Julien Labreuche

Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors

Background Several mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC have been described including the T790M mutation and MET amplification. Whereas T790M mutation confers prolonged survival and sensitivity to 3rd generation TKIs, data are lacking on clinical features and outcome of MET-driven resistant EGFR-mutated NSCLC patients. Methods Patients with metastatic EGFR-mutated NSCLC displaying high MET overexpression or MET amplification, detected on a biopsy performed after progression on EGFR TKI, were identified in 15 centers. Clinical and molecular data were retrospectively collected. Results Forty two patients were included. The median overall survival (OS), and the median post EGFR TKI progression overall survival (PPOS) were 36.2 months [95%CI 27.3-66.5] and 18.5 months [95%CI 10.6-27.4] respectively. Nineteen out of 36 tumors tested for MET FISH had MET amplification. A T790M mutation was found in 11/41 (26.8%) patients. T790M-positive patients had a better OS than T790M-negative patients (p=0.0224). Nineteen patients received a MET TKI. Objective response was reported in 1 out of 12 evaluable patients treated with a MET inhibitor as a single agent and in 1 of 2 patients treated with a combination of MET and EGFR TKIs. Conclusion MET-driven resistance to EGFR TKI defines a specific pattern of resistance characterized by low objective response rate to MET inhibitors given alone and overlapping with T790M mutations. Further studies are warranted to define adequate therapeutic strategies for MET-driven resistance to EGFR TKI.

Contact aspiration versus stent retriever front-line for recanalisation in acute cerebral infarction: The ASTER trial

RATIONALE Mechanical thrombectomy (MT) with a stent retriever (SR), in association with intravenous (IV) rtPA, is now the standard of care in anterior circulation ischemic stroke caused by large vessel occlusion (LVO). Favorable outcome is strongly associated with the successful reperfusion status. New techniques for MT such as contact aspiration (CA) seem promising to increase reperfusion status and clinical outcome in retrospective studies. We aim at ascertaining whether CA is more efficient than stent retriever as a front-line endovascular procedure. METHODS AND DESIGN The ASTER trial is a prospective, randomized, multicenter, controlled, open-label with blinded outcome evaluation (PROBE) design. Patients admitted with suspected ischemic anterior circulation stroke secondary to LVO, with onset of symptoms <6hours, were randomized 1:1 to CA or SR; stratified by center and prior IV thrombolysis. If the assigned treatment technique was not successful after three attempts, the procedure was continued with another technique at the operators discretion. The primary outcome will be the successful recanalization (modified thrombolysis in cerebral infarction [mTICI] score 2b-3) at the end of the treatment. Secondary outcome will include the successful recanalization after the assigned treatment technique, procedural times, the need for a rescue technique, complications and modified Rankin Scale (mRS) at 3-month. With a two-sided test (alpha=5%, power=90%), an anticipate rate of spontaneous recanalization and catheterization failures of 15%, the sample size estimate will be 380 patients to detect an absolute difference of 15% in primary outcome (assuming a rate of 70% in the control arm). RESULTS Patient enrollment has been completed within 12 months between October 2015 and October 2016. Data analysis is ongoing and final results will be presented at the SFNR meeting. ClinicalTrials.gov Identifier NCT02523261.

Mechanical thrombectomy for minor and mild stroke patients harboring large vessel occlusion in the anterior circulation: A multicenter case control study

BACKGROUND AND PURPOSE Proximal large vessel occlusion (LVO) is present in up to 30% of minor strokes. There is no proven effectiveness of MT in the subgroup of minor stroke with LVO in the anterior circulation and data about mechanical thrombectomy (MT) in this subgroup of patients are sparse, with optimal management of these patients being yet not definitely addressed. The purpose of this case-control study was to evaluate MT in patients suffering from acute ischemic stroke (AIS) and LVO in the anterior circulation, presenting with minor to mild stroke symptoms (NIHSS<8). MATERIAL AND METHODS Case-control study involving 4 comprehensive stroke centers, having two approaches regarding management of minor and mild AIS patients harboring LVO in the anterior circulation. An intention-to-treat analysis was conducted. The primary end point was the rate of excellent outcome defined as the achievement of a modified Rankin Scale score of 0-1 at 3 months. RESULTS In total, 301 patients were included, 170 with MT associated to best medical management (BMM, case group) and 131 with BMM alone as first line treatment (control group). Patients treated with MT were younger, more often received intravenous thrombolysis, and had shorter time to imaging. Twenty-four patients (18.3%) belonging to the medical group had rescue MT due to neurologic worsening. Overall, excellent outcome was achieved in 64.5% of patients, with no difference between the two groups. Stratified analysis according to key subgroups did not find heterogeneity in the treatment effect size. CONCLUSION Patients having underwent MT or BMM achieve excellent and favorable functional outcome at 3 months in similar proportions. However, baseline characteristics were different between the 2 groups, highlighting the urgent need for randomized clinical trials in this subset of patients.

Therapeutic body wraps (TBW) for treatment of severe injurious behaviour in children with autism spectrum disorder (ASD): A 3-month randomized controlled feasibility study

Introduction The use of therapeutic body wraps (TBW) has been reported in small series or case reports, but has become controversial. Objectives This is a feasibility, multicentre, randomized, controlled, open-label trial with blinded outcome assessment (PROBE design). Setting Children with autism and severe-injurious behaviours (SIB) were enrolled from 13 specialized clinics. Interventions Dry-sheet TBW (DRY group) vs. wet-sheet TBW (WET group). Primary outcome measures 3-month change in the Aberrant Behaviour Checklist irritability score (ABC-irritability) within per-protocol (PP) sample. Results From January 2008 to January 2015, we recruited 48 children (age range: 5.9 to 9.9 years, 78.1% male). Seven patients (4 in the DRY group, 3 in the WET group) were dropped from the study early and were excluded from PP analysis. At endpoint, ABC-irritability significantly improved in both groups (means (standard deviation) = -11.15 (8.05) in the DRY group and -10.57 (9.29) in the WET group), as did the other ABC scores and the Children Autism Rating scale score. However, there was no significant difference between groups. All but 5 patients were rated as much or very much improved. A repeated-measures analysis confirmed the significant improvement in ABC-irritability scores according to time (p < .0001), with no significant difference between the two groups (group effect: p = .55; interaction time x group: p = .27). Pooling both groups together, the mean 3-month change from baseline in ABC-irritability score was -10.90 (effect size = 1.59, p < .0001). Conclusions We found that feasibility was overall satisfactory with a slow recruitment rate and a rather good attrition rate. TBW was a safe complementary therapy in this population. There was no difference between wet and dry TBW at 3 months, and ABC-irritability significantly decreased with both wet and dry sheet TBW. To assess whether TBW may constitute an alternative to medication or behavioural intervention for treating SIB in ASD patients, a larger randomized comparative trial (e.g. TBW vs. antipsychotics) is warranted. Trial registration ClinicalTrials.gov NCT03164746.

Risk of cesarean delivery among pregnant women with class III obesity

To identify factors associated with cesarean delivery among women with class III obesity attempting vaginal delivery.