Filamin A Is a Prognostic Serum Biomarker for Differentiating Benign Prostatic Hyperplasia from Prostate Cancer in Caucasian and African American Men.

Prostate cancer represents a significant health risk to aging men, in which diagnostic challenges to the identification of aggressive cancers remain unmet. Prostate cancer screening is driven by the prostate-specific antigen (PSA); however, in men with benign prostatic hyperplasia (BPH) due to an enlarged prostate and elevated PSA, PSA's screening utility is diminished, resulting in many unnecessary biopsies. To address this issue, we previously identified a cleaved fragment of Filamin A (FLNA) protein (as measured with IP-MRM mass spectrometry assessment as a prognostic biomarker for stratifying BPH from prostate cancer and subsequently evaluated its expanded utility in Caucasian (CA) and African American (AA) men. All men had a negative digital rectal examination (DRE) and PSA between 4 and 10 ng/mL and underwent prostate biopsy. In AA men, FLNA serum levels exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.71 AUC and 12.2 OR in 48 men with BPH and 60 men with PCa) and outperformed PSA (0.50 AUC, 2.2 OR). In CA men, FLNA serum levels also exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.74 AUC and 19.4 OR in 191 men with BPH and 109 men with PCa) and outperformed PSA (0.46 AUC, 0.32 OR). Herein, we established FLNA alone as a serum biomarker for stratifying men with BPH vs. those with high Gleason (7-10) prostate cancers compared to the current diagnostic paradigm of using PSA. This approach demonstrates clinical actionability of FLNA alone without the requirement of prostate volume measurement as a test with utility in AA and CA men and represents a significant opportunity to decrease the number of unnecessary biopsies in aggressive prostate cancer diagnoses.

Educational Approaches Using Simulation for Psychiatric Risk Assessment: a Scoping Review.

OBJECTIVE: The ability to assess a patient's risk of harm to self or others is a core competency for mental health clinicians which can have significant patient outcomes. With the growth of simulation in medical education, there is an opportunity to enhance education outcomes for psychiatric risk assessment. The purpose of this study was to determine how simulation is used to build competency in risk assessment and map its educational outcomes. METHODS: The authors conducted a systematic scoping review using the Arksey and O'Malley framework. Electronic database searches were conducted by an academic librarian. Studies published before August 2022 which described simulation activities aimed at training clinicians in suicide, self-harm, and/or violence risk assessment were screened for eligibility. RESULTS: Of the 21,814 articles identified, 58 studies were selected for inclusion. The majority described simulations teaching suicide risk assessment, and there was a notable gap for building competency in violence risk assessment. Simulation utility was demonstrated across emergency, inpatient, and outpatient settings involving adult and pediatric care. The most common simulation modality was patient actors. A smaller subset implemented technological approaches, such as automated virtual patient avatars. Outcomes included high learner satisfaction, and increases in psychiatric risk assessment knowledge, competency, and performance. CONCLUSION: Simulation as an adjuvant to existing medical curricula can be used to teach risk assessment in mental health. Based on the results of our review, the authors provide recommendations for medical educators looking to design and implement simulation in mental health education.

Validation of diagnostic accuracy of a handheld, smartphone-based rhythm recording device.

AIM: Evaluation of the diagnostic accuracy of a rhythm recording device, for detection of atrial tachyarrhythmia (ATA) and atrial fibrillation (AF) compared to 12-lead-electrocardiogram (12-L-ECG). RESEARCH DESIGN AND METHODS: Two hundred 12-L-ECGs (reference standard) and Coala Heart Monitor (CHM) recordings (index test) were collected from 189 patients. Two electrophysiologists independently performed manual analysis of all 12-L-ECGs and CHM recordings in random order. The CHM recordings were also analyzed by an automatic algorithm and compared to the results of the reference standard. RESULTS: Manual analysis of CHM for ATA showed a sensitivity of 98.9% (95% confidence interval (CI): 94.0-100) and a specificity of 100% (CI: 96.6-100). Manual analysis for AF had a sensitivity of 100% (CI: 95.3-100) and a specificity of 97.5% (CI: 93.0-99.5). Automatic analysis for ATA showed a sensitivity of 93.5% (CI: 86.3-97.6) and a specificity of 92.6% (CI: 85.9-96.7). Automatic analysis for AF showed a sensitivity of 97.4% (CI: 91.0-99.7) and a specificity of 86.1% (CI: 78.6-91.7). CONCLUSION: CHM has a very high accuracy for ATA and AF in manual analysis and a high accuracy for ATA and AF in automatic analysis, making the device suitable for screening.

Elements That Influence the Development of Attention Deficit Hyperactivity Disorder (ADHD) in Children.

Various factors may have a role in the development of attention deficit hyperactivity disorder (ADHD). Although the specific pathophysiology of this disease is still not entirely understood, it is believed to be caused by a mix of genetic, maternal, dietary, and environmental factors. The effect of these factors can determine the severity of ADHD; for example, some of them are dose-dependent, but there is a typical pattern that all are known to be associated with either early childhood exposure or maternal exposure during pregnancy. Some factors share a similar mechanism of affecting pathways and increasing the risk of ADHD. ADHD is not a disorder that can be detected before symptoms appear in a child, making it more challenging to anticipate even if a child has been exposed to a known trigger. Environmental pollutants were investigated, and it was shown that there was a link between ADHD in childhood and exposure to pollutants throughout childhood or during pregnancy. It is well known that maternal health is a significant factor in the unborn child's development in many health aspects. The central nervous system (CNS) is a primary system that can suffer irreversible damage from health conditions, stress, depression, or specific nutritional deficiency when the pregnant mother is subjected to these conditions. Even though numerous studies have been conducted to investigate the probable causes of ADHD, with some of them having robust findings, no conclusive explanation can be provided to identify a definitive cause or a risk factor.

Can Phosphodiesterase 4 Inhibitor Therapy Be Used in Respiratory Diseases Other Than Chronic Obstructive Pulmonary Disease?

Selective phosphodiesterase 4 (PDE4) inhibitors have been extensively studied for the treatment of various respiratory diseases due to their broad anti-inflammatory and/or bronchodilator effects. Roflumilast, an oral selective PDE4 inhibitor, is currently used as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) with chronic bronchitis. Despite its proven efficacy in other respiratory disorders, including asthma, no other PDE4 inhibitor is approved for respiratory pathologies. This systematic review summarizes the therapeutic action of PDE4 inhibitors, their limitations, recent therapeutic success, and future targets for their use in respiratory diseases other than COPD. An electronic literature search was conducted on four databases, namely, PubMed, PubMed Central, Google Scholar, and ScienceDirect, to collect data on related studies done in humans and published in the English language in the last five years. After extensive analysis and quality appraisal, 11 studies were eligible and thus included in this review, consisting of two randomized controlled trials (RCT), one systematic review and meta-analysis, and eight literature reviews. Roflumilast is not approved for the treatment of asthma due to associated adverse effects and comparable efficacy to inhaled corticosteroids, which are considered the mainstay of asthma maintenance therapy. Hence, the importance of balancing the efficacy with minimizing the side effects is highlighted. Tanimilast (CHF6001), an inhalational selective PDE4 inhibitor, and ensifentrine, a combined PDE3/4 inhibitor, demonstrate the recent therapeutic success in asthma and warrant further large-scale clinical studies. Future researchers will focus on the specific endotype than the phenotype in asthma as a meaningful therapeutic approach due to the high heterogeneity noted in asthma. Current evidence suggests the possibility of PDE4 inhibitors as a novel therapeutic option for chronic cough, allergic rhinitis, and cystic fibrosis. Further evidence from new studies is eagerly anticipated to better understand the efficacy and safety of PDE4 inhibitors in these respiratory diseases.

Are There Any Cardioprotective Effects or Safety Concerns of Erythropoietin in Patients With Myocardial Infarction? A Systematic Review.

Myocardial infarction (MI) is a global cause of morbidity and mortality. MI is the outcome of a chronic process termed atherosclerosis, a buildup of fatty and other substances called plaques inside the coronary vessels, causing hardening and thickening of the arterial wall. Erythropoietin (EPO) is a pleiotropic cytokine released mainly by the kidneys in adults. Besides its well-known erythropoietic functions, EPO possesses anti-apoptotic, mitogenic, and angiogenic effects. This review aims to analyze the strength of any therapeutic or protective value of EPO on the heart and safety concerns regarding its administration in MI individuals. This systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Four databases (PubMed, PubMed Central, Google Scholar, and Sciences Direct) were employed to search for articles published in the last 10 years. Focused studies were relevant articles in the English language, trials, reviews, meta-analyses, and studies with a control group. Following the quality assessment process, nine studies were eligible and hence were included in the review consisting of six randomized controlled trials and three systematic reviews and meta-analyses. Contrary to preclinical studies, EPO administration did not significantly have notable effects on mortality, major adverse cardiovascular events, or infarction size reduction. Significant left ventricle ejection fraction amelioration was not appreciated either. However, EPO seems to reduce the incidence of post-MI arrhythmias.

Recognizing Histopathological Simulators of Melanoma to Avoid Misdiagnosis.

Melanocytic lesions have a wide morphological spectrum, ranging from benign nevi to malignant melanoma. In contrast to a diagnosis of a benign nevus, a diagnosis of melanoma could mean intensive treatment, lifetime monitoring, and a worse prognosis. Therefore, melanocytic tumors are notoriously challenging and associated with a high risk of litigation in surgical pathology. After describing the basic features of nevi and melanoma, this article describes the detailed clinical and histological features of those lesions that share many similar features with melanoma. The entities included are Spitz nevi and atypical Spitz tumors (AST), Reed nevus, dysplastic nevus, cellular blue nevus (CBN), deep penetrating nevus, combined nevus, recurrent nevus, irritated nevus, congenital pattern nevus, acral nevus, and nevi of special sites. Knowledge of these imitators can help pathologists distinguish between benign and malignant cases and avoid misdiagnosis.

The Role of Type 2 Diabetes in Pancreatic Cancer.

The incidence of type 2 diabetes mellitus (T2DM) and its potential complications, such as cancers, are increasing worldwide at an astounding rate. There are many factors such as obesity, diabetes, alcohol consumption, and the adoption of sedentary lifestyles that are driving pancreatic cancer (PC) to become one of the leading causes of cancer mortality in the United States. PC is notorious for its generic symptoms and late-stage presentation with rapid metastasis. The connection between T2DM and the risk of PC development is multifaceted and complex. Some of the proposed theories reveal that chronic inflammation, insulin resistance, hyperinsulinemia, hyperglycemia, and abnormalities in the insulin and insulin-like growth factor axis (IGF) contribute to the disease association between these two conditions. This literature review aims to highlight relevant studies and explore the molecular mechanisms involved in the etiology of diabetes and its impact on PC development, as well as the role of anti-diabetic agents on PC. Despite extensive studies, the exact interaction between T2DM and PC remains obscure and will need further investigation. According to current knowledge, there is a substantial link between diabetes, obesity, and dietary patterns in the development and progression of PC. Consequently, focusing our efforts on preventive measures by reducing modifiable risk factors remains the most effective strategy to reduce the risk of PC at this time. Antidiabetic drugs can have various effects on the occurrence and prognosis of PC with metformin offering a clear benefit of inhibiting PC and insulin increasing the risk of PC. The development of future novel therapies will require a deeper knowledge of the triggering mechanisms and interplay between these two disease states.

A Systematic Review of Maternal Serum Syndecan-1 and Preeclampsia.

Exploration of novel biomarkers has been gaining popularity in preeclampsia, which is currently being diagnosed based on clinical criteria alone. Soluble syndecan-1, released from one of the proteoglycans associated with the syncytiotrophoblastic layer of the placenta, is affected in patients with abnormal placentation. This article is the first systematic literature review that evaluates the relationship between the antepartum serum levels of the syndecan-1 and preeclampsia. Eight studies were selected after screening and quality appraisal, and data were analyzed. The serum concentration of syndecan-1 was found to correlate positively with the gestational age in all pregnancies and negatively with the systolic blood pressure in patients with preeclampsia. Extremely low levels of soluble syndecan-1 may be helpful as a predictor for the development of preeclampsia during gestation.

Effect of Thyroxine and Thyrotropin on Bone Mineral Density in Postmenopausal Women: A Systematic Review.

The effect of thyroid hormones on bone mineral density in postmenopausal women has been reported but is not completely established. To better understand this relationship, this systematic review of the reported association, differences, and effects of thyroxine and/or thyrotropin levels on bone mineral density was conducted. An electronic literature search was conducted on MEDLINE, PMC, Google Scholar, Cochrane Library, and Science Direct from inception to April 2022; 20 studies were identified which include five quasi-experimental studies, three community cohort studies, and 12 hospital-based cross-sectional studies. Following an extensive evaluation, it was difficult to conclusively determine the association or effect of thyroxine or thyrotropin levels on bone mineral density in postmenopausal women. It is therefore suggested to conduct additional non-randomized or randomized control studies on this topic for the benefit of postmenopausal women. Particular attention should be given to the adjustment of age, body mass index, smoking status, alcohol consumption, and dietary calcium in future research on this topic for rigorous analysis.

Exercise Prescription and the Minimum Dose for Bone Remodeling Needed to Prevent Osteoporosis in Postmenopausal Women: A Systematic Review.

The aim of this review is to analyze previously conducted randomized controlled trials and investigate the relationship between various exercise regimes and their effect on bone mineral density in postmenopausal women. To determine whether exercise can be used as a non-pharmacological modality for osteoporosis prevention, a thorough search was performed on various databases (PubMed, ScienceDirect, and Google Scholar). Only bone mineral density studies and trials with intervention versus control groups were included, and 13 randomized controlled trials were deemed relevant. The majority of trials concluded that exercise positively impacted bone mineral density in postmenopausal women. High-impact exercises seem to have the most significant effect on bone mineral density due to compression, shear stress, and high loading on the bone, causing bone remodeling. Considering all the limitations, exercise seems to be an effective tool for preventing postmenopausal osteoporosis.

The Outcome of Surgical Intervention (Ventriculoperitoneal Shunt and Endoscopic Third Ventriculostomy) in Patients With Hydrocephalus Secondary to Tuberculous Meningitis: A Systematic Review.

The objective of this study is to analyze the outcome of the safety and efficiency of the surgical interventions (ventriculoperitoneal shunt [VPS] and endoscopic third ventriculostomy [ETV]) in patients with hydrocephalus due to tuberculous (TB) meningitis. A systematic literature search has been conducted using PubMed, Google Scholar, PMC, and ScienceDirect databases from 2001 to 2022 April. A total of 16 studies have been included, irrespective of their design. These studies include patients diagnosed with hydrocephalus secondary to TB meningitis (TBM) treated with VPS or ETV. A systematic review was conducted to determine the efficiency of surgical procedures based on the outcomes and complications associated with these procedures. A total of 2207 patients (aged one month to 68 years) have been included in this study, out of which 1723 underwent VPS and 484 underwent ETV. The overall success rate in the VPS group varied from 21.1% to 77.5%. The overall success rate in the ETV group ranged from 41.1% to 77%. The overall complications rate in the VPS group varied from 10% to 43.8%, and the complications rate in the ETV group varied from 3.8% to 22.5%. After ruling out the significant differences in the average percentages of outcomes and complications followed by VPS and ETV, ETV is suggested in patients with chronic phases of illness because the chances of ETV failure are high during the initial stage. The uncertainty of the ETV gradually decreases over time. To attain favourable long-term outcomes with ETV in patients with TBM hydrocephalus (TBMH), ETV should be performed after chemotherapy, anti-tubercular treatment, and steroids. In addition, ETV is considered beneficial over VP shunt as associated long-term complications are significantly less compared to VP shunt. In contrast, VP shunt is suggested as a modified Vellore grading which shows a more favourable outcome in patients with acute illness than ETV.

Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes.

In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.

An Overview of Ascariasis Involvement in Gallbladder Disease: A Systematic Review of Case Reports.

Ascaris lumbricoides is the most common type of helminth infection in humans. It affects more than one billion of the world's population. Children living in developing nations are prone to ascariasis, presenting with obstructive biliary illnesses. Migration of Ascaris worms through the major duodenal papilla to the hepatobiliary system leads to symptoms of biliary colic and complications along the biliary tree. In April 2022, we performed a systematic review of case reports to identify and examine cases of gallbladder ascariasis worldwide. A methodical search using PubMed, Semantic Scholar, ScienceDirect, and Directory of Open Access Journals yielded 2773 studies. After duplicate removal, title, abstract, and content screening, retrieval, and quality assessment, 13 studies met the criteria for this systematic review of case reports. The cases and results from these 13 studies revealed gallbladder ascariasis in different age groups worldwide. This systematic review discusses ascariasis, explicitly highlighting its presence in the gallbladder, symptomatic presentation, laboratory/imaging findings, complications, and approach to management.

Clinical utility of a serum biomarker panel in distinguishing prostate cancer from benign prostate hyperplasia.

Prostate-specific antigen (PSA) screening for prostate cancer (PCa) is limited by the lack of specificity but is further complicated in the benign prostatic hyperplasia (BPH) population which also exhibit elevated PSA, representing a clear unmet need to distinguish BPH from PCa. Herein, we evaluated the utility of FLNA IP-MRM, age, and prostate volume to stratify men with BPH from those with PCa. Diagnostic performance of the biomarker panel was better than PSA alone in discriminating patients with negative biopsy from those with PCa, as well as those who have had multiple prior biopsies (AUC 0.75 and 0.87 compared to AUC of PSA alone 0.55 and 0.57 for patients who have had single compared to multiple negative biopsies, respectively). Of interest, in patients with PCa, the panel demonstrated improved performance than PSA alone in those with Gleason scores of 5-7 (AUC 0.76 vs. 0.56) and Gleason scores of 8-10 (AUC 0.74 vs. 0.47). With Gleason scores (8-10), the negative predictive value of the panel is 0.97, indicating potential to limit false negatives in aggressive cancers. Together, these data demonstrate the ability of the biomarker panel to perform better than PSA alone in men with BPH, thus preventing unnecessary biopsies.

A Urine Exosome Gene Expression Panel Distinguishes between Indolent and Aggressive Prostate Cancers at Biopsy.

PURPOSE: Prostate cancer is predominantly indolent at diagnosis with a small fraction (15% to 25%) representing aggressive subtype (Gleason score 7-10), which is prone to metastatic progression. It is critical to explore noninvasive assays for the early detection of this aggressive subtype, when it still can be treated effectively. Additionally, there is an emerging need to develop markers that perform equally well across races, as racial differences in the prevalence and mortality of prostate cancer has become evident. MATERIALS AND METHODS: First catch, nondigital rectal examination urine specimens were collected from patients undergoing diagnostic biopsy. Total RNA was extracted from urinary exosomes and a quantitative expression assay protocol using droplet digital polymerase chain reaction was developed for detection of candidate genes in exosomal mRNAs from urine. Clinical performance for the gene expression assay was evaluated to predict high grade cancer (Gleason score 7-10) from low grade cancer (Gleason score 6) and cancer negative cases at biopsy. Assay performance was examined in combination with standard of care to determine improvement in model prediction. RESULTS: In a racially diverse patient cohort a 2-gene panel (PCA3, PCGEM1), in combination with standard of care variables, significantly improved the prediction of high grade cancer at diagnosis compared to standard of care variables alone (AUC 0.88 vs 0.80, respectively, p=0.016). Decision curve analysis showed that there is a benefit of adopting the gene panel for detection of high grade cancer compared to standard of care alone. CONCLUSIONS: This study highlights the potential for developing broadly applicable prostate cancer diagnostic biomarker panels for aggressive prostate cancer using our novel gene expression assay platform.

Association of germline genetic variants with TMPRSS2-ERG fusion status in prostate cancer.

INTRODUCTION: Oncogenic activation of ERG resulting from TMPRSS2-ERG gene fusion is a key molecular genetic alteration in prostate cancer (CaP). The frequency of ERG fusion is variable by race; however, there are limited data available on germline polymorphisms associating with ERG fusion status. The goal of this study is to identify the inherited risk variants associating with ERG status of CaP. MATERIALS AND METHODS: SNP genotyping was performed on the Illumina platform using Infinium Oncoarray SNP chip on blood derived genomic DNA samples from 400 patients treated by radical prostatectomy at a single military institution. ERG status was determined in whole mounted prostate specimens by immuno-histochemistry (IHC) for ERG protein expression. Data analysis approaches included association analyses based on EMMAX and imputation by IMPUTE2. Imputed SNPs were validated by ddPCR. RESULTS: SNP genotyping analysis using imputation identified rs34349373 (p 4.68 × 10 -8 ) and rs2055272 (p 5.62 × 10-8) in TBC1D22B to be significantly associated with ERG fusion status in index tumor and non-index tumor foci. Imputed SNP rs2055272 was further experimentally validated by ddPCR with 98.04% (100/102) concordance. Initial discovery analysis based on SNPs on Oncoarray SNP chip, showed significant (p 10-5) association for SNPs (rs6698333, rs1889877, rs3798999, rs10215144, rs3818136, rs9380660 and rs1792695) with ERG fusion status. The study also replicated two previously known ERG fusion associated SNPs (rs11704416 in chromsome 22; rs16901979 in chromosome 8). CONCLUSIONS: This study identified SNPs associated with ERG status of CaP. IMPACT: The findings may contribute towards defining the underlying genetics of ERG positive and ERG negative CaP patients.

Multi-omic serum biomarkers for prognosis of disease progression in prostate cancer.

BACKGROUND: Predicting the clinical course of prostate cancer is challenging due to the wide biological spectrum of the disease. The objective of our study was to identify prostate cancer prognostic markers in patients 'sera using a multi-omics discovery platform. METHODS: Pre-surgical serum samples collected from a longitudinal, racially diverse, prostate cancer patient cohort (N = 382) were examined. Linear Regression and Bayesian computational approaches integrated with multi-omics, were used to select markers to predict biochemical recurrence (BCR). BCR-free survival was modeled using unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis, adjusted for key pathologic variables. Receiver operating characteristic (ROC) curve statistics were used to examine the predictive value of markers in discriminating BCR events from non-events. The findings were further validated by creating a training set (N = 267) and testing set (N = 115) from the cohort. RESULTS: Among 382 patients, 72 (19%) experienced a BCR event in a median follow-up time of 6.9 years. Two proteins-Tenascin C (TNC) and Apolipoprotein A1V (Apo-AIV), one metabolite-1-Methyladenosine (1-MA) and one phospholipid molecular species phosphatidic acid (PA) 18:0-22:0 showed a cumulative predictive performance of AUC = 0.78 [OR (95% CI) = 6.56 (2.98-14.40), P < 0.05], in differentiating patients with and without BCR event. In the validation set all four metabolites consistently reproduced an equivalent performance with high negative predictive value (NPV; > 80%) for BCR. The combination of pTstage and Gleason score with the analytes, further increased the sensitivity [AUC = 0.89, 95% (CI) = 4.45-32.05, P < 0.05], with an increased NPV (0.96) and OR (12.4) for BCR. The panel of markers combined with the pathological parameters demonstrated a more accurate prediction of BCR than the pathological parameters alone in prostate cancer. CONCLUSIONS: In this study, a panel of serum analytes were identified that complemented pathologic patient features in predicting prostate cancer progression. This panel offers a new opportunity to complement current prognostic markers and to monitor the potential impact of primary treatment versus surveillance on patient oncological outcome.

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.

Autoantibodies against oncogenic ERG protein in prostate cancer: potential use in diagnosis and prognosis in a panel with C-MYC, AMACR and HERV-K Gag.

Overdiagnosis and overtreatment of prostate cancer (CaP) is attributable to widespread reliance on PSA screening in the US. This has prompted us and others to search for improved biomarkers for CaP, to facilitate early detection and disease stratification. In this regard, autoantibodies (AAbs) against tumor antigens could serve as potential candidates for diagnosis and prognosis of CaP. Towards this, our goals were: i) To investigate whether AAbs against ERG oncoprotein (overexpressed in 25-50% of Caucasian American and African American CaP) are present in the sera of CaP patients; ii) To evaluate an AAb panel to enhance CaP detection. The results using an enzyme-linked immunosorbent assay (ELISA) showed that anti-ERG AAbs are present in a significantly higher proportion in the sera of CaP patients compared to healthy controls (p = 0.0001). Furthermore, a panel of AAbs against ERG, AMACR and human endogenous retrovirus-K Gag successfully differentiated CaP patient sera from healthy controls (AUC = 0.791). These results demonstrate for the first time that anti-ERG AAbs are present in the sera of CaP patients. In addition, the data also suggest that AAbs against ERG together with AMACR and HERV-K Gag may be a useful panel of biomarkers for diagnosis and prognosis of CaP.