Current Treatment Modalities Targeting Tumor Microenvironment in Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) is responsible for significant cancer-related morbidity and mortality following local treatment failure in men. The initial stages of PCa are typically managed with a combination of surgical resection and/or androgen deprivation therapy (ADT). Unfortunately, a significant proportion of PCa continues to progress despite being at castrate levels of testosterone (<50 ng/dl), at which point it is coined castration-resistant prostate cancer (CRPC). In recent years, many novel therapeutics and drug combinations have been created for CRPC patients. These include immune checkpoint inhibitors, chemokine receptor antagonists, steroidogenic enzyme inhibition, and novel tyrosine kinase inhibitors as well as combinations of drugs. The selection of the most appropriate therapy depends on several factors like stage of the disease, age of the patient, metastasis, functional status, and response towards previous therapies. Here, we review the current state of the literature regarding treatment modalities, focusing on the treatment recommendations per the American Urological Association (AUA), recent clinical trials, and their limitations. An accurate and reliable overview of the strengths and limitations of PCa therapeutics could also allow personalized therapeutic interventions against PCa.

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer.

Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.

Factors associated with the use of salvage whole brain radiation therapy versus salvage stereotactic radiosurgery after initial stereotactic radiosurgery for brain metastases.

Objectives: Patients undergoing stereotactic radiosurgery (SRS) for brain metastases require additional radiation for relapse. Our objective is to determine the factors associated with salvage SRS versus whole brain radiation therapy (WBRT) for salvage of first intracranial failure (ICF) after upfront SRS. Method: We identified a cohort of 110 patients with brain metastases treated with SRS in the definitive or postoperative setting followed by subsequent salvage WBRT or SRS at least one month after initial SRS. Clinical and demographic characteristics were retrospectively recorded. Results: 78 Patients received SRS and 32 patients received WBRT at the time of first ICF. On multivariate analysis (MVA) factors associated with decreased use of salvage SRS were male gender (p=0.044) and local progression (p<0.001). Conclusions: Local progression and male gender were the strongest factors associated with selection of salvage WBRT. Possible etiologies of this difference could be provider or patient driven, but warrant further exploration.

Survival and Yield of Surveillance Imaging in Long-Term Survivors of Brain Metastasis Treated with Stereotactic Radiosurgery.

OBJECTIVES: The optimal frequency of surveillance brain magnetic resonance imaging (MRI) in long-term survivors with brain metastases after stereotactic radiosurgery (SRS) is unknown. Our aim was to identify the optimal frequency of surveillance imaging in long-term survivors with brain metastases after SRS. METHODS: Eligible patients were identified from a cohort treated with SRS definitively or postoperatively at our institution from 2014 to 2019 with no central nervous system (CNS) failure within 12 months from SRS. Time to CNS disease failure diagnosis and cost per patient were estimated using theoretical MRI schedules of 2, 3, 4, and 6 months starting 1 year after SRS until CNS failure. Time to diagnosis was calculated from the date of CNS progression to the theoretical imaging date on each schedule. RESULTS: This cohort included 55 patients (median follow-up from SRS: 2.48 years). During the study period, 20.0% had CNS disease failure (median: 2.26 years from SRS treatment). In this cohort, a theoretical 2-month, 3-month, 4-month, and 6-month MRI brain surveillance schedule produced a respective estimated time to diagnosis of CNS disease failure of 1.11, 1.74, 1.65, and 3.65 months. The cost of expedited diagnosis for the cohort (dollars/month) for each theoretical imaging schedule compared with a 6-month surveillance schedule was $6600 for a 2-month protocol, $4496 for a 3-month protocol, and $2180 for a 4-month protocol. CONCLUSIONS: Based on cost-benefit, a 4-month MRI brain schedule should be considered in patients with metastatic disease to the brain treated definitively or postoperatively with SRS without evidence of CNS recurrence at 1 year.

A systematic review and evidence-based analysis of ingredients in popular male testosterone and erectile dysfunction supplements.

The objective was to study available evidence for ingredients of popular over-the-counter testosterone and erectile dysfunction (ED) supplements. The top 16 male testosterone and 16 ED supplements in the USA were identified from the most popular online retailers: A1 Supplements, Amazon, Vitamin Shoppe, and Walmart. In total, 37 ingredients were identified and PUBMED online database was reviewed for randomized-controlled trials (RCT) studying their efficacy. Ingredients were categorized based on evidence quantity using an adapted version of the American Heart Association scoring system. In total, 16 ingredients from testosterone supplements and 21 from ED supplements were identified. Tribulus, Eurycoma longifolia, Zinc, L-arginine, Aspartate, Horny goat weed, and Yohimbine were most common. In all, 105 RCTs studying the identified ingredients were found. No whole supplement products have published RCT evidence. 19% of ingredients received an A grade for strong positive evidence with net positive evidence in two or more RCTs. In total, 68% received C or D grades for contradicting, negative, or lacking evidence. Overall, 69% of ingredients in testosterone supplements and 52% of ingredients in ED supplements have published RCT evidence. Many male supplements claim to improve testosterone or ED parameters; however, there is limited evidence, which should be considered when counseling patients.

The Yin Yang Role of Nitric Oxide in Prostate Cancer.

Nitric oxide (NO) is a ubiquitous signaling molecule in the human body with well-known roles in many different processes and organ systems. In cancer, the two-concentrations hypothesis of NO has dictated that low levels of NO are cancer promoting, while high levels of NO are protective against cancer. Although prostate cancer is a hormonally driven malignancy, research has been shifting away from androgen-responsive epithelial cells and evolving to focus on NO therapies, the tumor microenvironment (TME), and inflammation. NO is reported to be able to inhibit activity of the androgen receptor. This may prevent prostate growth, but low levels of NO could conversely select for castration-resistant prostate cells, creating an aggressive cancer phenotype. At high levels, nitrosative stress created from NO overproduction can be protective against prostate neoplasia. In this review, we discuss development and possibilities of NO-based therapies for prostate cancer.

A Systematic Review and Evidence-based Analysis of Ingredients in Popular Male Fertility Supplements.

OBJECTIVE: To study the level of evidence available for ingredients of popular over-the-counter male fertility supplements. METHODS: The top 17 male fertility supplements in the United States were identified from the most popular online retailers: A1 Supplements, Amazon, Vitamin Shoppe, and Walmart. Individual ingredients were identified for each supplement. The PUBMED and Cochrane online databases were reviewed for randomized controlled trials studying the efficacy of each ingredient. Each ingredient was categorized based on availability of evidence using an adapted version of the scoring system by the American Heart Association. Scores were assigned to each categorical level of evidence for each ingredient and a composite score for each supplement was calculated. RESULTS: Ninety unique ingredients were identified. The 5 most commonly used ingredients were vitamin E, folic acid, zinc, vitamin C, and selenium whereas the 5 ingredients with most evidence were L-carnitine, Vitamin E, Vitamin C, CoQ10, and Zinc. In all, only 22% of ingredients used were found to have published evidence for improvement in semen parameters and only 17% of ingredients had data published showing a positive effect. Our evidence-based analysis demonstrated an average composite rating of 1.66 (on a scale to 5). Evolution 60 and Conception XR had the highest composite scores with 3.6 and 3.5, respectively. CONCLUSION: Many male fertility supplements claim to improve fertility; however, their products are rarely backed by evidence and their efficacy remains unproven. Few ingredients used in popular fertility supplements have positive evidence in randomized clinical trials and should therefore be used cautiously.

Comparison of Robotic Percutaneous Coronary Intervention With Traditional Percutaneous Coronary Intervention: A Propensity Score-Matched Analysis of a Large Cohort.

BACKGROUND: Robotic percutaneous coronary intervention (R-PCI) has been shown to benefit the operator but has not shown any significant benefit to the patient. We sought to compare a large cohort of R-PCI to traditional percutaneous coronary intervention (PCI) procedures performed at a tertiary care center in the same time frame. METHODS: A total of 996 consecutive patients referred for PCI between December 2017 and March 2019 were studied, of which 310 (31.1%) patients were selected to undergo R-PCI and 686 (68.9%) patients underwent traditional PCI. The coprimary study outcome measures were air kerma, dose-area product, fluoroscopy time, volume of contrast, and total procedural time. Caliper propensity-matching technique was used (caliper, 0.05) to match each R-PCI patient to the nearest traditional PCI patient without replacement. RESULTS: Air kerma (mGy; median [interquartile range]; P; 884 [537-1398] versus 1110 [699-1498]; P=0.002) and dose-area product (cGycm2; 4734 [2695-7746] versus 5746 [3751-7833]; P=0.003) were significantly lower in the R-PCI group. There was no difference in fluoroscopy time (minutes; 5.51 [3.53-8.31] versus 5.48 [3.31-9.37]; P=0.936) and contrast volume (mL; 130 [103-170] versus 140 [100-180]; P=0.905). Total procedural time (minutes) was significantly higher in the R-PCI group (27 [21-40] versus 37 [27-50]; P<0.0005). CONCLUSIONS: R-PCI is associated with a significant decrease in radiation exposure to the patient with no increase in fluoroscopy time, as well as contrast utilization, and a minor increase in procedure duration compared with traditional PCI.