Pro-tumoural CXCL10/CXCR3-A autocrine loop in invasive mucinous lung adenocarcinoma

International audienceInvasive mucinous adenocarcinoma (IMA) is a mucinous variant of lepidic predominant lung adenocarcinoma (LPA) and associated with a worse prognosis. We postulated that cytokine expression would enable us to differentiate IMA from LPA in terms of prognosis and acquisition of pro-tumoural capacities. A 30-cytokine panel was assessed in bronchoalveolar lavage fluids (BALF) from IMA (n=38), LPA (n=25) and control samples (n=7). We investigated the expression of differentially expressed cytokines and splice variants of their receptors in surgical samples. The presence of EGFR and KRAS mutations were determined. We also examined the expression of cytokines and splice variants of their receptors in different cell lines, exploring their functional impact on signalling pathways, proliferation and migration. Only C-X-C motif chemokine 10 (CXCL10) was differentially expressed, namely overexpressed in IMA BALF compared with LPA. CXCL10 overexpression in BALF was linked to a worse prognosis. In surgical samples, CXCL10 and its receptor C-X-C motif chemokine receptor 3 (CXCR3) were overexpressed in IMA compared to LPA. A pro-tumoural CXCR3-A splice variant was overexpressed in IMA, suggesting a CXCL10/CXCR3-A autocrine loop in IMA. CXCL10 and CXCR3 expression were not correlated with EGFR or KRAS status. CXCL10 up-regulated CXCR3-A expression, Erk1/2 phosphorylation and enhanced migration in the mucinous H2228 cell line. CXCL10/CXCR3-A may play a pro-tumoural role in IMA via an autocrine mechanism

Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers

International audienceObjectives: To evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers.Materials and methods: MUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4α immunohistochemistry was performed on surgical samples from 52 patients with IMA (n = 25) or LPA (n = 27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements.Results: MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4α-positive IMA (n = 11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4α-negative IMA (n = 14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression.Conclusions: LPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4α expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes

Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project-Part 2)

Background: Epidermal growth factor and v-Ki-ras2 Kirsten ras sarcoma (KRAS) mutation status, although associated with EGFR- tyrosine kinase inhibitor (TKI) efficacy, has not been used in clinical practice until recently. The prospective Evaluation of the EGFR Mutation status for the administration of EGFR-TKIs in non small cell lung Carcinoma (ERMETIC) study aimed to implement these biomarkers in France. Methods: Between March 2007 and April 2008, EGFR and KRAS were studied by sequencing DNA tumor specimens from 522 consecutive advanced non-small-cell lung cancer patients treated with EGFR-TKI, mostly in second- or third-line settings. Cox models were used to investigate the impact of patient characteristics and mutations on progression-free survival (PFS) and overall survival (OS). Added value from mutation status was evaluated using likelihood ratio (LR) tests. Classification and regression tree analysis aimed to identify homogeneous groups in terms of survival. Results: Among the 522 patients, 87% were white, 32% were women, and 18% were never-smokers, with 65% presenting with adenocarcinoma. Biological data were available for 307 patients, showing 44 EGFR mutations (14%) and 42 KRAS (14%) mutations. Median PFS was 2.4 months (interquartile range, 1.4-4.6) and median OS 5.6 months (interquartile range, 2.2-14.0). Factors independently associated with PFS were performance status 1 or 2 to 3 (hazards ratio [HR] = 1.5, 95% confidence interval [CI] 1.1-1.9; and HR = 2.3, CI 1.7-3.1, respectively; p < 0.001); former or current smoker status (HR = 1.8, CI 1.4-2.4 and 2.0,CI 1.4-2.8, respectively; p < 0.001); nonadenocarcinoma histology (squamous cell: HR = 0.9 CI 0.7-1.2]; others: HR = 1.6, 1.3-2.1; p < 0.001); at least two metastatic sites (HR = 1.3, CI 1.1-1.6 and 1.6, CI 1.3-2.1, respectively; p < 0.001); prior taxane-based chemotherapy (HR = 1.3, CI 1.0-1.3, p = 0.01); non-white (HR = 0.7, CI 0.5-0.9, p = 0.009). Similar results were found for OS. In addition, EGFR and KRAS mutations were significantly associated with PFS (HR = 0.5, CI 0.3-0.7 and HR = 1.2, CI 0.8-1.8, respectively, versus no mutation; LR p = 0.001). In the OS model, adjusted HR was 0.7 (0.4-1.0) for EGFR mutation and 1.7 (1.1-2.4) for KRAS (LR p = 0.004). Classification and regression tree analysis revealed EGFR mutation to be the primary factor for identifying homogeneous patient subgroups in terms of PFS. Conclusions: EGFR and KRAS status independently impacts outcomes in advanced non-small-cell lung cancer patients treated with EGFR-TKI. However, EGFR status impacts both PFS and OS whereas KRAS only impacts OS. These findings support the nationwide use of EGFR status for patient selection before EGFR-TKI therapy. The role of KRAS mutations remains to be elucidated. Copyright © 2012 by the International Association for the Study of Lung Cancer.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cross-Validation Study for Epidermal Growth Factor Receptor and KRAS Mutation Detection in 74 Blinded Non-small Cell Lung Carcinoma Samples: A Total of 5550 Exons Sequenced by 15 Molecular French Laboratories (Evaluation of the EGFR Mutation Status for the Administration of EGFR-TKIs in Non-Small Lung Carcinoma [ERMETIC] Project-Part 1).

International audienceINTRODUCTION:: The Evaluation of the epidermal growth factor receptor (EGFR) Mutation status for the administration of EGFR-Tyrosine Kinase Inhibitors in non-small cell lung Carcinoma (NSCLC) (ERMETIC) project part 1 assessed the accuracy of EGFR and KRAS mutations detection in NSCLC among 15 French centers. METHODS:: The 15 ERMETIC centers selected 74 NSCLC surgical specimens from previously untreated patients. Paraffin and paired frozen DNA were sequenced for EGFR exons 18 to 21 and KRAS exon 2 by an external molecular laboratory, yielding a gold standard. The 74 blinded paraffin DNAs were redistributed to the 15 ERMETIC laboratories for sequencing of a total of 5550 exons. Results were compared with the gold standard and between centers by discordance rates and kappa statistics. RESULTS:: The gold standard included 39 mutated samples with 22 EGFR and 17 KRAS mutated samples. Kappa statistics showed that 10, 6, and 6 of the 15 ERMETIC centers had a moderate to good kappa score, when compared with external laboratory for EGFR exon 19, EGFR exon 21, and KRAS exon 2, respectively. Kappa statistics showed moderate score between centers which increased to good for EGFR exon 19 mutation when removing 16 poor-quality samples with high nonamplificable rates. CONCLUSIONS:: Paraffin-embedded specimens may represent a suitable source of DNA for sequencing analyses in ERMETIC centers. EGFR exon 19 deletions were most accurately detected by ERMETIC centers. Ease and accuracy of results, depended more on the quality of sample than on the difference in molecular sequencing procedures between centers, emphasize the need of preanalytical quality control programs

Musées et mondes numériques

La culture numérique concerne aujourd’hui toutes les institutions et traverse toutes les pratiques sociales. Elle fait l’objet de discours enthousiastes et d’injonctions pressantes car elle est synonyme d’innovation, voire de cure de jouvence, pour les mondes de la culture, dont le champ muséal qui a toujours manifesté de l’intérêt pour les outils de la modernité. Pour autant, cette intégration, parfois à marche forcée, du numérique dans les institutions patrimoniales n’est pas la seule perspective pour analyser la manière dont ses contenus culturels sont aujourd’hui diffusés, médiés et appropriés. L’objectif de ce numéro est de relire trois fondamentaux du musée, que sont la collection, l’exposition et le public, au regard de la culture numérique, de manière critique et réflexive. Les contributions qu’il rassemble montrent comment le numérique au musée et hors du musée impacte son organisation, ses formes de médiation et son existence dans l’écosystème du web. Digital culture today concerns all institutions and cuts across all social practices. It is the subject of enthusiastic speeches and urgent injunctions because it is synonymous with innovation, even a makeover for culture, including the museum field which has always shown interest in tools of modernity. However, this integration of digital technology in heritage institutions, sometimes at a forced pace, is not the only perspective to analyze the way in which its cultural content is today disseminated, mediated and appropriated. The goal of this journal issue is to reread three fundamentals of museum, which are the collection, the exhibition and the public, in view of digital culture, in a critical and reflective way. The contributions it gathers show how digital technology inside and outside the museum impacts its organization, its ways of mediation and its existence in the web ecosystem. Hoy en día, la cultura digital involucra a todas las instituciones y atraviesa todas las prácticas sociales. Es objeto de discursos entusiastas y mandatos urgentes puesto que es sinónimo de innovación, incluso de rejuvenecimiento de los mundos de la cultura, incluyendo el campo de los museos que siempre ha mostrado interés por las herramientas de la modernidad. Sin embargo, esta integración, a veces forzada, de lo digital en las instituciones patrimoniales no es la única perspectiva de análisis de la forma en que sus contenidos culturales se difunden, median y se apropian en el presente. El objetivo de este número es releer tres fundamentos del museo, como son la colección, la exposición y el público, mediante la cultura digital, de manera crítica y reflexiva. Las contribuciones que reúne, muestran cómo lo digital dentro y fuera del museo, afecta a su organización, sus formas de mediación y su existencia en el ecosistema de la web