Ligand-gated ion channels as potential biomarkers for ADT-mediated cognitive decline in prostate cancer patients.

Men with prostate cancer are at increased risk of developing cognitive decline by the use of second-generation androgen signaling inhibitors. To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high-throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements-cytoscape, and bioinformatic analyses employing Advaita® iPathwayGuide and DisGeNET for identification of disease-related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real-time polymerase chain reaction assay. Our systematic analysis of androgen deprivation-associated genes involved multiple biological processes, including neuroactive ligand-receptor interaction, axon guidance, cytokine-cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma-aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein-protein interaction network analysis highlighted the role of ligand-gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene-disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type-1 angiotensin II receptor, brain-derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5-hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT-mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.

Melatonin and Prostate Cancer: Anti-tumor Roles and Therapeutic Application.

Melatonin is an endogenous indoleamine that has been shown to inhibit tumor growth in laboratory models of prostate cancer. Prostate cancer risk has additionally been associated with exogenous factors that interfere with normal pineal secretory activity, including aging, poor sleep, and artificial light at night. Therefore, we aim to expand on the important epidemiological evidence, and to review how melatonin can impede prostate cancer. More specifically, we describe the currently known mechanisms of melatonin-mediated oncostasis in prostate cancer, including those that relate to the indolamine's ability to modulate metabolic activity, cell cycle progression and proliferation, androgen signaling, angiogenesis, metastasis, immunity and oxidative cell status, apoptosis, genomic stability, neuroendocrine differentiation, and the circadian rhythm. The outlined evidence underscores the need for clinical trials to determine the efficacy of supplemental, adjunct, and adjuvant melatonin therapy for the prevention and treatment of prostate cancer.

Treatment patterns and survival of low and intermediate-risk prostate cancer in end-stage kidney disease: A retrospective population cohort study.

BACKGROUND: In accordance with guidelines, observation with or without active surveillance for low-risk prostate cancer increased in recent years in the general population. We compared treatment patterns and mortality for low- and intermediate-risk prostate cancer and mortality rates among end-stage kidney disease (ESKD) and non-ESKD patients. METHODS: This is a retrospective population-based observational cohort study of Surveillance, Epidemiology, and End Results-Medicare data of men aged 66 years and older with localized prostate cancer (2004-2015). ESKD status was determined using Medicare billing codes. Multivariable logistic regression models and Cox-proportional hazards models were used to study definitive treatment patterns and mortality, respectively. RESULTS: For low-risk prostate cancer, dialysis patients (N = 83) had lower but not statistically significant odds (OR, 0.74; 95% CI: 0.48-1.16) of receiving definitive treatment than non-ESKD patients (N = 24,935). For those with intermediate-risk prostate cancer, dialysis patients (N = 254) had lower odds to receive definitive treatment (OR, 0.54; 95% CI: 0.42-0.72) than non-ESKD patients (N = 60,883). From 2004-2010 to 2011-2015, for patients with low-risk prostate cancer, while the receipt of definitive treatment for non-ESKD patients trended down from 72% to 48%, it trended up for dialysis patients from 55% to 65%. Kidney transplant patients (N = 33 for low-risk and N = 91 for intermediate-risk) had lower rates of definitive treatment for low-risk and similar rates of treatment for intermediate-risk prostate cancer compared to non-ESKD patients. CONCLUSIONS: The disparity in definitive treatment rates for low-risk prostate cancer among dialysis patients exists despite their high mortality, compared to the general population.

Five-Year Patient-Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 week and a day [twice a week]) or 12 fractions (4.3Gy in 2.5 weeks [5 times a week]). Secondary objectives assessed patient-reported toxicity at 5 years using the EPIC. Chi-square tests were used to assess the proportion of patients with a deterioration from baseline of >5 points for bowel, >2 points for urinary, and >11 points for sexual score. RESULTS: The study enrolled 127 patients to 5 fractions (121 eligible) and 128 patients to 12 fractions (125 eligible). The median follow-up for all patients at the time of analysis was 5.38 years. The 5-year frequency for >5 point change in bowel score were 38.4% (P = .27) and 23.4% (P = 0.98) for 5 and 12 fractions, respectively. The 5-year frequencies for >2 point change in urinary score were 46.6% (P = .15) and 36.4% (P = .70) for 5 and 12 fractions, respectively. For 5 fractions, 49.3% (P = .007) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points; for 12 fractions, 54% (P < .001) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points. Disease-free survival at 5 years is 89.6% (95% CI: 84.0-95.2) in the 5-fraction arm and 92.3% (95% CI: 87.4-97.1) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on long-term changes in bowel and urinary domains and toxicity, the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

Human Gut Mycobiome and Fungal Community Interaction: The Unknown Musketeer in the Chemotherapy Response Status in Bladder Cancer.

Background: Until recently, the properties of microbiome and mycobiome in humans and its relevance to disease have largely been unexplored. While the interest of microbiome and malignancy over the past few years have burgeoned with advent of new technologies, no research describing the composition of mycobiome in bladder cancer has been done. Deciphering of the metagenome and its aggregate genetic information can be used to understand the functional properties and relationships between the bacteria, fungi, and cancer. Objective: The aim of this project is to characterize the compositional range of the normal versus bladder cancer mycobiome of the gut. Design setting and participants: An internal transcribed spacer (ITS) survey of 52 fecal samples was performed to evaluate the gut mycobiome differences between noncancer controls and bladder cancer patients. Outcome measurements and statistical analysis: Our study evaluated the differences in mycobiome among patients with bladder cancer, versus matched controls. Our secondary analysis evaluated compositional differences in the gut as a function of response status with neoadjuvant chemotherapy. Data demultiplexing and classification were performed using the QIIME v.1.1.1.1 platform. The Ion Torrent-generated fungal ITS sequence data were processed using QIIME (v.1.9.1), and the reads were demultiplexed, quality filtered, and clustered into operation taxonomic units using default parameters. Alpha and beta diversity were computed and plotted in Phyloseq, principal coordinate analysis was performed on Bray-Curtis dissimilarity indices, and a one-way permutational multivariate analysis of variance was used to test for significant differences between cohorts. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was applied to infer functional categories associated with taxonomic composition. Results and limitations: We found distinctive mycobiome differences between control group (n = 32) and bladder cancer (n = 29) gut flora, and identified an increasing abundance of Tremellales, Hypocreales, and Dothideales. Significant differences in alpha and beta diversity were present between the groups (control vs bladder; p = 0.002), noting distinct compositions within each cohort. A subgroup analysis by sex and neoadjuvant chemotherapy status did not show any further differences in mycobiome composition and diversity. Our results indicate that the gut mycobiome may modulate tumor response to preoperative chemotherapy in bladder cancer patients. We propose that patients with a "favorable" mycobiome composition (eg, high diversity, and low abundance of Agaricomycetes and Saccharomycetes) may have enhanced systemic immune response to chemotherapy through antigen presentation. Conclusions: Our study is the first to characterize the enteric mycobiome in patients with bladder cancer and describe complex ecological network alterations, indicating complex bacteria-fungi interactions, particularly highlighted among patients with complete neoadjuvant chemotherapy response. Patient summary: Our study has demonstrated that the composition of stool mycobiome (fungal inhabitants of the gastrointestinal tract) in patients with bladder cancer is different from that in noncancer individuals. Furthermore, when evaluating how patients respond to chemotherapy given prior to their surgery, our study noted significant differences between patients who responded and those who did not.

Increased cytokine gene expression and cognition risk associated with androgen deprivation therapy.

BACKGROUND: Androgen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high-risk, and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment likely develops side-effects that include changes in cognition or onset of dementia. However, the molecular understanding of this effect remains elusive. We attempt to establish a link between ADT and changes in cognitive function using patient databases and bioinformatics analyses. METHODS: Gene expression profiling was performed using RNA sequencing data from Alzheimer patient cohort and compared with the data from advanced-stage prostate cancer patients receiving neoadjuvant antiandrogen therapy. Differentially expressed genes (DEGs) were analyzed using the Ingenuity knowledge database. RESULTS: A total of 1952 DEGs in the Alzheimer patient cohort and 101 DEGs were identified in ADT treated prostate cancer patients. Comparing both data sets provided a subset of 33 commonly expressed genes involving cytokine-cytokine signaling with an over representation of cytokine-cytokine receptor interaction, inflammatory cytokines, signaling by interleukins together with alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production, and changes in T-cell subsets. Additionally, lipopolysaccharide, tumor necrosis factor, and toll-like receptors were identified as upstream transcriptional regulators of these pathways. The most commonly expressed genes viz. IL-17A, CCL2, IL-10, IL-6, IL-1RN, LIF/LIFR were further validated by quantitative RT-PCR exhibited higher expression in antiandrogen treated neuronal, glial, and androgen-responsive prostate cancer cells, compared to no-androgen antagonist treatment. CONCLUSIONS: Our findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with cognitive impairment presenting new avenues for diagnostic and therapeutic development in combating brain deficits.

Identification of Key Genes Associated with Progression and Prognosis of Bladder Cancer through Integrated Bioinformatics Analysis.

Bladder cancer prognosis remains dismal due to lack of appropriate biomarkers that can predict its progression. The study aims to identify novel prognostic biomarkers associated with the progression of bladder cancer by utilizing three Gene Expression Omnibus (GEO) datasets to screen differentially expressed genes (DEGs). A total of 1516 DEGs were identified between non-muscle invasive and muscle invasive bladder cancer specimens. To identify genes of prognostic value, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A total of seven genes, including CDKN2A, CDC20, CTSV, FOXM1, MAGEA6, KRT23, and S100A9 were confirmed with strong prognostic values in bladder cancer and validated by qRT-PCR conducted in various human bladder cancer cells representing stage-specific disease progression. ULCAN, human protein atlas and The Cancer Genome Atlas datasets were used to confirm the predictive value of these genes in bladder cancer progression. Moreover, Kaplan-Meier analysis and Cox hazard ratio analysis were performed to determine the prognostic role of these genes. Univariate analysis performed on a validation set identified a 3-panel gene set viz. CDKN2A, CTSV and FOXM1 with 95.5% sensitivity and 100% specificity in predicting bladder cancer progression. In summary, our study screened and confirmed a 3-panel biomarker that could accurately predict the progression and prognosis of bladder cancer.

Systematic Review of the Management of Ureteroarterial Fistulas After Ileal Conduit Urinary Diversion.

OBJECTIVE. No studies or guidelines exist to direct management of ureteroarterial fistula (UAF) after ileal conduit urinary diversion in which the possible risks and complications associated with stent-graft infection from the conduit flora must be reconciled with those of open surgical repair. This study seeks to characterize the clinical presentation, pathogenesis, and optimal diagnostic and therapeutic management of this entity through a systematic review of the literature. MATERIALS AND METHODS. A systematic search of the English-language literature using the PubMed, Scopus, and ScienceDirect databases was performed: 264 abstracts were identified. From those abstracts, 32 studies comprising 40 patients with 43 UAFs were selected for analysis. Data points including demographics, clinical presentation, UAF specifications, procedural details, postprocedural complications, and clinical outcomes were reviewed. RESULTS. Predisposing factors included female sex, chronic ureteral stent placement, and past surgical intervention and irradiation for pelvic malignancy. Fistulization was overwhelmingly unilateral (95.0% of patients) and included the common iliac artery (90.7% of UAFs). Combined endovascular and endoureteral modalities presented similar outcomes compared with surgical approaches in terms of UAF-related mortality (7.1% vs 13.3%, respectively) and complication rates (28.6% vs 26.7%) during a similar median follow-up period (9.5 vs 14.0 months). Endovascular stent-graft infections were present in 14.3% of cases and represented a leading indication for reintervention after endovascular management (50.0%). CONCLUSION. Short- and intermediate-term outcomes of combined endovascular and endoureteral techniques compare favorably with those of surgical approaches in the treatment of UAF after ileal conduit urinary diversion. Although there is a relatively low stent-graft infection rate, close follow-up within the first year after the procedure is required given the propensity of complications to develop during this window. The use of postprocedural antibiotics is uncertain but is likely prudent.

Oxidative Stress and Antioxidant Status in High-Risk Prostate Cancer Subjects.

The oxidant/antioxidant balance has been implicated in the pathophysiology of prostate cancer. We investigated oxidative damage and antioxidant status in high-risk prostate cancer subjects. Reduced glutathione (GSH) levels were measured in erythrocytes, 8-hydroxydeoxyguanosine (8-OHdG) in leukocytes and plasma levels of catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSH-R), glutathione S-transferase (GST), superoxide dismutase (SOD), and lipid peroxide products were measured in high-risk and age-matched healthy subjects. Serum PSA levels were significantly higher (p < 0.0001) in high-risk subjects, whereas GST (p < 0.0001) and GSH (p < 0.002) were higher in healthy controls. Levels of 8-OHdG, an oxidized nucleoside of DNA, were significantly increased (p < 0.0001) in high-risk subjects. No marked difference in the levels of CAT (p = 0.237), GSH-Px (p = 0.74), GSH-R (p = 0.344), SOD (p = 0.109), and lipid peroxide products (p = 0129) were observed between two groups. Pearson's correlation between GST and PSA (r = -0.69 (p < 0.0001)), GST and 8-OHdG (r = -0.62 (p < 0.0004)), GSH and 8-OHdG (r= -0.39 (p = 0.038)), and CAT and GSH-Px (r= -0.33 (p = 0.04)) were found to be negatively correlated, whereas 8-OHdG and PSA were positively associated (r= 0.57 (p < 0.002). These results indicate a significant role of oxidative damage in prostate carcinogenesis, particularly during the early stages of development. In conclusion, our data support the importance of antioxidant defense as a valuable diagnostic and/or prognostic marker in prostate cancer.

Preoperative Testing for Urethroplasty is Not Associated With Outcomes-A NSQIP Study.

OBJECTIVE: To assess the current practice of routine preoperative testing before urethroplasty and to determine if the results are clinically significant. METHODS: Data was obtained from the National Surgical Quality Improvement Program (NSQIP) database. We identified 1527 patients who underwent urethroplasty from 2010 to 2017. Chi-square and one-way ANOVA tests were used to compare categorical and continuous variables, respectively. Multivariable logistic regression analyses were utilized to assess the rate of complications between testing groups. RESULTS: A total of 8455 individual laboratory tests were performed on 1156 patients (average of 7 tests per patient), with only 959 labs (11.3%) showing abnormal results. Of the 1156 patients, 629 (54.4%) patients had at least one abnormal lab. Patients who had at least one abnormal preoperative lab were found to be significantly older (51.49 ± 16.57 years vs 48.14 ± 16.32 years; P < .001), and to be smokers (112 [17.8%] vs 63 [12%]; P = 0.005). Additionally, they were more likely to have diabetes mellitus (112 [17.8%] vs 63 [12%]; P < 0.001), dyspnea (18 [2.9%] vs 16 [3.0%]; P = .029), and ASA class ≥3 when compared to the group with normal preoperative labs. On a multivariable logistic regression, abnormal preoperative tests were not predictive of intra- or postoperative complications in patients with ASA ≤2 (n = 1112) when adjusted for age and race. In patients with ASA class ≥3, the only lab predictive of postoperative complications was an abnormal coagulation profile. CONCLUSION: Obtaining routine preoperative labs, especially in patients with ASA ≤2, does not affect postoperative outcomes in patients undergoing urethroplasty.

MR Fingerprinting and ADC Mapping for Characterization of Lesions in the Transition Zone of the Prostate Gland.

BackgroundPreliminary studies have shown that MR fingerprinting-based relaxometry combined with apparent diffusion coefficient (ADC) mapping can be used to differentiate normal peripheral zone from prostate cancer and prostatitis. The utility of relaxometry and ADC mapping for the transition zone (TZ) is unknown.PurposeTo evaluate the utility of MR fingerprinting combined with ADC mapping for characterizing TZ lesions.Materials and MethodsTZ lesions that were suspicious for cancer in men who underwent MRI with T2-weighted imaging and ADC mapping (b values, 50-1400 sec/mm2), MR fingerprinting with steady-state free precession, and targeted biopsy (60 in-gantry and 15 cognitive targeting) between September 2014 and August 2018 in a single university hospital were retrospectively analyzed. Two radiologists blinded to Prostate Imaging Reporting and Data System (PI-RADS) scores and pathologic diagnosis drew regions of interest on cancer-suspicious lesions and contralateral visually normal TZs (NTZs) on MR fingerprinting and ADC maps. Linear mixed models compared two-reader means of T1, T2, and ADC. Generalized estimating equations logistic regression analysis was used to evaluate both MR fingerprinting and ADC in differentiating NTZ, cancers and noncancers, clinically significant (Gleason score ≥ 7) cancers from clinically insignificant lesions (noncancers and Gleason 6 cancers), and characterizing PI-RADS version 2 category 3 lesions.ResultsIn 67 men (mean age, 66 years ± 8 [standard deviation]) with 75 lesions, targeted biopsy revealed 37 cancers (six PI-RADS category 3 cancers and 31 PI-RADS category 4 or 5 cancers) and 38 noncancers (31 PI-RADS category 3 lesions and seven PI-RADS category 4 or 5 lesions). The T1, T2, and ADC of NTZ (1800 msec ± 150, 65 msec ± 22, and [1.13 ± 0.19] × 10-3 mm2/sec, respectively) were higher than those in cancers (1450 msec ± 110, 36 msec ± 11, and [0.57 ± 0.13] × 10-3 mm2/sec, respectively; P < .001 for all). The T1, T2, and ADC in cancers were lower than those in noncancers (1620 msec ± 120, 47 msec ± 16, and [0.82 ± 0.13] × 10-3 mm2/sec, respectively; P = .001 for T1 and ADC and P = .03 for T2). The area under the receiver operating characteristic curve (AUC) for T1 plus ADC was 0.94 for separation. T1 and ADC in clinically significant cancers (1440 msec ± 140 and [0.58 ± 0.14] × 10-3 mm2/sec, respectively) were lower than those in clinically insignificant lesions (1580 msec ± 120 and [0.75 ± 0.17] × 10-3 mm2/sec, respectively; P = .001 for all). The AUC for T1 plus ADC was 0.81 for separation. Within PI-RADS category 3 lesions, T1 and ADC of cancers (1430 msec ± 220 and [0.60 ± 0.17] × 10-3 mm2/sec, respectively) were lower than those of noncancers (1630 msec ± 120 and [0.81 ± 0.13] × 10-3 mm2/sec, respectively; P = .006 for T1 and P = .004 for ADC). The AUC for T1 was 0.79 for differentiating category 3 lesions.ConclusionMR fingerprinting-based relaxometry combined with apparent diffusion coefficient mapping may improve transition zone lesion characterization.© RSNA, 2019Online supplemental material is available for this article.

Observed racial disparity in the negative predictive value of multi-parametric MRI for the diagnosis for prostate cancer.

OBJECTIVE: To evaluate the trend that despite recent advances in the screening, diagnosis, and management of prostate cancer (PCa), African-Americans (AAs) continue to have poorer outcomes compared to their Caucasian (CAU) counterparts. The reason for this may be rooted in biological differences in the cancer between the two groups; however, there may be some inherent disparities within the efficacy of the screening modalities. In this study, we aim to evaluate the negative predictive value (NPV) of multi-parametric MRI (mpMRI) between AA compared to CAUs. METHODS: All mpMRI between January 2014 and June 2017 were evaluated. The MRIs were read by dedicated genitourinary radiologists. Subsequently, the readings were correlated to final pathology after the patients underwent radical prostatectomy. The NPV and negative likelihood ratios (-LR) of mpMRI were evaluated in AAs versus CAUs based on four cutoffs (≥ Grade I, ≥ Grade II, ≥ Grade III and ≥ Grade IV). RESULTS: The mpMRI was almost equally as effective between AAs and CAUs in excluding Grade III (NPV = 89 and 94, respectively), and Grade IV or above (NPV = 96 and 98, respectively) PCa; however, the NPV of mpMRI was significantly lower for Grade I (NPV = 32 and 52, respectively) and Grade II (NPV = 50 and 79, respectively) PCa. CONCLUSION: Despite advances in the screening for PCa, there are disparities noted in the efficacy of screening tools between AAs and CAUs. For this reason, patients should be risk stratified and their screening results should be evaluated with consideration given to their baseline risk.

Targeted Biopsy Validation of Peripheral Zone Prostate Cancer Characterization With Magnetic Resonance Fingerprinting and Diffusion Mapping.

OBJECTIVE: This study aims for targeted biopsy validation of magnetic resonance fingerprinting (MRF) and diffusion mapping for characterizing peripheral zone (PZ) prostate cancer and noncancers. MATERIALS AND METHODS: One hundred four PZ lesions in 85 patients who underwent magnetic resonance imaging were retrospectively analyzed with apparent diffusion coefficient (ADC) mapping, MRF, and targeted biopsy (cognitive or in-gantry). A radiologist blinded to pathology drew regions of interest on targeted lesions and visually normal peripheral zone on MRF and ADC maps. Mean T1, T2, and ADC were analyzed using linear mixed models. Generalized estimating equations logistic regression analyses were used to evaluate T1 and T2 relaxometry combined with ADC in differentiating pathologic groups. RESULTS: Targeted biopsy revealed 63 cancers (low-grade cancer/Gleason score 6 = 10, clinically significant cancer/Gleason score ≥7 = 53), 15 prostatitis, and 26 negative biopsies. Prostate cancer T1, T2, and ADC (mean ± SD, 1660 ± 270 milliseconds, 56 ± 20 milliseconds, 0.70 × 10 ± 0.24 × 10 mm/s) were significantly lower than prostatitis (mean ± SD, 1730 ± 350 milliseconds, 77 ± 36 milliseconds, 1.00 × 10 ± 0.30 × 10 mm/s) and negative biopsies (mean ± SD, 1810 ± 250 milliseconds, 71 ± 37 milliseconds, 1.00 × 10 ± 0.33 × 10 mm/s). For cancer versus prostatitis, ADC was sensitive and T2 specific with comparable area under curve (AUC; (AUCT2 = 0.71, AUCADC = 0.79, difference between AUCs not significant P = 0.37). T1 + ADC (AUCT1 + ADC = 0.83) provided the best separation between cancer and negative biopsies. Low-grade cancer T2 and ADC (mean ± SD, 75 ± 29 milliseconds, 0.96 × 10 ± 0.34 × 10 mm/s) were significantly higher than clinically significant cancers (mean ± SD, 52 ± 16 milliseconds, 0.65 ± 0.18 × 10 mm/s), and T2 + ADC (AUCT2 + ADC = 0.91) provided the best separation. CONCLUSIONS: T1 and T2 relaxometry combined with ADC mapping may be useful for quantitative characterization of prostate cancer grades and differentiating cancer from noncancers for PZ lesions seen on T2-weighted images.

Green tea-induced epigenetic reactivation of tissue inhibitor of matrix metalloproteinase-3 suppresses prostate cancer progression through histone-modifying enzymes.

Green tea polyphenols (GTPs) and their major constituent, epigallocatechin-3-gallate (EGCG), have been reported to demonstrate many interesting biological activities, including anticancer properties. Recent studies on prostate cancer provide strong evidence that epigenetic mechanisms are major players in the regulation of matrix metalloproteinases (MMPs) and their binding partner tissue inhibitor of MMPs (TIMPs) involved in prostate cancer progression. Here we demonstrate that GTP/EGCG mediate epigenetic reactivation of TIMP-3 that plays a key role in suppressing invasiveness and cancer progression. Treatment of human prostate cancer DUPRO and LNCaP cells with 10 µg/mL GTP and 20 µM EGCG induced TIMP-3 mRNA and protein expression. This transcriptional activation of TIMP-3 was associated with the decrease in the expression of both enhancers of zeste homolog 2 (EZH2) and its catalytic product trimethylation of histone H3 at lysine 27 (H3K27me3) repressive marks at the TIMP-3 promoter with an accompanying increase in histone H3K9/18 acetylation. In addition, GTP/EGCG treatment significantly reduced class I histone deacetylase (HDAC) activity/expression and EZH2 and H3K27me3 levels in prostate cancer cells. EGCG/GTP exposure also reduced MMP-2/MMP-9 gelatinolytic activity and abrogated invasion and migration capabilities in these cells. Silencing of EZH2 and class I HDACs strikingly increased the expression of TIMP-3 independent of DNA methylation. Furthermore, clinical trials performed on patients undergoing prostatectomy consuming 800 mg EGCG (Polyphenon E) up to 6 weeks and grade-matched controls demonstrate an increase in plasma TIMP-3 levels. A marked reduction in class I HDACs activity/expression and EZH2 and H3K27me3 levels were noted in GTP-supplemented prostate tissue. Our findings highlight that TIMP-3 induction, as a key epigenetic event modulated by green tea in restoring the MMP:TIMP balance suppresses prostate cancer progression.

Variability in Prices for Erectile Dysfunction Medications-Are All Pharmacies the Same?

BACKGROUND: Variability in prices of medications is a well-known phenomenon; however, this variability has not been quantified in the realm of erectile dysfunction (ED) medications. ED medications are ideal for this quantification, because they are often not covered by insurances; therefore, the cost is the most direct reflection of price variability among pharmacies as they affect the patients. AIM: To evaluate the variability in cash prices for phosphodiesterase type 5 inhibitors (PDEIs) for ED. We also evaluated whether certain types of pharmacies consistently offer better pricing than others, and whether there was any correlation with demographic factors. METHODS: 331 pharmacies were contacted within a 25-mile radius of our institution to obtain the cash price for 4 commonly used ED medications with prespecified doses. After exclusion, 323 pharmacies were categorized as chain, independent, wholesale, or hospital-associated. Cash prices for the specified medications were evaluated. In addition, we identified demographic and socioeconomic factors to determine if these had an impact on median drug pricing within each zip code. MAIN OUTCOME MEASURE: The main outcome was the cost for patients to fill each prescription. RESULTS: Independent pharmacies provided the lowest cost for 3 of 4 of the PDEIs. The largest price difference for 10 tablets of 100 mg sildenafil between all pharmacies was 38,000%. The median cost difference between independent pharmacies and chain pharmacies for sildenafil was >900%, and >1,100% for independent pharmacies vs hospital-associated pharmacies. Demographic and socioeconomic factors had no impact on the cost. CLINICAL IMPLICATIONS: Our goal is to promote patient counseling among practitioners and to empower patients to shop for the best prices for their medications. STRENGTH AND LIMITATIONS: A strength of the study is the large cohort that was surveyed; however, a weakness is that the large majority of the cohort was comprised of chain pharmacies. Mail pharmacies could not be evaluated as they required a valid prescription before offering prices. CONCLUSION: The drastic differences in cash prices for the PDEIs give us an insight into the variability and cost-inflation of medications in the United States. These patterns hold true for other essential medications as well, and improved transparency will allow patients to make informed decisions when choosing where to purchase their medications. It may also encourage certain pharmacies to provide medications at more affordable prices. Mishra K, Bukavina L, Mahran A, et al. Variability in prices for erectile dysfunction medications-Are all pharmacies the same? J Sex Med 2018;15:1785-1791.

Younger Men With Prostate Cancer Have Lower Risk of Upgrading While on Active Surveillance: A Meta-analysis and Systematic Review of the Literature.

Active surveillance has become a popular option for patients with low risk prostate cancer. Our objective was to examine the correlation between age and the risk of Gleason upgrading and biopsy progression. A systematic search was conducted. Eight studies met our eligibility criteria including 6522 patients with a median age of 65.8 (41-86) years. Per decade decrease in age, the pooled odds ratio and hazard ratio (CI 95%) for Gleason upgrading were 0.83 (0.73-0.94) and 0.87 (0.82-0.92), and for biopsy progression were 0.80 (0.74-0.86) and 0.88 (0.79-0.99), respectively. Overall, younger patients have a lower risk of GS upgrading and biopsy progression.

Patient Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test. RESULTS: The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

Comparative analysis for renal stereotactic body radiotherapy using Cyberknife, VMAT and proton therapy based treatment planning.

PURPOSE: We conducted this dosimetric analysis to evaluate the feasibility of a multi-center stereotactic body radiation therapy (SBRT) trial for renal cell carcinoma (RCC) using different SBRT platforms. MATERIALS/METHODS: The computed tomography (CT) simulation images of 10 patients with unilateral RCC previously treated on a Phase 1 trial at Institution 1 were anonymized and shared with Institution 2 after IRB approval. Treatment planning was generated through five different platforms aiming a total dose of 48 Gy in three fractions. These platforms included: Cyberknife and volumetric modulated arc therapy (VMAT) at institution 1, and Cyberknife, VMAT, and pencil beam scanning (PBS) Proton Therapy at institution 2. Dose constraints were based on the Phase 1 approved trial. RESULTS: Compared to Cyberknife, VMAT and PBS plans provided overall an equivalent or superior coverage to the target volume, while limiting dose to the remaining kidney, contralateral kidney, liver, spinal cord, and bowel. CONCLUSION: This dosimetric study supports the feasibility of a multi-center trial for renal SBRT using PBS, VMAT and Cyberknife.