Early Stage Prostate Cancer Research Articles

Population-based cohort of prostate cancer patients on active surveillance (AS): guideline adherence, conversion to treatment and decisional regret.

6512 Background: AS is recommended for early-stage prostate cancer, for which over-treatment has been widely described. In published studies from large academic institutions and/or controlled clinical trials, where patients are monitored rigorously, AS is safe and results in low rates of cancer-specific mortality. However, active surveillance in the community setting has not been previously examined. Methods: In collaboration with the North Carolina state cancer registry, 346 men with newly-diagnosed low- or intermediate-risk prostate cancer throughout the state from 2011–13 who pursued active surveillance were enrolled in an observational cohort; medical records and patient-reported outcomes (validated measures of prostate cancer anxiety [MAX-PC] and Clark’s prostate cancer decision regret) were collected prospectively. Guideline-adherent monitoring during active surveillance was assessed using contemporary NCCN guidelines: PSA testing every 3–6 months and prostate biopsy within 18 months of initial diagnosis. Results: 58% of patients received adequate PSA testing and 45% prostate biopsy; overall, 32% of patients received guideline-adherent monitoring. Urology follow-up in Year 1 was 97% but dropped to 67% in Year 2. Within the first 2 years, 16% of patients converted to treatment. Multivariable analysis showed MAX-PC scores (OR 1.8, p = 0.008) and younger age were significantly associated with conversion; no other sociodemographic (race, education, marital status, rural/urban) or diagnostic variable (risk group) was associated. At 2 years, 94% expressed no regret. Conclusions: In a non-controlled setting of patients pursuing AS in the community, adherence to guideline-recommended monitoring was only 32%. Few patients expressed decisional regret. Conversion to treatment was likely driven by patient anxiety but not disease-related factors. While there are continued efforts to increase AS uptake, these results highlight the importance of behavioral interventions during active surveillance to reduce anxiety and improve monitoring adherence. Whether AS in non-controlled settings is safe and effective requires further study.

NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells

Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a Food and Drug Administration-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period, tumors will develop drug resistance. In this study using RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYC gene expression positively correlated with AR expression in samples from patient with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide resistance. Cleaved NOTCH1, HES1 (Hes family BHLH transcription factor 1), and c-MYC protein expression levels are elevated in two enzalutamide-resistant cell lines, MR49F and C4-2R, indicating NOTCH signaling activation. Moreover, inhibition of the overexpressed ADAM metallopeptidase domain 10 (ADAM10) in the resistant cells induces an exclusive reduction in cleaved NOTCH1 expression. Furthermore, exposure of enzalutamide-resistant cells to both PF-03084014 and enzalutamide increased cell death, decreased colony formation ability, and resensitized cells to enzalutamide. Knockdown of NOTCH1 in C4-2R increased enzalutamide sensitivity by decreasing cell proliferation and increasing cleaved PARP expression. In a 22RV1 xenograft model, PF-03084014 and enzalutamide decreased tumor growth through reducing cell proliferation and increasing apoptosis. These results indicate that NOTCH1 signaling may contribute to enzalutamide resistance in prostate cancer, and inhibition of NOTCH signaling can resensitize resistant cells to enzalutamide.

Randomized trial evaluating the role of weight loss in overweight and obese men with early stage prostate Cancer on active surveillance: Rationale and design of the Prostate Cancer Active Lifestyle Study (PALS)

Active surveillance (AS) is increasingly used to monitor patients with low-risk prostate cancer; however, approximately 50% of AS patients experience disease reclassification requiring definitive treatment and little is known about patient characteristics that modify the risk of reclassification. Obesity may be one of the major contributing factors.The Prostate Cancer Active Lifestyle Study (PALS) is a clinical trial evaluating the impact of weight loss among overweight/obese (Body Mass Index (BMI) ≥ 25 kg/m2) men with clinically localized prostate cancer on AS. Two hundred participants will be randomized to either the PALS intervention, a 6-month structured diet and exercise program adapted from the Diabetes Prevention Program followed by 6 months of maintenance, or control (general diet and physical activity guidelines delivered in a single session). The PALS intervention involves one-on-one instruction with a registered dietitian and exercise physiologist to achieve the study goal of loss of 7% of baseline weight. Participation is coordinated so that the 6-month time point coincides with the participants' standard-of-care AS prostate biopsy. Primary outcomes will evaluate the intervention effects on circulating and tissue markers of glucose and insulin regulation, health-related quality of life and pathologic upgrading on follow-up prostate biopsies. Additional analyses will determine whether changes in weight and glucose regulation can be sustained for 6 months after the end of instruction. Findings from this trial may have wide reaching implications for men diagnosed with clinically-localized prostate cancer by providing an active lifestyle-based approach to improve prostate cancer patient outcomes.

Merging new-age biomarkers and nanodiagnostics for precision prostate cancer management.

The accurate identification and stratified treatment of clinically significant early-stage prostate cancer have been ongoing concerns since the outcomes of large international prostate cancer screening trials were reported. The controversy surrounding clinical and cost benefits of prostate cancer screening has highlighted the lack of strategies for discriminating high-risk disease (that requires early treatment) from low-risk disease (that could be managed using watchful waiting or active surveillance). Advances in molecular subtyping and multiomics nanotechnology-based prostate cancer risk delineation can enable refinement of prostate cancer molecular taxonomy into clinically meaningful and treatable subtypes. Furthermore, the presence of intertumoural and intratumoural heterogeneity in prostate cancer warrants the development of novel nanodiagnostic technologies to identify clinically significant prostate cancer in a rapid, cost-effective and accurate manner. Circulating and urinary next-generation prostate cancer biomarkers for disease molecular subtyping and the newest complementary nanodiagnostic platforms for enhanced biomarker detection are promising tools for precision prostate cancer management. However, challenges in merging both aspects and clinical translation still need to be overcome.

Single-fraction brachytherapy as monotherapy for early-stage prostate cancer: The UCSF experience

PurposeHigh-dose-rate (HDR) brachytherapy as monotherapy is an effective treatment option for localized prostate cancer, but experience with single-fraction brachytherapy is limited by studies with small sample size. We report a large single-institution experience with single-fraction HDR brachytherapy as monotherapy for early-stage prostate cancer. Methods and MaterialsRetrospective chart review was performed for men treated with HDR brachytherapy as monotherapy for low- to intermediate-risk prostate cancer. Competing risk analyses were performed to estimate subdistribution hazard ratio and cumulative incidence of biochemical recurrence (BCR) and prostate cancer–specific mortality. ResultsWe identified 124 men with a median followup of 2.2 years (interquartile range 25th to 75th percentile: 1.8–3). Overall, 21.0% of patients (n = 26) were low risk, 44.4% (n = 55) were favorable intermediate risk, and 34.7% (n = 43) were unfavorable intermediate risk. At 2 years, the cumulative incidence of BCR was 3.5%: 0% for low risk, 4.0% for favorable intermediate risk patients, and 4.5% for unfavorable intermediate risk patients. In total, 12 BCRs were observed (9.7%) and approximately half occurred after median followup of 2.2 years. Compared with low-risk and favorable intermediate-risk disease, unfavorable intermediate-risk disease was significantly associated with BCR (subdistribution hazard ratio: 3.6, 95% CI: 1.1 to 11.1, p = 0.03). Prostate cancer–specific mortality was 0%. No patient experienced Grade 3 or higher acute or late genitourinary toxicity. ConclusionsSingle-fraction brachytherapy for early-stage prostate cancer was safe with promising short-term disease control rates, especially for low-risk patients. Longer term followup is needed as we observed an overall BCR rate of 9.7%.

Early Stage Biomarkers Screening of Prostate Cancer Based on Weighted Gene Coexpression Network Analysis.

Although the morbidity and mortality rates of prostate cancer (PCa) are considerably high, many PCas are characterized as indolent and slow growing, which do not require overtreatment. Overdiagnosis and overtreatment of early detected PCa are an emerging problem, owing to a lack of biomarkers that detect advanced disease at an earlier stage. In this study, RNA-Seq data of 57,045 genes for 495 PCa samples and 52 normal samples in the The Cancer Genome Atlas (TCGA) database were downloaded. Subsequently, we performed weighted gene coexpression network analysis to identify the Gleason score-related coexpression gene module, and further screened out oncogenes and tumor suppressors that were upregulated or downregulated in the early stage of PCa as well as those related to the clinical prognosis of PCa patients. Based on this study, some novel biomarkers were identified for the disease-free survival, which are helpful for fast diagnosis and prognosis.

Providers’ inability to estimate health literacy among African American (AA) patients (pts) with early prostate cancer (PCa).

77 Background: Providers’ estimates of a pt’s health literacy are important for communication and shared decision making among men with early PCa. We explored differences between providers’ estimates of health literacy and measured health literacy among AA pts in a prospective cohort study at Grady Memorial Hospital and the Atlanta Veterans Administration Hospital. Methods: Providers (n=18) estimated the health literacy of 124 newly diagnosed, early-stage, AA PCa pts after discussions with each pt regarding his PCa treatment options, categorized as ≤Grade (Gr) 3; Gr 4-6; Gr 7-8; and High school. At a subsequent visit, prior to choosing his cancer treatment, each pt’s health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), using the same categories. Domains of numeracy, comprehension of common PCa terms, and anatomic knowledge were assessed using published methods. Concordance between estimated and actual health literacy was evaluated via Cohen’s Kappa coefficient (1.00 = perfect agreement). Results: Despite their discussions with the pts, providers consistently overestimated pts’ health literacy. Agreement between provider estimates and pts’ measured values was consistently low (32.0%-37.6%). These rates were approximately what would be expected by chance. Among the 75 patients with the lowest levels of health literacy, agreement was even lower (12.3%-35.6%). In this group 26.7% of provider assessments were off by ≥2 REALM categories. Conclusions: Healthcare providers are surprisingly ineffective at estimating the health literacy of their pts with early stage PCa. This poor accuracy may diminish providers’ ability to communicate successfully with pts and engage in shared decision making, especially among pts with poor health literacy. [Table: see text]

Stereotactic body radiotherapy (SBRT) versus conventional fractionated intensity-modulated radiotherapy (CF-IMRT) for patients with early-stage localized prostate cancer: One-year late toxicity results from a prospective randomized phase II study.

27 Background: It remains uncertain whether stereotactic body radiotherapy (SBRT) is superior to conventional fractionated intensity-modulated radiotherapy (CF-IMRT) in the treatment of early-stage prostate cancer. Here we report the 1-year late toxicity results from this randomized phase II study comparing SBRT and CF-IMRT. Methods: The primary endpoint of this single centre randomized phase II study is the health-related quality of life (HRQOL), as measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC) instrument. The secondary endpoints include toxicities, biochemical control and overall survival. We enrolled low and intermediate risk localized prostate cancer patients (T1-T2, Gleason score ≤7 and PSA <20). Patients were randomly assigned in a 1:1 ratio to receive either CF-IMRT with 38 fractions of 2 Gy in 7.5 weeks (five fractions per week) or SBRT with 5 fractions of 7.25 Gy in 2 weeks (three fractions per week). Neoadjuvant androgen-deprivation treatment is optional for the intermediate risk patients. A 1-year late adverse event is defined as the first occurrence of worst severity of the adverse event within 1 year after the completion of RT, and it was evaluated with the Common Terminology Criteria for Adverse Events (version 4.0). Patient recruitment was completed in May 2017. Results: Between Jan 2015 and May 2017, 68 patients were recruited and 4 patients were not eligible. 64 patients were randomized to treatments with SBRT (n=31) or CF-IMRT (n=33). At 1- year follow-up, two grade 3 genitourinary (GU) late toxicities, one in each arm (3%), were reported. SBRT patients experienced significantly less ≥ grade 1 late gastrointestinal (GI) toxicities (SBRT vs IMRT: 64% vs 84%, p=0.041) and similar ≥grade 1 late GU toxicities (SBRT vs IMRT: 93% vs 100%, p=0.2307) to IMRT patients. Conclusions: SBRT results in significantly less 1-year late GI toxicities than CF-IMRT in with low and intermediate risk prostate cancer. The study is registered at ClinicalTrials.gov (NCT02339701). Clinical trial information: NCT02339701.

Time to initial cancer treatment in the United States and association with survival over time: An observational study.

BackgroundDelays in time to treatment initiation (TTI) for new cancer diagnoses cause patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of increased TTI and association with overall survival.Methods and findingsWe utilized prospective data from the National Cancer Database for newly diagnosed United States patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004–13. TTI was defined as days from diagnosis to first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (N = 363,863), renal (N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 to 29 days (P<0.001). Aside from year of diagnosis, determinants of increased TTI included care at academic center, race, education, prior history of cancer, transfer of facility, comorbidities and age. Increased TTI was associated with worsened survival for stages I and II breast, lung, renal and pancreas cancers, and stage I colorectal cancers, with hazard ratios ranging from 1.005 (95% confidence intervals [CI] 1.002–1.008) to 1.030 (95% CI 1.025–1.035) per week of increased TTI.ConclusionsTTI has lengthened significantly and is associated with absolute increased risk of mortality ranging from 1.2–3.2% per week in curative settings such as early-stage breast, lung, renal and pancreas cancers. Studies of interventions to ease navigation and reduce barriers are warranted to diminish potential harm to patients.

The Quality of Life for Patients with Early Stage Prostate Cancer in Brachytherapy and Radical Prostatectomy Surgery

The Quality of Life for Patients with Early Stage Prostate Cancer in Brachytherapy and Radical Prostatectomy Surgery

Pre-diagnostic carbohydrate intake and treatment failure after radical prostatectomy for early-stage prostate cancer.

An association between dietary carbohydrate intake and prostate cancer (PCa) prognosis is biologically plausible, but data are scarce. This prospective cohort study examined the relation between pre-diagnostic carbohydrate intake and treatment failure following radical prostatectomy for clinically early-stage PCa. We identified 205 men awaiting radical prostatectomy and assessed their usual dietary intake of carbohydrates using the 110-item Block food frequency questionnaire. We also evaluated carbohydrate intake quality using a score based on the consumption of sugars relative to fiber, fat, and protein. Logistic regression analyzed their associations with the odds of treatment failure, defined as a detectable and rising serum prostate-specific antigen (PSA) or receiving androgen deprivation therapy (ADT) within 2years. Sucrose consumption was associated with a higher odds and fiber consumption with a lower odds of ADT after accounting for age, race/ethnicity, body mass index, and tumor characteristics (odds ratio [OR] (95% confidence interval [CI]) 5.68 (1.71, 18.9) for 3rd vs. 1st sucrose tertile and 0.88 (0.81, 0.96) per gram of fiber/day, respectively). Increasing carbohydrate intake quality also associated with a lower odds of ADT (OR (95% CI) 0.78 (0.66, 0.92) per unit increase in score, range 0-12). Pre-diagnostic dietary carbohydrate intake composition and quality influence the risk of primary treatment failure for early-stage PCa. Future studies incorporating molecular aspects of carbohydrate metabolism could clarify possible underlying mechanisms.

Melatonin and Docosahexaenoic Acid Decrease Proliferation of PNT1A Prostate Benign Cells via Modulation of Mitochondrial Bioenergetics and ROS Production.

Prostate cancer development has been associated with changes in mitochondrial activity and reactive oxygen species (ROS) production. Melatonin (MLT) and docosahexaenoic acid (DHA) have properties to modulate both, but their protective role, mainly at early stages of prostate cancer, remains unclear. In this study, the effects of MLT and DHA, combined or not, on PNT1A cells with regard to mitochondria bioenergetics, ROS production, and proliferation-related pathways were examined. Based on dose response and lipid accumulation assays, DHA at 100 μM and MLT at 1 μM for 48 h were chosen. DHA doubled and MLT reduced (40%) superoxide anion production, but coincubation (DM) did not normalize to control. Hydrogen peroxide production decreased after MLT incubation only (p < 0.01). These alterations affected the area and perimeter of mitochondria, since DHA increased whereas MLT decreased, but such hormone has no effect on coincubation. DHA isolated did not change the oxidative phosphorylation rate (OXPHOS), but decreased (p < 0.001) the mitochondrial bioenergetic reserve capacity (MBRC) which is closely related to cell responsiveness to stress conditions. MLT, regardless of DHA, ameliorated OXPHOS and recovered MBRC after coincubation. All incubations decreased AKT phosphorylation; however, only MLT alone inhibited p-mTOR. MLT increased p-ERK1/2 and, when combined to DHA, increased GSTP1 expression (p < 0.01). DHA did not change the testosterone levels in the medium, whereas MLT alone or coincubated decreased by about 20%; however, any incubation affected AR expression. Moreover, incubation with luzindole revealed that MLT effects were MTR1/2-independent. In conclusion, DHA increased ROS production and impaired mitochondrial function which was probably related to AKT inactivation; MLT improved OXPHOS and decreased ROS which was related to AKT/mTOR dephosphorylation, and when coincubated, the antiproliferative action was related to mitochondrial bioenergetic modulation associated to AKT and ERK1/2 regulation. Together, these findings point to the potential application of DHA and MLT towards the prevention of proliferative prostate diseases.

Overexpression of the Long Non-Coding RNA NeSt and FOXCUT in Early Stages of Prostate Cancer Samples as Promising Biomarkers.

Prostate cancer is one of the most common cancers in males worldwide. Recently, it is well characterized that long non-coding RNAs (lncRNA) play critical roles in the initiation, development, and progression of prostate cancer. NeST, an intergenic lncRNA, was found to be a positive regulator of the pro-inflammatory cytokine, IFN-ɣ, which is responsible for both antitumor immunity properties as well as tumor evasion. FOXCUT, an-other lncRNA, is mainly a regulator of transcription factor, FOXC1 that is believed to be involved in tumor development and progression. In a case-control study, 66 paraffin-embedded prostate tissues representing 36 pathologically confirmed cancer and 30 control samples were examined. The cancer samples were classified in a total of three stages based on PSA levels, tumor volume, and Gleason score. RNA extraction was performed for quantitative determination of IFN-ɣ, lncRNA NeSt, and lncRNA FOXCUT gene expression in both case and control prostate tissues. Our results showed that NeST lncRNA was significantly up-regulated in prostate cancer samples compared to control, while NeST lncRNA and IFN-ɣ gene expression was detected mainly in early stages of prostate cancer. The patients with higher NeST and FOXCUT expression had poor clinical features including PSA levels and tumor volume comparing those with lower expression. Moreover, there was a strong correlation between lncRNA FOXCUT and IFN-ɣ expression. Our data suggests that lncRNA NeST and lncRNA FOXCUT may be able to be introduced as novel molecules involved in prostate cancer development and may provide a potential prognostic biomarker and therapeutic target.

Antibody-modified reduced graphene oxide film for circulating tumor cell detection in early-stage prostate cancer patients.

In recent years, liquid biopsies, especially for detecting circulating tumor cells (CTCs), have received great attention for cancer diagnosis and treatment monitoring. For clinical diagnosis of prostate cancer (PCa), prostate specific antigen (PSA) has been widely used as a standard method for PCa screening. However, PSA diagnostic efficacy within early-stage PCa patients with a PSA level of 4–10 ng mL−1 is always controversial. Therefore, the development of new methods to assist clinical PSA diagnosis is greatly desired. Herein, we report the fabrication of antibody-modified reduced graphene oxide films, which can be used to efficiently detect CTCs in PCa patients with PSA levels of 4–10 ng mL−1. The antibody-modified reduced graphene oxide (rGO) films were fabricated by spray coating reduced graphene oxide solution onto a smooth glass slide and then modifying it with anti-epithelial cell adhesion molecules (anti-EpCAMs) and anti-prostate specific membrane antigen (anti-PSMA). The rGO films exhibited an excellent ability to capture CTCs from the blood of PCa patients with PSA levels of 4–10 ng mL−1 and the efficiency could reach 60% (6/10). Our approach for highly efficient detection of CTCs in early-stage PCa patients may provide great potential in assisting clinical cancer diagnosis.

Two-stage residual inclusion for survival data and competing risks-An instrumental variable approach with application to SEER-Medicare linked data.

Instrumental variable is an essential tool for addressing unmeasured confounding in observational studies. Two-stage predictor substitution (2SPS) estimator and two-stage residual inclusion (2SRI) are two commonly used approaches in applying instrumental variables. Recently, 2SPS was studied under the additive hazards model in the presence of competing risks of time-to-events data, where linearity was assumed for the relationship between the treatment and the instrument variable. This assumption may not be the most appropriate when we have binary treatments. In this paper, we consider the 2SRI estimator under the additive hazards model for general survival data and in the presence of competing risks, which allows generalized linear models for the relation between the treatment and the instrumental variable. We derive the asymptotic properties including a closed-form asymptotic variance estimate for the 2SRI estimator. We carry out numerical studies in finite samples and apply our methodology to the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database comparing radical prostatectomy versus conservative treatment in early-stage prostate cancer patients.

Cost Effectiveness of the Oncotype DX Genomic Prostate Score for Guiding Treatment Decisions in Patients With Early Stage Prostate Cancer

ObjectiveTo determine the cost-effectiveness of using the Oncotype DX Genomic Prostate Score (GPS), a 17-gene expression assay that can be used to inform decisions regarding active surveillance (AS) vs immediate treatment. MethodsWe developed a Markov model simulating 20-year outcomes for 65-year-old men with very low-, low-, or favorable intermediate-risk prostate cancer undergoing AS vs immediate treatment using GPS vs no testing. Utilities, costs, and probabilities were extracted from the literature and National Medicare Fee Schedules to determine incremental cost-effectiveness ratios (ICER) from a payer perspective. ResultsIn the overall cohort, the ICER of GPS-guided therapy was $31,394 per quality-adjusted life-year (QALY). When stratified by risk group, the ICER was $25,343 per QALY in very low-risk, $28,911 per QALY in low-risk, and $39,695 per QALY in favorable intermediate-risk patients. On sensitivity analysis, findings were robust against a willingness-to-pay of $100,000 per QALY to variations in key model parameters, including the cost of annual management of AS, probability of exiting AS to treatment, cost of treatment, and probability of biochemical failure post-treatment. However, the cost-effectiveness was sensitive to small differences in the utility of AS and the utility of no evidence of disease post-treatment states. ConclusionThe use of the GPS was cost-effective in guiding treatment decisions regarding AS vs immediate treatment. The cost-effectiveness was sensitive to small differences in the utilities of the AS and no evidence of disease post-treatment states, highlighting the importance of assessing patient preferences.

Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population

Background:Germline mutations in BRCA2 have been linked to a higher risk of prostate cancer (PCa), and high frequency of BRCA1 and BRCA2 (BRCA1/2) gene alterations was recently reported in metastatic castration-resistant PCa specimens. Mutations in BRCA2 vary in racial and ethnic groups including African-American (AA) and Caucasian-American (CA) populations.Methods:BRCA1 and BRCA2 genes were sequenced (Ion AmpliSeq targeted sequencing) in archived blood DNA specimens in 1240 PCa patients, including 30% AA patients, in three different cohorts: localized early stage (T2) PCa (N = 935); advanced PCa (50% T3–4) (N = 189); and metastatic PCa (N = 116). The sequences were analyzed for known and novel mutations in BRCA1/2. Statistical analyses were performed to determine associations of the mutations with clinico-pathological parameters.Results:BRCA2 mutations with known pathogenic annotation were significantly more prevalent in men with advanced and metastatic PCa (3.1%) compared to patients with an organ-confined disease (0.7%). AA patients carried more frequently BRCA1/2 variants of unknown significance (VUS) when compared to Caucasian Americans (4.6 vs. 1.6%, respectively). Significantly, pathogenic BRCA2 mutations in men with localized early stage PCa increased the risk of distant metastasis.Conclusions:Germline variants of unknown significance in BRCA1/2 are more frequent in AA than CA PCa patients; however, the prevalence of pathogenic mutations were similar across the races. Patients carrying BRCA2 pathogenic mutations are more likely to progress to metastasis.

Metformin alters H2A.Z dynamics and regulates androgen dependent prostate cancer progression.

Epigenetic mechanisms involved in prostate cancer include hypermethylation of tumor suppressor genes, general hypomethylation of the genome, and alterations in histone posttranslational modifications (PTMs). In addition, over expression of the histone variant H2A.Z as well as deregulated expression of Polycomb group proteins including EZH2 have been well-documented. Recent evidence supports a role for metformin in prostate cancer (PCa) treatment. However, the mechanism of action of metformin in PCa is poorly understood. We provide data showing that metformin epigenetically targets PCa by altering the levels and gene binding dynamics of histone variant H2A.Z. Moreover, we show that the increase in H2A.Z upon metformin treatment occurs preferentially due to H2A.Z.1 isoform. Chromatin immunoprecipitation (ChIP)-RT PCR analysis indicates that metformin treatment results in an increased H2A.Z occupancy on the androgen receptor (AR) and AR-regulated genes that is more prominent in the androgen dependent AR positive LNCaP cells. Repression of H2A.Z.1 gene by siRNA–mediated knock down identified this H2A.Z isoform to be responsible. Based on preliminary data with an EZH2-specific inhibitor, we suggest that the effects of metformin on the early stages of PCa may involve both EZH2 and H2A.Z through the alteration of different molecular pathways.

Classification of Prostate Cancer using Wavelet Neural Network

&lt;p&gt;Prostate cancer is the century disease that endanger the life of men. The earlier to diagnose the disease, the probability of curing this disease is higher. Therefore, new approaches of diagnosis is required to effectively detect the prostate cancer in early stage compared to the traditional methods. Therefore, WNN is a new adopted approach in prostate cancer diagnosis. Morlet function is used as an activation function of wavelet neural network (WNN) and back propagation (BP) is applied to train the Wavelet network. WNN classifies prostate cancer according to three factors: patient age, PSA level, and prostate volume. WNN performance is evaluated based on the percentage of classification and the computational complexity of several cases. The results of the simulation show that WNN has lower mean squared error (MSE) than the Neural Network (NN).&lt;/p&gt;

Active Surveillance for Low-risk Prostate Cancer: Are All Criteria Similar?

Active Surveillance (AS) is a therapeutic strategy for early-stage Prostate Cancer (PCa) conceived to balance early detection of aggressive disease and overtreatment of indolent tumor. Several active surveillance protocols have been published over the years, however the risk of misclassification still exist. In this review, we revised the current criteria of AS and evaluated the characteristics of potential risk factors of misclassification or deferred treatment. We did a systematic search of the MEDLINE database, from 1993 to May 2015, according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement guidelines and limited to the English language. The search terms used included "prostate cancer" and "active surveillance" and "criteria. We have excluded from the study reviews and editorial comments as well as multiple papers from the same data sets. Although the follow-up of reported studies was a quite short compared to the duration of the disease, the data are sufficient to conclude that active surveillance should be offered to men with low-risk disease and to men with intermediate risk and poor life expectancy. The present challenge, in fact, is to differentiate the clinically silent disease from the unfavorable course by identifying the right timing for any deferred treatment. This is made particularly difficult by the absence of randomized controlled trials directly comparing different AS monitoring methods. As summarized in this review, it is still difficult to select patients eligible for active surveillance and differentiate them from those that should move to active treatment. From the data, currently available in the literature, however, it is possible to recommend active surveillance to men with low-risk disease and to men with intermediate-risk disease but with short life expectancy.