Les lipides et les cancers urologiques - approches épidémiologiques. L’importance du temps immortel

Objectif: Définir l’effet des lipides et du traitement de la dyslipidémie sur les cancers de la prostate et de la vessie en utilisant différents devis d’étude et en tenant compte de la présence de plusieurs biais, particulièrement le biais du temps immortel. Devis: Le premier volet utilise un devis rétrospectif de type cas témoins. Un questionnaire semi-quantitatif de fréquence de consommation alimentaire validé a été utilisé. Le génotype COX2 de neuf polymorphisme nucléotidique unique (SNP) a été mesuré avec une plateforme Taqman. Des modèles de régression logistique non conditionnelle ont été utilisés pour comparer le risque de diagnostic d’un cancer de la prostate et l’interaction. Le deuxième volet utilise un devis rétrospectif de type cohorte basée sur les données administratives de la Régie de l’assurance-maladie du Québec (RAMQ). Des modèles de régression de Cox ont été employés pour mesurer l’association entre les statines et l’évolution du cancer de la vessie. Le troisième volet, porte un regard méthodologique sur le biais du temps immortel en examinant sa présence dans la littérature oncologique. Son importance est illustrée avec les données de la cohorte du deuxième volet, et les méthodes de correction possibles son appliquées. Résultats: L’étude du premier volet démontre qu’une diète riche en acides gras oméga-3 d’origine marine était fortement associée à un risque diminué de cancer de la prostate agressif (p<0.0001 pour la tendance). Le ratio de cote pour le cancer de la prostate du quartile supérieur d’oméga-3 était de 0.37 (IC 95% = 0.25 à 0.54). L’effet diététique était modifié par le génotype COX-2 SNP rs4648310 (p=0.002 pour l’interaction). En particulier, les hommes avec faible apport en oméga-3 et la variante rs4648310 avait un risque accru de cancer de la prostate (ratio de cote = 5.49, IC 95%=1.80 à 16.7), effet renversé par un apport en oméga-3 plus grand. L’étude du deuxième volet a observé que l’utilisation de statines est associée à une diminution du risque de progression du cancer de la vessie (risque relatif = 0.44, IC 95% = 0.20 à 0.96, p=0.039). Cette association était encore plus forte pour le décès de toute cause (HR = 0.57, 95% CI = 0.43 to 0.76, p=0.0001). L’effet des statines semble être dose-dépendant. L’étude du troisième volet démontre que le biais du temps immortel est fréquent et important dans les études épidémiologiques oncologiques. Il comporte plusieurs aspects dont certains sont mieux prévenus au stade du choix du devis d’étude et différentes méthodes statistiques permettent un contrôle de ce biais. Conclusion: 1) Une diète riche en oméga-3 aurait un effet protecteur pour le cancer de la prostate. 2) L’utilisation de statines aurait un effet protecteur sur la progression du cancer non invasif de la vessie. Les lipides semblent avoir un effet sur les cancers urologiques.Purpose: To define the effects of dietary lipids and of treatment of dyslipidemia with statins on prostate and bladder cancers, using different epidemiologic study designs and accounting for biases, particularly immortal time bias. Study Design: The first part used a retrospective a case-control study design. Diet was assessed with a semi-quantitative food frequency questionnaire, and nine COX-2 tag single nucleotide polymorphisms (SNPs) were genotyped. We used logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and p-values for association and interaction. The second part used a retrospective cohort study design based on administrative databases of Québec, Canada. Cox regression models were used to measure association between statin use and bladder cancer evolution. The third part focuses on the immortal time bias by describing its presence in the oncologic literature. The importance of this bias is illustrated with data from the cohort used in the second part and statistical correction methods are applied. Results: The first part showed that an increasing intake of omega-3 fatty acids of marine origin was strongly associated with a decreased risk of aggressive prostate cancer (trend p<=0.0001). The OR (95% CI) for prostate cancer comparing the highest to the lowest quartile of omega-3 intake was of 0.37 (0.25 – 0.54). The dietary effect was modified by the rs4648310 COX-2 SNP (interaction p=0.02). This reflected the observation that men with low marine omega-3 intake and the variant rs4648310 SNP had an increased risk of disease (OR = 5.49; 95% CI: 1.80-16.7), which was reversed by increasing intake of marine omega-3. The second part showed that statin use was associated with a decreased risk of bladder cancer progression (HR = 0.44, 95% CI = 0.20 to 0.96, p=0.0388). The inverse association was even stronger for risk of mortality from all causes (HR = 0.57, 95% CI = 0.43 to 0.76, p=0.0001). The statin use effect appears dose-dependent. The third part showed that the immortal time bias is frequent and important in many epidemiological studies in oncology. It has many aspects and some of these are better prevented at time of study design selection. Various statistical methods also allowed control of this bias. Conclusion. 1) Dietary omega-3 appears to decrease prostate cancer risk. 2) Statin use appears to decrease risk of bladder cancer progression. Lipids seem to have an effect on urological cancers

High infiltration of CD209+ dendritic cells and CD163+ macrophages in the peritumor area of prostate cancer is predictive of late adverse outcomes

IntroductionProstate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions.MethodsInfiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves.ResultsPositive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209+ and CD163+ cells were more abundant at the tumor margin. Higher CD209+/CD83+ cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163+ cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively.ConclusionA higher level of infiltration of CD209+ immature DC and CD163+ M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes

METSTOR: a GIS to look for potential storage zones in France

International audienceCommunication : http://minh.haduong.com/files/Bonijoly.ea-2008-METSTOR-GHGT9.pdf - Actes : http://web.mit.edu/ghgt9

METSTOR: A GIS to look for potential CO2 storage zones in France

International audienceThe METSTOR project offers a methodology to look for potentially interesting CO2 storage areas in France at the initial stage, before the "site selection" step. Our tool, embodied in a Geographic Information System, is based on an interactive map of CO2 storage capacities. Other relevant information layers are included. The geographic layers are complemented with a series of online technical notices. It seems to be the first open online GIS that offers policy makers, businesses and the public at large an integrated access to that necessary information. Our prototype, limited mainly to the Paris Basin, is released online at www.metstor.fr

METSTOR: A GIS to look for potential CO2 storage zones in France

The METSTOR project offers a methodology to look for potentially interesting CO2 storage areas in France at the initial stage, before the "site selection" step. Our tool, embodied in a Geographic Information System, is based on an interactive map of CO2 storage capacities. Other relevant information layers are included. The geographic layers are complemented with a series of online technical notices. It seems to be the first open online GIS that offers policy makers, businesses and the public at large an integrated access to that necessary information. Our prototype, limited mainly to the Paris Basin, is released online at www.metstor.fr.CO2 storage; Carbone capture and storage; Methodology; France; Site selection; Geographic information system; Storage capacities; Aquifers; Coal deposits; Depleted fields; Risk assessment

A new murine model of osteoblastic/osteolytic lesions from human androgen-resistant prostate cancer

BACKGROUND: Up to 80% of patients dying from prostate carcinoma have developed bone metastases that are incurable. Castration is commonly used to treat prostate cancer. Although the disease initially responds to androgen blockade strategies, it often becomes castration-resistant (CRPC for Castration Resistant Prostate Cancer). Most of the murine models of mixed lesions derived from prostate cancer cells are androgen sensitive. Thus, we established a new model of CRPC (androgen receptor (AR) negative) that causes mixed lesions in bone. METHODS: PC3 and its derived new cell clone PC3c cells were directly injected into the tibiae of SCID male mice. Tumor growth was analyzed by radiography and histology. Direct effects of conditioned medium of both cell lines were tested on osteoclasts, osteoblasts and osteocytes. RESULTS: We found that PC3c cells induced mixed lesions 10 weeks after intratibial injection. In vitro, PC3c conditioned medium was able to stimulate tartrate resistant acid phosphatase (TRAP)-positive osteoclasts. Osteoprotegerin (OPG) and endothelin-1 (ET1) were highly expressed by PC3c while dikkopf-1 (DKK1) expression was decreased. Finally, PC3c highly expressed bone associated markers osteopontin (OPN), Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP) and produced mineralized matrix in vitro in osteogenic conditions. CONCLUSIONS: We have established a new CRPC cell line as a useful system for modeling human metastatic prostate cancer which presents the mixed phenotype of bone metastases that is commonly observed in prostate cancer patients with advanced disease. This model will help to understand androgen-independent mechanisms involved in the progression of prostate cancer in bone and provides a preclinical model for testing the effects of new treatments for bone metastases

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations