Five-Year Prospective Observational Study of African-American Men on Active Surveillance for Prostate Cancer Demonstrates Race Is Not Predictive of Oncologic Outcomes.

INTRODUCTION: This study aimed to evaluate if race impacted outcomes or risk of disease progression in men on active surveillance (AS) for prostate cancer. We present the results from our majority African-American cohort of men in an equal access setting over a 5-year follow-up period. PATIENTS AND METHODS: All patients who elected AS for prostate cancer at the Southeast Louisiana Veterans Health Care System are entered into a prospectively managed observational database. Patients were divided into groups based on self-reported race. Grade group progression was defined as pathologic upgrading above International Society of Urological Pathology Grade Group 1 disease on subsequent biopsies following diagnostic biopsy. All tests were 2 sided using a significance of .05. RESULTS: A total of 228 men met inclusion criteria in the study, including 154 non-Hispanic African American and 74 non-Hispanic Caucasian American men, with a median follow-up of 5 years from the initiation of AS. Race was not predictive of Gleason grade progression, AS discontinuation, or biochemical recurrence on Cox multivariate analysis (HR = 1.01, 0.94, 0.85, P = .96, .79, .81, respectively). On Kaplan-Meier analysis at 5 years, African-American progression-free, AS discontinuation free, and overall survival probability was comparable to their Caucasian American counterparts (P > .05 for all). CONCLUSIONS: Active surveillance is a safe treatment option for low and very low risk prostate cancer, regardless of race. African-American and Caucasian-American men did not have any significant difference in Gleason grade group progression in our cohort with 5-year follow-up.

Hematologic parameters are not predictors of upgrading or treatment in a racially diverse prospective study of men with prostate cancer on active surveillance.

INTRODUCTION: Neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) are useful clinical biomarkers for prognosis in several malignancies. Their predictive value has been less clearly demonstrated with prostate cancer (PCa), particularly, their utility within active surveillance (AS) protocols. We aim to evaluate NLR and PLR in AS patients. METHODS: We identified 98 patients who met inclusion criteria in our cohort of 274 men diagnosed with PCa on AS. Patients were then categorized into high and low NLR and PLR groups. RESULTS: The 2.5 and 5-year Gleason upgrading free probability for our high NLR cohort was 73.9%(CI 56.3% to 97.0%) and 46.2%(CI 22.4% to 95.1%) compared to 76.3%(CI 65.7% to 88.7%) and 61.7%(CI 47.7% to 80.0%) in the low NLR cohort(p = .73). The 2.5 and 5-year Gleason upgrading free probability for our High PLR cohort was 73.5%(CI 57.3% to 94.2%) and 60.1(CI 41.4% to 87.4%) compared to 76.8%(CI 65.8% to 89.65) and 58.1%(CI 42.2% to 80.1%) in our low PLR group(p = .41). A multivariant analysis demonstrated these groups were not significant predictors of upgrading or treatment. CONCLUSION: Despite their usefulness in many types of malignancy, NLR and PLR were not predictors of upgrading or treatment in men on AS for localized PCa in our cohort.

Annual mpMRI surveillance: PI-RADS upgrading and increasing trend correlated with patients who harbor clinically significant disease.

INTRODUCTION: Prostate cancer screening has routinely identified men with very low- or low-risk disease, per the National Comprehensive Cancer Network guidelines. Current literature has demonstrated that the most appropriate management strategy for these patients is active surveillance (AS). The mainstay of AS includes periodic biopsies and biannual prostate-specific antigen tests. However, multiparametric magnetic resonance imaging (mpMRI) is uniquely posed to improve patient surveillance. This study aimed to evaluate the utility of an annual mpMRI in patients on AS, focusing on radiologic upgrading and Prostate Imaging-Reporting and Data System (PI-RADS) trends as indicators of clinically significant disease. METHODS: This prospective, single intuition, study enrolled 208 patients on AS who had at least two biopsies and 1 mpMRI with a median follow-up of 5.03 years. The main outcome variable was time to Gleason grade (GG) reclassification. RESULTS: After delineating patients on their initial PI-RADS score, men with score 3 and 5 lesions at first MRI had comparable GG reclassification-free survival to their counterparts. Conversely, men with initial PI-RADS 4 lesions showed a lower 5-year GG reclassification-free survival compared to those with PI-RADS score 1-2. The cohort was then subset to 70 patients who obtained ≥2 mpMRIs on protocol. Men experiencing uptrending mpMRI scores had an increased risk of GG reclassification, with a 35.4% difference in 5 year GG reclassification-free survival probability on the Kaplan-Meier curve analysis. CONCLUSION: In conclusion, this study demonstrates that for men on AS with stable recapitulated disease, an annual MRI may replace repeat biopsies after confirmatory sampling has been obtained. On the other hand, men who initiate AS with PI-RADS 4 and/or who display uptrending mpMRI scores require periodic biopsies along with repeat imaging. This study highlights the utility of integrating an annual MRI into AS protocols, thus promising a more effective approach to management.

Extended Opioid Exposure Modulates the Molecular Metabolism of Clear Cell Renal Cell Carcinoma.

Opioids are commonly prescribed for extended periods of time to patients with advanced clear cell renal cell carcinoma to assist with pain management. Because extended opioid exposure has been shown to affect the vasculature and to be immunosuppressive, we investigated how it may affect the metabolism and physiology of clear cell renal cell carcinoma. RNA sequencing of a limited number of archived patients' specimens with extended opioid exposure or non-opioid exposure was performed. Immune infiltration and changes in the microenvironment were evaluated using CIBERSORT. A significant decrease in M1 macrophages and T cells CD4 memory resting immune subsets was observed in opioid-exposed tumors, whereas the changes observed in other immune cells were not statistically significant. Further RNA sequencing data analysis showed that differential expression of KEGG signaling pathways was significant between non-opioid-exposed specimens and opioid-exposed specimens, with a shift from a gene signature consistent with aerobic glycolysis to a gene signature consistent with the TCA cycle, nicotinate metabolism, and the cAMP signaling pathway. Together, these data suggest that extended opioid exposure changes the cellular metabolism and immune homeostasis of ccRCC, which might impact the response to therapy of these patients, especially if the therapy is targeting the microenvironment or metabolism of ccRCC tumors.

Molecular mechanisms of penile traction for penile rehabilitation in a bilateral cavernous nerve crush injury rat model.

Background: Prostate cancer is the most common solid-organ malignancy in adult men. Early detection and treatment of prostate cancer with radical prostatectomy (RP) has improved cancer-specific survival but is associated with penile shortening and erectile dysfunction. Penile traction therapy (PTT) has been demonstrated to increase stretched penile length (SPL) prior to penile prosthesis placement and may improve erectile function (EF) in patients with Peyronie's disease. We aimed to evaluate the efficacy of PTT in preserving penile length and EF after bilateral cavernous nerve crush injury (BCNI) in a rat model. Methods: Twenty-four male Sprague-Dawley rats aged 11-13 weeks were randomly assigned to three groups (n=8, each): sham operation with no PTT (Sham), BCNI without PTT (Crush), and BCNI with PTT (Traction). PTT was started on postoperative day 3. A traction force of 1 Newton was applied to the penis for 30 minutes each day for 28 days. After 28 days of traction, the cavernous nerve was stimulated while recording the intracavernosal pressure (ICP) and the mean arterial pressure (MAP) simultaneously. Cavernosal tissue was excised, and western blot analysis for endothelial nitric oxide synthase (eNOS) was performed. Significance was determined by using ANOVA with Tukey-Kruger post-hoc testing. Results: At 4 weeks after nerve injury, the Traction group had significantly greater SPL compared to the Sham and Crush groups (30 vs. 28 and 27 mm, respectively). The Sham group had significantly greater EF (ΔICP/MAP) compared to the Crush group at 2.5, 5, and 7.5 V. The EF of the Traction group was between that of the Sham and Crush groups and was not significantly different from the Sham group at any voltages. Further downstream analysis revealed that the Traction group had significantly greater eNOS expression in cavernosal tissue compared to the Crush group, which was confirmed on western blot analysis and immunohistochemistry (IHC) staining. Conclusions: Findings from this animal study suggest that PTT has the potential to mitigate penile retraction after RP. While more studies are needed to determine the effect of PTT on preservation of EF, the increased eNOS expression observed in the Traction group offers a potential protective mechanism of action.

A narrative review of biparametric MRI (bpMRI) implementation on screening, detection, and the overall accuracy for prostate cancer.

Prostate cancer is the most common malignancy in American men following skin cancer, with approximately one in eight men being diagnosed during their lifetime. Over the past several decades, the treatment of prostate cancer has evolved rapidly, so too has screening. Since the mid-2010s, magnetic resonance imaging (MRI)-guided biopsies or 'targeted biopsies' has been a rapidly growing topic of clinical research within the field of urologic oncology. The aim of this publication is to provide a review of biparametric MRI (bpMRI) utilization for the diagnosis of prostate cancer and a comparison to multiparametric MRI (mpMRI). Through single-centered studies and meta-analysis across all identified pertinent published literature, bpMRI is an effective tool for the screening and diagnosis of prostate cancer. When compared with the diagnostic accuracy of mpMRI, bpMRI identifies prostate cancer at comparable rates. In addition, when omitting dynamic contrast-enhanced (DCE) protocol to the MRI, patients incur reduced costs and shorter imaging time while providers can offer more tests to their patient population.

Combination of Tipifarnib and Sunitinib Overcomes Renal Cell Carcinoma Resistance to Tyrosine Kinase Inhibitors via Tumor-Derived Exosome and T Cell Modulation.

BACKGROUND: Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance. METHODS: 786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Exosomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis. RESULTS: SR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated with increased expression of PD-L1 on SR exosomes when compared to sunitinib-sensitive (SS) exosomes. Additionally, Tipi treatment downregulated PD-L1 expression on exosomes derived from SR cell lines. Tipi's ability to downregulate PD-L1 in exosomes has a significant application within patients. Exosomes collected from patients with RCC showed increased PD-L1 expression over subjects without RCC. Next, exosome concentrations were then compared after Tipi treatment, with all SS cell lines displaying an even greater reduction. On immunoblot assay, 293T cells showed a dose-dependent increase in Alix with no change in either nSMase or Rab27a. Conversely, all the SS and SR cell lines displayed a decrease in all three markers. After a cell proliferation employed a 48-h treatment on all SS and SR cell lines, the drug combination displayed synergistic ability to decrease tumor growth. CONCLUSIONS: Tipifarnib attenuates both the exosome endosomal sorting complex required for endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways, thereby blocking exosome biogenesis and secretion as well as downregulating PD-L1 on SS and SR cells.

Considering Predictive Factors in the Diagnosis of Clinically Significant Prostate Cancer in Patients with PI-RADS 3 Lesions.

The use of multi-parametric magnetic resonance imaging (mpMRI) in conjunction with the Prostate Imaging Reporting and Data System (PI-RADS) is standard practice in the diagnosis, surveillance, and staging of prostate cancer. The risk associated with lesions graded at a PI-RADS score of 3 is ambiguous. Further characterization of the risk associated with PI-RADS 3 lesions would be useful in guiding further work-up and intervention. This study aims to better characterize the utility of PI-RADS 3 and associated risk factors in detecting clinically significant prostate cancer. From a prospectively maintained IRB-approved dataset of all veterans undergoing mpMRI fusion biopsy at the Southeastern Louisiana Veterans Healthcare System, we identified a cohort of 230 PI-RADS 3 lesions from a dataset of 283 consecutive UroNav-guided biopsies in 263 patients from October 2017 to July 2020. Clinically significant prostate cancer (Gleason Grade ≥ 2) was detected in 18 of the biopsied PI-RADS 3 lesions, representing 7.8% of the overall sample. Based on binomial analysis, PSA densities of 0.15 or greater were predictive of clinically significant disease, as was PSA. The location of the lesion within the prostate was not shown to be a statistically significant predictor of prostate cancer overall (p = 0.87), or of clinically significant disease (p = 0.16). The majority of PI-RADS 3 lesions do not represent clinically significant disease; therefore, it is possible to reduce morbidity through biopsy. PSA density is a potential adjunctive factor in deciding which patients with PI-RADS 3 lesions require biopsy. Furthermore, while the risk of prostate cancer for African-American men has been debated in the literature, our findings indicate that race is not predictive of identifying prostate cancer, with comparable Gleason grade distributions on histology between races.

Prostate Cancer Lesions by Zone and Race: Does Multiparametric MRI Demonstrate Racial Difference in Prostate Cancer Lesions for African American Men?

African American (AA) men have increased risk of prostate cancer diagnosis and mortality, but the cause remains unknown. MRI fusion improves diagnosis of localized prostate cancer, particularly in anterior lesions; however, cost and access are limited in a community practice setting. By utilizing a diverse cohort of veterans with equal access to care in a single payer system, we describe prostate cancer detection. We queried a prospectively maintained institutional review board-approved database of men undergoing prostate biopsy for untreated prostate cancer. We included all consecutive patients from October 2017 to February 2020. Statistical analysis including Kaplan-Meier Curves, Fisher's exact test, and Forest plot was performed. From 246 consecutive patients, 166 were AA and 80 were non-AA. There were similar distributions of PSA, PSAD, and number of targetable lesions between the AA and non-AA cohort (p > 0.05 for all). We found no difference in location on MRI between race groups. There was similar cancer detection, focusing on anterior lesions and rate of positive Gleason grade (≥GG1) and clinically significant (≥GG2) cancer between cohorts. In a predominant AA cohort of veterans, we found similar distribution of location for MRI-targeted lesions, along with rates of tumor detection and aggressiveness of disease. In this single payer veteran population, we did not identify specific biologic differences inherent to tumor detection between AA and non-AA patients.

Integrins mediate placental extracellular vesicle trafficking to lung and liver in vivo.

Membrane-bound extracellular vesicles (EVs) mediate intercellular communication in all organisms, and those produced by placental mammals have become increasingly recognized as significant mediators of fetal-maternal communication. Here, we aimed to identify maternal cells targeted by placental EVs and elucidate the mechanisms by which they traffic to these cells. Exogenously administered pregnancy-associated EVs traffic specifically to the lung; further, placental EVs associate with lung interstitial macrophages and liver Kupffer cells in an integrin-dependent manner. Localization of EV to maternal lungs was confirmed in unmanipulated pregnancy using a transgenic reporter mouse model, which also provided in situ and in vitro evidence that fetally-derived EVs, rarely, may cause genetic alteration of maternal cells. These results provide for the first time direct in vivo evidence that placental EVs target maternal immune cells, and further, that EVs can alter cellular phenotype.

Prospective Observational Study of a Racially Diverse Group of Men on Active Surveillance for Prostate Cancer.

OBJECTIVE: To evaluate the risk upgrading of active surveillance (AS), we reviewed the outcomes of African American men (AA) after electing AS. AS is the standard of care for men with low-grade prostate cancer (PCa). AA are known to have more advanced PCa features and are more likely to die from PCa, thus subsequent disease progression for AA on AS is unclear. METHODS: A prospectively maintained AS database from the Southeast Louisiana Veterans Administration Medical Center, New Orleans, Lousiana was queried. We identified men with low- and very low-risk PCa (Gleason 3 + 3, PSA <10, ≤CT2a) who had undergone at least 2 prostate biopsies, including initial diagnostic and subsequent confirmatory prostate biopsies. Descriptive and comparative statistical analysis was performed using R version 3.5.1. RESULTS: From a total of 274 men on AS (70% AA), 158 men met inclusion criteria (104 AA [66%]). All patients underwent at least 2 biopsies, and 29% underwent 3 or more biopsies. The median follow-up was 2.7 years. At 3 years on AS protocol, 57% AA and 61% Caucasians demonstrated no evidence of upgrading or treatment. No significant difference was observed between upgrading or progression to treatment when comparing racial groups. Seven (4%) patients in this cohort died from non PCa-specific causes, but no patients demonstrated metastasis or death from PCa over the course of study. CONCLUSION: AA men with low-risk PCa can be safely followed with the same AS protocol as non-AA men. Further analysis with longer follow up is ongoing.

A Systematic Review of Penile Prosthesis Surgery in Organ Transplant Recipients.

INTRODUCTION: There is an increased prevalence of erectile dysfunction in patients with solid organ transplant (SOT) compared with the general population. Many of these patients may become refractory to medical treatment of erectile dysfunction and penile prosthesis (PP) is often recommended. Concerns regarding the safety of PP in patients with SOT are due to their immunosuppressed state. OBJECTIVE: We aim to review all current literature on the outcomes of patients with SOT who have received PP. METHODS: A PubMed search was performed to identify articles pertaining to the outcomes of PP in patients with SOT. RESULTS: We identified and included 14 studies that report on outcomes of PP placement in 143 patients with SOT and 191 non-SOT controls from interval period from 1979 to 2019. Studies included retrospective cohort studies, case series, and case reports. Compared with non-SOT controls who had PP, aggregate analysis demonstrated that patients with SOT who had PP did not develop significantly increased overall complications. However, they were significantly more likely to experience future surgical complications. CONCLUSION: Our aggregate analysis demonstrated that patients with SOT are not at a significantly increased risk of overall complications when receiving a PP. Nevertheless, there is an increased risk of experiencing PP injury during subsequent surgeries, which may be mitigated by the earlier involvement of a urologist. Given the lack of recent data, large studies are prerequisite to further evaluate the safety and overall outcome of PP surgery in patients with SOT. Dick B, Greenberg JW, Polchert M, et al. A Systematic Review of Penile Prosthesis Surgery in Organ Transplant Recipients. Sex Med Rev 2021;9:636-640.

Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma.

Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ's inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.

Robotic vs. open surgical management of ureteroenteric anastomotic strictures: technical modifications to enhance success.

Development of ureteroanastamotic strictures (UAS) after urinary diversion is not uncommon, but is challenging to treat. Poor outcomes are likely with endoscopic and radiologic management, and definitive surgical treatment can cause significant morbidity. The comparative advantages of an operative approach have not yet been fully described in the literature. We retrospectively reviewed the prospectively maintained Tulane University Department of Urology quality assurance database of 12 patients who underwent operative UAS repair between 2012 and 2018. Data were reviewed for operative approach, demographics, baseline disease characteristics, operative variables, and perioperative and pathological outcomes. Of the 12 patients analyzed, 5 underwent open repair (OR) (2 bilateral, 2 right, 1 left) and 7 underwent robotic repair (RR) (3 right, 4 left). One robotic case required conversion to open due to significant intestinal and peri-ureteral adhesions. The median ages were 59 years in OR and 60 years in RR. Two patients in each group had failed previous endoscopic repair. Median time from cystectomy to treatment of enteroanastamotic stricture was 13 months for OR and 10 months for RR (p = 0.25). Median estimated blood loss was 80 mL in both OR and RR (p = 1.0), median operative time was 260 min in OR and 255 min in RR (p = 0.13), and median hospital stay was 8 and 4 days, respectively (p = 0.06). There were two intra-operative and one post-operative complication in the OR group, one of whom required further surgical intervention, and no complications in the robotic cohort. A minimally invasive, robotic approach offers a non-inferior alternative to OR with similar outcomes for appropriately selected patients with UAS. High success rates combined with minimal morbidity may provide definitive therapy at an earlier stage of the stricture state.

Synchronous Urothelial Bladder and Renal Malignancies. Case Report and Review of Urologic Cancers in Patients With Familial Rb Mutations.

We present a urologic case report associated with retinoblastoma (RB1) mutation. A 65-year-old man, who has a history of bilateral retinoblastoma treated with primary radiation therapy at approximately 1 year of age. He presented with a 3-month history of gross hematuria and, on initial workup, was found to have synchronous renal and urothelial malignancies. The patient underwent complete transurethral resection of high grade Ta urothelial cancer and robotic-assisted partial nephrectomy for a pT3a leiomyosarcoma. He remains responsive to Bacillus Calmette-Guerin, and shows no recurrence of his renal malignancy. Through targeted sequencing, Rb mutations can predispose patients to several urologic malignancies.

Quantifying murine placental extracellular vesicles across gestation and in preterm birth data with tidyNano: A computational framework for analyzing and visualizing nanoparticle data in R.

Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication that carry protein, lipids, and nucleic acids via the circulation to target cells whereupon they mediate physiological changes. In pregnancy, EVs are released in high quantities from the placenta and have been postulated to target multiple cell types, including those of the vascular and immune systems. However, most studies of pregnancy-associated EVs have used clinical samples and in vitro models; to date, few studies have taken advantage of murine models in which pregnancy can be precisely timed and manipulated. In this study, we used a murine model to determine whether the quantity of EVs is altered during healthy pregnancy and during inflammation-associated preterm birth. To facilitate data analysis, we developed a novel software package, tidyNano, an R package that provides functions to import, clean, and quickly summarize raw data generated by the nanoparticle tracking device, NanoSight (Malvern Panalytical). We also developed shinySIGHT, a Shiny web application that allows for interactive exploration and visualization of EV data. In mice, EV concentration in blood increased linearly across pregnancy, with significant rises at GD14.5 and 17.5 relative to EV concentrations in nonpregnant females. Additionally, lipopolysaccharide treatment resulted in a significant reduction in circulating EV concentrations relative to vehicle-treated controls at GD16.5 within 4 hours. Use of tidyNano facilitated rapid analysis of EV data; importantly, this package provides a straightforward framework by which diverse types of large datasets can be simply and efficiently analyzed, is freely available under the MIT license, and is hosted on GitHub (https://nguyens7.github.io/tidyNano/). Our data highlight the utility of the mouse as a model of EV biology in pregnancy, and suggest that placental dysfunction is associated with reduced circulating EVs.