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Gallium 68 prostate-specific membrane antigen PET/MRI improved specificity for clinically significant prostate cancer, with a similar sensitivity to multiparametric MRI.

Purpose:Recent studies demonstrated reduced cardiovascular (CV) risk with gonadotropin-releasing hormone (GnRH) antagonist, yet the underlying mechanism remains undetermined. The objective of this ...

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 fe...

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., The impact of 1 year’s supplementation with oral 3,3-diindolylmethane 100 mg × 1/day on breast density and estrogen metabolism was evaluated in 23 healthy BRCA carriers. MRI showed a significant decrease in average Breast Imaging and Reporting Data System score for fibroglandular tissue from before to after treatment.

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.

Background Gallium 68 (

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. 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. 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

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.

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.

Take Home Message The COVID-19 pandemic has changed the world. Urology needs to overcome these challenges. Our duty is to provide care under any circumstances and our privilege is to re-examine and advance our field. The use of novel communication and health technologies will ensure safety while maintaining high-quality care.

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.

Background Male-carriers of BRCA1/2 gene mutations have an increased risk of prostate cancer (PCa) with a more aggressive phenotype. Current screening-guidelines suggest the use of prostate-specific antigen (PSA) only among BRCA2 carriers. Female carriers have extensive guidelines that include imaging. Our objective was to test the prevalence of PCa among BRCA carriers and examine screening strategies, using PSA and multiparametric magnetic resonance imaging (mpMRI). Patients and methods We recruited men aged 40–70 years with BRCA1/2 germline mutations and no prior history of prostate biopsy. All men underwent an initial round of screening which included PSA, and prostate mpMRI. PSA was considered elevated using an age-stratified threshold of ≥1 ng/ml for 40–50 years of age, ≥2 ng/ml for 50–60 years of age, and 2.5 ng/ml for 60–70 years of age. Men with elevated PSA and/or suspicious lesion on mpMRI were offered a prostate biopsy. PSA levels, MRI findings, PCa incidence, and tumor characteristics were evaluated. Decision curve analysis was used to compare screening strategies. Results We recruited 188 men (108 BRCA1, 80 BRCA2), mean age 54 years (9.8). One hundred and ten (57%) had either elevated age-stratified PSA (75; 40%), a suspicious MRI lesion (67; 36%), or both (32; 17%). Of these, 92 (85%) agreed to perform a prostate biopsy. Sixteen (8.5%) were diagnosed with PCa; 44% of the tumors were classified as intermediate- or high-risk disease. mpMRI-based screening missed only one of the cancers (6%), while age-stratified PSA would have missed five (31%). Decision curve analysis showed that mpMRI screening, regardless of PSA, had the highest net benefit for PCa diagnosis, especially among men younger than 55 years of age. We found no difference in the risk of PCa between BRCA1 and BRCA2 (8.3% versus 8.7%, P = 0.91). Ninety percent had a Jewish founder mutation, thus the results cannot be generalized to all ethnic groups. Conclusions PCa is prevalent among BRCA carriers. Age may affect screening strategy for PCa in this population. Young carriers could benefit from initial MRI screening. BRCA carriers aged older than 55 years should use PSA and be referred to mpMRI if elevated. Trial registration ClinicalTrial.gov ID: NCT02053805 .

545 Background: Intravesical bacillus Calmette Guerin (BCG) is the standard of care adjuvant therapy for high risk non-muscle invasive bladder cancer (NMIBC), yet many patients experience recurrence or disease progression. The mechanism of action of BCG is believed to be related to stimulation of immune surveillance. Relatedly, systemic immune checkpoint inhibition is currently being utilized in advanced bladder cancer and approved for BCG unresponsive NMIBC. We sought to determine the association between PD-L1 expression and BCG treatment. Methods: We identified 102 BCG-naïve patients with high grade (HG) NMIBC treated with BCG. All patients underwent initial transurethral resection (TUR) for pathologic diagnosis. Dako 22c3 assay was used to determine PD-L1 expression. Patients were defined as PD-L1 positive if the combined positive score (CPS) > 0. BCG unresponsiveness was defined by presence of high grade disease at 6 months following adequate BCG (one induction and maintenance cycle or two induction cycles) for pT1 or 12 months for CIS or presence of pT1 at 3 months following induction. HG relapse was defined as presence of any HG disease after being followed for 6 months after BCG. Results: The median follow-up time was 57 months. Median number of BCG maintenance cycles was 1, and 17 (16.7%) patients underwent immediate reinduction BCG. PD-L1 expression was observed 5.9% of pTa, 30.0% of pT1, and 3.6% of CIS. BCG unresponsiveness and HG relapse were observed in 32 (35.6%) and 29 (34.5%) patients, respectively. On univariate analysis, PD-L1 expression was inversely associated with BCG unresponsiveness (OR = 0.112; 95% CI 0.014-0.898) but not high grade relapse (OR = 0.296; 95% CI 0.061-1.440). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression for BCG responsiveness were 22%, 97%, 93%, and 41%, respectively. The post-test probability of BCG responsiveness was 93% in patients positive for PD-L1 based on a positive likelihood ratio of 7.33 for PD-L1 expression. On multivariate regression, pT1 (OR = 0.159; 95% CI 0.045-0.600), CIS (OR = 0.247; 95% CI 0.071-0.857), and PD-L1 expression (OR = 15.625; 95% CI 1.779-142.857) were independently associated with BCG responsiveness. Conclusions: PD-L1 expression in HG NMIBC was low, and patients with PD-L1 expression at initial TUR were more likely to harbor invasive disease. Patients showing PD-L1 expression were more likely to demonstrate BCG responsiveness. These findings suggest a role of PD-L1 in the immune surveillance mechanism of BCG at initial pathologic diagnosis and may assist in predicting responses to BCG among patients with HG NMIBC. Further investigation is required to determine if additional immune checkpoint markers have strong correlation with BCG response, particularly among patients without PD-L1 expression.

Autophagy is an intracellular degradation process essential for adaptation to metabolic stress. DAPK2 is a calmodulin-regulated protein kinase, which has been implicated in autophagy regulation, though the mechanism is unclear. Here, we show that the central metabolic sensor, AMPK, phosphorylates DAPK2 at a critical site in the protein structure, between the catalytic and the calmodulin-binding domains. This phosphorylation activates DAPK2 by functionally mimicking calmodulin binding and mitigating an inhibitory autophosphorylation, providing a novel, alternative mechanism for DAPK2 activation during metabolic stress. In addition, we show that DAPK2 phosphorylates the core autophagic machinery protein, Beclin-1, leading to dissociation of its inhibitor, Bcl-XL. Importantly, phosphorylation of DAPK2 by AMPK enhances DAPK2’s ability to phosphorylate Beclin-1, and depletion of DAPK2 reduces autophagy in response to AMPK activation. Our study reveals a unique calmodulin-independent mechanism for DAPK2 activation, critical to its function as a novel downstream effector of AMPK in autophagy., DAPK2 is a calmodulin-regulated protein kinase implicated in autophagy regulation, but how physiological stress leads to its activation is yet unknown. Here, the authors show that the central metabolic sensor AMPK phosphorylates DAPK2 to promote autophagy in a calmodulin-independent mechanism.

To measure needle tip deflection during transrectal ultrasound (TRUS) prostate biopsy and evaluate predictors for needle tip deflection.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.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.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.

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.

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.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.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).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.

INTRODUCTION AND OBJECTIVES:Male BRCA germline mutation carriers are at high risk for prostate cancer. IMPACT study results support routine PSA screening among BRCA carriers. Guidelines for female ...

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.

// Guy Witberg 1 , 2 , * , Eli Lev 1 , 4 , 5 , * , Yaara Ber 3 , Tzlil Tabachnik 3 , Sivan Sela 3 , Ira Belo 3 , Dorit Leshem-Lev 1 , 2 and David Margel 2 , 3 1 Department of Cardiology, Rabin Medical Center, Petach Tikva, Israel 2 The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Department of Urology, Rabin Medical Center, Petach Tikva, Israel 4 Department of Cardiology, Assuta Ashdod University Hospital, Ashdod, Israel 5 Faculty of Medicine, Ben Gurion University, Be'er Sheva, Israel * These authors contributed equally to this work Correspondence to: David Margel, email: sdmargel@gmail.com Keywords: BRCA; DNA repair; endothelial progenitor cells; vascular endothelium damage; cardiovascular system Received: January 31, 2019 Accepted: June 29, 2019 Published: August 20, 2019 ABSTRACT 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.

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.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.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.We measured the learning curve of fusion biopsies graphically and mathematically. We demonstrated that proficiency occurs after 110 transrectal and 125 transperineal fusion-biopsies.

1556 Background: 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 (I3C) found in cruciferous vegetables, can potentially prevent carcinogenesis and tumor development. The primary aim of this prospective study was to investigate the effect of DIM supplementation on breast density, a recognized predictive factor of breast-cancer risk. Methods: Participants were 23 healthy female BRCA carriers (median age 47 years; 78% postmenopausal) who were treated with oral DIM 100 mgx1/d for one year. The amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE) on magnetic resonance imaging (MRI) performed before and after the intervention were scored by two independent expert radiologists using the Breast Imaging and Reporting Data System (BI-RADS). Each woman in the cohort was matched by age (within 3 years) and menopausal status to a woman attending the clinic who was not participating in the study and who underwent breast MRI in parallel year. Results: A decrease in the average score for FGT amount from 2.8±0.8 at onset to 2.65±0.842.8 after one year (p = 0.031), with no significant change in BPE (p = 0.429). A group of DIM-untreated age- and menopausal-status-matched clinic patients 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, from 0.42 to 0.31 pmol/L (p = 0.007). Side effects were grade 1. Conclusions: One year’s supplementation with DIM 100 mgX1/d in BRCA carriers was associated with a significant decline in FGT amount on MRI. Larger randomized studies are warranted to corroborate these findings. Clinical trial information: NCT02197000.

// Hanan Goldberg 1 , Liat Shavit Grievink 1 , Roy Mano 1 , Yaara Ber 1 , Rachely Ozalbo 1 , Sivan Tuval 1 , Jack Baniel 1 and David Margel 1 1 Division of Urology, Rabin Medical Center, Petah Tikva and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to: Hanan Goldberg, email: gohanan@gmail.com Keywords: BRCA mutations, free androgen index, luteinizing hormone, prostate cancer, testosterone Received: February 03, 2017 Accepted: September 16, 2017 Published: October 10, 2017 ABSTRACT 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.

Autophagy is a tightly regulated catabolic process, which is upregulated in cells in response to many different stress signals. Inhibition of mammalian target of rapmaycin complex 1 (mTORC1) is a crucial step in induction of autophagy, yet the mechanisms regulating the fine tuning of its activity are not fully understood. Here we show that death-associated protein kinase 2 (DAPK2), a Ca(2+)-regulated serine/threonine kinase, directly interacts with and phosphorylates mTORC1, and has a part in suppressing mTOR activity to promote autophagy induction. DAPK2 knockdown reduced autophagy triggered either by amino acid deprivation or by increases in intracellular Ca(2+) levels. At the molecular level, DAPK2 depletion interfered with mTORC1 inhibition caused by these two stresses, as reflected by the phosphorylation status of mTORC1 substrates, ULK1 (unc-51-like kinase 1), p70 ribosomal S6 kinase and eukaryotic initiation factor 4E-binding protein 1. An increase in mTORC1 kinase activity was also apparent in unstressed cells that were depleted of DAPK2. Immunoprecipitated mTORC1 from DAPK2-depleted cells showed increased kinase activity in vitro, an indication that DAPK2 regulation of mTORC1 is inherent to the complex itself. Indeed, we found that DAPK2 associates with components of mTORC1, as demonstrated by co-immunoprecipitation with mTOR and its complex partners, raptor (regulatory-associated protein of mTOR) and ULK1. DAPK2 was also able to interact directly with raptor, as shown by recombinant protein-binding assay. Finally, DAPK2 was shown to phosphorylate raptor in vitro. This phosphorylation was mapped to Ser721, a site located within a highly phosphorylated region of raptor that has previously been shown to regulate mTORC1 activity. Thus, DAPK2 is a novel kinase of mTORC1 and is a potential new member of this multiprotein complex, modulating mTORC1 activity and autophagy levels under stress and steady-state conditions.

5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.

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.

The rapid accumulation of knowledge on biological signaling pathways and their regulatory mechanisms has highlighted the need for specific repositories that can store, organize and allow retrieval of pathway information in a way that will be useful for the research community. SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction. To make database population and pathway comprehension straightforward, a simple yet informative data model is used, and pathways are laid out as maps that reflect the curator’s understanding and make the utilization of the pathways easy. The database currently focuses primarily on pathways describing DNA damage response, cell cycle, programmed cell death and hearing related pathways. Pathways are regularly updated, and additional pathways are gradually added. The complete database and the individual maps are freely exportable in several formats. The database is accompanied by a stand-alone software tool for analysis and dynamic visualization of pathways.

SummaryApoptosis and autophagy are distinct biological processes, each driven by a different set of protein-protein interactions, with significant crosstalk via direct interactions among apoptotic and autophagic proteins. To measure the global profile of these interactions, we adapted the Gaussia luciferase protein-fragment complementation assay (GLuc PCA), which monitors binding between proteins fused to complementary fragments of a luciferase reporter. A library encompassing 63 apoptotic and autophagic proteins was constructed for the analysis of ∼3,600 protein-pair combinations. This generated a detailed landscape of the apoptotic and autophagic modules and points of interface between them, identifying 46 previously unknown interactions. One of these interactions, between DAPK2, a Ser/Thr kinase that promotes autophagy, and 14-3-3τ, was further investigated. We mapped the region responsible for 14-3-3τ binding and proved that this interaction inhibits DAPK2 dimerization and activity. This proof of concept underscores the power of the GLuc PCA platform for the discovery of biochemical pathways within the cell death network.

Systems biology, a combined computational and experimental approach to analyzing complex biological systems, has recently been applied to understanding the pathways that regulate programmed cell death. This approach has become especially crucial because recent advances have resulted in an expanded view of the network, to include not just a single death module (apoptosis) but multiple death programs, including programmed necrosis and autophagic cell death. Current research directions in the systems biology field range from quantitative analysis of subprocesses of individual death pathways to the study of interconnectivity among the various death modules of the larger network. These initial studies have provided great advances in our understanding of programmed cell death and have important clinical implications for drug target research.

The mammalian cell death network comprises three distinct functional modules: apoptosis, autophagy and programmed necrosis. Currently, the field lacks systems level approaches to assess the extent to which the intermodular connectivity affects cell death performance. Here, we developed a platform that is based on single and double sets of RNAi-mediated perturbations targeting combinations of apoptotic and autophagic genes. The outcome of perturbations is measured both at the level of the overall cell death responses, using an unbiased quantitative reporter, and by assessing the molecular responses within the different functional modules. Epistatic analyses determine whether seemingly unrelated pairs of proteins are genetically linked. The initial running of this platform in etoposide-treated cells, using a few single and double perturbations, identified several levels of connectivity between apoptosis and autophagy. The knock down of caspase3 turned on a switch toward autophagic cell death, which requires Atg5 or Beclin-1. In addition, a reciprocal connection between these two autophagic genes and apoptosis was identified. By applying computational tools that are based on mining the protein-protein interaction database, a novel biochemical pathway connecting between Atg5 and caspase3 is suggested. Scaling up this platform into hundreds of perturbations potentially has a wide, general scope of applicability, and will provide the basis for future modeling of the cell death network.