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Abstract Abstract Objective The aim of this study is to evaluate male awareness of developing prostate cancer (PCa) in families with germline DNA‐repair genes (DRG) variants. Materials and methods Data were collected from a prospective, monocentric cohort study. The study was conducted in a university hospital with a multidisciplinary approach to the patient (collaboration of the Departments of Oncology, Urology, Pathology, Radiology, and Medical Genetics Laboratory). We recruited healthy males, relatives of families of women with breast or ovarian cancer who tested positive for pathogenic variants (PVs) or likely pathogenic variants (LPVs) in DRGs. A dedicated PCa screening was designed and offered to men aged 35 to 69 years, based on early visits with digital rectal examination (DRE), prostate health index (PHI) measurement, multiparametric magnetic resonance imaging (mpMRI) and, if necessary, targeted/systematic prostate biopsies. The primary endpoint was to evaluate the willingness of healthy men from families with a DRG variants detected in female relatives affected with breast and/or ovarian cancer to be tested for the presence of familial PVs. The secondary endpoints were the acceptance to participate if resulted positive and compliance with the screening programme. Results Over 1256 families, of which 139 resulted positive for PVs in DRGs, we identified 378 ‘healthy’ men aged between 35 and 69 years old. Two hundred sixty‐one (69.0%) refused to be tested for DRG variants, 66 (17.5%) declared to have been previously tested, and 51 (13.5%) males were interested to be tested. Between those previously tested and those who accepted to be tested, 62 (53.0%) were positive for a DRG variant, and all of them accepted to participate in the subsequent surveillance steps. The main limitation is that is a single‐centre study and a short follow‐up. Conclusions All men tested positive for a DRG variants agreed to go under the surveillance scheme. However, only 31% of ‘men at risk’ (i.e., relative of a DRG variant carrier) expressed their willingness to be tested for the familial DRG variant. This observation strongly supports the urgent need to implement awareness of genetic risk for PCa within the male population.

Objective: To report the outcomes of intra- and extra-peritoneal robot-assisted radical prostatectomy (RARP) and robot-assisted radical cystectomy (RARC) with Hugo™ robot-assisted surgery (RAS) system (Medtronic, Minneapolis, MN, USA). Methods: Data of twenty patients who underwent RARP and one RARC at our institution between February 2022 and January 2023 were reported. The primary endpoint of the study was to report the surgical setting of Hugo™ RAS system to perform RARP and RARC. The secondary endpoint was to assess the feasibility of RARP and RARC with this novel robotic platform and report the outcomes. Results: Seventeen patients underwent RARP with a transperitoneal approach, and three with an extraperitoneal approach; and one patient underwent RARC with intracorporeal ileal conduit. No intraoperative complications occurred. Median docking and console time were 12 (interquartile range [IQR] 7–16) min and 185 (IQR 177–192) min for transperitoneal RARP, 15 (IQR 12–17) min and 170 (IQR 162–185) min for extraperitoneal RARP. No intraoperative complications occurred. One patient submitted to extraperitoneal RARP had a urinary tract infection in the postoperative period that required an antibiotic treatment (Clavien-Dindo Grade 2). In case of transperitoneal RARP, two minor complications occurred (one pelvic hematoma and one urinary tract infection; both Clavien-Dindo Grade 2). Conclusion: Hugo™ RAS system is a novel promising robotic platform that allows to perform major oncological pelvic surgery. We showed the feasibility of RARP both intra- and extra-peritoneally and RARC with intracorporeal ileal conduit with this novel platform.

Background: The diagnostic process for prostate cancer after a negative biopsy is challenging. This study compares the diagnostic accuracy of micro-ultrasound (mUS) with multiparametric magnetic resonance imaging (mpMRI) for such cases. Methods: A retrospective cohort study was performed, targeting men with previous negative biopsies and using mUS and mpMRI to detect prostate cancer and clinically significant prostate cancer (csPCa). Results: In our cohort of 1397 men, 304 had a history of negative biopsies. mUS was more sensitive than mpMRI, with better predictive value for negative results. Importantly, mUS was significantly associated with csPCa detection (adjusted odds ratio [aOR]: 6.58; 95% confidence interval [CI]: 1.15–37.8; p = 0.035). Conclusions: mUS may be preferable for diagnosing prostate cancer in previously biopsy-negative patients. However, the retrospective design of this study at a single institution suggests that further research across multiple centers is warranted.

IntroductionTo externally validate and directly compare the performance of the Briganti 2012 and Briganti 2019 nomograms as predictors of lymph node invasion (LNI) in a cohort of patients treated with robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection (ePLND).Materials and MethodsAfter the exclusion of patients with incomplete biopsy, imaging, or clinical data, 752 patients who underwent RARP and ePLND between December 2014 to August 2021 at our center, were included. Among these patients, 327 (43.5%) had undergone multi-parametric MRI (mpMRI) and mpMRI-targeted biopsy. The preoperative risk of LNI was calculated for all patients using the Briganti 2012 nomogram, while the Briganti 2019 nomogram was used only in patients who had performed mpMRI with the combination of targeted and systematic biopsy. The performances of Briganti 2012 and 2019 models were evaluated using the area under the receiver-operating characteristics curve analysis, calibrations plot, and decision curve analysis.ResultsA median of 13 (IQR 9–18) nodes per patient was removed, and 78 (10.4%) patients had LNI at final pathology. The area under the curves (AUCs) for Briganti 2012 and 2019 were 0.84 and 0.82, respectively. The calibration plots showed a good correlation between the predicted probabilities and the observed proportion of LNI for both models, with a slight tendency to underestimation. The decision curve analysis (DCA) of the two models was similar, with a slightly higher net benefit for Briganti 2012 nomogram. In patients receiving both systematic- and targeted-biopsy, the Briganti 2012 accuracy was 0.85, and no significant difference was found between the AUCs of 2012 and 2019 nomograms (p = 0.296). In the sub-cohort of 518 (68.9%) intermediate-risk PCa patients, the Briganti 2012 nomogram outperforms the 2019 model in terms of accuracy (0.82 vs. 0.77), calibration curve, and net benefit at DCA.ConclusionThe direct comparison of the two nomograms showed that the most updated nomogram, which included MRI and MRI-targeted biopsy data, was not significantly more accurate than the 2012 model in the prediction of LNI, suggesting a negligible role of mpMRI in the current population.

Background: The diagnostic process for prostate cancer after a negative biopsy is challenging. This study compares the diagnostic accuracy of micro-ultrasound (mUS) with multiparametric magnetic resonance imaging (mpMRI) for such cases. Methods: A retrospective cohort study was performed, targeting men with previous negative biopsies and using mUS and mpMRI to detect prostate cancer and clinically significant prostate cancer (csPCa). Results: In our cohort of 1397 men, 304 had a history of negative biopsies. mUS was more sensitive than mpMRI, with better predictive value for negative results. Importantly, mUS was significantly associated with csPCa detection (adjusted odds ratio [aOR]: 6.58; 95% confidence interval [CI]: 1.15–37.8; p = 0.035). Conclusions: mUS may be preferable for diagnosing prostate cancer in previously biopsy-negative patients. However, the retrospective design of this study at a single institution suggests that further research across multiple centers is warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a growing trend towards exploring the use of non-invasive liquid biopsy (LB) for prostate cancer (PCa) detection. The primary objective of this study is to identify the rate of patients who accepted and were able to collect seminal fluid. The secondary objective was to evaluate the efficiency of our protocol in collecting prostate-derived cells. Our study shows that only one third (139/356) of patients affected by locally advanced PCa, who accepted to collect their seminal fluid, were able to donate. The main favorable predictors for semen collection were young age and lower prostate volume. Putative cancer cells (PSMA + EpCAMhigh) were 2% of the isolated cells in urine and semen. The fraction of EpCAMhigh cells over prostate-enriched cells (PSMA+) significantly correlated with patient age in both semen and urine, but not with other clinical parameters. Liquid biopsy (LB) for prostate cancer (PCa) detection could represent an alternative to biopsy. Seminal fluid (SF) is a source of PCa-specific biomarkers, as 40% of ejaculate derives from the prostate. We tested the feasibility of an SF-based LB by evaluating the yield of semen self-sampling in a cohort of >750 patients with clinically localized PCa. The overall SF collection yield was 18.2% (39% when considering only compliant patients), with about a half of the patients (53.15%) not consenting to SF donation. Independent favorable predictors for SF collection were younger age and lower prostate volume. We implemented a protocol to enrich prostate-derived cells by multi-color flow cytometry and applied it on SF and urine samples from 100 patients. The number of prostate-enriched cells (SYTO-16+ PSMA+ CD45−) was variable, with higher numbers of cells isolated from SF than urine (p value < 0.001). Putative cancer cells (EpCAMhigh) were 2% of isolated cells in both specimens. The fraction of EpCAMhigh cells over prostate-enriched cells (PSMA+) significantly correlated with patient age in both semen and urine, but not with other clinical parameters, such as Gleason Score, ISUP, or TNM stage. Hence, enumeration of prostate-derived cells is not sufficient to guide PCa diagnosis; additional molecular analyses to detect patient-specific cancer lesions will be needed. [ABSTRACT FROM AUTHOR]

The human endogenous retrovirus (HERV)-K, human mouse mammary tumor virus like-2 (HML-2) subgroup of HERVs is activated in several tumors and has been related to prostate cancer progression and motor neuron diseases. The cellular splicing factor 2/alternative splicing factor (SF2/ASF) is a positive regulator of gene expression, coded by a potent proto-oncogene, amplified, and abnormally expressed in tumors. TAR DNA-binding protein-43 (TDP-43) is a DNA/RNA-binding protein, negative regulator of alternative splicing, known for causing neurodegeneration, and with complex roles in oncogenesis. We used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, with the Cas9 system from Staphylococcus aureus (SaCas9), to disrupt the HERV-K(HML-2)env gene, and evaluated the effects on cultured cells. The tool was tested on human prostate cancer LNCaP cells, whose HERV-Kenv transcription profile is known. It caused HERV-K(HML-2)env disruption (the first reported of a HERV gene), as evaluated by DNA sequencing, and inhibition of env transcripts and proteins. The HERV-K(HML-2)env disruption was found to interfere with important regulators of cell expression and proliferation, involved in manaling, RNA-binding, and alternative splicing, such as epidermal growth factor receptor (EGF-R), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), SF2/ASF, and TDP-43. These novel findings suggest that HERV-K is not an innocent bystander, they reinforce its links to oncogenesis and motor neuron diseases, and they open potential innovative therapeutic options.

In our multicenter European study involving 1020 patients with Gleason grade group ≥2 prostate cancer on magnetic resonance imaging–targeted biopsy, the rate of downgrading at radical prostatectomy specimen was 17.5%, but the overall risk of targeted biopsy–induced overtreatment was only ∼2.7%. Our findings indicate that targeted biopsy results are accurate and should be used for decision-making without fearing overtreatment caused by imaging guidance. Targeted biopsy of the index prostate cancer (PCa) lesion on multiparametric magnetic resonance imaging (MRI) is effective in reducing the risk of overdiagnosis of indolent PCa. However, it remains to be determined whether MRI-targeted biopsy can lead to a stage shift via overgrading of the index lesion by focusing only on the highest-grade component, and to a subsequent risk of overtreatment. Our aim was to assess whether overgrading on MRI-targeted biopsy may lead to overtreatment, using radical prostatectomy (RP) specimens as the reference standard. Patients with clinically localized PCa who had positive MRI findings (Prostate Imaging-Reporting and Data System [PI-RADS] score ≥3) and Gleason grade group (GG) ≥2 disease detected on MRI-targeted biopsy were retrospectively identified from a prospectively maintained database that records all RP procedures from eight referral centers. Biopsy grade was defined as the highest grade detected. Downgrading was defined as lower GG for the RP specimen than for MRI-targeted biopsy. Overtreatment was defined as downgrading to RP GG 1 for cases with GG ≥2 on biopsy, or to RP low-burden GG 2 for cases with GG ≥3 on biopsy. We included 1020 consecutive biopsy-naïve patients with GG ≥2 PCa on MRI-targeted biopsy in the study. Pathological analysis of RP specimens showed downgrading in 178 patients (17%). The transperineal biopsy route was significantly associated with a lower risk of downgrading (odds ratio 0.364, 95% confidence interval 0.142–0.814; p = 0.022). Among 555 patients with GG 2 on targeted biopsy, only 18 (3.2%) were downgraded to GG 1 on RP. Among 465 patients with GG ≥3 on targeted biopsy, three (0.6%) were downgraded to GG 1 and seven were downgraded to low-burden GG 2 on RP. The overall risk of overtreatment due to targeted biopsy was 2.7% (28/1020). Our multicenter study revealed no strong evidence that targeted biopsy results could lead to a high risk of overtreatment. [ABSTRACT FROM AUTHOR]

The human endogenous retrovirus (HERV)-K, human mouse mammary tumor virus like-2 (HML-2) subgroup of HERVs is activated in several tumors and has been related to prostate cancer progression and motor neuron diseases. The cellular splicing factor 2/alternative splicing factor (SF2/ASF) is a positive regulator of gene expression, coded by a potent proto-oncogene, amplified, and abnormally expressed in tumors. TAR DNA-binding protein-43 (TDP-43) is a DNA/RNA-binding protein, negative regulator of alternative splicing, known for causing neurodegeneration, and with complex roles in oncogenesis. We used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, with the Cas9 system from Staphylococcus aureus (SaCas9), to disrupt the HERV-K(HML-2)env gene, and evaluated the effects on cultured cells. The tool was tested on human prostate cancer LNCaP cells, whose HERV-Kenv transcription profile is known. It caused HERV-K(HML-2)env disruption (the first reported of a HERV gene), as evaluated by DNA sequencing, and inhibition of env transcripts and proteins. The HERV-K(HML-2)env disruption was found to interfere with important regulators of cell expression and proliferation, involved in manaling, RNA-binding, and alternative splicing, such as epidermal growth factor receptor (EGF-R), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), SF2/ASF, and TDP-43. These novel findings suggest that HERV-K is not an innocent bystander, they reinforce its links to oncogenesis and motor neuron diseases, and they open potential innovative therapeutic options. [ABSTRACT FROM AUTHOR]

Introduction: Magnetic Resonance Imaging (MRI) has emerged as the most accurate diagnostic tool, showing a high sensitivity in the diagnosis of clinically significant prostate cancer (csCaP). However only a minority of patients with a PI-RADS 3 lesion at multiparametric magnetic resonance imaging (MRI) are diagnosed with csCaP. The aim of the current study was to assess whether high resolution micro-ultrasound (microUS) could help in sub-stratifying the risk of csCaP in this specific population.Material and Methods: We retrospectively analyzed the records of 111 consecutive patients scheduled for a prostate biopsy with at least 1 PI-RADS 3 lesions at MRI. We excluded patients with a PIRADS >3 lesion, even if they had a coexisting PIRADS 3 lesions. MicroUS was performed in all patients before prostate biopsy by an operator blind to MRI results. The Prostate Risk Identification using MicroUS (PRI-MUS) protocol was used to assess the risk of CaP and csCaP. All patients received both targeted and systematic biopsies. The primary endpoint was to determine the diagnostic accuracy of microUS in detection of csCaP in patients with a PI-RADS 3 lesion at MRI. Specifically, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of microUS were determined. Multivariable logistic regression models (MLRMs) were fitted to identify predictors of CaP. The diagnostic accuracy was reported as area under the receiver operator characteristic (ROC) curve.Results: Overall, 43 patients (38.7%) harboured CaP and 22 (20%) csCaP. MicroUS showed a high sensitivity and negative predictive value (100%), while its specificity and positive predictive value were 33.7% and 27.2%, respectively. Among patients without lesions at microUS, 25 (83.3%) did not harbour CaP, while 5 (16.7%) patients were diagnosed with a Gleason score 6 CaP, with no patients harbouring csCaP. Using microUS, the csCaP detection would have remained 100%, while reducing the detection of insignificant CaP of a 23.8% extent (n = 5). In MLRMs, lesion identified at microUS and continuously-coded PSAd were independent predictors of CaP. The accuracy of a model including PRI-MUS score, digital rectal examination (DRE), PSA density, age and family history was 0.744 (95% CI: 0.645 - 0.843).Conclusion: In our single-institutional retrospective study, microUS was potentially capable to stratify the presence of CaP in patients with an equivocal MRI. Further prospective studies on larger populations are needed to validate our results. [ABSTRACT FROM AUTHOR]