Search

There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte-macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival. No dose-limiting toxicity was encountered in 21 patients enrolled and treated. Combination treatment achieved a pathologic complete response rate of 42.1% and a 1-year recurrence-free survival rate of 70.4%. Pathologic response was associated with baseline free E2F activity and tumor mutational burden but not PD-L1 status. Although T cell infiltration was broadly induced after intravesical oncolytic immunotherapy, the formation, enlargement and maturation of tertiary lymphoid structures was specifically associated with complete response, supporting the importance of coordinated humoral and cellular immune responses. Together, these results highlight the potential of this combination regimen to enhance therapeutic efficacy in cisplatin-ineligible patients with muscle-invasive bladder cancer, warranting additional study as a neoadjuvant therapeutic option. ClinicalTrials.gov identifier: NCT04610671 ., Competing Interests: Competing interests: R.L. reports research support from Predicine, Veracyte, CG Oncology, Valar Labs, Merck and Janssen; clinical trial protocol committee participation with CG Oncology, Merck and Janssen; and is scientific advisor/consultant for Bristol Myers Quibb, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, Janssen, Thericon, Iconovir, ImmunityBio and Pfizer. W.J.S. reports consultant work for Pacific Edge and Urogen Pharma. P.E.S. reports being the Vice Chair of the NCCN guidelines committee for bladder and penile cancer. J.Z. reports consultant work for Sanofi, AstraZeneca, Dendreon, Seagen, Bayer and Pfizer. G.D.G. reports consultant work for MyCareGorithm and stock options in Lantheus. J.M.B. reports consultant work for CG Oncology and Kalivir Immunotherapeutics and being a shareholder of CG Oncology and Kalivir Immunotherapeutics. C.P.N.D. reports consultant work for AstraZeneca and CG Oncology and intellectual property ownership related to the use of genetic alterations as a predictive biomarker for response to nadofaragene firadenovec. R.K.J. reports consultant work for AVEO, Bristol Myers Squibb, Sanofi, EMD Serono, Gilead Sciences, IDEOlogy Pfizer and Seattle Genetics/Astellas; speaker’s bureau for Gilead Sciences, Seagen and Seattle Genetics/Astellas; research funding from Bristol Myers Squibb, Gilead Sciences and the National Cancer Institute; and honoraria from FLASCO, Curio Science, DAVA Oncology, NCCN/Pfizer and OncLive/MJH Life Sciences. J.J.M. reports membership on the CG Oncology Board of Directors; being the Associate Center Director at Moffitt Cancer Center; ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics and AffyImmune Therapeutics; and consultant work for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix and Aleta Biotherapeutics. J.R.C.-G. reports consultant work for Anixa Biosciences and Alloy Therapeutics; stock options in Compass Therapeutics, Anixa Biosciences and Alloy Therapeutics; patent licensed by Anixa Biosciences; intellectual property filed with Compass Therapeutics; and being the co-founder of Cellepus Therapeutics, a CAR T cell company. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

Background: Prostate cancer affects African American men disproportionately compared with men of other racial/ethnic groups. To identify biological bases for this health disparity, we sought to create a state-wide biobank of African American prostate cancer survivors in Florida., Methods: African American men diagnosed with prostate cancer between 2013 and 2017 and living in Florida at diagnosis were identified through the State of Florida's cancer registry. Individuals were approached via mail and telephone, assessed for eligibility, and asked for informed consent. χ2 and t tests were conducted to identify differences between eligible and reachable individuals (i.e., had valid contact information) versus consented participants., Results: Of the 5,960 eligible and reachable individuals, 3,904 were eligible and contacted at least once, and 578 consented [overall consent rate = 10% (578/5,960); adjusted consent rate = 15% (578/3,904)]. Statistically significant (Ps < 0.05) but small differences in demographic and clinical variables were observed. Consented participants were less likely to be older than 64 (35% vs. 41%) and less likely to have received radiotherapy (36% vs. 41%) and hormone therapy (16% vs. 21%), but more likely to have regional prostate cancer (13% vs. 11%) and have undergone surgery (44% vs. 39%). Consented participants did not differ from reachable individuals on other demographic and clinical factors (Ps > 0.05)., Conclusions: Recruiting African American prostate cancer survivors to biobanking research through a cancer registry is feasible. However, the consent rate was low, and existing challenges limit consent and participation., Impact: Strategies for overcoming barriers to informed consent and increasing participation in biospecimen research are needed to address cancer disparities., (©2023 American Association for Cancer Research.)

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

Background: Emerging evidence suggests that a subset of Black men with National Comprehensive Cancer Network (NCCN) low-risk prostate cancer (PCa) may harbor high volume and genomically aggressive disease. However, limited, and ambiguous research exist to evaluate the risk of extreme Gleason reclassification in Black men with low-risk PCa., Methods: This retrospective cohort study included 45,674 low-risk PCa patients who underwent prostatectomy and were not on active surveillance, from National Cancer Database (NCDB). A propensity score matched-pair design was employed, and the final cohort was limited to 1:1 matched 12,340 patients. Gleason score reclassification was used as primary endpoint. As such, any migration to pathologic Gleason score ≥7(3 + 4) was identified as overall, whereas migration to ≥7(4 + 3) was defined as extreme reclassification. A conditional Poisson regression model was used to estimate the risk of reclassification. Whereas spline model was used to estimate the impact of increasing time to treatment as a non-linear function on Gleason reclassification between race group., Results: Upon matching there were no differences in the baseline characteristics between race groups. In a matched cohort, higher proportion of low-risk Black men (6.6%) reported extreme reclassification to pathologic Gleason score than White men (5.0%), p < 0.001. In a conditional Poisson regression model adjusted for time to treatment, the risk of overall (RR = 1.09, 95% CI, 1.05-1.13, p < 0.001) and extreme (RR = 1.30, 95% CI, 1.12-1.50, p = 0.004) reclassification was significantly higher in Black men as compared to their White counterpart. In spline model, the probability of Gleason reclassification in Black men was elevated with increasing time to treatment, especially after 180 days (53% vs. 43% between Black and White men)., Conclusion: Risk of Gleason score reclassification is disparately elevated in Black men with low-risk PCa. Furthermore, time to treatment can non-linearly impact Gleason reclassification in Black men., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Grade group 4 and 5 (GG-45) prostate cancer (PCa) patients are at the highest risk of lethal outcomes, yet lack genomic risk stratification for prognosis and treatment selection. Here, we assess whether transcriptomic interactions between tumor immune content score (ICS) and the Decipher genomic classifier can identify most lethal subsets of GG-45 PCa. We utilized whole transcriptome data from 8071 tumor tissue (6071 prostatectomy and 2000 treatment-naïve biopsy samples) to derive four immunogenomic subtypes using ICS and Decipher. When compared across all grade groups, GG-45 samples had the highest proportion of most aggressive subtype-ICS High /Decipher High . Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICS High /Decipher High subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICS High /Decipher High subtype had a significantly higher risk of distant metastasis (hazard ratio [HR] = 5.41; 95% confidence interval [CI], 2.76-10.6; p ≤  0.0001) and PCa-specific mortality (HR = 10.6; 95% CI, 4.18-26.94; p ≤  0.0001) as compared with ICS Low /Decipher Low . The novel immunogenomic subtypes establish a very strong synergistic interaction between ICS and Decipher in identifying GG-45 patients who experience the most lethal outcomes. PATIENT SUMMARY: In this analysis, we identified a novel interaction between the total immune content of prostate tumors and genomic classifier to identify the most lethal subset of patients with grade groups 4 and 5. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the effectiveness and safety of prostatic artery embolization (PAE) on lower urinary tract symptoms (LUTS) in the setting of localized prostate cancer (PCa)., Materials and Methods: This was a retrospective, single-center, institutional review board-approved study from December 2016 to June 2020 of 21 patients (median age, 72; range, 63-83 years) with moderate LUTS and localized PCa. Clinical effectiveness was evaluated at 6 and 12 weeks using International Prostate Symptom Score (IPSS) and quality of life (QoL) improvement. Seventeen patients were scheduled to receive definitive radiotherapy (RT) after PAE; 13 patients completed RT. Short-term imaging signs of oncologic progression were evaluated at 6 and 12 weeks defined by at least one of the following on magnetic resonance imaging: increased Prostate Imaging-Reporting and Data System score of index lesion(s) to at least 4, new extracapsular extension, seminal vesicle involvement, or pelvic lymphadenopathy. Nonparametric Wilcoxon signed-rank test was used for analysis., Results: IPSS improved by a median of 12 (n = 19, P < .0001) and 14 (n = 14, P < .0001) at 6 and 12 weeks, respectively. QoL improved by a median of 2 (n = 19, P < .0001) and 3 (n = 3, P < .0001) at 6 and 12 weeks. Prostate volume decreased by a median of 24% (n = 19, P < .0001) and 36% (n = 12, P = .015) at 6 and 12 weeks. No patients demonstrated disease progression at 6 (n = 16) or 12 (n = 8) weeks by imaging. No patients experienced increased prostate-specific antigen after RT, grade ≥3 adverse events, or greater genitourinary toxicity., Conclusions: PAE is effective and safe for the treatment of men with LUTS from benign prostatic hyperplasia in the setting of concomitant, localized, non-obstructive PCa., (Copyright © 2021 SIR. Published by Elsevier Inc. All rights reserved.)

Background: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa., Methods: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189)., Results: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders., Conclusion: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

Background: The use of a novel strategy known as adaptive abiraterone therapy based on mathematical modeling of evolutionary dynamics of tumor subpopulations was shown in a clinical trial to extend the time to disease progression in patients with metastatic castration-resistant prostate cancer (CRPC) and reduced the use of abiraterone therapy. Although the clinical impact of adaptive abiraterone treatment is clear, the economic impact of this strategy has not been investigated., Objective: To compare the cost of care with adaptive abiraterone therapy versus standard continuous abiraterone therapy in patients with metastatic CRPC, using patient billing data., Methods: We performed a retrospective review of billing data for patients with metastatic CRPC who received abiraterone treatment at a large cancer center between June 1, 2012, and August 31, 2018. Patients were divided into 2 groups based on whether they received adaptive abiraterone therapy (N = 15) or continuous abiraterone therapy (N = 21). All patients with refractory, metastatic prostate cancer after castration that was indicated for abiraterone therapy were eligible for this study. Each patient in the adaptive abiraterone therapy cohort received abiraterone plus prednisone treatment until the patient reached a target threshold of 50% or more reduction in prostate-specific antigen (PSA) level compared with his PSA level before abiraterone therapy; treatment was then suspended until the PSA level rose above the 50% of PSA before abiraterone therapy target threshold. The continuous therapy cohort received abiraterone plus prednisone daily until radiographic progression. The primary outcomes were the mean annual cost of care per patient, including and excluding the cost of abiraterone, and the cost of care, by clinical category., Results: The median time to disease progression was 25.8 months for patients who received adaptive abiraterone therapy compared with 12.1 months for patients who received continuous abiraterone therapy. Overall, the mean total, including the cost of drug, annual cost per patient who received adaptive abiraterone therapy was $79,093 compared with $146,782 for patients who received continuous abiraterone therapy ( P <.0001). The annual cost of care per patient, excluding the cost of abiraterone, was $13,883 for those who received adaptive therapy versus $22,322 for those who received continuous abiraterone therapy ( P = .2757), which was not statistically significant., Conclusion: Practical precision medicine strategies, such as adaptive abiraterone treatment or pharmacogenomics-targeted dosing, can use known biomarkers, such as PSA, to tailor therapy, generate improved outcomes, and reduce costs without the need for novel drug and diagnostic discovery and development. The results of this study suggest that a large clinical study of adaptive abiraterone therapy is warranted to validate the potential of this strategy to extend the time to disease progression and reduce costs of treatment of metastatic CRPC., (Copyright © 2021 by Engage Healthcare Communications, LLC.)

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

Background: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERG negative ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied., Methods: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections., Results: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERG negative 81.4% vs. ERG positive 18.6%; p = .005) and EAM (ERG negative 60.4% vs. ERG positive 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERG negative (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERG negative were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC)., Conclusions: ERG negative tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location., (© 2020 Wiley Periodicals LLC.)

Purpose: The toxicity of topical chemotherapeutics has been well-characterized in extra-genital squamous cell carcinoma; however, there is limited data regarding the use of topical agents for penile squamous cell carcinoma in situ (CIS). We aim to describe the clinical outcomes and toxicities associated with the use of topical fluorouracil and imiquimod for penile CIS., Materials and Methods: We performed an observational analysis of penile CIS cases treated with topical chemotherapy from 2009 to 2019 at a tertiary cancer center., Results: Twenty patients with penile CIS received fluorouracil (n= 17, 85%) or imiquimod (n = 3, 15%). The median age was 66 years. The median follow-up was 18 months. Complete response (CR) was achieved in 65% (n= 13/20), partial response in 25% (n = 5/20), and no response in 10% (n = 2/20). Overall, 50% required additional alternative treatments due to lack of CR or relapse. The median recurrence-free survival was 14 months. Fifty percent of patients reported Common Terminology Criteria for Adverse Events v5.0 grade 1 to 2 acute toxicities, including local skin irritation (40%), pain (35%), dysuria (5%), or nausea (5%). Only 65% completed the full course of treatment. Nonadherence was associated with a diminished CR rate of 28.6%., Conclusions: Topical chemotherapy is a reasonable first-line therapy for penile CIS. A substantial proportion of patients experience acute toxicity and are unable to complete the full course of therapy. We recommend that patients with penile CIS be monitored regularly in order to promptly address issues with adherence and toxicity associated with topical treatment., (Published by Elsevier Inc.)

Objectives: To evaluate the safety and feasibility of focal bipolar radiofrequency ablation in men with localized prostate cancer., Methods: A review of 10 patients treated with a novel bipolar radiofrequency ablation probe integrated in a coil design (Encage; Trod Medical, Bradenton, FL, USA) between 2011 and 2017 in two prospective pilot trials. All men had clinical stage T1c prostate cancer, prostate-specific antigen <10 ng/mL and Gleason score ≤7. Ablation was carried out under general anesthesia, and bipolar probes were inserted transperineally under transrectal ultrasound guidance. Treatment-related adverse events, quality of life and negative biopsy rate were evaluated at 6 months after ablation. The Wilcoxon signed-rank test was used to compare baseline and post-treatment symptom scores., Results: The median age was 58 years (range 50-64 years) and the median prostate volume was 49.65 cc (range 21-68 cc). Prostate cancer with a Gleason score of 6 (3 + 3) and 7 (3 + 4) was noted in seven and three patients, respectively. The median number of radiofrequency ablation cycles was 2.5 (range 2-5). All patients were catheter-free and able to void the day of surgery. Within 6 months after ablation, all adverse events were low grade, with the exception of one grade 3 hematuria that required cystoscopy without coagulation. Six months after ablation bowel, urinary and hormonal functions, and overall satisfaction remained stable. Erectile dysfunction occurred in two out of four patients who had normal sexual function before the procedure. Neither urinary incontinence nor urinary infection was noted., Conclusions: This first report on focal bipolar radiofrequency ablation documents a safe and feasible treatment option for selected patients with localized prostate cancer., (© 2020 The Japanese Urological Association.)

Background: Identification of imaging traits to discriminate clinically significant prostate cancer is challenging due to the multi focal nature of the disease. The difficulty in obtaining a consensus by the Prostate Imaging and Data Systems (PI-RADS) scores coupled with disagreements in interpreting multi-parametric Magnetic Resonance Imaging (mpMRI) has resulted in increased variability in reporting findings and evaluating the utility of this imaging modality in detecting clinically significant prostate cancer. This study assess the ability of radiological traits (semantics) observed on multi-parametric Magnetic Resonance images (mpMRI) to discriminate clinically significant prostate cancer., Methods: We obtained multi-parametric MRI studies from 103 prostate cancer patients with 167 targeted biopsies from a single institution. The study was approved by our Institutional Review Board (IRB) for retrospective analysis. The biopsy location had been identified and marked by a clinical radiologist for targeted biopsy based on initial study interpretation. Using the target locations, two study radiologists independently re-evaluated the scans and scored 16 semantic traits on a point scale (up to 5 levels) based on mpMRI images. The semantic traits describe size, shape, and border characteristics of the prostate lesion, as well as presence of disease around lymph nodes (lymphadenopathy). We built a linear classifier model on these semantic traits and related to pathological outcome to identify clinically significant tumors (Gleason Score ≥ 7). The discriminatory ability of the predictors was tested using cross validation method randomly repeated and ensemble values were reported. We then compared the performance of semantic predictors with the PI-RADS predictors., Results: We found several semantic features individually discriminated high grade Gleason score (ADC-intensity, Homogeneity, early-enhancement, T2-intensity and extraprostatic extention), these univariate predictors had an average area under the receiver operator characteristics (AUROC) ranging from 0.54 to 0.68. Multivariable semantic predictors with three features (ADC-intensity; T2-intensity, enhancement homogenicity) had an average AUROC of 0.7 [0.43, 0.94]. The PI-RADS based predictor had average AUROC of 0.6 [0.47, 0.75]., Conclusion: We find semantics traits are related to pathological findings with relatively higher reproducibility between radiologists. Multivariable predictors formed on these traits shows higher discriminatory ability compared to PI-RADS scores.

Background: Further biomarkers are warranted to improve prognostic stratification of penile squamous cell carcinoma (PSCC) patients undergoing inguinal lymph node dissection (ILND)., Objective: To assess the prognostic value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in PSCC patients undergoing ILND and to investigate its role in predicting pathologic node-positive (pN+) disease., Design, Setting, and Participants: In total, 84 consecutive patients undergoing ILND for PSCC at our institution between 1994 and 2014 were identified. Sixty-eight patients with a complete blood count and differential prior to surgery were included. Median follow-up was 35.5 mo., Outcomes Measurements and Statistical Analysis: Cut-off point analysis of NLR was performed using the Contal and O'Quigley method. Estimates of overall survival (OS), cancer-specific survival, and recurrence-free survival stratified by NLR were provided by the Kaplan-Meier method. Cox regression models were performed to determine predictors of survival and recurrence. Logistic regression models were used to identify factors associated with pathologic node-positivity., Results and Limitations: The cut-off point value was determined to be 3. Median OS was significantly shorter for patients with NLR ≥3 than those with NLR <3 (30 vs 158 mo, p<0.001). NLR ≥3 was an independent predictor of worse OS (hazard ratio=2.48; 95% confidence interval [CI]: 1.02-6.06, p=0.046). On univariable analysis, NLR ≥3 was associated with an increased risk of pN+ disease (odds ratio [OR]=3.75; 95% CI: 1.30-10.81, p=0.014). However, on multivariable analysis adjusted for primary tumor grade, lymphovascular invasion, clinical N stage, and neoadjuvant treatment receipt, the association between NLR and pN+ disease was no longer significant (OR=3.66; 95% CI: 0.82-16.42, p=0.091). The retrospective design and limited size of the study are acknowledged limitations., Conclusions: Pretreatment NLR is an independent predictor of OS in PSCC patients undergoing ILND and highlights the association between systemic inflammation and survival. Our data suggests that a simple biomarker of inflammation can serve as a prognosticator in PSCC., Patient Summary: Penile cancer is a rare malignancy in North America and Europe. Therefore, there is a lack of prognostic parameters to help predict oncologic and survival outcomes. In this report, patients with an elevated neutrophil-to-lymphocyte ratio had an increased risk of mortality., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

Objective: To evaluate the mortality rates for prostate cancer according to geographical areas in Peru between 2005 and 2014., Materials and Methods: Information was extracted from the Deceased Registry of the Peruvian Ministry of Health. We analysed age-standardised mortality rates (world population) per 100 000 men. Spatial autocorrelation was determined according to the Moran Index. In addition, we used Cluster Map to explore relations between regions., Results: Mortality rates increased from 20.9 (2005-2009) to 24.1 (2010-2014) per 100 000 men, an increase of 15.2%. According to regions, during the period 2010-2014, the coast had the highest mortality rate (28.9 per 100 000), whilst the rainforest had the lowest (7.43 per 100 000). In addition, there was an increase in mortality in the coast and a decline in the rainforest over the period 2005-2014. The provinces with the highest mortality were Piura, Lambayeque, La Libertad, Callao, Lima, Ica, and Arequipa. Moreover, these provinces (except Arequipa) showed increasing trends during the years under study. The provinces with the lowest observed prostate cancer mortality rates were Loreto, Ucayali, and Madre de Dios. This study showed positive spatial autocorrelation (Moran's I: 0.30, P = 0.01)., Conclusion: Mortality rates from prostate cancer in Peru continue to increase. These rates are higher in the coastal region compared to those in the highlands or rainforest., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

[This corrects the article DOI: 10.18632/oncotarget.26437.].

Background: The impact of treatment delays on prostate cancer-specific outcomes remains ill-defined. This study investigates the effect of time to treatment on biochemical disease control after prostatectomy., Methods: This retrospective study includes 1,807 patients who received a prostatectomy as a primary treatment at two large tertiary referral centers from 1987 to 2015. Multivariate cox model with restricted cubic spline was used to identify optimal time to receive treatment and estimate the risk of biochemical recurrence., Results: Median follow-up time of the study was 46 (interquartile range, 18-86) months. Time to treatment was subcategorized based on multivariate cubic spline cox model. In multivariate spline model, adjusted for all the pertinent pretreatment variables, inflection point in the risk of biochemical recurrence was observed around 3 months, which further increased after 6 months. Based on spline model, time to treatment was then divided into 0 to 3 months (61.5%), >3 to 6 months (31.1%), and 6 months (7.4%). In the adjusted cox model, initial delays up to 6 months did not adversely affect the outcome; however, time to treatment >6 months had significantly higher risk of biochemical recurrence (HR, 1.84; 95% confidence interval, 1.30-2.60; P < 0.01)., Conclusions: The initial delays up to 6 months in prostate cancer primary treatment may be sustainable without adversely affecting the outcome. However, significant delays beyond 6 months can unfavorably affect biochemical disease control., Impact: Time to treatment can aid clinicians in the decision-making of prostate cancer treatment recommendation and educate patients against unintentional treatment delays., (©2018 American Association for Cancer Research.)

Motivation: The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP-SNP interactions., Results: We tested two candidate approaches: the 'Five-Full' and 'AA9int' method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP-SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP-SNP interactions in large-scale studies., Availability and Implementation: The 'AA9int' and 'parAA9int' functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY&#95;Software/., Supplementary Information: Supplementary data are available at Bioinformatics online.

Prostate cancer diagnosis and treatment continues to be a major public health challenge. The heterogeneity of the disease is one of the major factors leading to imprecise diagnosis and suboptimal disease management. The improved resolution of functional multi-parametric magnetic resonance imaging (mpMRI) has shown promise to improve detection and characterization of the disease. Regions that subdivide the tumor based on Dynamic Contrast Enhancement (DCE) of mpMRI are referred to as DCE-Habitats in this study. The DCE defined perfusion curve patterns on the identified tumor habitat region are used to assess clinical significance. These perfusion curves were systematically quantified using seven features in association with the patient biopsy outcome and classifier models were built to find the best discriminating characteristics between clinically significant and insignificant prostate lesions defined by Gleason score (GS). Multivariable analysis was performed independently on one institution and validated on the other, using a multi-parametric feature model, based on DCE characteristics and ADC features. The models had an intra institution Area under the Receiver Operating Characteristic (AUC) of 0.82. Trained on Institution I and validated on the cohort from Institution II, the AUC was also 0.82 (sensitivity 0.68, specificity 0.95)., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing interest.

Background: The perioperative period can be a critical period with long-term implications on cancer-related outcomes. In this study, we evaluate the influence of regional anesthesia on cancer-specific outcomes in a radical cystectomy (RC) cohort of patients., Methods: We performed a retrospective analysis of patients with clinically-nonmetastatic urothelial carcinoma of the bladder who underwent RC at our institution from 2008 to 2012. Patients were retrospectively registered and stratified based on two anesthetic techniques: perioperative epidural analgesia with general anesthesia (epidural) versus general anesthesia alone (GA). Epidural patients received a sufentanil-based regimen (median intraoperative sufentanil dose 50 mcg (45,85). Propensity-score was used to make 1:1 case-control matching. Cumulative risk of recurrence with competing risks was calculated based on anesthetic technique. Kaplan-Meier curves were used to compare recurrence-free (RFS) and cancer-specific survival (CSS). Univariable and multivariable analyses were performed with Cox proportional hazard regression models for RFS and CSS., Results: Only patients with complete data on anesthetic technique were included. Out of 439 patients, 215-pair samples with complete follow-up were included in the analysis. Median follow-up was 41.4 months (range: 0.20-101). Patients with epidurals received higher median total intravenous morphine equivalents (ivMEQ) versus those in the GA group (75 (11-235) vs. 50 ivMEQ (7-277), p < 0.0001). Cumulative risk of recurrence at two years was 25.2% (19.6, 31.2) for epidural patients vs. 20.0% (15.0, 25.7) for GA patients (Gray test p = 0.0508). Epidural analgesic technique was a significant predictor of worse RFS (adjusted HR = 1.67, 1.14-2.45; p = 0.009) and CSS (HR = 1.53, 1.04-2.25; p = 0.030) on multivariable analyses., Conclusions: Epidural anesthesia using sufentanil was associated with worse recurrence and disease-free survival in bladder cancer patients treated with surgery. This may be due use of epidural sufentanil or due to the increased total morphine equivalents patient received as a consequence of this drug.

Importance: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy improves survival compared with cystectomy alone for patients with bladder cancer. Although gemcitabine with cisplatin has become a standard NAC regimen, a dose-dense combination of methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) is being adopted at some institutions., Objective: To assess the association of neoadjuvant ddMVAC vs standard regimens with downstaging and overall survival among patients treated with radical cystectomy for bladder cancer., Design, Setting, and Participants: Cross-sectional analysis of data extracted from the medical records of a consecutive sample, after exclusions, of 1113 patients with bladder cancer of whom 824 had disease stage T2 or greater, who were treated with cystectomy at the Moffitt Cancer Center in Tampa, Florida, a tertiary care cancer center, between January 1, 2007, and May 31, 2017. Data were collected between November 14, 2016, and July 21, 2017, and analyzed between August 21, 2017, and December 8, 2017. Patients were compared based on type of NAC. Those who did not receive NAC were included as controls., Main Outcomes and Measures: Comparative rates and the association of any downstaging, complete response, and overall survival with ddMVAC and other NAC regimens and surgery alone. Outcomes were examined using Kaplan-Meier, adjusted logistic, Cox regression, and propensity-weighted models., Results: Of the 1113 patients who underwent cystectomy for bladder cancer, 861 (77.4%) were male, the median (interquartile range) age was 67 (60-74) years, 1051 (94.4%) were white, 27 (2.4%) black, 37 (3.3%) Hispanic/Latino, and 35 (3.1%) other race/ethnicity. Of 824 patients with muscle-invasive bladder cancer, 332 (40%) received NAC. Downstaging rates were 52.2% for ddMVAC, 41.3% for gemcitabine-cisplatin, and 27.0% for gemcitabine with carboplatin, and complete response (pT0N0) rates were 41.3% for ddMVAC, 24.5% for gemcitabine-cisplatin, and 9.4% for gemcitabine-carboplatin (2-sided P < .001). Adjusted analysis comparing ddMVAC with gemcitabine-cisplatin demonstrated a higher likelihood of downstaging (odds ratio [OR], 1.84; 95% CI, 1.10-3.09) and complete response (OR, 2.67; 95% CI, 1.50-4.77) with ddMVAC. Similar results were achieved with propensity score matching (OR, 1.52; 95% CI, 0.99-2.35). Patients who received ddMVAC had better overall survival than those treated with other chemotherapy regimens, although the observed survival benefit did not reach statistical significance in adjusted or propensity-matched models (hazard ratio, 0.44; 95% CI, 0.14-1.38; P = .16)., Conclusions and Relevance: This study suggest that neoadjuvant ddMVAC followed by cystectomy is associated with a higher complete response (ypT0N0) rate than standard NAC. These data highlight and suggest the need to further investigate ddMVAC vs standard NAC in a prospective, randomized fashion.

Background: Primary urethral carcinoma (PUC) is rare, and standard treatment recommendations are lacking. We examined the variation in treatments and survival outcomes of female PUC at a single, tertiary referral cancer center., Methods: Records of women with PUC referred to our multidisciplinary genitourinary oncology service between 2003 and 2017 were reviewed. Clinical, demographic, pathologic, primary and salvage therapy details, and overall (OS) and recurrence-free survival (RFS) were recorded. Survival outcomes were analyzed for the entire cohort, and cases of locally-advanced (≥ T2 tumor), non-metastatic PUC were evaluated according to treatment intensity. Multimodal treatment (cystourethrectomy + concomitant therapy) was compared with non-multimodal therapy. Contingency analyses and Kaplan-Meier estimates were performed., Results: Thirty-nine women with PUC were identified. In total, median OS was 36 months (95% confidence interval, 10.6-61.4 months). Twenty-four had T3 to T4 disease, 12 were node-positive, and 3 had distant metastases. Histology included 22 adenocarcinomas, 11 urothelial, 5 squamous, and 1 neuroendocrine. Patients with locally advanced, non-metastatic disease (n = 25) had significantly reduced OS (36 vs. 99 months; P = .016) and RFS (46 months vs. unmet; P = .011) compared with patients with locally confined tumors. Approximately one-half of locally advanced cases were managed with multimodal therapy (4 with neoadjuvant therapy + cystourethrectomy, 8 with cystourethrectomy + adjuvant therapy, and 1 with chemoradiation + consolidative cystourethrectomy). Multimodal therapy had nonsignificant longer OS (36 vs. 16 months) and RFS (58 vs. 16 months), P > .05., Conclusions: Locally advanced female PUC has relatively poor survival outcomes. Although we observed a nonsignificant interval improvement in survival with multimodality therapy, the treatment paradigm is inconsistent. Because it is a rare disease, collaborative multi-institutional studies are needed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Advanced bladder cancer patients have limited therapeutic options resulting in a median overall survival (OS) between 12 and 15 months. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) has been used successfully in treating patients with metastatic melanoma, resulting in a median OS of 52 months. In this study, we investigated the feasibility of expanding TIL from the tumors of bladder cancer patients. Primary bladder tumors and lymph node (LN) metastases were collected. Tumor specimens were minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. Expanded TIL were phenotyped by flow cytometry and anti-tumor reactivity was assessed after co-culture with autologous tumor digest and IFN-gamma ELISA. Of the 28 transitional cell bladder or LN tumors collected, 14/20 (70%) primary tumors and all of the LN metastases demonstrated TIL expansion. Expanded TIL were predominantly CD3 + (median 63%, range 10-87%) with a median of 30% CD8 + T cells (range 5-70%). TIL secreted IFN-gamma in response to autologous tumor. Addition of agonisitic 4-1BB antibody improved TIL expansion from primary bladder tumors regardless of pre-treatment with chemotherapy. This study establishes the practical first step towards an autologous TIL therapy process for therapeutic testing in patients with bladder cancer.

Significant racial disparities in prostate cancer (PCa) outcomes have been reported, with African-American men (AAM) more likely to endure adverse oncologic outcomes. Despite efforts to dissipate racial disparities in PCa, a survival gap persists and it remains unclear to what extent this disparity can be explained by known clinicodemographic factors. In this study, we leveraged our large institutional database, spanning over 25 years, to investigate whether AAM continued to experience poor PCa outcomes and factors that may contribute to racial disparities in PCa. A total of 7307 patients diagnosed with PCa from 1989 through 2015 were included. Associations of race and clinicodemographic characteristics were analyzed using chi-square for categorical and Mann-Whitney U-test for continuous variables. Racial differences in prostate cancer outcomes were analyzed using competing risk analysis methods of Fine and Gray. Median follow-up time was 106 months. There were 2304 deaths recorded, of which 432 resulted from PCa. AAM were more likely to be diagnosed at an earlier age (median 60 vs. 65 years, P = <0.001) and were more likely to have ≥1 comorbidities (13.6% vs. 7.5%, P < 0.001). In a multivariate competing risk model, adjusted for baseline covariates, AAM experienced significantly higher risk of PCSM compared to NHW men (HR, 1.62, 95% CI, 1.02-2.57, P = 0.03) NHW. Among men diagnosed at an older age (>60 years), racial differences in PCSM were more pronounced, with AAM experiencing higher rates of PCSM (HR, 2.05, 95% CI, 1.26-3.34, P = 0.003). After adjustment of clinicodemographic and potential risk factors, AAM continue to experience an increased risk of mortality from PCa, especially older AAM. Furthermore, AAM are more likely to be diagnosed at an early age and more likely to have higher comorbidity indices., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Inguinal lymph node dissection is an integral part in the management of invasive penile tumors with intraoperative assessment often aiding decision-making during dissection. In this study, we evaluate the diagnostic value of intraoperative frozen section (FS) and analyze clinicopathologic factors that affect its accuracy., Material and Methods: We, retrospectively, reviewed 84 patients with squamous cell carcinoma of the penis who underwent inguinal lymph node dissection at our institution. Intraoperative FS from the superficial inguinal nodes was available in 65 patients and compared with correspondent permanent sections (pathologic node staging [pN]). Sensitivity and specificity were calculated and factors associated with a false negative event were analyzed using logistic regression., Results: The total positive node rate was 60% (39/65). Of 39 pN+ cases, 10 (25.6%) had false-negative FS, whereas the remaining 29 were concordant intraoperatively. Sensitivity and specificity were 0.74 and 1, respectively. On univariable analysis, higher body mass index was associated with a false negative event although there was no association with age, receipt of neoadjuvant therapy, or clinical node stage., Conclusion: Intraoperative FS is highly specific and moderately sensitive for the detection of positive superficial inguinal lymph nodes in penile cancer. Its use can help guide intraoperative surgical planning while limiting its reliance for patients with higher body mass index., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: To our knowledge it is unknown whether concomitant inguinal lymph node dissection at the time of penectomy improves outcomes in patients with penile cancer. We analyzed predictors of regional recurrence as well as disease specific survival based on time of inguinal lymph node dissection. We also determined an optimal time to perform inguinal lymph node dissection., Materials and Methods: We reviewed the records of 84 consecutive patients with available nodal pathology findings. Recurrence-free and disease specific survival was estimated using the Kaplan-Meier method. Optimal time to inguinal lymph node dissection was assessed by ROC curves and used for dichotomization. Cox proportional HRs were used to identify predictors of regional recurrence after inguinal lymph node dissection., Results: A total of 47 (56%) and 37 patients (44%) presented with cN0 and cN+ disease, respectively, during a median followup of 21 months. A cutoff point of 3 months to perform inguinal lymph node dissection was used to dichotomize the cohort into early vs delayed groups. Early dissection in 51 men demonstrated 5-year recurrence-free survival of 77% vs 37.8% in 33 who underwent delayed dissection. Positive node disease (HR 23.2, 95% CI 2.98-181.2) and early inguinal lymph node dissection (HR 0.48, 95% CI 0.21-0.98) were predictors of regional recurrence. Five-year disease specific survival was 64.1% and 39.5% in the early and late dissection groups, respectively., Conclusions: Three months appears to be an optimal window for performing inguinal lymph node dissection. While prospective trials are needed to define the role of upfront groin dissection, our results may help delineate patterns of referral and timing of inguinal lymph node dissection in patients with penile cancer., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: We reviewed the outcomes for an octogenarian population to investigate whether active surveillance (AS) provides comparable survival to partial nephrectomy (PN) or radical nephrectomy (RN)., Patients and Methods: Data were collected from 115 octogenarian patients referred for management of renal masses at Moffitt Cancer Center from 2000 to 2013. Patients were treated with AS, PN, or RN. Univariable and multivariable Cox regression models measured the association between management modality and survival. Kaplan-Meier survival analysis was used to calculate survival, and log-rank tests were used to compare survival curves., Results: The median age was 82 years (interquartile range, 81-85 years). The median follow-up period was 51 months (interquartile range, 23-81 months). Of the 115 patients, 31 (27%) underwent AS, 31 (27%) underwent PN, and 53 (46%) underwent RN. The patients who underwent RN had a larger mean tumor size at 5.5 cm, with 19 patients (36%) having stage ≥ pT3 (P < .001). We found no difference in overall survival or disease-specific survival among the 3 management strategies on univariable analysis (P = .39 and P = .1, respectively). On multivariable analysis for overall survival, only the Charlson comorbidity index was associated with worse survival (hazard ratio, 1.2; 95% confidence interval, 1.1-1.3; P = .002). In a subgroup analysis of cT1a patients, we also found no difference in overall or disease-specific survival among the treatment arms on univariable analysis (P = .74 and P = .9, respectively)., Conclusion: Active treatment with PN and RN might not provide a survival advantage compared with AS in the octogenarian population with a small renal mass. However, larger renal masses should undergo active treatment in appropriately selected patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To compare perioperative charges induced at the initial phase of a standardized enhanced recovery after surgery (ERAS) program from a tertiary referral center., Methods: A multidisciplinary ERAS protocol was implemented in our department on July 2015. During the subsequent year, all patients were treated according to this protocol (ERAS group). The patients were compared in terms of real in-hospital charges per surgical episode with a control group consisting of consecutive patients before the start of ERAS. Individual charges were analyzed per sample population and compared with the Wilcoxon rank-sum test or t test. Additionally, cost variances for each group were evaluated., Results: A total of 257 consecutive patients were evaluated of which the last 112 were ERAS patients. The median length of stay for each group was 6 days (P = .748). ERAS patients incurred higher medication charges ($1939 vs $1729, P = .036). Control patients incurred higher supplies ($861 vs $692), treatment ($90 vs $72), and miscellaneous charges ($537 vs $388) (all, P < .001). The median total charges per patient were $59,539 for the control group and $60,655 for the ERAS group (P = .175). ERAS adoption significantly reduced variance in billed charges (P < .001)., Conclusion: ERAS implementation did not significantly increase expenditure for cystectomy patients. ERAS showed decreased variance in charges likely due to standardization of care while eliciting savings in supplies, treatment, and miscellaneous costs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of leukoreduced-only perioperative blood transfusion (PBT) and corresponding survival outcomes in a radical cystectomy cohort of patients., Materials and Methods: We analyzed data from 1026 patients who underwent radical cystectomy at our institution. PBT was defined as transfusion in the intraoperative or within the postoperative hospitalization period. Multivariable analyses using Cox proportional hazards were performed to measure the association between PBT, patient variables, and 3 primary end points: recurrence-free survival, disease-specific survival, and overall survival. Kaplan-Meier curves estimated survival times and were compared with log-rank test., Results: Overall, of a total of 1026 patients, 341 (33.2%) received leukoreduced PBT. The median follow-up was 27.5 months. Transfused patients were more likely to be female, had higher estimated blood loss, lower preoperative hemoglobin, were more likely to have received neoadjuvant chemotherapy, or had undergone a continent urinary diversion. Higher pathologic tumor and nodal stage were observed more frequently in patients who received PBT. On multivariable analysis, PBT was not associated with worse recurrence-free survival, disease-specific survival, and overall survival (all P > .05). Kaplan-Meier curves did not show any significant differences (all P > .05) between the transfused and nontransfused groups. In addition, no differences were found in regard to timing of transfusion, that is, intraoperative vs postoperative, in distinct analysis., Conclusion: No significant association was found between leukoreduced PBT and worse survival outcomes at short-term follow-up in a contemporary cohort of cystectomy patients. Prospective long-term follow-up is warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The benefits of robotic-assisted radical cystectomy (RARC) are unclear, especially in patients with high-risk disease (pT3/T4). We evaluated pathological and postoperative outcomes of RARC versus open radical cystectomy (ORC) in these patients., Methods: We identified bladder cancer patients treated with RARC or ORC from January 2010-August 2014. Clinicodemographic factors were examined for potential confounding. Our primary outcome of interest was positive soft-tissue surgical margins (STSMs). Secondary outcomes included post-operative complications and length of stay (LOS). We used logistic regression to define the association between clinical factors with outcomes of interest, focusing on patients with locally advanced disease., Results: We identified 472 patients treated with ORC (407, 86.2 %) or RARC (65, 13.8 %) of which 215 (45.6 %) were high-risk cases based on advanced pathologic stage (pT3/4). RARC patients were more commonly men (96.9 vs. 73.2 %, p < 0.01), had better performance status (ECOG 0, 78.5 vs. 59.7 %, p = 0.031), and received less neoadjuvant chemotherapy (21.5 vs. 39.3 %, p = 0.006). Total (52.3 vs. 59.7 %, p = 0.26) and high-grade complication rates (13.8 vs. 19.7 %, p = 0.27) were similar, but median LOS was shorter after RARC (6 vs. 7 days, p < 0.01). On multivariate analysis, prior pelvic radiation (OR: 4.78, 95 % CI: 2.16-10.57), and advanced tumor stage (OR: 3.06, 95 % CI: 1.56-6.03) were independently associated with positive STSMs in high-risk patients but robotic surgical approach was not (OR: 0.81, 95 % CI: 0.29-2.30; p = 0.69)., Conclusion: RARC had similar short-term postoperative outcomes compared to ORC and did not compromise oncological control in patients with extravesical disease.

Motivation: Testing SNP-SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP-SNP interactions are underdeveloped., Results: We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45 biologically meaningful interaction patterns for a binary outcome. SIPI takes non-hierarchical models, inheritance modes and mode coding direction into consideration. The simulation results show that SIPI has higher power than MDR (Multifactor Dimensionality Reduction), AA&#95;Full, Geno&#95;Full (full interaction model with additive or genotypic mode) and SNPassoc in detecting interactions. Applying SIPI to the prostate cancer PRACTICAL consortium data with approximately 21 000 patients, the four SNP pairs in EGFR-EGFR , EGFR-MMP16 and EGFR-CSF1 were found to be associated with prostate cancer aggressiveness with the exact or similar pattern in the discovery and validation sets. A similar match for external validation of SNP-SNP interaction studies is suggested. We demonstrated that SIPI not only searches for more meaningful interaction patterns but can also overcome the unstable nature of interaction patterns., Availability and Implementation: The SIPI software is freely available at http://publichealth.lsuhsc.edu/LinSoftware/ ., Contact: hlin1@lsuhsc.edu., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Introduction: The published data on salvage robot assisted radical prostatectomy (sRARP) is limited. Our aim was to perform a systematic review of the literature on sRARP after radiation failure in patients with prostate cancer and systematically analyse the available evidence for operative and oncological outcomes., Evidence Acquisition: A systematic review of the literature using Pubmed, Scopus, Cochrane library and ScienceDirect databases was performed in June 2016 using medical subject headings and free-text protocol. The search was conducted by applying the following search terms: salvage therapy, salvage, prostatectomy and robotics., Evidence Synthesis: We report on ten case series including 197 men undergoing sRARP after varying modalities of radiotherapy. Over two thirds are recurrence free at the time of follow-up but with continence rates of only 60% and potency rates of only 26%. Complications requiring intervention are few at 16% though higher than primary RARP., Conclusions: sRARP is increasingly acceptable as a treatment modality to be offered to men who fail initial radiation treatment but should be accompanied by appropriate counselling regarding the potential functional outcomes and complications. Series with longer follow up will be helpful to assess the durability of oncological outcomes while improvements in patient selection and adaption of meticulous surgical technique around the apex could improve continence rates. The concept of concomitant extended PLND remains an issue for debate and the experience with this approach at the time of sRARP and its benefit need further scrutiny.

Introduction: The treatment paradigm for stage I testicular cancer has changed in the setting of accurate staging, reliable followup and a greater understanding of treatment related side effects. We assessed the influences on management decisions in patients with stage I testicular cancer., Methods: We retrospectively identified 121 patients with stage I testicular cancer who were evaluated at our institution from 1999 to 2013. Sociodemographic characteristics, pathological features and provider specific factors were compared in patients who underwent surveillance vs treatment. Differences in medians and proportions were determined using the Kruskal-Wallis and chi-square tests. Multivariate logistic regression analysis was performed to identify independent predictors of treatment., Results: A total of 87 patients had stage I nonseminomatous germ cell tumor and 34 had pure seminoma. Patients with nonseminomatous germ cell tumor who were evaluated before 2011 and those seen by urological oncologists were more likely to undergo primary retroperitoneal lymph node dissection (p <0.01). Patients with nonseminomatous germ cell tumor who were evaluated by medical oncologists more often received chemotherapy (p <0.01). For nonseminomatous germ cell tumors treatment was independently associated with advanced tumor stage and lymph node invasion (OR 15.3, 95% CI 3.26-71.95, p = 0.001). In patients with pure seminoma the use of radiation therapy decreased from 40% to 5% after 2010 while surveillance increased from 47% to 74% (p = 0.056) and no recorded variable was predictive of treatment., Conclusions: Advanced stage and lymph node invasion in patients with stage I nonseminomatous germ cell tumor are drivers of treatment. Management also depends on the specialty of the treating provider, suggesting the possibility of bias during patient counseling. In turn, this suggests the need for patient assessment through a multidisciplinary approach.

Purpose: Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes., Experimental Design: Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed., Results: Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets., Conclusions: Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. ©2016 AACR., Competing Interests: There are no conflicts of interest to disclose by the authors., (©2016 American Association for Cancer Research.)

Purpose: Neoadjuvant chemotherapy (NAC) can downstage invasive bladder cancers prior to radical cystectomy (RC) and improve overall survival. However, the optimal management in patients with persistent non-organ confined disease (pT3-T4 and/or pN+) following RC has not been completely defined. The aim of this study was to describe outcomes associated with the use of adjuvant chemotherapy (AC) in patients with residual non-organ confined cancer at RC following NAC., Materials and Methods: Using data from a high-volume referral institution, pT3-T4 and/or pN+ patients who received NAC and then also RC were identified. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with Kaplan-Meier analysis., Results: From 2001 to 2013, 161 patients received NAC and then RC. Eighty-eight pT3-T4 and/or pN+ patients were identified. Twenty-nine (33 %) received AC. Adjuvant chemotherapy in the majority of patients was carboplatin-based (16), followed by cisplatin (8) and other, mainly taxane-containing regimens (5). The median RFS was 17.5 months in the AC and 13.7 months in the non-AC group (p = 0.78). AC remained an insignificant predictor for RFS after adjusting for pT, pN and margin status (HR 0.89, 95 % CI 0.48-1.68]). CSS was 23 and 22 months (p = 0.65) and remained insignificant after adjusting for pathologic confounders., Conclusions: In our current study population, adjuvant conventional cytotoxic chemotherapy was not associated with significant improvements in RFS or CSS. The choice of AC regimens, and incorporation of newer treatments, may be the key for improving outcomes in this high-risk patient group.

Background: Recommendations for cancer screening are uncertain for the early detection or prevention of prostate cancer in African American men. Thus, chemoprevention strategies are needed to specifically target African American men., Methods: The evidence was examined on the biological etiology of disparities in African Americans related to prostate cancer. Possible chemopreventive agents and biomarkers critical to prostate cancer in African American men were also studied., Results: High-grade prostatic intraepithelial neoplasia may be more prevalent in African American men, even after controlling for age, prostate-specific antigen (PSA) level, abnormal results on digital rectal examination, and prostate volume. Prostate cancer in African American men can lead to the overexpression of signaling receptors that may mediate increased proliferation, angiogenesis, and decreased apoptosis. Use of chemopreventive agents may be useful for select populations of men., Conclusions: Green tea catechins are able to target multiple pathways to address the underlying biology of prostate carcinogenesis in African American men, so they may be ideal as a chemoprevention agent in these men diagnosed with high-grade prostatic intraepithelial neoplasia.

Background: Treatment variation in prostate cancer is common, and it is driven by clinical and clinician factors, patient preferences, availability of resources, and access to physicians and treating facilities. Most research on treatment disparities in men with prostate cancer has focused on race and socioeconomic factors. However, the geography of disparities - capturing racial and socioeconomic differences based on where patients live - can provide insight into barriers to care and help identify outlier areas in which access to care, health resources, or both are more pronounced., Methods: Research regarding treatment patterns and disparities in prostate cancer using the Geographical Information System (GIS) was searched. Studies were limited to English-language articles and research focused on US populations. A total of 43 articles were found; of those, 30 provided information about or used spatial or geographical analyses to assess and describe differences or disparities in prostate cancer and its treatment. Two additional GIS resources were included., Results: The research on geographical and spatial determinants of prostate cancer disparities was reviewed. We also examined geographical analyses at the state level, focusing on Florida. Overall, we described a geographical framework to disparities that affect men with prostate cancer and reviewed existing published evidence supporting the interplay of geographical factors and disparities in prostate cancer., Conclusions: Disparities in prostate cancer are common and persistent, and notable differences in treatment are observable across racial and socioeconomic strata. Geographical analysis provides additional information about where disparate groups live and also helps to map access to care. This information can be used by public health officials, health-systems administrators, clinicians, and policymakers to better understand and respond to geographical barriers that contribute to disparities in care.

The ability to rapidly assess the efficacy of therapeutic strategies for incurable bone metastatic prostate cancer is an urgent need. Pre-clinical in vivo models are limited in their ability to define the temporal effects of therapies on simultaneous multicellular interactions in the cancer-bone microenvironment. Integrating biological and computational modeling approaches can overcome this limitation. Here, we generated a biologically driven discrete hybrid cellular automaton (HCA) model of bone metastatic prostate cancer to identify the optimal therapeutic window for putative targeted therapies. As proof of principle, we focused on TGFβ because of its known pleiotropic cellular effects. HCA simulations predict an optimal effect for TGFβ inhibition in a pre-metastatic setting with quantitative outputs indicating a significant impact on prostate cancer cell viability, osteoclast formation and osteoblast differentiation. In silico predictions were validated in vivo with models of bone metastatic prostate cancer (PAIII and C4-2B). Analysis of human bone metastatic prostate cancer specimens reveals heterogeneous cancer cell use of TGFβ. Patient specific information was seeded into the HCA model to predict the effect of TGFβ inhibitor treatment on disease evolution. Collectively, we demonstrate how an integrated computational/biological approach can rapidly optimize the efficacy of potential targeted therapies on bone metastatic prostate cancer.

Objective: To evaluate the incidence and degree of change from a pathologic second opinion of bladder biopsies at a Comprehensive Cancer Center that were initially performed at referring community hospitals. The secondary objective was to determine the impact the potential changes would have on a patient's treatment., Materials and Methods: Dedicated genitourinary pathologists reviewed 1191 transurethral biopsies of the bladder and/or prostatic urethra from 2008 to 2013. Major and minor treatment changes were defined as altering recommendations for cystectomy, systemic chemotherapy, or primary cancer diagnosis, and alterations in intravesical regimens, respectively., Results: There were 326/1191 patients (27.4%) with a pathologic change on second opinion: grade (62/1191, 5.2%), stage (115/1191, 9.7%), muscle in the specimen (29/1191, 2.4%), presence or absence of carcinoma in situ (34/1191, 2.9%). Outside pathology did not address the presence or absence of lymphovascular invasion in 620/759 (81.7%) of invasive cases (≥cT1), of which 35/620 (5.6%) had lymphovascular invasion. There were 212 mixed, variant, or nonurothelial histologies detected in 199/1191 (16.7%) patients, with 114/212 (53.7%) resulting in reclassification by our pathologists. Potential treatment alterations accounted for 182/1191 (15.3%) of cases, with 141/1191 (11.8%) imparting major changes. There were 82/1191 (6.8%) changes in recommendation for a radical cystectomy, 38/1191 (3.2%) had a complete change in primary tumor type, and 21/1191 (1.8%) for change in chemotherapy regimen., Conclusion: The amount and degree of pathologic changes and its potential impact on treatment emphasize the importance of bladder cancer patients having their histology reviewed by genitourinary-dedicated pathologists. In our cohort, 15.3% of patients could see a treatment alteration, with 11.8% being a major change., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Up to 50% of patients will have disease reclassification while on active surveillance (AS) for their prostate cancer. Determining which patients will have reclassification that will impact their survival is difficult. We investigated clinicopathologic factors associated with disease reclassification and differences in both overall and metastasis free survival between those treated and those remaining on AS., Materials and Methods: We performed a retrospective review of patients who were enrolled in an AS protocol between 1994 and 2000. Inclusion criteria for AS were: < cT2a disease, PSA < 10 ng/mL, < 50% of single core involvement, and Gleason score < 7, as well as sufficient follow up for evaluation (at least 1 subsequent transrectal ultrasound guided biopsy after initial diagnosis)., Results: There were 102 patients that met the inclusion criteria with median age of 70 years (IQR 68-73), follow up of 9.25 years (IQR 6.1-12.2) and time to disease reclassification of 4.7 years (IQR 2.8-7.9). Only prostate-specific antigen (PSA) density ≥ 0.15 was a significant predictor of disease reclassification with a hazard ratio of 5.5 (95% confidence interval 2.3-13.4, p < 0.01). There was no significant difference in metastasis free and overall survival between patients who received treatment and those that continued on AS despite reclassification of disease; this remained true even while stratifying patients by age ≥ 70 compared to those < 70 years old., Conclusions: PSA density is a significant predictor of disease reclassification and AS remains a safe option for patients with low risk prostate cancer with up to 10 years of follow up.

Background: In the absence of iliac or obturator nodal involvement, the role of pelvic lymphadenectomy (PLND) for melanoma is controversial, but for select patients, long-term survival can be achieved with the combination of superficial inguinal (inguinofemoral) and PLND. Open PLND (oPLND) is often limited in visual exposure and can be associated with considerable postoperative pain. Robotic PLND (rPLND) is a minimally invasive technique that provides excellent visualization of the iliac and obturator nodes. Outcomes comparing the open and robotic techniques have not been reported previously for patients with melanoma., Study Design: We reviewed our experience with rPLND for melanoma and compared clinical and pathologic results with oPLND. We evaluated operative times, nodal yield, and short-term oncologic outcomes., Results: Thirteen rPLND (2013 to 2015) (15 attempted, 87% success rate) and 25 oPLND (2010 to 2015) consecutive cases were completed. Pelvic lymphadenectomy was combined with an open inguinofemoral dissection in 8 of 13 (62%) robotic and 17 of 25 (68%) open cases. Median length of stay was shorter in the rPLND group, with 1.0 vs 3.5 days for pelvic-only cases (p < 0.001) and 2.5 vs 4.0 days (p < 0.001) for combined ilioinguinal cases. Median operative time (227 vs 230 minutes; p = 0.96) and nodal yield (11 vs 10 nodes; p = 0.53) were not different between rPLND and oPLND., Conclusions: Robotic PLND offers a safe, effective, minimally invasive approach to resect the pelvic lymph nodes in patients with melanoma, with no significant difference in nodal yield or operative times, but a shorter length of stay compared with oPLND., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

In pursuit of improving the quality of residents' education, the Southeastern Section of the American Urological Association (SES AUA) hosts an annual robotic training course for its residents. The workshop involves performing a robotic live porcine nephrectomy as well as virtual reality robotic training modules. The aim of this study was to evaluate workload levels of urology residents when performing a live porcine nephrectomy and the virtual reality robotic surgery training modules employed during this workshop. Twenty-one residents from 14 SES AUA programs participated in 2015. On the first-day residents were taught with didactic lectures by faculty. On the second day, trainees were divided into two groups. Half were asked to perform training modules of the Mimic da Vinci-Trainer (MdVT, Mimic Technologies, Inc., Seattle, WA, USA) for 4 h, while the other half performed nephrectomy procedures on a live porcine model using the da Vinci Si robot (Intuitive Surgical Inc., Sunnyvale, CA, USA). After the first 4 h the groups changed places for another 4-h session. All trainees were asked to complete the NASA-TLX 1-page questionnaire following both the MdVT simulation and live animal model sessions. A significant interface and TLX interaction was observed. The interface by TLX interaction was further analyzed to determine whether the scores of each of the six TLX scales varied across the two interfaces. The means of the TLX scores observed at the two interfaces were similar. The only significant difference was observed for frustration, which was significantly higher at the simulation than the animal model, t (20) = 4.12, p = 0.001. This could be due to trainees' familiarity with live anatomical structures over skill set simulations which remain a real challenge to novice surgeons. Another reason might be that the simulator provides performance metrics for specific performance traits as well as composite scores for entire exercises. Novice trainees experienced substantial mental workload while performing tasks on both the simulator and the live animal model during the robotics course. The NASA-TLX profiles demonstrated that the live animal model and the MdVT were similar in difficulty, as indicated by their comparable workload profiles.

Unlabelled: We assessed 126 patients with cT1-4, N0-2 urothelial carcinoma of the bladder who were treated with neoadjuvant chemotherapy followed by radical cystectomy. Twenty patients (16%) had squamous or glandular histological variation (HV). Significant pathologic downstaging (pT<2, N0) was seen in the HV patients (60% vs. 32%; P [ .02) and this difference remained significant after controlling for other clinical and pathological confounders., Background: To assess the pathological response rates and survival outcomes in patients with squamous or glandular histological variation (HV) treated with neoadjuvant chemotherapy (nCT) and radical cystectomy (RC), and compare these with patients with pure urothelial carcinoma of the bladder (PUCB)., Patients and Methods: We performed a retrospective review of patients with clinical stage T1-4, N0-2 urothelial cancer treated with cisplatin-based nCT and RC in a single institution setting. Patients who received neoadjuvant carboplatin-based regimens were excluded. The primary end point was pathological response. Overall survival (OS) was a secondary end point. Logistic regression and Cox proportional hazard models were used for multivariate analyses., Results: We evaluated 126 patients, including 20 (16%) with HV. Median estimated glomerular filtration rate (79.6 vs. 73.6 mL/min; P = .07) and the rate of complete endoscopic resection (75% vs. 40%; P = .01) were higher in the HV patients. Complete pathological response was similar between the groups (21% PUCB vs. 25% HV; P = .77). However, a significantly higher rate of pathologic downstaging (pT<2, N0 [pDS]) was seen in the HV patients (60% vs. 32%; P = .02). In a logistic regression model to predict pDS, in which clinically relevant confounding variables were included, HV (odds ratio, 4.01; 95% confidence interval, 1.16-13.9) remained an independent predictor of pDS. OS was similar between the 2 groups (HV: 45.7 vs. PUCB: 48.3 months; P = .73)., Conclusion: When controlling for confounding factors, improved pDS rates were seen in the HV patients although there were no significant differences in the OS stratified according to histology. These results support the continued use of systemic nCT for this subgroup of patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: To evaluate whether varying degrees of seminomatous elements in the primary orchiectomy specimen would be predictive of patient morbidity during post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) since the desmoplastic reaction with seminoma is associated with increased intraoperative complexity., Materials and Methods: We retrospectively identified 127 patients who underwent PC-RPLND for residual retroperitoneal masses. Clinicodemographic, intraoperative, and 30 day postoperative outcomes were compared for patients with pure seminoma (SEM), mixed germ cell tumors (GCT) containing seminoma elements (NS+SEM), and tumors with no seminoma elements (NS). Multivariate logistic regression was used to determine independent predictors of intraoperative and postoperative 30 day complications., Results: We excluded 19 patients who received chemotherapy prior to orchiectomy, 2 patients with primary extragonadal GCT, and 3 patients who underwent re-do RPLND, leaving 103 patients for analysis. Fourteen patients (13.6%) had SEM, 18 (17.5%) had NS+SEM, and 71 (68.9%) had only NS elements. SEM patients were older (p = 0.03), had more intraoperative blood loss (p = 0.03), and were more likely to have residual seminomatous components in their post-chemotherapy lymph node (LN) histology (p = 0.01). Percent seminoma in the orchiectomy specimen was an independent predictor of estimated blood loss > 1.5 liters (odds ratio: 1.04, 95% confidence interval: 1.01-1.07; p = 0.013) after adjusting for age, stage, IGCCC risk category, preop chemotherapy, number and largest LN removed, need for vascular or adjacent organ resection (including nephrectomy), and LN histology., Conclusions: Higher percentage of seminoma in the orchiectomy specimen is associated with increased estimated blood loss during PC-RPLND. Percent seminoma, therefore, may be a useful prognostic tool for appropriate pre-surgical planning prior to PC-RPLND.

Unlabelled: In an analysis of a large single-institution experience in the surgical management of renal cell carcinoma (RCC) and inferior vena cava (IVC) thrombus, the authors present the effect of RCC characteristics on survival, and aim to identify potential preoperative variables predictive of intraoperative complexity with regard to estimated blood loss, transfusion volume, surgical time, length of stay, and postoperative complication rates. Age, American Society of Anesthesiologists score, Charlson Comorbidity Index, preoperative calcium, preoperative creatinine, and IVC wall invasion were significantly related to complication rates., Introduction: Preoperative laboratory values are commonly used as markers of health and potential disease burden, however, their effect on perioperative complexity has not previously been assessed. The authors aimed to evaluate the effect of renal cell carcinoma and inferior vena cava (IVC) thrombus characteristics on cancer-specific survival (CSS), and identify potential preoperative variables predictive of intraoperative complexity., Materials and Methods: In a retrospective chart review we identified 144 patients who underwent nephrectomy and IVC thrombectomy. Univariate and multivariate analyses were used to assess the effect of disease characteristics on CSS and postoperative complications. Linear regression analysis was used to determine the association between preoperative laboratory values and intraoperative complexity characterized by estimated blood loss (EBL), transfusion volume (TV), operative time, and length of hospital stay (LOS)., Results: Analysis of intraoperative complexity revealed a significant correlation between preoperative creatinine (Cr) and EBL (P = .022), TV (P = .041), and LOS (P = .005), and preoperative hemoglobin (Hgb) was associated with increased EBL (P < .001) and TV (P < .001). Multivariate analyses showed a significant relationship between overall complication rates and preoperative calcium (Ca; P = .012), American Society of Anesthesiologists (ASA) score (P = .003), and IVC wall invasion (P = .005), and a significant association between major complications and preoperative Ca (P = .011), preoperative Cr (P = .041), age (P = .050), and Charlson Comorbidity Index (CCI; P = .002)., Conclusion: With regard to intraoperative complexity and postoperative complications, preoperative Cr and Hgb were significantly associated with increased EBL, TV, and LOS, and ASA score, preoperative Ca, preoperative Cr, IVC wall invasion, age, and CCI were found to have significant relationships with complication rates., (Copyright © 2016 Elsevier Inc. All rights reserved.)