PSA density is complementary to prostate MP-MRI PI-RADS scoring system for risk stratification of clinically significant prostate cancer.

BACKGROUND: While prostate multiparametric-magnetic resonance imaging (MP-MRI) has improved the diagnosis of clinically significant prostate cancer (CSPC), the complementary use of prostate-specific antigen (PSA) levels to risk-stratify for CSPC requires further study. The objective of this project was to determine if prostate MP-MRI and PSA can provide complementary insights into CSPC risk stratification. METHODS: In an IRB-approved study, pathologic outcomes from patients who underwent MR/US fusion-targeted prostate biopsy were stratified by various parameters including PSA, PSA density (PSAD), age, race, and PI-RADS v2 score. CSPC was defined as a Gleason score ≥7. Logistic regression was used to determine odds ratios (OR) with 95% confidence intervals (CI). P values were reported as two-sided with p < 0.05 considered statistically significant. ROC curves were generated for assessing the predictive value of tests and sensitivity + specificity optimization was performed to determine optimal testing cutoffs. RESULTS: A total of 327 patients with 709 lesions total were analyzed. PSAD and PI-RADS scores provided complementary predictive value for diagnosis of CSPC (AUC PSAD: 0.67, PI-RADS: 0.72, combined: 0.78, p < 0.001). When controlling for PI-RADS score, age, and race, multivariate analysis showed that PSAD was independently associated with CSPC (OR 1.03 per 0.01 PSAD increase, 95% CI 1.02-105, p < 0.001). The optimal cutoff of PSAD ≥ 0.1 ng/ml/cc shows that a high versus low PSAD was roughly equivalent to an increase in 1 in PI-RADS score for the presence of CSPC (4% of PI-RADS ≤3 PSAD low, 6% of PI-RADS 3 PSAD high vs. 5% of PI-RADS 4 PSAD low, 22% of PI-RADS 4 PSAD high vs. 29% of PI-RADS 5 PSAD low, 46% of PI-RADS 5 PSAD high were found to have CSPC). CONCLUSIONS: PSAD with a cutoff of 0.1 ng/ml/cc appears to be a useful marker that can stratify the risk of CSPC in a complementary manner to prostate MP-MRI.

Racial Analysis of Clinical and Biochemical Outcomes in Patients With Prostate Cancer Treated With Low-Dose-Rate Brachytherapy.

PURPOSE: Black men in the United States experience significantly higher incidence of and mortality from prostate cancer (PCa) than non-Black men. The cause of this disparity is multifactorial, though inequitable access to curative radiation modalities, including low-dose-rate (LDR) brachytherapy, may contribute. Despite this, there are few analyses evaluating the potential of different radiation therapies to mitigate outcome disparities. Therefore, we examined the clinical outcomes of Black and non-Black patients treated with definitive LDR brachytherapy for PCa. METHODS: Data were collected for all patients treated with definitive LDR brachytherapy between 2005 and 2018 on a retrospective institutional review board approved protocol. Pearson χ2 analysis was used to assess demographic and cancer differences between Black and non-Black cohorts. Freedom from biochemical failure (FFBF) was calculated using Kaplan-Meier analysis. Univariate and multivariate analyses were used to identify factors predictive of biochemical failure. RESULTS: One hundred and sixty-seven patients were included in the analysis (Black: n = 81; 48.5%) with a median follow-up of 88.4 months. Black patients were from lower income communities (P < .01), had greater social vulnerability (P < .01), and had a longer interval between diagnosis and treatment (P = .011). Overall cumulative FFBF was 92.3% (95% confidence interval [CI], 87.8%-96.8%) at 5 years and 87.7% (95% CI, 82.0%-93.4%) at 7 years. There was no significant difference in FFBF in Black and non-Black patients (P = .114) and Black race was not independently predictive of failure (hazard ratio, 1.51; 95% CI, 0.56-4.01; P = .42). Overall survival was comparable between racial groups (P = .972). Only nadir prostate-specific antigen was significantly associated with biochemical failure on multivariate (hazard ratio, 3.57; 95% CI, 02.44-5.22; P < .001). CONCLUSIONS: Black men treated with LDR brachytherapy achieved similar FFBF to their non-Black counterparts despite poorer socioeconomic status. This suggests that PCa treatment with brachytherapy may eliminate some disparities in clinical outcomes.

A Phase II Study Evaluating Bone Marrow-Sparing, Image-guided Pelvic Intensity-Modulated Radiotherapy (IMRT) With Cesium-131 Brachytherapy Boost, Adjuvant Chemotherapy, and Long-Term Hormonal Ablation in Patients With High Risk, Nonmetastatic Prostate Cancer.

PURPOSE/OBJECTIVE(S): Management of localized high-risk prostate cancer remains challenging. At our institution we performed a prospective phase II study of 2 years of androgen deprivation therapy (ADT), pelvic radiation, Cesium (Cs)-131 brachytherapy boost, and adjuvant docetaxel in high risk, localized prostate cancer with a primary endpoint of 3-year disease-free survival. MATERIALS/METHODS: Acute/chronic hematologic, gastrointestinal (GI) and genitourinary (GU) toxicities were scored based on the CTCAE v3.0/RTOG-EORTC criteria, respectively. Actuarial biochemical recurrence free survival (bRFS), bRFSdisease free survival (DFS) and overall survival (OS) were calculated. Patients had a median age of 62 years (range, 45 to 82), median Gleason score 8 (74% Gleason 8-10), median PSA of 11.2 (range, 2.8 to 96), and 47% cT2-T3a stage disease. Androgen deprivation was given for 2 years, 45 Gy whole-pelvis IMRT was followed by an 85 Gy Cs-131 boost to the prostate gland, and adjuvant docetaxel was given for 4 cycles. RESULTS: In total 38 patients enrolled from 2006 to 2014, with 82% completing protocol specified treatment, and 84.2% completing 4 cycles of docetaxel. Median follow-up for the entire and alive cohorts were 44 months and 58 months (range, 3.4 to 118), respectively. Acute grade ≥2 GI and GU toxicity rates were 18.4% and 23.7%, respectively. Chronic grade ≥2 GI and GU toxicity rates were 2.6% and 2.6%, respectively. Twelve patients (31.6%) developed grade 4 hematologic toxicity, with no grade 5 toxicity. The 5-year DFS, bRFS and OS rates were 74.1%, 86.0%, and 80.3%, respectively. CONCLUSIONS: This aggressive pilot multimodal approach appears to be safe and well-tolerated, providing disease control in a significant proportion of patients with particularly high-risk prostate cancer.

Twitter Mentions and Academic Citations in the Urologic Literature.

OBJECTIVE: To quantify the relationship between the number of Twitter mentions and the number of academic citations a urologic publication receives. MATERIALS AND METHODS: Two hundred and thirteen papers from 7 prominent urologic journals were examined 37 months after publication. Articles were evaluated with 2 citation based "bibliometrics" (Scopus, Google Scholar) and Twitter mentions were tracked using the Altmetric Bookmarklet. The number of article citations and Twitter mentions were compared using one-way Analysis of variance (ANOVA) and bivariate fit analysis. RESULTS: Seventy-three percent of articles had at least 1 Twitter mention. Forty-two percent of Twitter mentions occurred within the first week of the online publication date. Articles mentioned on Twitter had 2.0-fold more Scopus citations (P <.01), and 2.3-fold more Google Scholar citations (P <. 01) compared to articles with no Twitter mentions. Female urologic articles had the greatest number of Twitter mentions (5.7 mentions/article) while pediatric urology had the fewest mean number of Twitter mentions (0.8 mentions/article). A total of 8.9% of papers were tweeted by their authors. Author tweeted articles were associated with a 12.3 (2.0-fold) and 15.5 (1.8-fold) mean citation increase for Scopus and Google Scholar (P <. 01 and P = . 01) compared to articles not shared by their authors on Twitter. CONCLUSION: The majority of urologic publications are being shared on Twitter. The number of citations a urologic publication receives up to 3 years after release is positively associated with the number of mentions it has on Twitter. Twitter activity may be an early indicator of ultimate academic impact of an academic urologic paper.

Salvage external beam radiotherapy for locally recurrent prostate cancer after definitive brachytherapy.

PURPOSE: Patients with locally recurrent prostate cancer after definitive prostate brachytherapy have few evidence-based salvage options. We evaluate the efficacy and treatment-related side-effects of salvage external-beam radiotherapy (EBRT) after definitive prostate brachytherapy (PBT). METHODS AND MATERIALS: Eleven patients previously treated with definitive PBT and with biopsy-proven local-only recurrence received salvage reirradiation with EBRT. Genitourinary (GU) function was assessed with International Prostate Symptom Scores. Treatment-related toxicities were graded using CTCAE v 4.03. RESULTS: Median follow-up was 26.5 months (range, 1-53.6 months); median age at EBRT salvage was 67 years (range, 61-81 years). Salvage EBRT included the whole pelvis in 8 patients. Two patients were treated with 3D-CRT; 9 underwent IMRT. Five patients (45%) received androgen deprivation therapy concurrent with salvage EBRT as part of long- or short-course hormone therapy. The median prostate dose was 70.2 Gy (range, 64.8-75.6 Gy). Actuarial 3-year overall and biochemical failure-free survival were 77% and 69%, respectively. Five patients (45%) had worsening GU symptoms, and 9 (82%) experienced a decline in erectile function. One patient experienced acute grade 2 GU toxicity. Four patients (36%) experienced late grade ≥2 GI/GU toxicities, including 2 who experienced grade 3 toxicities (rectourethral fistula/incontinence, bladder outlet obstruction). No grade 4/5 toxicities were noted. CONCLUSIONS: Our data suggest that salvage EBRT can provide similar disease control and treatment-related toxicity to more established salvage therapies. This approach warrants further investigation on a larger scale.

Zinc Ionophore (Clioquinol) Inhibition of Human ZIP1-Deficient Prostate Tumor Growth in the Mouse Ectopic Xenograft Model: A Zinc Approach for the Efficacious Treatment of Prostate Cancer.

Prostate cancer remains the second leading cause of cancer deaths in males. This is mainly due to the absence of an available efficacious chemotherapy despite decades of research in pursuit of effective treatment approaches. A plausible target for the treatment is the established clinical relationship that the zinc levels in the malignant cells are markedly decreased compared to the normal epithelium in virtually all cases of prostate cancer, and at all stages malignancy. The decrease in zinc results from the downregulation of the functional zinc uptake transporter, ZIP1; which occurs during early development of prostate malignancy. This is an essential requirement for the development of malignancy to prevent the cytotoxic/tumor-suppressor effects of increased zinc on the premalignant and malignant cells. Thus prostate cancer is a ZIP1-deficient malignancy. This relationship provides the basis for a treatment regimen that will facilitate the uptake and accumulation of zinc into the premalignant and malignant cells. In this report we employed a zinc ionophore (clioquinol) approach in the treatment of mice with human ZIP1-deficient prostate tumors (ectopic xenograft model). Clioquinol treatment resulted in 85%inhibition of tumor growth due to the cytotoxic effects of zinc. Coupled with additional results from earlier studies, the compelling evidence provides a plausible approach for the effective treatment of human prostate cancer; including primary site malignancy, hormone-resistant cancer, and metastasis. Additionally, this approach might be effective in preventing the development of malignancy in individuals suspected of presenting with early development of malignancy. Clinical trials are now required in leading to the potential for an efficacious zinc-treatment approach, which is urgently needed for the treatment of prostate cancer.

An Immune-Inflammation Gene Expression Signature in Prostate Tumors of Smokers.

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers.

Evidence that Human Prostate Cancer is a ZIP1-Deficient Malignancy that could be Effectively Treated with a Zinc Ionophore (Clioquinol) Approach.

Despite decades of research, no efficacious chemotherapy exists for the treatment of prostate cancer. Malignant prostate zinc levels are markedly decreased in all cases of prostate cancer compared to normal/benign prostate. ZIP1 zinc transporter down regulation decreases zinc to prevent its cytotoxic effects. Thus, prostate cancer is a "ZIP1-deficient" malignancy. A zinc ionophore (e.g. Clioquinol) treatment to increase malignant zinc levels is a plausible treatment of prostate cancer. However, skepticism within the clinical/biomedical research community impedes significant progress leading to such a zinc treatment. This report reviews the clinical and experimental background, and presents new experimental data showing Clioquinol suppression of prostate malignancy; which provides strong support for a zinc ionophore treatment for prostate cancer. Evaluation of often-raised opposing issues is presented. These considerations lead to the conclusion that the compelling evidence dictates that a zinc-treatment approach for prostate cancer should be pursued with additional research leading to clinical trials.

Recruitment and Participation of African American Men in Church-Based Health Promotion Workshops.

Health promotion interventions in African American communities are frequently delivered in church settings. The Men's Prostate Awareness Church Training (M-PACT) intervention aimed to increase informed decision making for prostate cancer screening among African American men through their churches. Given the significant proportion and role of women in African American churches, the M-PACT study examined whether including women in the intervention approach would have an effect on study outcomes compared with a men-only approach. The current analysis discusses the men's participation rates in the M-PACT intervention, which consisted of a series of 4 bimonthly men's health workshops in 18 African American churches. Data suggest that once enrolled, retention rates for men ranged from 62 to 69 % over the workshop series. Among the men who were encouraged to invite women in their lives (e.g., wife/partner, sister, daughter, friend) to the workshops with them, less than half did so (46 %), suggesting under-implementation of this "health partner" approach. Finally, men's participation in the mixed-sex workshops were half the rate as compared to the men-only workshops. We describe recruitment techniques, lessons learned, and possible reasons for the observed study group differences in participation, in order to inform future interventions to reach men of color with health information.

MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer.

We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent data set and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a candidate predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair and actin dynamics. This observation was further corroborated with protein expression analysis and 3'-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that the miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters the cellular organization of F-actin and inhibits tumor cell invasion and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.

Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.

CONTEXT: Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). OBJECTIVE: To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. INTERVENTIONS: One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. MAIN OUTCOME MEASURES: Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. RESULTS: Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. CONCLUSION: Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603304.

A review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the enlarged prostate.

BACKGROUND: Enlargement of the prostate is common among aging men, with an incidence of 90% by the age of 85 years. It is a progressive condition, with growth in prostate size accompanied by lower urinary tract symptoms that can result in long-term complications (eg, acute urinary retention [AUR], need for enlarged prostate-related surgery). Current pharmacologic treatment options include alpha-blockers (alfuzosin, doxazosin, tamsulosin, and terazosin) and 5alpha-reductase inhibitors (5ARIs) (finasteride and dutasteride). OBJECTIVES: This article reviews the natural history of enlarged prostate and the data supporting management of this condition with alpha-blocker and 5ARI therapy, either as monotherapy or combination therapy, for symptomatic relief and a reduction in long-term disease progression. METHODS: Pertinent English-language articles were identified through a search of MEDLINE (1966-week 2, May 2006) using such search terms as 5alpha-reductase inhibitor, alpha-blocker, benign prostatic hyperplasia, dutasteride, efficacy, enlarged prostate, finasteride, and safety. RESULTS: Clinical trials of alpha-blockers in men with enlarged prostate have reported improvements in total symptom scores of 10% to 20% compared with placebo; however, these agents were not shown to reduce the risk of long-term complications or disease progression. Studies of the 5ARIs have reported significant reductions compared with placebo in the relative risk for AUR and enlarged prostate-related surgery, slowing of disease progression, and relief of symptoms. In studies of dutasteride, improvements in symptom scores were greater after 4 years of therapy compared with 2 years (-6.4 vs -4.3 points, respectively) and flow rates were better (2.6 vs 2.3 mL/sec). Six-year data for finasteride showed maintenance of the decreased risk for AUR and enlarged prostate-related surgery. Use of combination therapy with an alpha-blocker and a 5ARI may be of benefit in patients who require immediate relief of symptoms, with discontinuation of the alpha-blocker after several months of therapy. 5ARIs were generally well tolerated, with sexual dysfunction the most frequently reported adverse effect, although in only a small proportion of men (1%-8%). CONCLUSIONS: The use of 5ARI therapy is a rational approach to symptom management and prevention of long-term negative outcomes in men with enlarged prostates.V 3.

The effect of dysfunctional voiding on the costs of treating vesicoureteral reflux: a computer model.

PURPOSE: We created a computer model for evaluating the effect of dysfunctional voiding on the costs of managing vesicoureteral reflux in children. MATERIALS AND METHODS: The literature on vesicoureteral reflux was reviewed to create a set of assumptions regarding the epidemiology, likelihood of resolution, need for operative intervention, risk of infection and appropriate regimen for nonoperative surveillance. Recent literature describing the effect of dysfunctional voiding on the clinical course of vesicoureteral reflux was included in the model to compare the costs of treating vesicoureteral reflux in children with and without dysfunctional voiding. A 5-year management period was considered. RESULTS: Dysfunctional voiding in children with vesicoureteral reflux increased the cost of treatment per patient by 51.2%. The cost per patient increased with increasing grade in those with and without dysfunctional voiding. The difference in costs in the 2 groups increased from 18.7% for grade 1 reflux to 62.1% for grade 5. Sensitivity analysis was performed, in which the risk of urinary tract infection, rate of surgical resolution, incidence of dysfunctional voiding and discount rate varied. The cost in children with dysfunctional voiding remained higher in all scenarios studied, showing the robustness of the model. CONCLUSIONS: Dysfunctional voiding substantially increases the costs of treating children with vesicoureteral reflux due to the higher rate of urinary tract infection in children with dysfunctional voiding. Methods that would decrease the rate of urinary tract infection in children with dysfunctional voiding and vesicoureteral reflux would lead to a significant saving of health care dollars.

Magnetic resonance spectroscopic imaging-guided brachytherapy for localized prostate cancer.

PURPOSE: Prostate brachytherapy (PB) entails the placement of radioactive sources throughout the entire prostate gland to treat localized cancer. Typically, the target volume in PB encompasses the entire prostate gland because of the inability to localize the cancer and the multifocal nature of this malignancy. However, because of the unique biochemical nature of the prostate gland, recent advances in magnetic resonance spectroscopic imaging (MRSI) of the prostate have allowed precise delineation of the cancer location within the prostate gland. This report reveals our initial experience of MRSI-guided PB. METHODS: A MRSI study was obtained in 15 localized prostate cancer patients before their scheduled PB. The results of this study were used to internally map 7 x 7 x 9-mm volumes of prostate tissue to assign cancerous areas a higher dose of radiation. Such tumor-bearing areas had a low citrate/(choline+creatine) ratio consistent with cancer. On the basis of the anatomic MRI and MRSI correlation, three-dimensional coordinates were assigned to the locations of MRSI-defined cancer. The entire target volume was treated to a standard prescription dose using I-125 or Pd-103. Abnormal citrate regions, termed the biologic tumor volume, were prescribed a dose of 130% of the target volume dose to dose escalate in the abnormal citrate regions while respecting the normal radiation tolerances of the surrounding areas. Three-dimensional treatment planning was used to perform the implant. RESULTS: Of the 15 prostate cancer patients evaluated, all had successful three-dimensional MRSI acquisition before their scheduled PB procedure. In 14 of the 15 patients planned with MRSI, the data were successfully incorporated into their treatment planning and were used to increase the radiation dose prescription to 130% in the MRSI-defined volumes. In 1 patient, MRSI revealed significant background artifact that made a focal boost impractical. Postimplant dosimetry confirmed a median V100 of 95% (range 72%-100%) in the 15 evaluated patients for the prescription dose. Furthermore, the median BTV100 for the abnormal citrate region was 90% (range 80-100%) as determined by postimplant dosimetry. Urethral and rectal dose-volume histograms were within normal limits. Morbidity was comparable with that for conventionally treated patients. CONCLUSION: MRSI offers a promising new approach for the delivery of ionizing radiation in PB. Although this series was small and with a short follow-up, MRSI-guided implants are feasible and warrant further investigation as a means of improving the therapeutic ratio in PB [corrected].