Understanding natural isotopic variations in cultured cancer cells.

RATIONALE: Natural variations in the abundance of the stable isotopes of nitrogen (δ15N) and carbon (δ13C) offer valuable insights into metabolic fluxes. In the wake of strong interest in cancer metabolism, recent research has revealed δ15N and δ13C variations in cancerous compared to non-cancerous tissues and cell lines. However, our understanding of natural isotopic variations in cultured mammalian cells, particularly in relation to metabolism, remains limited. This study aims to start addressing this gap using metabolic modulations in cells cultured under controlled conditions. METHODS: Prostate cancer cells (PC3) were cultured in different conditions and their δ15N and δ13C were measured using isotope ratio mass spectrometry. Isotopic variations during successive cell culture passages were assessed and two widely used cell culture media (RPMI and DMEM) were compared. Metabolism was modulated through glutamine deprivation and hypoxia. RESULTS: Successive cell culture passages generally resulted in reproducible δ15N and δ13C values. The impact of culture medium composition on δ15N and δ13C of the cells highlights the importance of maintaining a consistent medium composition across conditions whenever possible. Glutamine deprivation and hypoxia induced a lower δ13C in bulk cell samples, with only the former affecting δ15N. Gaps between theory and experiments were bridged and the lessons learned throughout the process are provided. CONCLUSIONS: Exposing cultured cancer cells to hypoxia allowed us to further investigate the relation between metabolic modulations and natural isotopic variations, while mitigating the confounding impact of changing culture medium composition. This study highlights the potential of natural δ13C variations for studying substrate fluxes and nutrient allocation in reproducible culture conditions. Considering cell yield and culture medium composition is pivotal to the success of this approach.

PARP inhibitors in prostate cancers, is it time for combinations?

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.

Circulating Biomarkers Predictive of Treatment Response in Patients with Hormone-sensitive or Castration-resistant Metastatic Prostate Cancer: A Systematic Review.

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 177Lu 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.

PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. METHODS: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1. RESULTS: Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were "double-positive", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). CONCLUSION: These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases.

AIMS: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2-fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. METHODS AND RESULTS: Five patients were male and the median age was 79 years (ranges: 59-95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. CONCLUSION: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement.

Endogenous ether lipids differentially promote tumor aggressiveness by regulating the SK3 channel.

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.

Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients.

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.

Variable effects of periprostatic adipose tissue on prostate cancer cells: Role of adipose tissue lipid composition and cancer cells related factors.

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.

Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma.

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.

Endemic statistical paradoxes in epidemiologic studies distort knowledge on prostate cancer: mitigation and caution of fallacies in prostate cancer causal epidemiological studies.

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.

Pivotal role of the ORAI3-STIM2 complex in the control of mitotic death and prostate cancer cell cycle progression.

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 (Ca2+) channels and their protein regulators are now considered as hallmarks of cancer and some of them have been well examined in PCa. Among these Ca2+ channels, isoform 3 of the ORAI channel family has been shown to regulate the proliferation of PCa cells via the Arachidonic Acid-mediated Ca2+ 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 Ca2+ 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.

Association Between 5α-Reductase Inhibitors and Prostate Cancer Mortality: A Systematic Review and Meta-analysis.

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.

Expanding inclusion criteria for active surveillance in intermediate-risk prostate cancer: a machine learning approach.

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.

Persistent organochlorine pesticides in periprostatic adipose tissue from men with prostate cancer: Ethno-geographic variations, association with disease aggressiveness.

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.

Micro-ultrasound-guided biopsies versus systematic biopsies in the detection of prostate cancer: a systematic review and meta-analysis.

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, I2 = 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, I2 = 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.

What is the ideal combination therapy in de novo, oligometastatic, castration-sensitive prostate cancer?

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.

Heterogeneity of contemporary grade group 4 prostate cancer in radical prostatectomy specimens.

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.

Interplay between Prostate Cancer and Adipose Microenvironment: A Complex and Flexible Scenario.

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.

Grade group 1 prostate cancer on biopsy: are we still missing aggressive disease in the era of image-directed therapy?

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.

Impact of Novel Hormonal Agents (Abiraterone, Enzalutamide) on the Development of Visceral and/or Brain Metastases in Patients With Bone-metastatic Castration-resistant Prostate Cancer.

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.