantly differ amongst time-to-treatment tertiles in multivariable modelling., Conclusion: In this pooled meta-dataset of patients with high-risk or VHR prostate cancer, time from diagnosis to RP did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Type I interferon (IFN-I) has potent anti-tumor effects against urothelial carcinoma (UC) and may be an alternative treatment option for patients who do not respond to Bacillus Calmette-Guerin. However, the mechanisms that mediate the IFN-I-stimulated immune responses against UC have yet to be elucidated. Herein, we evaluated the anti-tumor mechanisms of IFN-I in UC in human patients and in mice. Patient tumors from a Phase I clinical trial with adenoviral interferon-α (Ad-IFNα/Syn3) showed increased expression of T cell and checkpoint markers following treatment with Ad-IFNα/Syn3 by RNAseq and immunohistochemistry analysis in 25% of patients. In mice, peritumoral injections of poly(I:C) into MB49 UC tumors was used to incite an IFN-driven inflammatory response that significantly inhibited tumor growth. IFN-I engaged both innate and adaptive cells, seen in increased intratumoral CD8 T cells, NK cells, and CD11b + Ly6G + cells, but tumor inhibition was not reliant on any one immune cell type. Nonetheless, poly(I:C)-mediated tumor regression and change in the myeloid cell landscape was dependent on IL-6. Mice were also treated with poly(I:C) in combination with anti-PD-1 monoclonal antibody (mAb) to assess for additional benefit to tumor growth and animal survival. When used in combination with anti-PD-1 mAb, IFN-I stimulation prolonged survival, coinciding with inhibition of angiogenesis and enriched gene signatures of metabolism, extracellular matrix organization, and MAPK/AKT signaling. Altogether, these findings suggest IFN-I's immune-driven antitumor response in UC is mediated by IL-6 and a collaboration of immune cells, and its use in combination with checkpoint blockade therapy can increase clinical benefit.

Background: Among men with localized high-risk prostate cancer (PCa), patients who meet very high-risk (VHR) criteria have been shown to experience worse outcomes after radical prostatectomy (RP) in a previous study. Variations of VHR criteria have been suggested to be prognostic in other single-center cohorts, but multicenter outcomes validating VHR criteria have not been described. This study was designed to validate VHR criteria for identifying which PCa patients are at greatest risk for cancer progression., Methods: Patients with high-risk PCa undergoing RP (2005-2015) at 3 tertiary centers were pooled. The outcomes of men with VHR PCa were compared with the outcomes of those who did not meet VHR criteria. The high-risk criteria were a clinical stage of T3 to T4, a prostate-specific antigen level > 20 ng/mL, or a biopsy Gleason grade sum of 8 to 10. The VHR criteria were multiple high-risk features, >4 biopsy cores with a Gleason grade sum of 8 to 10, or primary Gleason grade pattern 5. Biochemical recurrence, metastasis (METS), and cancer-specific mortality (CSM) were assessed with competing risks regressions. Overall mortality was assessed with Cox survival models., Results: Among 1981 patients with high-risk PCa, men with VHR PCa (n = 602) had adverse pathologic outcomes: 37% versus 25% for positive margins and 37% versus 15% for positive lymph nodes (P <  .001 for both comparisons). Patients with VHR PCa also had higher adjusted hazard ratios for METS (2.78; 95% confidence interval [CI], 2.08-3.72), CSM (6.77; 95% CI, 2.91-15.7), and overall mortality (2.44; 95% CI, 1.56-3.80; P <  .001 for all comparisons)., Conclusions: In a validation study of patients who underwent treatment for high-risk PCa, VHR criteria were strongly associated with adverse pathologic and oncologic outcomes., (© 2018 American Cancer Society.)

Background: Certain patients presenting with either low or very-low-risk prostate cancer (PCa) can represent a therapeutic dilemma for physicians. The oncologic outcomes of active surveillance (AS) for men with very-low-risk PCa are overall excellent. However, there are concerns about AS related to the potential for upgrading or upstaging. The African American (AA) population is under-represented in studies evaluating AS outcomes and this is particularly important because of the unique epidemiology of PCa in AA men., Methods: A literature review through the Medline database published from 1990 until August 2015 was performed to identify studies reporting outcomes of the AA population with low-risk PCa that underwent either AS or treatment. An additional search for studies on genetic mechanisms involved in development of PCa in AA men was also performed., Results: Eleven studies on pathologic results of AA men who would qualify for AS were identified and in eight of these studies AA race was found to be associated with adverse pathological outcomes such as positive surgical margins, upgrading or upstaging. The other three studies reported no significance in these parameters with respect to race. Five more studies reported outcomes of AS in AA men with different study end points. AA men were mainly found to have a higher rate of disease reclassification subsequent to active treatment. The studies on genetic mechanisms also identified different genetic alterations in the AA population., Conclusions: AA men with clinically defined low-risk PCa may have either a higher grade or volume of cancer that was not detected on routine evaluation. Therefore, AS among such patients should be approached with caution. We recommend discussing such risks with AA patients with an acknowledgement that existing favorable outcomes noted in largely Caucasian populations may not be applicable to AA patients. We propose a modified evaluation plan for AA patients that includes an early confirmatory biopsy preceded by an magnetic resonance imaging to optimally detect occult cancer foci.

Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic "recycling" technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC's) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFβ pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL.

African-American (AA) men have a higher risk of lethal prostate cancer (PCa) compared to European-American (EA) men. However, the molecular basis of this difference, if any, remains unclear. In EA PCa, PTEN loss, but not ERG rearrangement, has been associated with poor outcomes in most studies. Although ERG rearrangement is less common in AA compared to EA PCa, the relative frequency of PTEN loss and the association of PTEN/ERG molecular subtypes with outcomes is unknown for AA PCa. We examined PTEN/ERG status by immunohistochemistry in self-identified AA patients undergoing radical prostatectomy at Johns Hopkins with tumor tissue available on tissue microarray (TMA; n=169) and matched these cases by pathologic parameters to 169 EA patients from the same TMAs. The rate of PTEN loss was significantly lower in AA compared to EA PCa (18% vs 34%; p=0.001), similar to the lower rate of ERG expression (25% vs 51%; p<0.001). To examine the association of PTEN/ERG status with oncologic outcomes, we created an additional TMA of 87 AA tumors with Gleason score > 4 + 3 = 7. Among the total population of AA men with outcome data from all TMAs (n=222), PTEN loss was associated with higher risk of biochemical recurrence (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.82) and metastasis (HR 3.90, 95% CI 1.46-10.4) in multivariable models., Patient Summary: PTEN and ERG alterations in prostate cancer are less likely in African-American than in European-American men. However, PTEN loss remains associated with poor prostate cancer outcomes among African-American men., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Intravesical immunotherapy with live attenuated BCG remains the standard of care for patients with high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but recurrence is frequent and progression to invasive cancer is a concern. No established and effective intravesical therapies are available for patients whose tumours recur after BCG, representing a clinically important unmet need. Development and discovery of treatment options for BCG-unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care expenditures, and mortality related to bladder cancer. This Review of treatment options after BCG failure focuses on principles of optimal management emerging therapies, thus enabling a synthesis of recommendations for management for such patients.

Purpose: The impact of African-American race on oncologic outcomes for low risk prostate cancer is unclear due to conflicting data. We investigated the effect of African-American race on pathological upgrading and/or up staging at prostatectomy in men with clinically low risk prostate cancer., Materials and Methods: We queried the National Cancer Database for men with low risk prostate cancer (clinical stage T2a or less, Gleason score 6 or less, prostate specific antigen less than 10 ng/ml) treated with radical prostatectomy between 2010 and 2013. The outcomes were pathological upgrading to Gleason score greater than 6 (primary) or Gleason score greater than 3+4=7 (secondary) and/or up staging (pathological T3-4 or N1 disease). The association between race and the end points was assessed using multivariable logistic regression. To further adjust for potential confounders, stratification by urban residence and comorbidity score, and subgroup analyses were performed., Results: With adjustment for age, comorbidity, income, urban residence, T stage, prostate specific antigen and percentage of positive biopsy cores, African-American race conferred 1.2-fold higher odds of pathological upgrading to Gleason score greater than 6 and/or up staging (OR 1.2, 95% CI 1.1-1.3, p <0.01). African-American race also was an independent predictor of pathological upgrading to Gleason score greater than 3+4=7 and/or up staging (p=0.03)., Conclusions: African-American men with low risk prostate cancer are more likely to harbor higher risk disease, which may lead to adverse outcomes. This finding alone does not preclude active surveillance. However, race should be considered as men weigh the risks and benefits of active surveillance vs treatment., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, p<0.001). AA men were more likely to be m-SPINK1(+) (13% vs 7%; p=0.069) and triple-negative (50% vs 37%; p=0.043). Racial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling., Patient Summary: This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships., (Copyright © 2015. Published by Elsevier B.V.)

Background: It remains unclear whether men selecting active surveillance (AS) are at increased risk of unfavorable longer term outcomes as compared with men who undergo immediate treatment., Objective: To compare adverse pathologic outcomes in men with favorable-risk prostate cancer who underwent delayed prostatectomy after surveillance (DPAS) to those who elected immediate prostatectomy (IRP)., Design, Setting, and Participants: We conducted a retrospective analysis of a prospective AS registry from 2004 to 2014. From the Johns Hopkins AS program (n = 1298), we identified a subset of men who underwent DPAS (n = 89) and was representative of the entire cohort, not just those that were reclassified to higher risk. These men were compared with men who underwent IRP (n = 3788)., Outcome Measurements and Statistical Analysis: We measured adverse pathologic features (primary Gleason pattern ≥ 4, seminal vesicle invasion [SVI], or lymph node [LN] positivity). Multivariable models were adjusted for age, prostate-specific antigen density, and baseline risk classification., Results and Limitations: Delayed prostatectomy occurred at a median of 2.0 yr (range: 0.6-9.0) after diagnosis. The DPAS and IRP cohorts demonstrated similar proportions of men with primary Gleason pattern ≥ 4 (17% vs 20%; p = 0.11), SVI (3.3% vs 3.2%; p = 0.53), LN positivity (2.3% vs 1.2%; p = 0.37), and overall adverse pathologic features (21.3% vs 17.0%; p = 0.32). The adjusted odds ratio of adverse pathology was 1.33 (95% confidence interval, 0.82-2.79; p = 0.13) for DPAS as compared with IRP. Limitations include a modest cohort size and a limited number of events., Conclusions: In men with favorable-risk cancer, the decision to undergo AS is not independently associated with adverse pathologic outcomes., Patient Summary: This report compares men with favorable-risk prostate cancer who elected active surveillance with those who underwent immediate surgery accounting for evidence that approximately one-third of men who choose surveillance will eventually undergo treatment. Our findings suggest that men who are closely followed with surveillance may have similar outcomes to men who elect immediate surgery, but additional research is needed., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Current guidelines suggest adjuvant radiation therapy for men with adverse pathologic features (APFs) at radical prostatectomy (RP). We examine at-risk men treated only with RP until the time of metastasis., Objective: To evaluate whether clinicopathologic risk models can help guide postoperative therapeutic decision making., Design, Setting, and Participants: Men with National Comprehensive Cancer Network intermediate- or high-risk localized prostate cancer undergoing RP in the prostate-specific antigen (PSA) era were identified (n=3089). Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis were included. APFs were defined as pT3 disease or positive surgical margins., Outcome Measurements and Statistical Analysis: Area under the receiver operating characteristic curve (AUC) for time to event data was used to measure the discrimination performance of the risk factors. Cumulative incidence curves were constructed using Fine and Gray competing risks analysis to estimate the risk of biochemical recurrence (BCR) or metastasis, taking censoring and death due to other causes into consideration., Results and Limitations: Overall, 43% of the cohort (n=1327) had APFs at RP. Median follow-up for censored patients was 5 yr. Cumulative incidence of metastasis was 6% at 10 yr after RP for all patients. Cumulative incidence of metastasis among men with APFs was 7.5% at 10 yr after RP. Among men with BCR, the incidence of metastasis was 38% 5 yr after BCR. At 10 yr after RP, time-dependent AUC for predicting metastasis by Cancer of the Prostate Risk Assessment Postsurgical or Eggener risk models was 0.81 (95% confidence interval [CI], 0.72-0.97) and 0.78 (95% CI, 0.67-0.97) in the APF population, respectively. At 5 yr after BCR, these values were lower (0.58 [95% CI, 0.50-0.66] and 0.70 [95% CI, 0.63-0.76]) among those who developed BCR. Use of risk model cut points could substantially reduce overtreatment while minimally increasing undertreatment (ie, use of an Eggener cut point of 2.5% for treatment of men with APFs would spare 46% from treatment while only allowing for metastatic events in 1% at 10 yr after RP)., Conclusions: Use of risk models reduces overtreatment and should be a routine part of patient counseling when considering adjuvant therapy. Risk model performance is significantly reduced among men with BCR., Patient Summary: Use of current risk models can help guide decision making regarding therapy after surgery and reduce overtreatment., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed., Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer., Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05-2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03-3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21-0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data., Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression., (©2015 American Association for Cancer Research.)

Background: The objective of this study was to evaluate the use of neoadjuvant chemoradiation in patients with prostate sarcoma treated at our institution and report oncological outcomes., Materials and Methods: The records of patients with intermediate- or high-grade prostate sarcoma treated with curative intent at our institution from 1993 to 2013 were reviewed. Patient demographic information, tumor characteristics, and treatment modalities used were assessed. Overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were calculated., Results: Eight patients met inclusion criteria. The mean age at presentation was 64 years, and urinary obstruction was the most common presenting symptom. All patients underwent surgical resection and neoadjuvant radiation and 6 had concurrent chemotherapy. Four patients received intraoperative radiation. With a median follow-up of 36 months, there were no local recurrences, 6 metastases, 4 deaths from disease, and no deaths from other causes. The median OS and CSS was 67.8 months, with actuarial OS and CSS rates of 100% at 1 year, 75% at 2 years, 62.5% at 3 years, and 62.5% at 5 years. Median RFS was 14.2 months, with actuarial RFS rate of 75% at 1 year, 37.5% at 2 years, and 25% at 3 years., Conclusion: Prostate sarcomas are rarely cured using surgical resection alone. Our cohort treated with a multimodality approach had favorable CSS and RFS compared with historic and contemporary series of surgery alone and no local recurrences. Most patients developed metastatic recurrence, highlighting the aggressive nature of this disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)