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Purpose: The use of open intra-peritoneal onlay mesh repairs (O-IPOMs) for treating medium/large incisional ventral hernias has come into question due to the development of minimally invasive and sublay procedures. This study aimed to identify factors that are associated with the use of O-IPOMs in France., Methods: We analysed prospectively collected data from the French Hernia Registry on incisional ventral hernia repairs (IVHR) for hernias ≥ 4 cm in width., Results: We obtained data for 2261 IVHR (from 11/09/2011 to 30/03/2020): 733 O-IPOMs and 1,528 other techniques. We found that the O-IPOMs were performed on patients with more patient-related risk factors compared with the other techniques. Specifically, there was a higher proportion of patients with ASA III/IV (40.47% vs. 28.02%; p < 0.00001) and at least one patient-related risk factor (66.17% vs. 58.51%; p = 0.0005). Of the 733 O-IPOMs, 195 used Ventrio ST™ (VST), the most commonly used mesh for such IPOMs in our database; the other 538 O-IPOMs used other meshes (OM). The VST subgroup had a higher proportion of patients with ASA III/IV (52.58% vs. 36.07%; p < 0.0001) and on anticoagulants (26.04% vs. 18.41%; p = 0.0229) compared with the OM subgroup; they also had a lower recurrence rate after 2 years (5.83% vs. 15.41%; p = 0.008). However, large (≥ 10 cm) or lateral defects were more common in the OM subgroup, and their mesh/defect area ratio was lower., Conclusion: O-IPOMs were performed on patients with more comorbidities and/or complex incisional hernias compared with other techniques., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Visceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies., Objective: To analyse genomic alterations in tumour samples according to their lymphatic, bone, and visceral metastatic stages and overall survival., Design, Setting, and Participants: We selected 200 patients with metastatic prostate cancer. Genomic profiling of 111 genes and molecular signatures (homologous recombination deficiency [HRD], microsatellite instability, and tumour burden mutation) was performed with the MyChoice test (Myriad Genetics, Inc, Salt Lake City, UT, USA)., Outcome Measurements and Statistical Analysis: The association between genomic profiles and visceral metastatic evolution was evaluated using logistic regression. Kaplan-Meier and Cox proportional hazard analyses were used for analyses of early death., Results and Limitations: A total of 173 (87%) genomic profiles were obtained. Eighty-four (49%) patients died during the follow-up period (median duration = 76 mo). TP53 was the most frequently mutated gene, followed by FANC genes, including BRCA2, and those of the Wnt-pathway (APC/CTNNB1). TP53 gene mutations were more frequent in patients of European (42%) than in those of African (16%) ancestry. An HRD score of >25 was predictive of FANC gene mutations. The mutational status of TP53 (p < 0.001) and APC (p = 0.002) genes were significantly associated with the risk of visceral metastases. The mutational status of CTNNB1 (p = 0.001), TP53 (p = 0.015), BRCA2 (p = 0.027), and FANC (p = 0.005) genes were significantly associated with an earlier age at death. The limitations are the retrospective study design based on a selection of genes and the low frequency of certain molecular events., Conclusions: Mutations in the TP53 gene and genes (APC/CTNNB1) related to the Wnt pathway are associated with metastatic visceral dissemination and early death. These genomic alterations could be considered as markers to identify prostate cancer patients at a high risk of life-threatening disease who might benefit from more intensified treatment or new targeted therapies., Patient Summary: In this report, we evaluated the relationships between genomic profiles (gene mutations and molecular signatures) of tumour samples from patients with metastatic prostate cancer and early death. We found that mutations of specific genes, notably TP53 and APC/CTNNB1 related to the Wnt pathway, are associated with visceral metastatic progression and an earlier age at death., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Metastatic prostate cancer (mPCa) harbors genomic alterations that may predict targeted therapy efficacy. These alterations can be identified not only in tissue but also directly in biologic fluids (ie, liquid biopsies), mainly blood. Liquid biopsies may represent a safer and less invasive alternative for monitoring patients treated for mPCa. Current research focuses on the description and validation of novel predictive biomarkers to improve precision medicine in mPCa. Our aim was to systematically review the current evidence on liquid biopsy biomarkers for predicting treatment response in mPCa., Methods: We systematically searched Medline, Web of Science, and evidence-based websites for publications on circulating biomarkers in mPCa between March 2013 and February 2024 for review. Endpoints were: prediction of overall survival, biochemical or radiographic progression-free survival after treatment (chemotherapy, androgen deprivation therapy, androgen receptor pathway inhibitors [ARPIs], immunotherapy, or PARP inhibitors [PARPIs]). For each biomarker, the level of evidence (LOE) for clinical validity was attributed: LOE IA and IB, high level of evidence; LOE IIB and IIC, intermediate level; and LOE IIIC and LOE IV-VD, weak level., Key Findings and Limitations: The predictive value of each biomarker for the response to several therapies was evaluated in both metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC). In patients with mCRPC, BRCA1/2 or ATM mutations predicted response to ARPIs (LOE IB) and PARPIs (LOE IIB), while AR-V7 transcripts or AR-V7 protein levels in circulating tumor cells (CTCs) predicted response to ARPIs and taxanes (LOE IB). CTC quantification predicted response to cabazitaxel, abiraterone, and radium-223 (LOE IIB), while TP53 alterations predicted response to 177 Lu prostate-specific membrane antigen radioligand treatment (LOE IIB). AR copy number in circulating tumor DNA before the first treatment line and before subsequent lines predicted response to docetaxel, cabazitaxel, and ARPIs (LOE IIB). In mHSPC, DNA damage in lymphocytes was predictive of the response to radium-223 (LOE IIB)., Conclusions and Clinical Implications: BRCA1/2, ATM, and AR alterations detected in liquid biopsies may help clinicians in management of patients with mPCa. The other circulating biomarkers did not reach the LOE required for routine clinical use and should be validated in prospective independent studies., Patient Summary: We reviewed studies assessing the value of biomarkers in blood or urine for management of metastatic prostate cancer. The evidence indicates that some biomarkers could help in selecting patients eligible for specific treatments., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2 . More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

SK3 channels are potassium channels found to promote tumor aggressiveness. We have previously demonstrated that SK3 is regulated by synthetic ether lipids, but the role of endogenous ether lipids is unknown. Here, we have studied the role of endogenous alkyl- and alkenyl-ether lipids on SK3 channels and on the biology of cancer cells. Experiments revealed that the suppression of alkylglycerone phosphate synthase or plasmanylethanolamine desaturase 1, which are key enzymes for alkyl- and alkenyl-ether-lipid synthesis, respectively, decreased SK3 expression by increasing micro RNA (miR)-499 and miR-208 expression, leading to a decrease in SK3-dependent calcium entry, cell migration, and matrix metalloproteinase 9-dependent cell adhesion and invasion. We identified several ether lipids that promoted SK3 expression and found a differential role of alkyl- and alkenyl-ether lipids on SK3 activity. The expressions of alkylglycerone phosphate synthase, SK3, and miR were associated in clinical samples emphasizing the clinical consistency of our observations. To our knowledge, this is the first report showing that ether lipids differentially control tumor aggressiveness by regulating an ion channel. This insight provides new possibilities for therapeutic interventions, offering clinicians an opportunity to manipulate ion channel dysfunction by adjusting the composition of ether lipids., Competing Interests: Conflict of interest The authors declare that they have no conflict of interests with the contents of article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Periprostatic adipose tissue (PPAT) is likely to modulate prostate cancer (PCa) progression. We analyzed the variations in the effect of PPAT on cancer cells, according to its fatty acid (FA) composition and tumor characteristics., Methods: The expression of markers of aggressiveness Ki67 and Zeb1, and epigenetic marks that could be modified during PCa progression, was analyzed by immunohistochemistry on a tissue-micro-array containing 59 pT3 PCa, including intra-prostatic areas and extra-prostatic foci in contact with PPAT belonging to the same tumor. In addition, we cocultivated PC3 and LNCaP cell lines with PPAT, which were then analyzed for FA composition., Results: Although the contact between PPAT and cancer cells led overall to an increase in Ki67 and Zeb1, and a decrease in the epigenetic marks 5MC, 5HMC, and H3K27ac, these effects were highly heterogeneous. Increased proliferation in extra-prostatic areas was associated with the international society of uropathology score. PC3 and LNCaP cocultures with PPAT led to increased Ki67, Zeb1 and H3K27me3, but only for PPAT associated with aggressive PCa. PC3 proliferation was correlated with high 20.2 n-6 and low 20.5n-3 in PPAT., Conclusions: These results suggest that the effects of PPAT on cancer cells may depend on both PCa characteristics and PPAT composition, and could lead to propose nutritional supplementation., (© 2023 Wiley Periodicals LLC.)

Prostate cancer (PCa) is a public health issue. The diagnostic strategy for PCa is well codified and assessed by digital rectal examination, PSA testing and multiparametric MRI, which may or may not lead to prostate biopsies. The formal benefit of organized PCa screening, studied more than 10 years ago at an international scale and for all incomers, is not demonstrated. However, diagnostic and therapeutic modalities have evolved since the pivotal studies. The contribution of MRI and targeted biopsies, the widespread use of active surveillance for unsignificant PCa, the improvement of surgical techniques and radiotherapy… have allowed a better selection of patients and strengthened the interest for an individualized approach, reducing the risk of overtreatment. Aiming to enhance coverage and access to screening for the population, the European Commission recently promoted the evaluation of an organized PCa screening strategy, including MRI. The lack of screening programs has become detrimental to the population and must shift towards an early detection policy adapted to the risk of each individual., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose of Review: Many studies on epidemiology of prostate cancer (PCa) are based on a diagnosis of PCa using PSA (prostate-specific antigen) level. However, biases can distort the interpretation of the results, which in turn limits policy and decision making on public health prevention strategies or clinical guidelines. The main confusion is to interpret the posterior probability of the outcome following the exposure as a change in the prevalence of the disease outcome, whereas this change reflects only the predictive values of the PSA test induced by the exposure of interest., Recent Findings: Many studies report potential causal factors involved in PCa risk. However, the lack of integration of how physiological changes in PSA values are associated with the exposures being investigated, they explain in part contradictory and controversial results on PCa risk factors in the literature., Summary: A strategy to perform case--control studies based on PSA stratification is suggested to avoid misinterpretation related to PSA misclassification. Real data are analysed, and we show that we can exploit the mechanism of selection biases using different modalities of controls recruitment based on biomarker stratification to distinguish real from false causal factors., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Prostate cancer (PCa) represents one of the most frequent diagnosed cancer in males worldwide. Due to routine screening tests and the efficiency of available treatments, PCa-related deaths have significantly decreased over the past decades. However, PCa remains a critical threat if detected at a late stage in which, cancer cells would have already detached from the primary tumor to spread and invade other parts of the body. Calcium (Ca 2+ ) channels and their protein regulators are now considered as hallmarks of cancer and some of them have been well examined in PCa. Among these Ca 2+ channels, isoform 3 of the ORAI channel family has been shown to regulate the proliferation of PCa cells via the Arachidonic Acid-mediated Ca 2+ entry, requiring the involvement of STIM1 (Stromal Interaction Molecule 1). Still, no study has yet demonstrated a role of the "neglected" STIM2 isoform in PCa or if it may interact with ORAI3 to promote an oncogenic behavior. In this study, we demonstrate that ORAI3 and STIM2 are upregulated in human PCa tissues. In old KIMAP (Knock-In Mouse Prostate Adenocarcinoma) mice, ORAI3 and STIM2 mRNA levels were significantly higher than ORAI1 and STIM1. In vitro, we show that ORAI3-STIM2 interact under basal conditions in PC-3 cells. ORAI3 silencing increased Store Operated Ca 2+ Entry (SOCE) and induced a significant increase of the cell population in G2/M phase of the cell cycle, consistent with the role of ORAI3 as a negative regulator of SOCE. Higher expression levels of CDK1-Y15/Cyclin B1 were detected and mitotic arrest-related death occurred after ORAI3 silencing, which resulted in activating Bax/Bcl-2-mediated apoptotic pathway and caspase-8 activation and cleavage. STIM2 and ORAI3 expression increased in M phase while STIM1 expression and SOCE amplitude significantly decreased. Taken together, ORAI3 -STIM2 complex allows a successful progression through mitosis of PCa cells by evading mitotic catastrophe., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets., Methods: We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort., Results: Unsupervised clustering identified two "TME subtypes", in each of the cohorts: the "immune-enriched" and the "immune-low". Within AXIPAP trial cohort, the "immune-enriched" cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the "immune-enriched" group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations., Conclusion: For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This "immune-enriched" group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies., Trial Registration Number: NCT02489695., Competing Interests: Competing interests: MdV-B: Research Grant: Ipsen. Board: AstraZeneca, AAA, BMS, Astellas. Travel expense: Pfizer. NR-L: Board: Ipsen, BMS, AstraZeneca. RF: Honoraria: Merck, Pfizer, Ipsen, MSD, Bayer. Board: Janssen, Merck, Pfizer. Expert: Ipsen, Janssen, Astellas. GG: Speaker bureau: Janssen, Amgen, BMS, Ipsen, AAA, AstraZeneca, Bayer, Pfizer, Merck, Astellas. Recipient my institution. Board: Janssen, Amgen, BMS, Curium, Bayer, Pfizer, Merck. Recipient my institution. Expert: BMS, Bayer, Pfizer, Merck. Recipient my institution. Travel expense: Janssen, BMS, AstraZeneca, Bayer, Pfizer Merck. Recipient: me. LG: Consulting or advisory role: BMS, MSD, Novartis, Ipsen, Janssen. CC: Consulting or advisory role: Pfizer, Novartis, BMS. FR: Consulting: Pfizer, Ipsen, BMS, MSD. AR: Consulting or advisory role: Pfizer, BMS, AstraZeneca, Roche, MSD, Ipsen. Travel expenses: Pfizer, BMS, AstraZeneca, Roche, MSD, Ipsen ; Institutional Grant: Pfizer. MG-G: Honoraria and travel expenses: Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Roche and Sanofi. BE: Advisory role: BMS, Pfizer, Novartis, Oncorena, Immunicum. Research grants: BMS, Novartis, Aveo. SN: Honoraria: Pfizer, Ipsen, MSD, BMS, Eisaï. Travel expenses: Pfizer, Ipsen, MSD. Research grant (institution): Pfizer, Ipsen. LA: Advisory role (Institution): BMS, MSD, Pfizer, Novartis, Amgen, Astellas, Ipsen, Roche, Merck, AstraZeneca, Exelixis, Peloton therapeutics, Corvus pharmaceuticals, Janssen, Eisai, 4D Pharma. Travel expenses: Merck/Pfizer. MM, JD, CP, ES-M, GF, EB, FL: no conflict., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To review current evidence regarding the management of de novo, oligometastatic, castration-sensitive prostate cancer (PCa)., Methods: A literature search was conducted on PubMed/Medline and a narrative synthesis of the evidence was performed in August 2022., Results: Oligometastatic disease is an intermediate state between localized and aggressive metastatic PCa defined by ≤ 3-5 metastatic lesions, although this definition remains controversial. Conventional imaging has limited accuracy in detecting metastatic lesions, and the implementation of molecular imaging could pave the way for a more personalized treatment strategy. However, oncological data supporting this strategy are needed. Radiotherapy to the primary tumor should be considered standard treatment for oligometastatic PCa (omPCa). However, it remains to be seen whether local therapy still has an additional survival benefit in patients with de novo omPCa when treated with the most modern systemic therapy combinations. There is insufficient evidence to recommend cytoreductive radical prostatectomy as local therapy; or stereotactic body radiotherapy as metastasis-directed therapy in patients with omPCa. Current data support the use of intensified systemic therapy with androgen deprivation therapy (ADT) and next-generation hormone therapies (NHT) for patients with de novo omPCa. Docetaxel has not demonstrated benefit in low volume disease. There are insufficient data to support the use of triple therapy (i.e., ADT + NHT + Docetaxel) in low volume disease., Conclusion: The present review discusses current data in de novo, omPCa regarding its definition, the increasing role of molecular imaging, the place of local and metastasis-directed therapies, and the intensification of systemic therapies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Recently, several large, high-quality analyses have shown opposing results regarding the association between 5α-reductase inhibitor (5-ARI) use and prostate cancer (PCa) mortality., Objective: To systematically evaluate the current evidence regarding 5-ARI use and PCa mortality., Data Sources: A literature search began in and was conducted through August 2022 using PubMed/Medline, Embase, and Web of Science databases., Study Selection: Studies were deemed eligible if they included male patients of any age who were 5-ARI users and were compared with those who were nonusers if they analyzed PCa mortality in randomized clinical trials and prospective or retrospective cohort studies., Data Extraction and Synthesis: This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Adjusted hazard ratios (HRs) were extracted from published articles. Data analysis was performed in August 2022., Main Outcomes and Measures: The primary outcome was PCa mortality among 5-ARI users vs nonusers. The inverse variance method with adjusted HRs and random-effect models were used to determine the association between 5-ARI use and PCa mortality. Two subgroup analyses were performed to assess the effect of 2 main confounders: prostate-specific antigen level and PCa diagnosis at baseline., Results: Among 1200 unique records screened, 11 studies met the inclusion criteria. A total of 3 243 575 patients were included: 138 477 users of 5-ARI and 3 105 098 nonusers. There was no statistically significant association between 5-ARI use and PCa mortality (adjusted HR, 1.04; 95% CI, 0.80-1.35; P = .79). No significant association was found when the analysis was restricted to studies that excluded patients with a diagnosis of PCa at baseline (adjusted HR, 1.00; 95% CI, 0.60-1.67; P = .99) or the analysis was restricted to prostate-specific antigen-adjusted studies (adjusted HR, 0.76; 95% CI, 0.57-1.03; P = .08)., Conclusions and Relevance: This systematic review and meta-analysis, which draws on 2 decades of epidemiologic literature and includes more than 3 million patients, found no statistically significant association between 5-ARI use and PCa mortality but provides important data to inform clinical care.

Purpose: To develop new selection criteria for active surveillance (AS) in intermediate-risk (IR) prostate cancer (PCa) patients., Methods: Retrospective study including patients from 14 referral centers who underwent pre-biopsy mpMRI, image-guided biopsies and radical prostatectomy. The cohort included biopsy-naive IR PCa patients who met the following inclusion criteria: Gleason Grade Group (GGG) 1-2, PSA < 20 ng/mL, and cT1-cT2 tumors. We relied on a recursive machine learning partitioning algorithm developed to predict adverse pathological features (i.e., ≥ pT3a and/or pN + and/or GGG ≥ 3)., Results: A total of 594 patients with IR PCa were included, of whom 220 (37%) had adverse features. PI-RADS score (weight:0.726), PSA density (weight:0.158), and clinical T stage (weight:0.116) were selected as the most informative risk factors to classify patients according to their risk of adverse features, leading to the creation of five risk clusters. The adverse feature rates for cluster #1 (PI-RADS ≤ 3 and PSA density < 0.15), cluster #2 (PI-RADS 4 and PSA density < 0.15), cluster #3 (PI-RADS 1-4 and PSA density ≥ 0.15), cluster #4 (normal DRE and PI-RADS 5), and cluster #5 (abnormal DRE and PI-RADS 5) were 11.8, 27.9, 37.3, 42.7, and 65.1%, respectively. Compared with the current inclusion criteria, extending the AS criteria to clusters #1 + #2 or #1 + #2 + #3 would increase the number of eligible patients (+ 60 and + 253%, respectively) without increasing the risk of adverse pathological features., Conclusions: The newly developed model has the potential to expand the number of patients eligible for AS without compromising oncologic outcomes. Prospective validation is warranted., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The diagnosis of prostate cancer (PCa) still relies on the performance of both targeted (TB) and systematic biopsies (SB). Micro-ultrasound (mUS)-guided biopsies demonstrated a high sensitivity in detecting clinically significant prostate cancer (csPCa), which could be comparable to that of magnetic resonance imaging (MRI)-TB, but their added value has not been compared to SB yet., Methods: We conducted a systematic review and meta-analysis, based on Medline, EMBASE, Scopus, and Web of Science, in accordance with PRISMA guidelines, to compare mUS-guided biopsies to SB., Results: Based on the literature search of 2957 articles, 15 met the inclusion criteria (2967 patients). Most patients underwent mUS-guided biopsies, followed by MRI-TB and SB. Respectively 5 (n = 670) and 4 (n = 467) studies, providing raw data on SB, were included in a random-effect meta-analysis of the detection rate of csPCa, i.e. Gleason Grade Group (GGG) ≥ 2 or non-csPCa (GGG = 1). Overall, PCa was detected in 56-71% of men, with 31.3-49% having csPCa and 17-25.4% having non-csPCa. Regarding csPCa, mUS-guided biopsies identified 196 and SB 169 cases (Detection Ratio (DR): 1.18, 95% CI 0.83-1.68, I 2  = 69%), favoring mUS-guided biopsies; regarding non-csPCa, mUS-guided biopsies identified 62 and SB 115 cases (DR: 0.55, 95% CI 0.41-0.73, I 2  = 0%), also favoring mUS-guided biopsies by decreasing unnecessary diagnosis., Conclusion: Micro-ultrasound-guided biopsies compared favorably with SB for the detection of csPCa and detected fewer non-csPCa than SB. Prospective trials are awaited to confirm the interest of adding mUS-guided biopsies to MRI-TB to optimize csPCa detection without increasing overdiagnosis of non-csPCa., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although several studies have examined the relationship between organochlorine pesticides (OCPs) and prostate cancer (PCa) risk, no data are available concerning the association between OCPs concentrations in periprostatic adipose tissue (PPAT), which reflects cumulative exposure, and PCa aggressiveness. Moreover, no previous study has compared OCPs exposure in two distinct ethno-geographical populations. The objectives were to analyze OCPs in PPAT of PCa patients from either Mainland France or French West Indies in correlation with features of tumor aggressiveness, after adjusting for potential confounders such age, BMI, and polyunsaturated fatty acid (PUFA) content of PPAT. PPAT was analyzed in 160 patients (110 Caucasians and 50 African-Caribbeans), 80 with an indolent tumor (ISUP group 1 + pT2), and 80 with an aggressive tumor (ISUP group more than 3 + pT3). The concentrations of 29 OCPs were measured in PPAT concomitantly with the characterization of PUFA content. Exposure patterns of OCPs differed according to the ethno-geographical origin. Most OCPs were found at higher concentration in Caucasian patients, whereas pp'-DDE content was twice as high in African-Caribbeans. Chlordecone was only detected in PPAT from African-Caribbean patients. Most OCP concentrations were positively correlated with age, and some with BMI. After adjusting for age, BMI, and PUFA composition of PPAT, no significant association was found between OCPs content and risk of aggressive disease, except of mirex which appeared inversely associated with aggressive features of PCa in Caucasian patients. These results highlight a significant ethno-geographic variation in internal exposure to OCPs, which likely reflects differences in consumption patterns. The inverse relationship observed between mirex concentration and markers of PCa aggressiveness need to be further investigated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The aim was to evaluate the prognostic role of sub-categories of ISUP 4 prostate cancer (PCa) on final pathology, and assess the tumor architecture prognostic role for predicting biochemical recurrence (BCR) after radical prostatectomy., Methods: From a prospectively-maintained database, we included 370 individuals with ISUP 4 on final pathology. The main outcomes were to evaluate the relationship between different ISUP patterns within the group 4 with pathological and oncological outcomes. Binary logistic regression and Kaplan-Meier estimator were used to evaluate the role of the different categories (3 + 5, 4 + 4, 5 + 3) and tumor architecture (intraductal and/or cribriform) on pathological and oncological outcomes., Results: Among the 370 individuals with ISUP considered for the study, 9, 85 and 6% had grade 3 + 5, 4 + 4 and 5 + 3 PCa, respectively. Overall, 74% had extracapsular extension, while lymph node invasion (LNI) was documented in 9%. A total of 144 patients experienced BCR during follow-up. After adjusting for PSA, pT, grade group, LNI and positive surgical margins (PSM), grade 3 + 5 was a protective factor (HR: 0.30, 95% CI: 0.13,0.68, p = 0.004) in predicting BCR relative to grade 4 + 4. Intraductal or cribriform architecture was correlated with BCR (HR: 5.99, 95% CI: 2.68, 13.4, p < 0.001) after adjusting for PSA, pT, grade group, LNI and PSM., Conclusions: Patients with tumor grade 3 + 5 had better pathological and prognostic outcomes compared to 4 + 4 or 5 + 3. When accounting for tumor architecture, the sub-stratification into subgroups lost its prognostic role and tumor architecture was the sole predictor of poorer prognosis in terms of biochemical recurrence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Recently, Eggener et al. reignited a debate consisting to redefine Gleason Grade Group (GGG) 1 prostate cancer (PCa) as a precancerous lesion to reduce overdiagnosis and overtreatment. However, historical cohorts showed that some GGG1-labeled disease at biopsy may be underestimated by the standard PCa diagnostic workup. The aim was to assess whether the risk of adverse features at radical prostatectomy (RP) in selected GGG1 patients still exists in the era of pre-biopsy mpMRI and image-guided biopsies., Methods: We retrospectively reviewed our data from a European RP dataset to assess in contemporary patients with GGG1 at mpMRI-targeted biopsy the rate of adverse features at final pathology, defined as ≥ pT3a and/or pN+ and/or GGG ≥ 3., Results: A total of 419 patients with cT1-T2 cN0 GGG1-PCa were included. At final pathology, 143 (34.1%) patients had adverse features. In multivariate analysis, only unfavorable intermediate-risk/high-risk disease (defined on PSA or stage) was predictive of adverse features (OR 2.45, 95% CI 1.11-5.39, p = 0.02). A significant difference was observed in the 3-year biochemical recurrence-free survival between patients with and without adverse features (93.4 vs 87.8%, p = 0.026). In sensitivity analysis restricted low- and favorable intermediate-risk PCa, 122/383 patients (31.8%) had adverse features and no preoperative factors were statistically associated with this risk., Conclusion: In this European study, we showed that there is still a risk of underestimating GGG1 disease at biopsy despite the routine use of image-guided biopsies. Future studies are warranted to improve the detection of aggressive disease in GGG1-labeled patients by incorporating the latest tools such as genomic testing or radiomics., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients has improved since 2011 with the use of novel hormonal agents (NHAs). The incidence of brain metastases (mets) has been reported to increase since 2004 with the use of docetaxel, but not the incidence of visceral mets. Our objective was to study whether the use of NHAs increases the risk of developing visceral or brain mets (VBMs)., Patients and Methods: mCRPC patients with mets limited to bone (bmCRPC), treated at Tours University Hospital between 2007 and 2015, were included retrospectively. The primary endpoint was to determine whether treatment with NHAs was associated with an increased incidence of VBMs. Secondary endpoints included the search for putative predictive factors to develop VBMs., Results: On 187 bmCRPC patients included, 65 developed VBMs. VBM incidence increased in bmCRPC patients alive after 2011, compared to patients who died before (39.7 vs. 24.6%, P = .04). Meanwhile, their median OS increased from 16.3 months to 28.5 months (P = .01). The longer was the treatment with NHAs, the lower was the risk of VBMs (HR = 0.96, 95% CI [0.94; 0.99]), whereas age < 70 years (HR = 3.33, 95% CI [1.50; 7.40]) and low PSA level at diagnosis (HR = 1.58, 95% CI [1.16; 2.15]) increased this risk., Conclusion: Though retrospective, our results showed an increased incidence of VBMs in bmCRPC patients after 2011. However, this was not associated with NHA exposure duration. The role of NHA exposure remains unclear and needs further investigation., (Copyright © 2022. Published by Elsevier Inc.)

Adipose tissue is part of the prostate cancer (PCa) microenvironment not only in the periprostatic area, but also in the most frequent metastatic sites, such as bone marrow and pelvic lymph nodes. The involvement of periprostatic adipose tissue (PPAT) in the aggressiveness of PCa is strongly suggested by numerous studies. Many molecules play a role in the reciprocal interaction between adipocytes and PCa cells, including adipokines, hormones, lipids, and also lipophilic pollutants stored in adipocytes. The crosstalk has consequences not only on cancer cell growth and metastatic potential, but also on adipocytes. Although most of the molecules released by PPAT are likely to promote tumor growth and the migration of cancer cells, others, such as the adipokine adiponectin and the n-6 or n-3 polyunsaturated fatty acids (PUFAs), have been shown to have anti-tumor properties. The effects of PPAT on PCa cells might therefore depend on the balance between the pro- and anti-tumor components of PPAT. In addition, genetic and environmental factors involved in the risk and/or aggressiveness of PCa, including obesity and diet, are able to modulate the interactions between PPAT and cancer cells and their consequences on the growth and the metastatic potential of PCa.

Introduction: The risk of recurrence is increased in localized high-risk prostate cancer (PCa). The implementation of an appropriate diagnostic and therapeutic strategy is essential. The objective of this update by the Prostate Committee of the French Association of Urology was to report the most recent data in the management of localized high-risk PCa., Material and Methods: This update is based on the data available in the literature on localized high-risk PCa. A PubMed search and narrative review of the recent data were performed in March 2022., Results: Compared with conventional imaging, PET-PSMA is more effective for the diagnosis of lymph nodes and distant metastases. Two recent randomized clinical trials have failed to prove the oncologic benefit of extended pelvic lymph node dissection during radical prostatectomy (RP). Postoperatively, early salvage radiotherapy is the standard of care, with adjuvant radiotherapy becoming an option in case of unfavorable pathological criteria (ISUP 4-5, pT3±positive margins) in young patients. Although promising, perioperative systemic therapies (chemotherapy, second-generation hormonotherapy) cannot be recommended at this time when the patient is treated by RP. Regarding radiotherapy, prophylactic lymph node irradiation during prostatic irradiation was associated with improved biochemical and metastasis-free survival in a recent randomized trial but it is still controversial. Since the publication of the results of the STAMPEDE trial, the addition of abiraterone acetate to radiation-hormone therapy should be considered the new standard of care for patients with localized (very) high-risk PCa, according to the inclusion criteria of the study., Conclusion: The most recent data of the literature regarding the management of high-risk localized PCa redefine the diagnostic performance of molecular imaging, the timing of postoperative radiotherapy, the oncologic benefit of pelvic lymph node treatment, and the intensification of systemic therapies., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs-albeit by different mechanisms-are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases.The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively.Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR).RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV( +) cases were consistently RB1-positive (p < 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p < 0.0001, LHR +  = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p < 0.001, LHR +  = 3.1).These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients treated by radical prostatectomy (RP) for localized prostate cancer (PCa) may experience biochemical recurrence (BCR) in approximately 30% of cases. Recently, advances in imaging modalities and in particular Positron-Emission Tomography with computed tomography (PET/CT) imaging allow for better detection and characterization of lesions outside the prostatic bed at recurrence. Thus, treatment at BCR can be significantly improved by a tailored strategy based on new generation imaging. A more precise and accurate staging of the disease at recurrence paves the way to more appropriate treatment, potentially translating into better survival outcomes of these patients. This review therefore highlights the interest of PET/CT at the time of BCR, its superiority over standard imaging in terms of staging, and its impact on guiding the different therapeutic possibilities depending on the site, number, and volumes of recurrence. Indeed, we will discuss below about different strategies and their indications: salvage radiotherapy of the prostate bed, systemic therapies, stereotactic body radiotherapy and others therapeutical strategies. The various innovative approaches based on PET/CT implementation are partly underway within protocol trials to prove their benefits on clinically meaningful endpoints. © 2022 Elsevier Masson SAS. All rights reserved., Competing Interests: Disclosure of interest A. Ruffion, M. Lasserre, P. Sargos, G. Fiard, E. Barret and J.-B. Beauval have no competing interest to declare regarding this article. C. Dariane declares competing interest by participating in clinical trials (as co-investigator, non-principal experimenter, or collaborator) for Janssen and Bayer; receiving compensation for advisory consultancies from Janssen, Bayer, Astellas; being invited to conference as a speaker by Janssen and being invited to congresses with paid expenses by Bayer. M. Rouprêt de declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Roche, Janssen, AstraZeneca and by receiving compensation for advisory consultancies from Astellas, Ferring, Roche, Janssen, AstraZeneca, Bayer and Ipsen. G. Ploussard declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer; by participating in clinical trials (as co-investigator, non-principal experimenter, or collaborator) for Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer; receiving compensation for advisory consultancies from Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer, Astellas, Intuitive, Thermo Fisher; being invited to conference as a speaker by Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer, Astellas, Intuitive, Thermo Fisher. M. Gauthé declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Curium Pharma, ABX Biochemical compounds, Endocyte/Novartis; receiving compensation for advisory consultancies from Curium Pharma; being invited to conference as a speaker by Novartis, Astellas; being invited to congresses with paid expenses by Curium Pharma, ABX Biochemical compounds, Endocyte/Novartis. G. Fromont declares competing interest by being invited as a speaker to conference by AstraZeneca and Astellas. R. Mathieu declares competing interest by receiving compensation for advisory consultancies from Bayer, Astellas, Janssen and by being invited as a speaker by Bayer, Astellas and Janssen. G. Roubaud declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Bayer, Janssen, AAA, Novartis, Astellas, MSD, AstraZeneca; by receiving compensation for advisory consultancies from Merck and AstraZeneca; by being invited as a speaker to conferences by Jansses, AAA, Novartis, Astellas, AstraZeneca, Merck and by being invited to congresses with paid expenses by Astellas, Janssen and AstraZeneca. L. Brureau, G. Créhange, R. Renard-Penna did not disclose their conflict of interest., (Copyright © 2022 Elsevier Masson SAS. Tous droits réservés.)

Introduction: The aim of this narrative review conducted by the Prostate Cancer Committee of the French Association of Urology (CC-AFU) was to provide an update on the current evidence for the impact of PET/CT in the management of men with non-metastatic castration-resistant prostate cancer (nmCRPC)., Material and Methods: This review is based on data available in the literature on PET/CT imaging for staging nmCRPC patients. A PubMed search and narrative review of the data were performed in March 2022. Only articles in French or English were considered., Results: Current guidelines recommend bone scan and CT scan as standard imaging modalities for staging and follow-up of patients with nmCRPC. Nearly one-third of asymptomatic patients with presumed nmCRPC ultimately have metastatic disease on conventional imaging. Increasing reports have shown that conventional imaging has limited accuracy in detecting metastatic disease in nmCRPC patients, leading to the development of next-generation imaging techniques. In a retrospective study, 18F-choline PET/CT detected distant metastases in 27/58 high-risk nmCRPC patients with prior negative conventional imaging. The implementation of radiolabeled ligands of the prostate-specific membrane antigen (PSMA) PET/CT in staging strategy has resulted in metastasis detection in 45% to 98% of patients with presumptive nmCRPC on conventional imaging. Such an early diagnosis of metastatic CRPC may allow patients to be referred for metastasis-directed therapies (i.e. stereotactic body radiotherapy), aimed at prolonging the efficacy of systemic therapies and improving clinical outcomes. However, current data are not strong enough to recommend this strategy, which must be properly evaluated in clinical trials. Indeed, the use of molecular imaging may lead to inappropriate undertreatment if the second-generation androgen receptor inhibitors (darolutamide, enzalutamide, apalutamide), which prolong life, are not used in the subgroup of patients with high PSA velocity (PSA doubling time <10 months)., Conclusion: Implementation of PSMA-PET/CT in the staging strategy would result in a migration of disease stage to extra-pelvic, M1 disease in at least half of presumed nmCRPC patients. The unprecedented accuracy of PSMA-PET/CT may pave the way for a more personalized treatment strategy. However, no data yet support this strategy for all nmCRPC patients as no oncologic benefit of early detection of M1 disease or MDT has been demonstrated. © 2022 Elsevier Masson SAS. All rights reserved., Competing Interests: Disclosure of interest A. Ruffion, M. Lasserre, P. Sargos, G. Fiard, E. Barret, J.-B. Beauval, and P. Rocchi have no competing interest to declare regarding this article. M. Gauthé declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Curium Pharma, ABX Biochemical compounds, Endocyte/Novartis; participating in clinical trials (as co-investigator, non-principal experimenter, or collaborator) for Amgen; receiving compensation for advisory consultancies from Curium Pharma; being invited to conference as a speaker by Novartis, Astellas. C. Dariane declares competing interest by participating in clinical trials (as co-investigator, non-principal experimenter, or collaborator) for Janssen and Bayer; receiving compensation for advisory consultancies from Janssen, Bayer, Astellas; being invited to conference as a speaker by Janssen and being invited to congresses with paid expenses by Bayer. M. Rouprêt de declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Roche, Janssen, AstraZeneca and by receiving compensation for advisory consultancies from Astellas, Ferring, Roche, Janssen, AstraZeneca, Bayer and Ipsen. G. Ploussard declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer; by participating in clinical trials (as co-investigator, non-principal experimenter, or collaborator) for Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer; receiving compensation for advisory consultancies from Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer, Astellas, Intuitive, Thermo Fisher; being invited to conference as a speaker by Ferring, Janssen, Ipsen, AstraZeneca, Pfizer, Bayer, Astellas, Intuitive, Thermo Fisher. G. Fromont declares competing interest by being invited as a speaker to conference by AstraZeneca and Astellas. R. Mathieu declares competing interest by receiving compensation for advisory consultancies from Bayer, Astellas, Janssen and by being invited as a speaker by Bayer, Astellas and Janssen. G. Roubaud declares competing interest by participating in clinical trials (as principal investigator, coordinator, or principal experimenter) for Bayer, Janssen, AAA, Novartis, Astellas, MSD, AstraZeneca; by receiving compensation for advisory consultancies from Merck and AstraZeneca; by being invited as a speaker to conferences by Jansses, AAA, Novartis, Astellas, AstraZeneca, Merck and by being invited to congresses with paid expenses by Astellas, Janssen and AstraZeneca. L. Brureau, G. Créhange, R. Renard-Penna did not disclose their conflict of interest., (Copyright © 2022 Elsevier Masson SAS. Tous droits réservés.)

Context: Previous reports have shown an association between vasectomy and prostate cancer (PCa). However, there exist significant discrepancies between studies and systematic reviews due to a lack of strong causal association and residual confounding factors such as prostate-specific antigen (PSA) screening., Objective: To assess the association between vasectomy and PCa, in both unadjusted and PSA screen-adjusted studies., Evidence Acquisition: We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses. The PubMed, Scopus, and Web of Science databases were searched in January 2022 for studies that analyzed the association between vasectomy and PCa., Evidence Synthesis: A total of 37 studies including 16 931 805 patients met our inclusion criteria. A pooled analysis from all studies showed a significant association between vasectomy and any-grade PCa (odds ratio [OR] 1.23; 95% confidence interval [CI], 1.10-1.37; p  < 0.001; I 2  = 96%), localized PCa (OR 1.08; 95% CI, 1.06-1.11; p  < 0.00001; I 2  = 31%), or advanced PCa (OR 1.07; 95% CI, 1.02-1.13; p  = 0.006; I 2  = 0%). The association with PCa remained significant when the analyses were restricted to studies with a low risk of bias (OR 1.06; 95% CI, 1.02-1.10; p  = 0.02; I 2  = 48%) or cohort studies (OR 1.09; 95% CI, 1.04-1.13; p  < 0.0001; I 2  = 64%). Among studies adjusted for PSA screening, the association with localized PCa (OR 1.06; 95% CI, 1.03-1.09; p  < 0.001; I 2  = 0%) remained significant. Conversely, vasectomy was no longer associated with localized high-grade ( p  = 0.19), advanced ( p  = 0.22), and lethal ( p  = 0.42) PCa., Conclusions: Our meta-analysis found an association between vasectomy and any, mainly localized, PCa. However, the effect estimates of the association were increasingly close to null when examining studies of robust design and high quality. On exploratory analyses including studies, which adjusted for PSA screening, the association for aggressive and/or advanced PCa diminished., Patient Summary: In this study, we found an association between vasectomy and the risk of developing localized prostate cancer without being able to determine whether the procedure leads to a higher prostate cancer incidence., (© 2022 The Author(s).)

Metastatic progression is a major burden for breast cancer patients and is associated with the ability of cancer cells to overcome stressful conditions, such as nutrients deprivation and hypoxia, and to gain invasive properties. Autophagy and epithelial-to-mesenchymal transition are critical contributors to these processes. Here, we show that the P2X4 purinergic receptor is upregulated in breast cancer biopsies from patients and it is primarily localised in endolysosomes. We demonstrate that P2X4 enhanced invasion in vitro, as well as mammary tumour growth and metastasis in vivo. The pro-malignant role of P2X4 was mediated by the regulation of lysosome acidity, the promotion of autophagy and cell survival. Furthermore, the autophagic activity was associated with epithelial-to-mesenchymal transition (EMT), and this role of P2X4 was even more pronounced under metabolic challenges. Pharmacological and gene silencing of P2X4 inhibited both autophagy and EMT, whereas its rescue in knocked-down cells led to the restoration of the aggressive phenotype. Together, our results demonstrate a previously unappreciated role for P2X4 in regulating lysosomal functions and fate, promoting breast cancer progression and aggressiveness., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Ether lipids are composed of alkyl lipids with an ether bond at the sn-1 position of a glycerol backbone and alkenyl lipids, which possess a vinyl ether bond at the sn-1 position of the glycerol. These ether glycerolipids are present either as polar glycerophospholipids or neutral glycerolipids. Before studying the biological role of molecular species of ether glycerolipids, there is a need to separate and quantify total alkyl and alkenyl glycerolipids from biological samples in order to determine any variation depending on tissue or physiopathological conditions. Here, we detail the development of the first high-performance thin-layer chromatography method for the quantification of total alkyl and alkenyl glycerolipids thanks to the separation of their corresponding alkyl and alkenyl glycerols. This method starts with a reduction of all lipids after extraction, resulting in the reduction of neutral and polar ether glycerolipids into alkyl and alkenyl glycerols, followed by an appropriate purification and, finally, the linearly ascending development of alkyl and alkenyl glycerols on high-performance thin-layer chromatography plates, staining, carbonization and densitometric analysis. Calibration curves were obtained with commercial alkyl and alkenyl glycerol standards, enabling the quantification of alkyl and alkenyl glycerols in samples and thus directly obtaining the quantity of alkyl and alkenyl lipids present in the samples. Interestingly, we found a differential quantity of these lipids in shark liver oil compared to chimera. We quantified alkyl and alkenyl glycerolipids in periprostatic adipose tissues from human prostate cancer and showed the feasibility of this method in other biological matrices (muscle, tumor).

Purpose: Periprostatic fat has a metabolic activity on the prostate via cytokines that act paracrine on several signaling pathways including tumorigenesis. We investigated whether there was an association between preprostatic fat abundance and prostate cancer (PCa) aggressiveness., Materials and Methods: We performed a retrospective study including patients who underwent radical prostatectomy in our center from the prospective RESCAP database. Preoperative MRIs were re-read and different measurements of preprostatic fat (PPF) were performed. The maximum thickness (PPFmax) and the minimum thickness (PPFmin) were measured on a median T2 sagittal section. The total volume of preprostatic fat (PPFV) and volume normalized by prostate volume (NPPFV) were calculated semi-automatically by segmentation on continuous axial sections of 3mm. The association of these parameters with the aggressiveness criteria of PCa (ISUP 3-5 on biopsies and on operative specimen, intermediate or high-risk disease according to D'AMICO, PSA>10, upgrading risk at radical prostatectomy) was measured as well as the association between normal, overweight, and obese BMI classes and the aggressiveness criteria used., Results: One hundred and twenty-one men were included in this study. In both the univariate analysis and the multivariate analysis, none of the preprostatic fat measurements (PPFmax, PPFmin, PPFV and NPPFV) were associated with PCa aggressiveness criteria. There was also no association between BMI class and tumor aggressiveness., Conclusion: In this study, there is no association between the abundance of preprostatic fat and PCa aggressiveness according to the periprostatic fat measurements achieved., Level of Evidence: III., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Despite recent improvements in survival, metastatic castration-resistant prostate cancers (mCRPCs) remain lethal. Alterations in genes involved in the homologous recombination repair (HRR) pathway are associated with poor prognosis. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPis) have demonstrated anti-tumoral effects by synthetic lethality in patients with mCRPCs harboring HRR gene alterations, in particular BRCA2 . While both olaparib and rucaparib have obtained government approvals for use, the selection of eligible patients as well as the prescription of these treatments within the clinical urology community are challenging. This review proposes a brief review of the rationale and outcomes of PARPi treatment, then a pragmatic vision of PARPi use in terms of prescription and the selection of patients based on molecular screening, which can involve potential genetic counseling in the case of associated germinal alterations.

Introduction: Current therapeutic developments in prostate cancer (PCa) tend to increasingly personalize the treatment strategy, in particular as a function of tumor genomics. Recently, poly ADP-ribose polymerase (PARPi) inhibitors have shown their efficacy at the stage of castration resistance, in case of alteration of DNA repair genes in tumor tissue., Material and Methods: A narrative review was carried out on recent data in the literature since 2000. A consensus among the members of the Committee was obtained in order to synthesize the current data, with a particular focus on the practical considerations regarding indications and developments of molecular testing circuits concerning DNA repair genes, for theranostics purpose., Results: The establishment of an efficient molecular testing network is based on the multidisciplinary organization of the various actors and the coordination of all material resources. Its goal is the routine search for somatic mutations (in tumor tissue) of BRCA1/2 genes in patients who may benefit from PARPi. The current indications are for BRCA1 or 2 mutated castration-resistant metastatic PCa after next-generation hormone therapy failure. The demand for molecular testing must be decided in the tumor board, giving priority to archived tissue less than 10 years old. In case of unsuccess, biopsies of the primary or metastases, or even analysis of circulating tumor DNA, may be necessary. Any demand for a genetic test on tumor tissue must be accompanied by detailed information for the patient on the possible familial consequences, in case of associated germline mutation., Conclusion: This article aims to guide the practical implementation of molecular testing circuits for DNA repair genes alterations, in order to guide the therapeutic management of patients with advanced PCa., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Lifestyle, environment and excess body weight are not only associated with an increased risk of metabolic disorders, such as type 2 diabetes, but also to other pathological processes, such as infertility. A hormone produced mainly by the liver called fibroblast growth factor 21 (FGF21) is closely linked to the energy status and is increased in patients suffering from obesity or insulin resistance. Recently, FGF21 has been shown to be associated with female fertility disorders, but no or few data about the role of FGF21 on human male fertility has been described. In the present study, FGF21 was measured in the seminal fluid at a lower level in comparison to the blood level. Thus, in the present in vitro study, we aimed to decipher the FGF21 system in human semen. To evaluate the putative role of FGF21 on spermatozoa function, we incubated human spermatozoa with increasing concentrations of recombinant human FGF21. The FGF21 in seminal fluid is potentially produced by male reproductive tract tissues. In spermatozoa, the FGF21 signal was transduced by the two main receptors FGFR1-c and FGFR3 and the cofactor β-klotho, which are colocalized in the middle piece of spermatozoa and stimulated the PI3K/Akt and MAPK pathways. Finally, in vitro treatment by FGF21 significantly increased sperm motility and ATP levels. Concomitantly, exposure to FGF21 improved the oxidative stress, as a lower ROS level was observed. Overall, these results seem to indicate that the metabolic factor, FGF21, positively modifies the activity and quality of the parameters of human spermatozoa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bourdon, Estienne, Chevaleyre, Ramé, Guérif, Brun, Vasseur, Fromont, Plotton, Dufour-Rainfray, Caldas-Silveira, Dupont, Froment and Ducluzeau.)

Background: The aim of this study was to assess whether the respective values of open and laparoscopic intraperitoneal repairs of umbilical hernias are related to the European Hernia Society diameter of defects., Methods: This registry-based study compared the early and 2-year outcomes of 776 open versus 1,019 consecutive laparoscopic intraperitoneal repairs performed from 2011 to 2019., Results: Intraperitoneal mesh repair, either laparoscopic or open, was found to be a safe procedure at the 2-year follow-up. The incidence of reoperated bowel obstructions was 0.3%. Compared with the open group: (1) postoperative surgical site occurrences in small (<2 cm) or medium (2-4 cm) hernias (0.3% vs 2.4%; P = .041; 1.4% vs 5.9%; P = .0002); (2) recurrence rates in large (≥4 cm) umbilical hernias (0.0% vs 8.6%; P = .0195); and (3) cumulative reoperation rates (0.9% vs 2.2%; P = .021) were significantly better in the laparoscopic group. Conversely, the rate of early pain on day 1 and 1 month postsurgery was higher in the laparoscopic group, for all hernia sizes (P < .001). The rate of moderate or severe chronic pain at 2 years was significantly higher in the laparoscopic group (8.1% vs 2.4%; P = .049) for small hernias., Conclusion: The respective benefit to drawback ratios for open versus laparoscopic intraperitoneal repairs were related to the European Hernia Society diameter of hernia defect. In medium-large hernias, the benefits of laparoscopic repair overrode its drawbacks. In small hernias, the low recurrence rate, reduced early and chronic pain, and better rate of ambulatory surgery suggest there is still a place for open repair., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Annual countrywide data are scarce when comparing surgical approaches in terms of hospital stay outcomes and costs for radical prostatectomy (RP). We aimed to assess the impact of surgical approach on post-operative outcomes and costs after RP by comparing open (ORP), laparoscopic (LRP), and robot-assisted (RARP) RP in the French healthcare system., Patients and Methods: Data from all patients undergoing RP in France in 2020 were extracted from the central database of the national healthcare system. Primary endpoints were length of hospital stay (LOS including intensive care unit (ICU) stay if present), complications (estimated by severity index), hospital readmission rates (at 30 and 90 days), and direct costs of initial stay., Results and Limitations: A total of 19,018 RPs were performed consisting in ORP in 21.1%, LRP in 27.6%, and RARP in 51.3% of cases. RARP was associated with higher center volume (p < 0.001), lower complication rates (p < 0.001), shorter LOS (p < 0.001), and lower readmission rates (p = 0.004). RARP was associated with reduced direct stay costs (2286 euros) compared with ORP (4298 euros) and LRP (3101 euros). The main cost driver was length of stay. The main limitations were the lack of mid-term data, readmission details, and cost variations due to surgery system., Conclusions: This nationwide analysis demonstrates the benefits of RARP in terms of post-operative short-term outcomes. Higher costs related to the robotic system appear to be balanced by patient care improvements and reduced direct costs due to shorter LOS., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Determination of microsatellite instability (MSI) using molecular test and deficient mismatch repair (dMMR) using immunohistochemistry (IHC) has major implications on colorectal cancer (CRC) management. The HSP110 T 17 microsatellite has been reported to be more monomorphic than the common markers used for MSI determination. Large deletion of HSP110 T 17 has been associated with efficacy of adjuvant chemotherapy in dMMR/MSI CRCs. The aim of this study was to evaluate the interest of HSP110 deletion/expression as a diagnostic tool of dMMR/MSI CRCs and a predictive tool of adjuvant chemotherapy efficacy. All patients with MSI CRC classified by molecular testing were included in this multicenter prospective cohort ( n = 381). IHC of the 4 MMR proteins was carried out. HSP110 expression was carried out by IHC ( n = 343), and the size of HSP110 T 17 deletion was determined by PCR (n = 327). In the 293 MSI CRCs with both tests, a strong correlation was found between the expression of HSP110 protein and the size of HSP110 T 17 deletion. Only 5.8% of MSI CRCs had no HSP110 T 17 deletion ( n = 19/327). HSP110 T 17 deletion helped to re-classify 4 of the 9 pMMR/MSI discordance cases as pMMR/MSS cases. We did not observe any correlation between HSP110 expression or HSP110 T 17 deletion size with time to recurrence in patients with stage II and III CRC, treated with or without adjuvant chemotherapy. HSP110 is neither a robust prognosis marker nor a predictor tool of adjuvant chemotherapy efficacy in dMMR/MSI CRC. However, HSP110 T 17 is an interesting marker, which may be combined with the other pentaplex markers to identify discordant cases between MMR IHC and MSI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tachon, Chong-Si-Tsaon, Lecomte, Junca, Frouin, Miquelestorena-Standley, Godet, Evrard, Randrian, Chautard, Auriault, Moulin, Guyetant, Fromont, Karayan-Tapon and Tougeron.)

The intracellular Ca 2+ concentration is mainly controlled by Ca 2+ channels. These channels form complexes with K + channels, which function to amplify Ca 2+ flux. In cancer cells, voltage-gated/voltage-dependent Ca 2+ channels and non-voltage-gated/voltage-independent Ca 2+ channels have been reported to interact with K + channels such as Ca 2+ -activated K + channels and voltage-gated K + channels. These channels are activated by an increase in cytosolic Ca 2+ concentration or by membrane depolarization, which induces membrane hyperpolarization, increasing the driving force for Ca 2+ flux. These complexes, composed of K + and Ca 2+ channels, are regulated by several molecules including lipids (ether lipids and cholesterol), proteins (e.g. STIM), receptors (e.g. S1R/SIGMAR1), and peptides (e.g. LL-37) and can be targeted by monoclonal antibodies, making them novel targets for cancer research., (© 2020. Springer Nature Switzerland AG.)

Deregulation of the PI3K-Akt-mTOR pathway plays a critical role in the development and progression of many cancers. In prostate cancer, evidence suggests that it is mainly driven by PTEN loss of function. For many years, the development of selective Akt inhibitors has been challenging. In recent phase II and III clinical trials, Ipatasertib and Capivasertib associated with androgen deprivation therapies showed promising outcomes in patients with metastatic castration-resistant prostate cancer and PTEN-loss. Ongoing trials are currently assessing several Akt inhibitors in prostate cancer with different combinations, at different stages of the disease.

There are no countrywide data regarding the utilization of same-day-discharge (SDD) surgery for robot-assisted radical prostatectomy (RARP). We aimed to evaluate the annual number of SDD RARP procedures in France and to compare postoperative outcomes in SDD versus non-SDD centers. Data for all 9651 patients undergoing RARP in France in 2020 were extracted from the central database of the national healthcare system. Endpoints were length of hospital stay, patient age, center volume, lymph node dissection, and the hospital readmission rate. Overall, 184 SDD cases (1.9%) were reported in 14.2% of RARP centers. The annual RARP and SDD RARP caseload ranged from 41 to 485, and from one to 47, respectively, in SDD centers. SDD was significantly associated with higher-volume centers ( p < 0.001). No difference in readmission rate (7.9% vs 5.1%; p = 0.141) was observed for SDD versus non-SDD centers. Direct stay costs were estimated at €1457 in SDD centers compared to €2021 in non-SDD centers. The main limitation is the lack of detailed patient characteristics and readmission causes. This annual nationwide analysis suggests that SDD RARP remains infrequently used in routine practice in France despite being associated with comparable short-term outcomes after RARP and potential cost benefits., Patient Summary: We evaluated the use of robot-assisted removal of the prostate (RARP) with same-day hospital discharge in France for men with prostate cancer. In 2020, only 1.9% of the 9651 RARP procedures involved same-day discharge, even though the data show that this approach has lower costs and comparable safety., (© 2021 The Author(s).)

Background: Prostate cancer (PCa) is more frequent and more aggressive in populations of African descent than in Caucasians. Since the fatty acid composition of peri-prostatic adipose tissue (PPAT) has been shown to differ according to the ethno-geographic origin and is involved in PCa aggressiveness, we aimed to analyze the cholesterol content of PPAT from Caucasian and African-Caribbean patients, in correlation with markers of disease aggressiveness and cholesterol metabolism in cancer tissues., Methods: The quantification of cholesterol in PPAT was analyzed in 52 Caucasian and 52 African-Caribbean PCa patients, with in each group 26 indolent tumors (ISUP Group1 and pT2) and 26 potentially aggressive tumors (ISUP Group 3-5 and/or pT3). The expression of proteins involved in cholesterol metabolism was analyzed by immunohistochemistry on cancer tissue samples included in tissue microarrays., Results: The amount of cholesterol esters was lower in PPAT from African-Caribbean patients compared with Caucasians, without any correlation with markers of disease aggressiveness. In cancer tissues from African-Caribbean patients, the expression of ABCA1 (involved in cholesterol efflux) was decreased, and that of SREBP-2 (involved in cholesterol uptake) was increased. In both groups of patients, SREBP-2 expression was strongly associated with that of Zeb1, a key player in the epithelial-to-mesenchymal transition (EMT) process., Conclusion: These results suggest that cholesterol metabolism differs according to the ethno-geographic origin, in both PPAT and cancer tissues. In African-Caribbeans, the orientation towards accumulation of cholesterol in cancer cells is associated with a more frequent state of EMT, which may promote PCa aggressiveness in this population., (© 2021 Wiley Periodicals LLC.)

The evolution in the past decade of recommendations for prostate cancer (PCa) management, from screening to surgical treatment, may have affected the radical prostatectomy (RP) landscape. However, comprehensive data at a national level remain scarce. We extracted 5-yr data for RP patients in France from the central database of the national health care system. The primary endpoints were surgical approach (open [ORP], laparoscopic [LRP], and robot-assisted RP [RARP]), length of stay (LOS), and complication and readmission rates. The annual number of RPs was stable during the study period. The proportion of RARPs increased from 39.8% in 2015 to 52.6% in 2019, whereas the proportion of ORPs decreased from 34.4% to 24.5%. LOS continuously decreased over time irrespective of the surgical approach. The proportion of centres in the highest quartile of hospital volume increased from 22.0% to 28.3% ( p  = 0.006). LOS and complication and readmission rates were significantly lower ( p  < 0.001) in the LRP cohort at each time point. National trends confirmed that RARP progressively replaced ORP, with a stable number of annual RPs over time. Greater centralisation and better early postoperative outcomes were observed with laparoscopy., Patient Summary: We reviewed French data for patients undergoing removal of the prostate for prostate cancer between 2015 and 2019. We found that robot-assisted minimally invasive surgery has increased over time and the length of hospital stays has decreased. Rates of complications and readmission were lower with minimally invasive surgery., (© 2021 The Author(s).)

Background: Two phase II trials (NCT00688753 and NCT00541008) reported efficacy data of sunitinib and everolimus in first-line treatment of metastatic papillary renal cell carcinoma (mpRCC). Although most patients receive sunitinib or a mammalian target of rapamycin (mTOR) inhibitor in first- and second-line treatment, the optimal strategy remained unknown., Material and Methods: In 23 centres of the Groupe d'Etude des Tumeurs Urogénitales group, after centralised pathological review, we analysed retrospectively progression-free survival (PFS) of patients with mpRCC treated in first-line treatment (PFS-1) with sunitinib or everolimus (primary end-point), PFS in second-line treatment (PFS-2), overall survival (OS), objective response rate, disease control rate (DCR), overall sequence and prognostic factors for OS (secondary end-points)., Results: One hundred thirty-eight patients (119 men and 19 women), median age 62.5 years, with mpRCC type 1 (n = 24) or non-type 1 (n = 114), received first-line sunitinib (n = 107) or everolimus (n = 31). With a median follow-up of 92 months, we found no significant difference between the treatment groups in terms of PFS-1 (5.5 versus 6.2 months) and DCR (69% versus 83%). Ninety-eight patients received a second-line treatment, 69% with mTOR inhibitors after sunitinib and 100% with tyrosine kinase inhibitors after everolimus, with similar DCR (64% versus 58%), median PFS-2 (3.4 versus 4.8 months) and OS (16.0 versus 20.3 months). No factor was prognostic for PFS-1, whereas leukocytosis, anaemia and the time from diagnosis to first systemic therapy < 1 year were prognostic for OS. We found no prognostic difference between both pRCC subtypes. The International Metastatic Renal Cell Database Consortium risk factors were prognostic for OS., Conclusion: Sunitinib and everolimus had similar efficacy in first-line treatment of patients with mpRCC., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is believed to play a role in prostate cancer (PCa) progression. Cancer cells can take up lipids from the microenvironment and store them in lipid droplets (LDs). Fatty acids released from LDs are used by PCa cells as preferential metabolic fuels to provide energy and promote cancer progression. Recently, fatty acids have been associated with autophagy, a cellular recycling pathway. Lipophagy is a selective form of autophagy involved in LD degradation, the role of which in PCa progression remains unknown. Here, we explored markers of autophagy and lipophagy in human PCa tissues in correlation with factors of aggressiveness, and we evaluated the influence of PPAT adipocytes on autophagy and lipophagy. We analyzed markers of autophagy (p62, LC3), lipid droplets (PLIN and Oil Red O), androgen receptor (AR), proliferation (Ki67), and epithelial-mesenchymal transition (Zeb1) on 465 PCa samples. Co-cultures of PCa cell lines PC3 and 22RV1 with adipocytes isolated from patients' PPAT were used to analyze the influence of PPAT on autophagy and lipophagy in vitro. In human PCa tissues, we observed a correlation between markers of LD and those of autophagy, which are associated with clinical and biological factors of disease aggressiveness. In addition, PLIN staining was associated with AR expression. In locally advanced PCa, p62, LC3, and PLIN were increased in extraprostatic areas where cancer cells are in contact with PPAT. Co-culture of PCa cell lines with adipocytes decreased autophagy activity and increased LD flux in PC3 cells. These results suggest an active process of lipophagy in PCa, linked to disease aggressiveness, to the proximity of PPAT, and induced in vitro in co-culture with adipocytes. Lipophagy is therefore likely to be a crucial player in PCa progression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Active surveillance (AS) in prostate cancer (PCa) represents a curative alternative for men with localised low-risk PCa. Continuous improvement of AS patient's selection and surveillance modalities aims at reducing misclassification, simplifying modalities of surveillance and decreasing need for invasive procedures such repeated biopsies. Biomarkers represent interesting tools to evaluate PCa diagnosis and prognosis, of which many are readily available or under evaluation. The aim of this review is to investigate the biomarker performance for AS selection and patient outcome prediction. Blood, urinary and tissue biomarkers were studied and a brief description of use was proposed along with a summary of major findings. Biomarkers represent promising tools which could be part of a more tailored risk AS strategy aiming to offer personalized medicine and to individualize the treatment and monitoring of each patient. The usefulness of biomarkers has mainly been suggested for AS selection, whereas few studies have investigated their role during the monitoring phase. Randomized prospective studies dealing with imaging are needed as well as larger prospective studies with long-term follow-up and strong oncologic endpoints.

Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.

Therapeutic strategies for metastatic castration-resistant prostate cancer aim to target androgen receptor signaling. Despite initial survival benefits, treatment resistance invariably occurs, leading to lethal disease. Therapies targeting the androgen receptor can induce the emergence of a neuroendocrine phenotype and reactivate embryonic programs associated with epithelial to mesenchymal transition. We recently reported that dysregulation of the calcium signal can induce the transcription factor Zeb1, a key determinant of cell plasticity during tumor progression. The aim of this study was to determine whether the androgen receptor-targeted treatment Enzalutamide could induce dysregulation of the calcium signal involved in the progression toward epithelial to mesenchymal transition and neuroendocrine differentiation, contributing to therapeutic escape. Our results show that Zeb1 and the SK3 potassium channel are overexpressed in vivo in neuroendocrine castration-resistant prostate cancer and in vitro in LNCaP cells neurodifferentiated after Enzalutamide treatment. Moreover, the neuroendocrine phenotype is associated with a deregulation of the expression of Orai calcium channels. We showed that Zeb1 and SK3 are critical drivers of neuroendocrine differentiation. Interestingly, Ohmline, an SK3 inhibitor, can prevent the expression of Zeb1 and neuroendocrine markers induced by Enzalutamide. This study offers new perspectives to increase hormone therapy efficacy and improve clinical outcomes.

Bone metastasis remains the most frequent and the deadliest complication of prostate cancer (PCa). Mechanisms leading to the homing of tumor cells to bone remain poorly characterized. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. Bone is an adipocyte-rich organ since 50 to 70% of the adult bone marrow (BM) volume comprise bone marrow adipocytes (BM-Ads), which are likely to produce chemokines within the bone microenvironment. Using in vitro migration assays, we demonstrated that soluble factors released by human primary BM-Ads are able to support the directed migration of PCa cells in a CCR3-dependent manner. In addition, we showed that CCL7, a chemokine previously involved in the CCR3-dependent migration of PCa cells outside of the prostate gland, is released by human BM-Ads. These effects are amplified by obesity and ageing, two clinical conditions known to promote aggressive and metastatic PCa. In human tumors, we found an enrichment of CCR3 in bone metastasis vs. primary tumors at mRNA levels using Oncomine microarray database. In addition, immunohistochemistry experiments demonstrated overexpression of CCR3 in bone versus visceral metastases. These results underline the potential importance of BM-Ads in the bone metastatic process and imply a CCR3/CCL7 axis whose pharmacological interest needs to be evaluated.

Objectives: To determine whether small cell neuroendocrine prostate cancers (NEPCa) emerging after anti-androgen treatments are different from the rarest cases diagnosed de novo, and to identify effective predictive markers., Material and Methods: The expression of neuroendocrine markers, androgen receptor (AR) and androgen-regulated genes, as well as markers of aggressiveness, were analyzed by immunohistochemistry on a tissue microarray containing samples of 30 sNEPCa, either pure or admixed with conventional PCa, and including 14 cases diagnosed de novo and 16 cases subsequent to prior androgen deprivation., Results: Chromogranin A is a better marker of NE differentiation than synaptophysin in post-treatment NEPCa, with 94% and 44% of positive tumors, respectively, while both markers are equally expressed in de novo cases. Despite the acquisition of a NE phenotype, more than half of NEPCa expressed AR and the androgen-regulated gene NKX3.1, more frequently in cases admixed with conventional PCa. TTF1 staining, present in half of NEPCa, was associated with loss of androgen-regulated genes and with markers of aggressiveness, including increased proliferation, Zeb1 expression and PTEN loss. In multivariate analysis, only TTF1 expression was significantly associated with shorter overall survival., Conclusion: These results suggest the persistence of androgen signaling in a number of NEPCa cases, and the interest of TTF1 staining as a predictive biomarker., (Copyright © 2020 Elsevier Inc. All rights reserved.)