Follicle-Stimulating Hormone Exacerbates Cardiovascular Disease in the Presence of Low or Castrate Testosterone Levels.

Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T, modulates the cardiovascular effects associated with low T or castration. FSHß-/-:low-density lipoprotein receptor (LDLR)-/- mice, untreated or castrated (orchiectomy, gonadotropin-releasing hormone agonist or antagonist), demonstrated significantly less atherogenesis compared with similarly treated LDLR-/- mice, but not following FSH delivery. Smaller plaque burden in LDLR-/- mice receiving gonadotropin-releasing hormone antagonists vs agonists were nullified in FSHß-/-:LDLR-/- mice. Atherosclerotic and necrotic plaque size and macrophage infiltration correlated with serum FSH/T. In patients with prostate cancer, FSH/T following androgen-deprivation therapy initiation predicted cardiovascular events. FSH facilitates cardiovascular disease when T is low or eliminated.

Diagnostic Performance of 68Ga Prostate-specific Membrane Antigen PET/MRI Compared with Multiparametric MRI for Detecting Clinically Significant Prostate Cancer.

Background Gallium 68 (68Ga) prostate-specific membrane antigen (PSMA) PET/MRI may improve detection of clinically significant prostate cancer (CSPC). Purpose To compare the sensitivity and specificity of 68Ga-PSMA PET/MRI with multiparametric MRI for detecting CSPC. Materials and Methods Men with prostate specific antigen levels of 2.5-20 ng/mL prospectively underwent 68Ga-PSMA PET/MRI, including multiparametric MRI sequences, between June 2019 and March 2020. Imaging was evaluated independently by two radiologists by using the Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. Sensitivity and specificity for CSPC (International Society of Urological Pathology grade group ≥ 2) were compared for 68Ga-PSMA PET/MRI and multiparametric MRI by using the McNemar test. Decision curve analysis compared the net benefit of each imaging strategy. Results Ninety-nine men (median age, 67 years; interquartile range, 62-71 years) were included; 79% (78 of 99) underwent biopsy. CSPC was detected in 32% (25 of 78). For CSPC, specificity was higher for 68Ga-PSMA PET/MRI than multiparametric MRI (76% [95% CI: 62, 86] vs 49% [95% CI: 35, 63], respectively; P < .001). Sensitivity was similar (88% [95% CI: 69, 98] vs 92% [95% CI: 74, 99], respectively; P > .99). For PI-RADS 3 lesions, specificity was also higher for 68Ga-PSMA PET/MRI than for multiparametric MRI: 86% (95% CI: 73, 95) versus 59% (95% CI: 43, 74), respectively (P = .002). Decision curve analysis showed that biopsies targeted to PSMA uptake increased the net benefit of multiparametric MRI only among PI-RADS 3 lesions. The net benefit of targeted biopsy for a PI-RADS 3 lesion with PSMA uptake was higher across all threshold probabilities over 8%. The net benefit of targeted biopsy was similar for PI-RADS 4 and 5 lesions, regardless of PSMA uptake. Conclusions Gallium 68 prostate-specific membrane antigen PET/MRI improved specificity for clinically significant prostate cancer compared with multiparametric MRI, particularly in Prostate Imaging Reporting and Data System grade 3 lesions. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Williams and Estes in this issue.

Cardiovascular Proteomics: A Post Hoc Analysis from a Phase II Randomized Clinical Trial Comparing GnRH Antagonist vs GnRH Agonist among Men with Advanced Prostate Cancer.

PURPOSE: Recent studies demonstrated reduced cardiovascular (CV) risk with gonadotropin-releasing hormone (GnRH) antagonist, yet the underlying mechanism remains undetermined. The objective of this study was to examine longitudinal changes over time in established CV related proteins among men treated with GnRH agonists vs GnRH antagonist. MATERIALS AND METHODS: We performed a proteomics analysis of serum samples collected during a phase II randomized study among 80 men with advanced prostate cancer and preexisting CV disease who were randomized to receive a GnRH agonist (39) or GnRH antagonist (41) for 1 year. Serum samples were collected at baseline and at 3, 6 and 12 months following treatment, and analyzed levels of 188 proteins using the CV panel II and III of the Olink Multiplex platform (Olink Proteomics AB, Uppsala, Sweden). We fitted a linear mixed effects model to assess evidence of a treatment effect across CV related protein values. This included terms for treatment arm, protein levels and time-by-treatment interaction. Results were corrected for multiple testing using the Benjamini-Hochberg method. RESULTS: The CV proteomics analysis included 283 samples from 78 subjects. We identified 5 proteins with distinct patterns over time depending on study arm: human chitotriosidase, macrophage receptor with collagenous structure, cathepsin D, superoxide dismutase 2 and hydroxyacid oxidase 1. All 5 are associated with plaque stability and demonstrated an increased level among subjects in the GnRH antagonist arm compared to agonist. CONCLUSIONS: We compared longitudinal changes in CV proteins among men using androgen deprivation therapy. Our results support a direct protective effect of GnRH antagonist on plaque stability rather than a hazardous consequence of GnRH agonists on plaque rupture. This is a hypothesis generating study, and requires further confirmation.

Role of Metabolic Syndrome in Prostate Cancer Development.

Prostate cancer and metabolic syndrome are common among men in the Western world. As the population grows older and life expectancy increases, the rates of both diseases are expected to increase. We now recognize that metabolic syndrome and prostate cancer interact. Metabolic syndrome may be a risk factor for prostate cancer and may also worsen outcomes. At the same time, treatment for prostate cancer may exacerbate metabolic syndrome and cardiac disease. This mini-review summarizes current evidence and puts it into clinical prospective. PATIENT SUMMARY: Metabolic syndrome is now a global epidemic. It is characterized by obesity, insulin resistance, high blood pressure, and high blood lipids. There is a complex interaction between metabolic syndrome and the risk of prostate cancer, as treatment of one disease may affect the other.

Diffusion Is Directional: Innovative Diffusion Tensor Imaging to Improve Prostate Cancer Detection.

In the prostate, water diffusion is faster when moving parallel to duct and gland walls than when moving perpendicular to them, but these data are not currently utilized in multiparametric magnetic resonance imaging (mpMRI) for prostate cancer (PCa) detection. Diffusion tensor imaging (DTI) can quantify the directional diffusion of water in tissue and is applied in brain and breast imaging. Our aim was to determine whether DTI may improve PCa detection. We scanned patients undergoing mpMRI for suspected PCa with a DTI sequence. We calculated diffusion metrics from DTI and diffusion weighted imaging (DWI) for suspected lesions and normal-appearing prostate tissue, using specialized software for DTI analysis, and compared predictive values for PCa in targeted biopsies, performed when clinically indicated. DTI scans were performed on 78 patients, 42 underwent biopsy and 16 were diagnosed with PCa. The median age was 62 (IQR 54.4-68.4), and PSA 4.8 (IQR 1.3-10.7) ng/mL. DTI metrics distinguished PCa lesions from normal tissue. The prime diffusion coefficient (λ1) was lower in both peripheral-zone (p < 0.0001) and central-gland (p < 0.0001) cancers, compared to normal tissue. DTI had higher negative and positive predictive values than mpMRI to predict PCa (positive predictive value (PPV) 77.8% (58.6-97.0%), negative predictive value (NPV) 91.7% (80.6-100%) vs. PPV 46.7% (28.8-64.5%), NPV 83.3% (62.3-100%)). We conclude from this pilot study that DTI combined with T2-weighted imaging may have the potential to improve PCa detection without requiring contrast injection.

Cardiac biomarkers in patients with prostate cancer and cardiovascular disease receiving gonadotrophin releasing hormone agonist vs antagonist.

BACKGROUND: Gonadotrophin releasing hormone (GnRH) agonists and antagonists reduce testosterone levels for the treatment of advanced and metastatic prostate cancer. Androgen deprivation therapy (ADT) is associated with increased risk of cardiovascular (CV) events and CV disease (CVD), especially in patients with preexisting CVD treated with GnRH agonists. Here, we investigated the potential relationship between serum levels of the cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NTproBNP), D-dimer, C-reactive protein (CRP), and high-sensitivity troponin (hsTn) and the risk of new CV events in prostate cancer patients with a history of CVD receiving a GnRH agonist or antagonist. METHODS: Post-hoc analyses were performed of a phase II randomized study that prospectively assessed CV events in patients with prostate cancer and preexisting CVD, receiving GnRH agonist or antagonist. Cox proportional hazards models were used to determine whether the selected biomarkers had any predictive effect on CV events at baseline and across a 12-month treatment period. RESULTS: Baseline and disease characteristics of the 80 patients who took part in the study were well balanced between treatment arms. Ischemic heart disease (66%) and myocardial infarction (37%) were the most common prior CVD and the majority (92%) of patients received CV medication. We found that high levels of NTproBNP (p = 0.008), and hsTn (p = 0.004) at baseline were associated with the development of new CV events in the GnRH agonist group but not in the antagonist. In addition, a nonsignificant trend was observed between higher levels of NTproBNP over time and the development of new CV events in the GnRH agonist group. CONCLUSIONS: The use of cardiac biomarkers may be worthy of further study as tools in the prediction of CV risk in prostate cancer patients receiving ADT. Analysis was limited by the small sample size; larger studies are required to validate biomarker use to predict CV events among patients receiving ADT.

3,3-Diindolylmethane (DIM): a nutritional intervention and its impact on breast density in healthy BRCA carriers. A prospective clinical trial.

Women who carry the BRCA mutation are at high lifetime risk of breast cancer, but there is no consensus regarding an effective and safe chemoprevention strategy. A large body of evidence suggests that 3,3-diindolylmethane (DIM), a dimer of indole-3-carbinol found in cruciferous vegetables, can potentially prevent carcinogenesis and tumor development. The primary aim of this prospective single-arm study was to investigate the effect of DIM supplementation on breast density, a recognized predictive factor of breast cancer risk. Participants were 23 healthy female BRCA carriers (median age 47 years; 78% postmenopausal) who were treated with oral DIM 100 mg × 1/day for 1 year. The amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE) on magnetic resonance imaging (MRI) performed before and after the intervention was scored by two independent expert radiologists using the Breast Imaging and Reporting Data System. The results showed a decrease in the average score for FGT amount from 2.8 ± 0.8 at the onset to 2.65 ± 0.84 after 1 year (P = 0.031), with no significant change in BPE (P = 0.429). A group of DIM-untreated age- and menopausal-status-matched women from the BRCA clinic did not show a significant change in FGT amount (P = 0.33) or BPE (P = 0.814) in a parallel year. Mean estradiol level decreased from 159 to 102 pmol/l (P = 0.01), and mean testosterone level decreased from 0.42 to 0.31 pmol/l (P = 0.007). Side effects were grade 1. In conclusion, 1 year's supplementation with DIM 100 mg × 1/day in BRCA carriers was associated with a significant decline in FGT amount on MRI. Larger randomized studies are warranted to corroborate these findings.

Short-Term Outcomes of Active Surveillance for Low Risk Prostate Cancer among Men with Germline DNA Repair Gene Mutations.

PURPOSE: Men with germline mutations in DNA repair genes have a higher risk of prostate cancer. Active surveillance is the preferred treatment modality for low risk prostate cancer. However, many fear offering this alternative to men with germline mutations. We describe the short-term oncologic outcomes of active surveillance in a population of men with a high genetic predisposition for prostate cancer. MATERIALS AND METHODS: A prospective cohort of men with germline DNA repair gene mutations were diagnosed with Grade Group 1 prostate cancer. All men were offered active surveillance. Followup consisted of prostate specific antigen every 3 months, multiparametric magnetic resonance imaging and a magnetic resonance imaging-ultrasound fusion confirmatory biopsy within 1 year of diagnosis. The primary end points included treatment and progression-free survival. RESULTS: Eighteen carriers of DNA repair gene mutations were diagnosed with low risk prostate cancer (BRCA1 [8], BRCA2 [6], CHEK2 [2], Lynch syndrome [2]). Of these patients 15 (83%) initiated active surveillance and 3 (17%) declined. All but 1 were fully compliant with the active surveillance protocol (93%). Overall 20% (3) had upgrading at confirmatory biopsy and were treated. At a median followup of 28 months (IQR 8.5-42) 80% of patients (12) on active surveillance are free from upgrading or radical treatment. CONCLUSIONS: Active surveillance may be feasible among carriers diagnosed with low risk prostate cancer. If embarking on active surveillance, carriers should be very carefully monitored at a specialized clinic, optimizing patient compliance and minimizing risk. Until larger scale studies with long-term followup become available, this option should be cautiously discussed with the patient.

A noninferiority within-person study comparing the accuracy of transperineal to transrectal MRI-US fusion biopsy for prostate-cancer detection.

BACKGROUND: Magnetic resonance imaging (MRI) and ultrasound (US) fusion prostate-biopsies can be performed in a transrectal (TR-fusion) or transperineal (TP-fusion) approach. Prospective comparative evidence is limited. In this study we compared the detection rate of clinically-significant prostate-cancer (csPCa) within an index lesion between TR and TP-fusion. PATIENTS AND METHODS: This was a prospective, noninferiority, and within-person trial. Men scheduled for MRI-US-fusion with a discrete MRI PI-RRAD ≥ 3 lesion were included. A dominant index lesion was determined for each subject and sampled by TR and TP-fusion during the same session. The order of biopsies was randomized and equipment was reset to avoid chronological and incorporation bias. For each subject, the index lesion was sampled 4-6 times in each approach. All biopsies were performed using Navigo fusion software (UC-Care, Yokneam, Israel). csPCa was defined as: Grade Group ≥ 2 or cancer-core length ≥ 6 mm. We used a noninferiority margin of 10% and a one-sided alpha level of 5%. RESULTS: Seventy-seven patients completed the protocol. Median age was 68.2 years (IQR:64.2-72.2), median PSA was 8.9 ng/ml (IQR:6.18-12.2). Ten patients (13%) were biopsy naive, others (87%) had a previous biopsy. csPCa was detected in 32 patients (42%). All of these cases were detected by TP-fusion, while only 20 (26%) by TR-fusion. Absolute difference for csPCa diagnosis was 15.6 (CI 90% 27.9-3.2%) in favor of TP-fusion (p = 0.029). TP-fusion was noninferior to TR-fusion. The lower boundary of the 90% confidence-interval between TP-fusion and TR-fusion was greater than zero, therefore TP-fusion was also found to be superior. Exploratory subgroup analyses showed TP-fusion was consistently associated with higher detection rates of csPCa compared with TR-fusion in patient and index-lesion derived subgroups (size, location, PI-RADS, PSA, and biopsy history). CONCLUSIONS: In this study, TP-fusion biopsies were found to be noninferior and superior to TR-fusion biopsies in detecting csPCa within MRI-visible index lesion. Centers experienced in both TP and TR-fusion should consider these results when choosing biopsy method.

Screening, Active Surveillance, and Treatment of Localized Prostate Cancer Among Carriers of Germline BRCA Mutations.

Male carriers of BRCA mutations are at higher risk of developing prostate cancer. Many issues are still unanswered and are currently being studied, including differences between BRCA1 and BRCA2, screening and specific protocols, the role of active surveillance, and the choice of definitive treatment.

Vascular endothelium function among male carriers of BRCA 1&2 germline mutation.

Background: Breast cancer susceptibility genes 1&2 (BRCA1&2) mutations hinder DNA-repair. Germline mutations in these genes are known to cause cancer; however, they may have other consequences. In this study we evaluated for the first time, the effect of the BRCA mutations on the vascular endothelium of young healthy males. Results: The study included 82 participants (53 BRCA mutation positive-carriers and 29 negative-carriers). Subjects mean age was 40. There were no significant differences in the baseline characteristics of the two groups. BRCA-carriers had significantly higher levels of EPCs (fraction of CD34+/VEGF or CD133+/VEGF positive-cells) compared to non-carriers of the mutation (median 6.78[1.96,14.48]% vs. 1.46[0.65,6.18]%, p < 0.001, and median 7.17[1.70,16.69]% vs. 1.54[0.85,5.10]%, p < 0.001, respectively). This difference remained consistent after multivariate adjustment. We did not identify differences in endothelial function, endothelial damage markers and EPCs activity between the two groups. Methods: This was a prospective cohort study to test the association between BRCA status and possible endothelial alterations. The Study population included males, 18-50 years, with no cardiovascular morbidity, who were referred for BRCA screening. We tested the endothelial system by: Endothelial progenitor cells (EPC) production, endothelial function (EndoPAT2000), endothelial damage and related hormonal levels. We stratified the cohort by germline BRCA status and compared measurements between BRCA mutation positive- and negative-carriers. Conclusions: Male BRCA1&2 mutation positive-carriers had increased level of EPCs which may reflect a subclinical accumulative endothelial damage. These novel findings suggest that the effect of mutations in BRCA is not limited to increased cancer risk, but may affect the cardiovascular system.

Cardiovascular Morbidity in a Randomized Trial Comparing GnRH Agonist and GnRH Antagonist among Patients with Advanced Prostate Cancer and Preexisting Cardiovascular Disease.

PURPOSE: Androgen deprivation therapy may increase the risk of cardiovascular disease. Limited data suggest that GnRH (gonadotropin-releasing hormone) antagonist may be associated with a lower risk of cardiovascular disease than GnRH agonist. MATERIALS AND METHODS: We performed a phase II, randomized, open label study in men with prostate cancer and preexisting cardiovascular disease who were randomized to receive GnRH agonists or antagonists for 1 year. The primary outcome was endothelial function measured by the EndoPAT 2000 device (Itamar Medical, Caesarea, Israel). The predefined secondary outcome was a new cardiovascular event. Patients were followed for the development of cardiovascular disease, defined as death, myocardial infarction, a cerebrovascular event, percutaneous angioplasty with coronary stent insertion or hospitalizations due to cardiac events. RESULTS: A total of 80 patients were enrolled in study, including 41 and 39 who received GnRH antagonist and agonist, respectively. Patients in each arm had similar baseline characteristics. We did not detect a difference in the primary end point (endothelial function) between the groups (mean ± SD reactive hyperemia index 2.07 ± 0.15 vs 1.92 ± 0.11, p=0.42). However, during the trial period a new cardiovascular event (the secondary end point) developed in 15 patients. Of cases new major cardiovascular and cerebrovascular events developed in 9, including death in 2, myocardial infarction in 1, a cerebrovascular event in 2 and percutaneous angioplasty with coronary stent insertion in 4. Of the patients 20% randomized to GnRH agonist experienced a major cardiovascular and cerebrovascular event compared to 3% of those on GnRH antagonist (p=0.013). The absolute risk reduction in major cardiovascular and cerebrovascular events at 12 months using GnRH antagonist was 18.1% (95% CI 4.6-31.2, p=0.032). CONCLUSIONS: To our knowledge this is the first prospective study to test cardiovascular outcomes among patients with prostate cancer who received androgen deprivation therapy. No differences in the primary end point were noted between the study arms. However, the secondary end point revealed that patients treated with GnRH agonist experienced significantly more major cardiovascular and cerebrovascular events than those treated with GnRH antagonist. These phase II results suggest that in patients with prostate cancer who have preexisting cardiovascular disease selecting the androgen deprivation therapy modality may differentially affect cardiac outcomes.

Characterizing the learning curve of MRI-US fusion prostate biopsies.

BACKGROUND: MRI-US fusion prostate biopsies are becoming a common procedure to diagnose prostate cancer. There is a paucity of information regarding the learning curve for fusion biopsies. We aim to study the amount of experience needed to be both accurate and time-efficient in this procedure. METHODS: We prospectively collected data on all MRI-US fusion biopsies performed from April 2014 to August 2017. We used two parameters to define the learning curve. Process Measurement (efficiency) was measured by time from the beginning of anesthesia to end of procedure. Outcome Measurement (accuracy) was measured by cancer detection rate for PI-RAD 3 lesions. The end of the learning curve was defined graphically and mathematically. We performed a separate analysis for transrectal and transperineal biopsies. RESULTS: We completed 779 fusion biopsies (523 transrectal, 256 transperineal). Patients median age was 66 years (IQR 61-70) and median PSA 6.95 ng/ml (IQR 4.2-10.6). Prostate cancer was diagnosed in 385 (49%). Process Measurement-Procedure time decreased from 45 min in the first transrectal fusion biopsy to 15 min after 109 biopsies and remained stable (p < 0.0001). Time decreased from 55 min in the first transperineal biopsy to 18 min after 124 biopsies (p < 0.0001). Outcome Measurement-In transrectal fusion-biopsies detection rate for PI-RADS 3 lesions increased from 35 to 50% after 104 biopsies. In transperineal fusion-biopsies, detection rate increased from 40 to 55% after 119 cases for PI-RADS 3 lesions. CONCLUSIONS: We measured the learning curve of fusion biopsies graphically and mathematically. We demonstrated that proficiency occurs after 110 transrectal and 125 transperineal fusion-biopsies.

Assessment of Needle Tip Deflection During Transrectal Guided Prostate Biopsy: Implications for Targeted Biopsies.

OBJECTIVES: To measure needle tip deflection during transrectal ultrasound (TRUS) prostate biopsy and evaluate predictors for needle tip deflection. MATERIALS AND METHODS: Analysis of 568 prostate biopsies obtained from 51 consecutive patients who underwent a standard 12-core TRUS guided prostate biopsy. TRUS guided prostate biopsies were performed using BK flex500, with a side-fire biplane probe. Each biopsy core image was captured and clinical data were recorded prospectively. The angle between the expected trajectory of the needle and actual needle course was measured using the longitudinal view of the captured image. The distance between expected and actual needle tip was calculated. We measured median and interquartile needle tip deflection rate stratified by side and location (apex, midgland, base). Univariable and multivariable linear regressions analysis were performed. RESULTS: The overall median needle tip deflection was 1.77 mm (IQR 1.35-2.47). Location did not significantly alter needle deflection measurements. On multivariable linear regression analysis, higher prostate volume (B = 0.007 95%, CI 0.004, 0.011; p < 0.001) and the right sided biopsy (B = 0.191 95%, CI 0.047, 0.336; p = 0.010) emerged as predictors of higher needle tip deflection. CONCLUSIONS: To the best of our knowledge this is the first study to measure needle tip deflection during TRUS guided prostate biopsies. We demonstrated that larger prostate size and biopsy side may affect the accuracy of biopsies. These results may have clinical implication to those performing targeted biopsies.

Is there a difference in testosterone levels and its regulators in men carrying BRCA mutations?

BACKGROUND: Male BRCA mutation carriers are at risk for an early onset aggressive prostate cancer. No data exist on the association of testosterone levels among these patients. We aimed to analyze testosterone and associated hormonal levels among male BRCA carriers and non-carriers. PATIENTS AND METHODS: Overall 87 male carriers and 43 non-carriers aged 40-70 were prospectively enrolled. Clinical data were collected and all patients were tested for total testosterone (TT), prostate specific antigen (PSA), follicle stimulating hormone (FSH), luteinizing hormone (LH), free androgen index (FAI), sex hormone binding globulin (SHBG) and prolactin. Multivariate linear regression analysis was performed to predict TT levels. RESULTS: The median age, mean BMI, comorbidities, PSA, FSH, LH and SHBG levels in both groups were similar. However, mean TT and FAI were higher in the carriers (16.7 nmol/l vs 13.5 nmol/l, p=0.03 and 39.5 vs 34.8, p=0.05, respectively), while prolactin was significantly lower. Multivariate analysis demonstrated that while BMI was inversely correlated to TT levels in both groups, LH was a predictor only in non-carriers. CONCLUSIONS: Carriers have higher TT and FAI levels and lower prolactin levels; but LH does not predict their TT levels. Further research in a larger cohort of BRCA carriers with and without prostate cancer should be performed.

Lower Urinary Tract Symptoms and Benign Prostate Hyperplasia Features Among Male BRCA Mutation Carriers.

OBJECTIVE: To analyze lower urinary tract symptoms and benign prostate hyperplasia features among male BRCA1 and 2 carriers and an age-matched control group. METHODS: Male BRCA carriers and noncarriers aged 40-70 years were enrolled in our cross-sectional study. Relevant clinical data were collected, and patients filled the International Prostate Symptom Score. Patients also underwent prostate-specific antigen (PSA) blood testing, digital rectal examination, uroflowmetry, and post-void residual ultrasound examination. As part of their routine follow-up, BRCA carriers underwent prostate magnetic resonance imaging. RESULTS: Overall, 87 carriers and 30 noncarriers were enrolled. The median age, mean body mass index, and comorbidities in both groups were similar. Maximal flow (QMAX) was higher in the noncarrier group (16.9 mL/s vs 12 mL/s, P = .01). Mean prostate volume among all BRCA carriers was 38.8 cc (19.7), but BRCA1 patients had larger glands with higher mean PSA and PSA density than BRCA2 patients (41.8 cc vs 33.1 cc, P = .047, 1.84 ng/mL vs 1.07 ng/mL, P = .006, and .044 vs .032, P = .042, respectively). Multivariate analysis demonstrated age being the sole significant predictor of PSA density in BRCA2 patients. CONCLUSION: Male carrying BRCA mutations have significantly lower QMAX than healthy men. BRCA1 patients have on average larger prostate glands and higher PSA than BRCA2 patients. Further research is required to decipher the association of lower urinary tract symptoms or benign prostate hyperplasia with BRCA carriers.

The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis.

Autophagy and apoptosis constitute important determinants of cell fate and engage in a complex interplay in both physiological and pathological settings. The molecular basis of this crosstalk is poorly understood and relies, in part, on "dual-function" proteins that operate in both processes. Here, we identify the essential autophagy protein Atg12 as a positive mediator of mitochondrial apoptosis and show that Atg12 directly regulates the apoptotic pathway by binding and inactivating prosurvival Bcl-2 family members, including Bcl-2 and Mcl-1. The binding occurs independently of Atg5 or Atg3 and requires a unique BH3-like motif in Atg12, characterized by interaction studies and computational docking. In apoptotic cells, knockdown of Atg12 inhibited Bax activation and cytochrome c release, while ectopic expression of Atg12 antagonized the antiapoptotic activity of Mcl-1. The interaction between Atg12 and Bcl-2 family members may thus constitute an important point of convergence between autophagy and apoptosis in response to specific signals.