Étude mécanobiologique in vivo : effets de la modulation mécanique de croissance dans la matrice extracellulaire des plaques de croissance de vertèbres caudales d'un modèle animal de rat

Le système squelettique -- Ostéogenèse -- Mécanobiologie des plaques de croissance -- Effects of In Vivo static compressive loading on aggrecan and type II and X collagens in the rat growth plate extracellular matrix -- Mesures de croissance -- Immunohistochimies et coloration à la safranine-O -- Mesures d'histomorphométrie sur la vertèbre caudale -- Localisation des néofragments de collagène de tye II

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

The Calcium-Sensing Receptor is A Marker and Potential Driver of Neuroendocrine Differentiation in Prostate Cancer

The mechanisms underlying neuroendocrine (NE) differentiation in prostate cancer (PCa) remain mostly uncharacterized. Since a deregulated calcium homeostasis has been reported in neuroendocrine prostate cancer (NEPC), we explored herein the link between NE differentiation and the calcium-sensing receptor (CaSR). CaSR expression was evaluated by immunohistochemistry—together with NE markers—on tissue microarrays containing samples of normal prostate, localized PCa, metastatic castration resistant PCa (MCRPC) and NEPC. In prostate tissues, we observed a strong association between CaSR and chromogranin expression. Both markers were strongly expressed in all cases of NEPC and co-expression was confirmed by double immunostaining. In MCRPC, the expression of CaSR was significantly associated with shorter overall survival. The involvement of CaSR in NE differentiation was evaluated in PCa cell lines. Inhibition of CaSR led to decrease the expression of neuronal (NSE, βtubulinIII) and NE (chromogranin, synaptophysin) markers in the NE PCa cell line NCI-H660. A decrease of neuronal and NE markers was also observed in siCaSR-transfected PC3 and 22RV1 cells, respectively, whereas CaSR activation increased both NSE and synaptophysin expression in PC3 cells. These results strongly suggest that CaSR is a marker and a driver of NE differentiation in PCa and emphasize the potential of CaSR directed therapy for NEPC patients

Specificities of small cell neuroendocrine prostate cancer: Adverse prognostic value of TTF1 expression

International audienceObjectives: 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

Lymphovascular invasion as a criterion for adjuvant chemotherapy for FIGO stage I-IIa clear cell carcinoma, mucinous,low grade serous and low grade endometrioid ovarian cancer

International audienceBACKGROUND: The aim of this study was to evaluate the impact of lymphovascular space invasion (LVSI) on overall survival (OS) and recurrence-free survival (RFS) in patients managed for stage I-IIa clear cell carcinoma, mucinous, low-grade serous and low-grade endometrioid ovarian cancer MATERIAL AND METHODS: Retrospective multicentre study of the research group FRANCOGYN between January 2001 and December 2018. All patients managed for stage I-IIa clear cell carcinoma, mucinous /low grade serous and endometrioid ovarian cancer and for whom the presence of histological slides for the review of LVSI was available, were included. Patient’s characteristics with LVSI (LVSI group) were compared to those without LVSI (No LVSI group). A cox analysis for OS and RFS analysis were performed in all population. RESULTS: Over the study period, 133 patients were included in the thirteen institutions. Among them, 12 patients had LVSI (9%). LVSI was an independent predictive factor for poorer Overall and recurrence free survivals. LVSI affected OS (p<0.001) and RFS (p=0.0007), CONCLUSION: The presence of LVSI in stage I-IIa clear cell carcinoma, mucinous /low grade serous and endometrioid ovarian cancer has an impact on OS and RFS and should put them at high risk and consider the option of adjuvant chemotherapy

Chemotherapy following immune checkpoint inhibitors in patients with locally advanced or metastatic urothelial carcinoma

BACKGROUND: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). METHODS: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities. RESULTS: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (< or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients. CONCLUSION: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study

International audienceAbstract Objective After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs. Design and methods This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally. Results Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center. Conclusions Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Significance statement This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs

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

International audienceIntroduction: 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, cMET), 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