Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients.

International audienceBackground: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p<0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p<0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit

Intermediate filaments in normal thyrocytes: modulation of vimentin expression in primary culture

In dog thyrocyte primary cultures, the antagonistic effects of thyrotropin (TSH) and epidermal growth factor (EGF) on differentiation expression were accompagnied by distinct long-term morphological changes: TSH-treated cells showed an epitheloid morphology; EGF reversibly induced a fusiform shape. Using indirect immunofluorescence microscopy and two-dimensional gel electrophoresis, we studied the modifications in the distribution and synthesis of the intermediate filament proteins of the cytoskeleton in response to TSH and EGF. These factors had little effect on the expression of cytokeratins 8 and 18, which were expressed in 98% of cells. However, TSH induced a profound redistribution of cytokeratins (and actin) with the appearance of a marked staining of cell junctions. Vimentin was coexpressed with cytokeratins in about 40% of cells from normal thyroid follicles freshly isolated by collagenase. During culture, immunostained vimentin network progressively developed in 90% of control and EGF-treated cells simultaneously with vimentin synthesis. In contrast, only 20% of TSH-treated cells reacted with vimentin antibody and we observed a marked decrease in vimentin synthesis in response to TSH. Therefore, vimentin synthesis, which should occur in at least some normal thyroid follicles in vivo, was inhibited in vitro by TSH which promotes differentiation expression. However, EGF-treated cells thereafter cultured with TSH regained an epitheloid morphology and differentiation in spite of the persistency of a complete network of vimentin.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Assessment of Circulating Tumor DNA in Newly Diagnosed DLBCL Patients Randomly Treated By R-CHOP or R-High Dose Chemotherapy Plus Autologous Stem Cell Support

International audienceMeeting Abstract 350

Reasons for switching to fingolimod in patients relapsing-remitting multiple sclerosis in France: the ESGILE study

International audienceBackground: Timely treatment switching is an important strategy in optimising management of patients with relapsing remitting multiple sclerosis (RRMS). Patient preferences, as well as clinical benefit, may contribute to the switch decision. Information on reasons determining switching choices and on outcome according to the reason for switching is scarce. Study objectives were to describe the consequences of switching to fingolimod in terms of clinical improvement according to the reasons underlying the switch and to evaluate treatment acceptability from the patient's perspective. Methods: This prospective observational study was conducted by 71 neurologists in France and included patients with RRMS switching to fingolimod following ≥6 months treatment with a first-line disease modifying treatment (DMT). Reasons for switching were documented. Patients were evaluated at inclusion and 12 months after initiating fingolimod. Physicians documented clinical status by relapse activity, disability (EDSS) at each visit and improvement with the Clinical Global Impression – Change (CGI-C) at Month 12. Patients rated improvement at Month 12 with the Patient Global Impression – Change (PGI-C) and treatment acceptability with the ACCEPT® questionnaire. Adverse events reported during fingolimod treatment were documented. Results: Overall 232 patients were recruited of whom 190 could be analysed. Multiple reasons for switching were frequently given; 113 patients (59.4%) switched from a first-line injectable DMT. Switching was motivated by disease worsening in 161 patients (84.7%), tolerability in 35 (18.4%) and patient preference in 58 (30.5%). During the follow-up period, 38 patients (20.0%) experienced at least one exacerbation. The mean EDSS score was stable (2.0 ± 1.3 at inclusion; 2.0 ± 1.5 at M12). With the CGI-C, 67 patients (38.7%) were considered improved and 23 (13.3%) worsened. Although no obvious differences in CGI-C ratings were observed as a function of the reason for switching, when patient preferences entered into the decision, the proportion of patients considered minimally improved was somewhat higher (37.7%) and the proportion considered unchanged somewhat lower (41.5%). With the PGI-C, more patients rated themselves improved than were rated as improved by the physician: of 64 patients rated as ‘no change’ on the CGI-C, 21 (32.8%) rated themselves as ‘improved’ and 10 (15.6%) as ‘worsened’. The overall level of agreement between the two measures was moderate (κ = 0.48 [95% CI: 0.35 – 0.60]). The mean general treatment acceptability score on the ACCEPT® questionnaire was 42.7 [95%CI: 34.5 – 50.9] at inclusion (reflecting acceptability of the previous DMT) and 64.6 [95%CI: 57.6 – 71.6] at M12 (reflecting acceptability of fingolimod). Mean dimension scores ranged from 36.7 for effectiveness to 72.2 for medication inconvenience at inclusion and from 63.4 for effectiveness to 96.8 for medication inconvenience at M12. The frequency and nature of reported adverse events was consistent with the well-characterised safety profile of fingolimod. Conclusion: Most patients switching from a first DMT to fingolimod do so due to persistent disease activity during the initial treatment, although patient preferences are also important. Switching is followed by a reduction in disease activity, perceived improvement in the clinical state of the patient and improved acceptability of treatment

Distinct Aeromonas Populations in Water Column and Associated with Copepods from Estuarine Environment (Seine, France)

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Influence of organic matters on AsIII oxidation by the microflora of polluted soils

International audienceThe global AsIII-oxidizing activity of microorganisms in eight surface soils from polluted sites was quantified with and without addition of organic substrates. The organic substances provided differed by their nature: either yeast extract, commonly used in microbiological culture media, or a synthetic mixture of defined organic matters (SMOM) presenting some common features with natural soil organic matter. Correlations were sought between soil characteristics and both the AsIII-oxidizing rate constants and their evolution in accordance with inputs of organic substrates. In the absence of added substrate, the global AsIII oxidation rate constant correlated positively with the concentration of intrinsic organic matter in the soil, suggesting that AsIII-oxidizing activity was limited by organic substrate availability in nutrient-poor soils. This limitation was, however, removed by 0.08 g/L of added organic carbon. In most conditions, the AsIII oxidation rate constant decreased as organic carbon input increased from 0.08 to 0.4 g/L. Incubations of polluted soils in aerobic conditions, amended or not with SMOM, resulted in short-term As mobilization in the presence of SMOM and active microorganisms. In contrast, microbial AsIII oxidation seemed to stabilize As when no organic substrate was added. Results suggest that microbial speciation of arsenic driven by nature and concentration of organic matter exerts a major influence on the fate of this toxic element in surface soils

Pan-HDAC Inhibitors May Restore PRDM1 Expression in Follicular Lymphoma

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Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse

International audienceFollicular lymphoma (FL), the most frequent indolent non-Hodgkin's B cell lymphoma, is considered as a prototypical centrocyte-derived lymphoma, dependent on a specific microenvironment mimicking the normal germinal center (GC). In agreement, several FL genetic alterations affect the crosstalk between malignant B cells and surrounding cells, including stromal cells and follicular helper T cells (Tfh). In our study, we sought to deconvolute this complex FL supportive synapse by comparing the transcriptomic profiles of GC B cells, Tfh, and stromal cells, isolated from normal versus FL tissues, in order to identify tumor-specific pathways. In particular, we highlighted a high expression of <i>IL-6</i> and <i>IL-7</i> in FL B cells that could favor the activation of FL Tfh overexpressing IFNG, able in turn to stimulate FL B cells without triggering MHC (major histocompatibility) class II expression. Moreover, the glycoprotein clusterin was found up-regulated in FL stromal cells and could promote FL B cell adhesion. Finally, besides its expression on Tfh, CD200 was found overexpressed on tumor B cells and could contribute to the induction of the immunosuppressive enzyme indoleamine-2,3 dioxygenase by CD200R-expressing dendritic cells. Altogether our findings led us to outline the contribution of major signals provided by the FL microenvironment and their interactions with malignant FL B cells