Prise en charge des premières crises épileptiques au CHU de Rouen : évaluation à deux ans de l’activité d’hôpital de jour

L’HAS a établi en 2015 des recommandations de prise en charge suite à la survenue d’une première crise épileptique. Objectifs : Evaluer la nouvelle activité d’hôpital de jour du CHU de Rouen, dédiée à la prise en charge des patients suite à leur première crise d’épilepsie. Méthodes : Cette étude prospective porte sur les patients admis en hôpital de jour (HDJ) de neurologie pour un bilan de première crise épileptique, depuis la mise en place de l’activité en février 2016 jusqu’en février 2018. Les patients, recrutés sur avis neurologique lors de leur malaise, étaient convoqués à un mois pour un bilan clinique (avis d’expert) et paraclinique (EEG, IRM cérébrale, ECG, Biologie). Les critères d’évaluation de l’activité d’HDJ étaient son apport diagnostique global (pourcentage de diagnostics certains), la performance diagnostique de l’avis de l’expert (nombre de diagnostics réalisés sur l’interrogatoire), de l’EEG (pourcentage d’EEG révélant des anomalies épileptiformes), et de l’IRM cérébrale (pourcentage d’IRM révélant des anomalies épileptogènes ou liées à un diagnostic différentiel), ainsi que le respect du délai de réalisation prévu. Résultats : 105 patients ont été convoqués pour un HDJ première crise. 88 s’y sont effectivement présentés et ont été analysés, dont 55,7% d’hommes. L’âge moyen était de 37,9 ± 18,7 ans. 80 patients (90,9%) ont reçu un diagnostic certain à l’issue de l’HDJ. 54 avaient présenté une crise épileptique avérée, 26 un malaise non épileptique. Parmi les crises, 47 étaient non provoquées : 35 patients avaient un haut risque de récidive identifié permettant un diagnostic d’épilepsie, pour 12 patients ce risque était faible. L’avis d’expert a suffi à l’établissement de 40 diagnostics (45,5%). L’IRM était l’élément déterminant du diagnostic pour 13 patients (14,8%). L’EEG l’était pour 7 patients (7,9% de la population totale, 13% des patients ayant eu une crise). Le délai moyen entre le recrutement et l’HDJ était de 44,2 ± 22 jours. 68 patients ont poursuivi un suivi neurologique, 20 ont été réorientés vers d’autres praticiens. Conclusion : Notre étude confirme la pertinence de l’organisation de la prise en charge des patients ayant présenté une première crise épileptique en un lieu unique dédié

Development of Theranostic Cationic Liposomes Designed for Image-Guided Delivery of Nucleic Acid

Cationic liposomes have been considered as potential vectors for gene delivery thanks to their ability to transfect cells with high efficiency. Recently, the combination of diagnostic agent and therapeutic agents in the same particle to form a theranostic system has been reported. Magnetic liposomes are one of these examples. Due to the magnetic nanoparticles encapsulated in the liposomes, they can act as a drug delivery system and, at the same time, a magnetic resonance imaging contrast enhancement agent or hyperthermia. In this work, nucleic acid delivery systems based on magnetic cationic liposomes (MCLs) were developed. Two different techniques, reverse phase evaporation and cosolvent sonication, were employed for liposome preparation. Both strategies produced MCLs of less than 200 nm with highly positive charge. Enhancement of their transverse and longitudinal relaxivities r2 and r1 was obtained with both kinds of magnetic liposomes compared to free magnetic nanoparticles. Moreover, these MCLs showed high capacity to form complexes and transfect CT-26 cells using the antibiotic-free pFAR4-luc plasmid. The transfection enhancement with magnetofection was also carried out in CT26 cells. These results suggested that our MCLs could be a promising candidate for image-guided gene therapy

Theranostic MRI liposomes for magnetic targeting and ultrasound triggered release of the antivascular CA4P

International audienceTheranostic nanocarriers of antivascular drug encapsulated in thermosensitive ultramagnetic liposomes can be advantageously designed to provide a locally high concentration and an active delivery, with image-guided Magnetic Resonance Imaging (MRI) so as to reliably cure tumor. We propose a novel therapeutic strategy consisting of the magnetic accumulation of Ultra Magnetic Liposomes (UML) followed by High-Intensity Focused Ultrasound (HIFU) to trigger the release of an antivascular agent monitored by MRI. For this purpose, we coencapsulated Combretastatin A4 phosphate (CA4P), a vascular disrupting agent, in the core of UML to obtain CA4P-loaded thermosensitive Ultra Magnetic Liposomes (CA4P-UML). To assess the HIFU parameters, the CA4P release has been triggered in vitro by local heating HIFU at the lipids transition temperature. Morphology of endothelial cells was assessed to evaluate the effect of encapsulated versus non-encapsulated CA4P. The efficiency of a treatment combining the magnetic targeting of CA4P-UML with the CA4P release triggered by HIFU was studied in CT26 murine tumors. Tumor perfusion and volume regression parameters were monitored by multiparametric quantitative anatomical and dynamic in vivo MRI at 7 T. Additionally, vascularization and cellularity were evaluated ex-vivo by histology. This thorough investigation showed that the combined treatment exhibited a full benefit. A 150-fold improvement compared with the chemotherapy alone was obtained using a magnetic targeting of CA4P-UML triggered by HIFU, and was consistent with an expected effect on vascularization 24 h after treatment

Multimodal RM and Optic Imaging using ultramagnetic liposomes to monitor a cancer therapy

Congrès sous l’égide de la Société Française de Génie Biologique et Médical (SFGBM)National audienceMagnetic liposomes present an opportunity for the development of theranostic systems. Ultra-magnetic liposomes (UML) are highly loaded with ultra-small particles of iron oxide (USPIO) and can accumulate in a biological area thanks to a magnet. The incorporation of a fluorophore such as cyanine 5.5 in the formulation of the UML forms a bimodal imaging agent (MRI and optic) to monitor the magnetic accumulation in the tumor. The addition of an antitumoral drug into the UML combined with the application of High Intensity Focused Ultrasounds (HIFU) in the tumor can be used for a specific release of the drug in the region of interest

In Vivo Evaluation of Magnetic Targeting in Mice Colon Tumors with Ultra-Magnetic Liposomes Monitored by MRI

International audiencePurposeThe development of theranostic nanocarriers as an innovative therapy against cancer has been improved by targeting properties in order to optimize the drug delivery to safely achieve its desired therapeutic effect. The aim of this paper is to evaluate the magnetic targeting (MT) efficiency of ultra-magnetic liposomes (UML) into CT26 murine colon tumor by magnetic resonance imaging (MRI).ProceduresDynamic susceptibility contrast MRI was applied to assess the bloodstream circulation time. A novel semi-quantitative method called %I0.25, based on the intensity distribution in T2*-weighted MRI images was developed to compare the accumulation of T2 contrast agent in tumors with or without MT. To evaluate the efficiency of magnetic targeting, the percentage of pixels under the intensity value I0.25 (I0.25 = 0.25(Imax − Imin)) was calculated on the intensity distribution histogram.ResultsThis innovative method of processing MRI images showed the MT efficiency by a %I0.25 that was significantly higher in tumors using MT compared to passive accumulation, from 15.3 to 28.6 %. This methodology was validated by ex vivo methods with an iron concentration that is 3-fold higher in tumors using MT.ConclusionsWe have developed a method that allows a semi-quantitative evaluation of targeting efficiency in tumors, which could be applied to different T2 contrast agents

Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade >/=3 cytokine release syndrome, 9%; grade >/=3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications