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

Les appels pour secours à personnes en Haute-Marne de février 1999 à avril 1999. Etude du prompt-secours

REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Lung Cancer Screening with Chest Computed Tomography in People Living with HIV: A Review by the Multidisciplinary CANCERVIH Working Group

International audienceA shift in mortality and morbidity has been observed in people living with human immunodeficiency virus (PLWHIV) from acquired immunodeficiency syndrome (AIDS) to non-AIDS diseases. Lung cancer has the highest incidence rates among all the non-AIDS-defining malignancies and is associated with mortality rates that exceed those of other cancers. Strategies to increase lung cancer survival in PLWHIV are needed. Lung cancer screening with chest LDCT has been shown to be efficient in the general population at risk. The objective of this review is to discuss lung cancer screening with chest computed tomography in PLWHIV. Lung cancer screening in PLWHIV is feasible. Whether PLWHIV could benefit from an age threshold for screening that is earlier than the minimum age of 55 years usually required in the general population still needs further investigation. Studies evaluating smoking cessation programs and how they could be articulated with lung cancer screening programs are also needed in PLWHIV

Clinical Significance of Aortic Root Modification Associated With Bicuspid Aortic Valve in Marfan Syndrome.

International audienceBACKGROUND:Both bicuspid aortic valve (BAV) and Marfan syndrome have been associated with aortic dissection risk, but it is unknown whether the presence of BAV is associated with an increased aortic risk in patients with an FBN1 gene mutation. We evaluated aortic diameters, aortic valve function, and aortic shape in Marfan syndrome patients with and without BAV and reported aortic events during follow-up.METHODS:All patients with an FBN1 gene mutation evaluated in our clinic were included. Aortic root diameters were measured, and the aortic valve was studied using echocardiography at each visit.RESULTS:Of the 1437 patients with an FBN1 gene mutation, 26 patients (1.8%) had a BAV. Both aortic root maximal diameter and normalized Z score were larger at all ages, in patients with BAV when compared with patients with tricuspid aortic valve. Prophylactic aortic root surgery tended to be performed in younger patients when BAV was present, although aortic diameter threshold was similar in the 2 populations. No aortic dissection was observed in Marfan syndrome patients with BAV.CONCLUSIONS:In patients with a FBN1 mutation, BAV is associated with larger aortic root diameter, with no difference in evolution of Z score with age. We found a trend towards prophylactic aortic root surgery at younger ages but similar aortic diameter thresholds without occurrence of aortic dissection. We did not find any evidence for lowering aortic diameter thresholds used to propose preventive aortic root surgery in the presence of BAV in patients with FBN1 mutations

Clinical relevance of genotype–phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants

International audiencePurpose: Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only.Methods: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations.Results: A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants.Conclusion: This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs

Pathogenic FBN1 Genetic Variation and Aortic Dissection in Patients With Marfan Syndrome

International audienceBackgroundAortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene.ObjectivesThis study sought to describe aortic risk in a population with Marfan syndrome with pathogenic variants in the FBN1 gene as a function of aortic root diameter.MethodsPatients carrying an FBN1 pathogenic variant who visited our reference center at least twice were included, provided they had not undergone aortic surgery or had an aortic dissection before their first visit. Aortic events (aortic surgery or aortic dissection) and deaths were evaluated during the 2 years following each patient visit. The risk was calculated as the number of events divided by the number of years of follow-up.ResultsA total of 954 patients were included (54% women; mean age 23 years). During follow-up (9.1 years), 142 patients underwent prophylactic aortic root surgery, 5 experienced type A aortic dissection, and 12 died (noncardiovascular causes in 3, unknown etiology in 3, post-operative in 6). When aortic root diameter was <50 mm, risk for proven type A dissection (0.4 events/1,000 patient-years) and risk for possible aortic dissection (proven aortic dissection plus death of unknown cause, 0.7 events/1,000 patients-years) remained low in this population that was treated according to guidelines. Three type A aortic dissections occurred in this population during the 8,594 years of follow-up, including 1 in a patient with a tubular aortic diameter of 50 mm, but none in patients with a family history of aortic dissection. The risk for type B aortic dissection in the same population was 0.5 events/1,000 patient-years.ConclusionsIn patients with FBN1 pathogenic variants who receive beta-blocker therapy and who limit strenuous exercise, aortic risk remains low when maximal aortic diameter is <50 mm. The risk of type B aortic dissection is close to the remaining risk of type A aortic dissection in this population, which underlines the global aortic risk

Osteoblastic Reaction in Non-small Cell Lung Carcinoma and its Association to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Response and Prolonged Survival

IntroductionThe aim of this study was to describe the characteristics and epidermal growth factor receptor (EGFR) mutational status of patients with non-small cell lung cancer (NSCLC) with osteoblastic reactions diagnosed before or during treatment with EGFR tyrosine kinase inhibitors (TKIs).MethodsRetrospective study including patients with 36 NSCLC with at least one site of osteoblastic reaction at the time of diagnosis or during treatment with EGFR-TKI.ResultsThe rate of patients with mutated EGFR tumors with osteoblastic reactions before or after EGFR-TKI treatment was similar. Median progression-free survival (PFS) for the entire group was more than 9 months and median survival was more than 12 months. There was no statistically significant difference in survival between patients with osteoblastic reactions before initiation of TKI and those diagnosed during TKI treatment. Patients with extraosseous metastases when treated with TKI had the lowest survival (P < 0.0001).ConclusionsIn patients with NSCLC treated with TKI, initial or development of an osteoblastic reaction seems to be related to a more favorable outcome. In patients with osteoblastic reactions, tumors present with clinical and biologic characteristics of better survival and response to TKI. The occurrence of osteoblastic reactions during treatment with TKI, while primary tumor and metastases are stable or in response, should not be considered as disease progression