Philippe JEAN-PIERRE

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• Type de publi. : Rapport
• Date de publi. : 25/11/2022
• Auteurs : Philippe DrobinskiJordi BadosaIsabelle BilgerBenjamin BrigaudPatricia CrifoAntoine EsnosLouis-Gaëtan GiraudetMarion GosselinMathias GuérineauJean-François GuillemolesFlorence HabetsJean-Pierre LévyJulie MayerBertrand QuélinFlorian RaymondDaniel SuchetQiqi TaoAlexis TantetVincent Viguie
• Organismes : Laboratoire de Météorologie Dynamique (UMR 8539) Laboratoire de Météorologie Dynamique (UMR 8539) Ecosystèmes forestiers Géosciences Paris Saclay Centre de Recherche en Économie et Statistique Laboratoire Techniques, Territoires et Sociétés Centre International de Recherche sur l'Environnement et le Développement Ecosystèmes forestiers Nantes Université - Institut d'Administration des Entreprises - Nantes Institut Photovoltaïque d’Ile-de-France (UMR) Laboratoire de géologie de l'ENS Laboratoire Techniques, Territoires et Sociétés Centre de Recherche en Gestion I3 Ecole des Hautes Etudes Commerciales Laboratoire Dynamiques Sociales et Recomposition des Espaces Institut Photovoltaïque d’Ile-de-France (UMR) Laboratoire de Météorologie Dynamique (UMR 8539) Laboratoire de Météorologie Dynamique (UMR 8539) Centre International de Recherche sur l'Environnement et le Développement

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Fichiers liés : carnets-grec-energie_2022.pdf

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• Type de publi. : Article dans une revue
• Date de publi. : 23/11/2022
• Auteurs : Gaëlle Pinto CardosoMarion Lagrée-ChastanMarion CaserisJoël GaudelusHervé HaasJean-Philippe LeroyPierre BakhacheJean-François PujolAndreas WernerMarie-Aliette DommerguesEmilie PauquetDidier Pinquier
• Organismes : Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé Service des maladies infectieuses et tropicales [Rouen]
• Publié dans Frontiers in Pediatrics le 24/10/2020

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Résumé : Background In Europe, meningococcal (Men) vaccines are available against 5 of the 6 serogroups responsible of nearly all cases of invasive meningococcal disease (IMD). Meningococcal vaccination has been introduced in the national immunization programs (NIPs) for children and adolescents of numerous European countries, but with no consistent strategy across countries. Objectives To describe IMD epidemiology, NIPs, and vaccination coverage rates (VCRs) in children and adolescents in 8 Western European countries. Methods Epidemiological data (from 1999 to 2019), NIPs regarding meningococcal vaccination status, and VCRs were collected from the European Centre for Disease Prevention and Control (ECDC) and/or national websites. Results MenB was the most common serogroup. In Belgium, Spain, France, the Netherlands, the United Kingdom (UK), and Portugal, incidence was greater for MenW than MenC. In 2019, MenB risk was covered in 2 countries (Italy, UK). MenC risk was covered in all countries, via MenC only (countries: N = 3), MenACWY only ( N = 2), or MenC (infants/children) and MenACWY (adolescents) ( N = 3) vaccination. VCRs were higher in children than adolescents. Conclusion Our study confirmed the diversity of NIPs, including in neighboring European countries with similar factors like economic resources and epidemiological risk, thus indicating that other factors underlie NIPs. Convergence toward a more common immunization program including MenACWY and MenB vaccination would promote equity and safe travel regarding infectious diseases for young people, and possibly improve the understanding of vaccination by patients and healthcare professionals.

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Fichiers liés : fped-10-1000657.pdf

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• Type de publi. : Pré-publication, Document de travail
• Date de publi. : 22/11/2022
• Auteurs : Marie LabatJ P Couperus CabadağAmin GhaithArie IrmanAnthony BerliouxPhilippe BerteaudFrédéric BlacheStefan BockFrançois BouvetFabien BriquezYen-Yu ChangSébastien CordeAlexander DebusCarlos de OliveiraJean-Pierre DuvalYannick DietrichMoussa El AjjouriChristoph EisenmannJulien GautierRené GebhardtSimon GramsUwe HelbigChristian HerbeauxNicolas HubertCharles KitegiOlena KononenkoMichael KuntzschMaxwell LabergeStéphane LéBruno LeluanAlexandre LoulergueVictor MalkaFabrice MarteauManh Huy N GuyenDriss Oumbarek-EspinosRichard PauschDamien PereiraThomas PüschelJean-Paul RicaudPatrick RommeluereEléonore RousselPascal RousseauSusanne SchöbelMourad SebdaouiKlaus SteinigerKeihan TavakoliCedric ThauryPatrick UferMathieu ValléauMarc VandenbergheJosé VétéranUlrich SchrammMarie-Emmanuelle Couprie
• Organismes : Synchrotron SOLEIL Helmholtz-Zentrum Dresden-Rossendorf Synchrotron SOLEIL Synchrotron SOLEIL Synchrotron SOLEIL Synchrotron SOLEIL Laboratoire d'Optique Appliquée Institute of Radiation Physics [Dresden] Synchrotron SOLEIL Synchrotron SOLEIL Laboratoire d'Optique Appliquée Laboratoire d'Optique Appliquée Weizmann Institute of Science [Rehovot, Israël] DYnamique des Systèmes COmplexes Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 Laboratoire d'Optique Appliquée Laboratoire d'Optique Appliquée Synchrotron SOLEIL

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Résumé : Free-electron lasers generate high-brilliance coherent radiation at wavelengths spanning from the infrared to the X-ray domains. The recent development of short-wavelength seeded free-electron lasers now allows for unprecedented levels of control on longitudinal coherence[1], opening new scientific avenues as ultra-fast dynamics on complex systems and X-ray nonlinear optics. While those devices rely on state-of-the-art large-scale accelerators, advancements on laser-plasma accelerators, which harness giga-volt-per-centimeter accelerating fields, showcase a promising technology as compact drivers for free-electron lasers. Using such miniaturized accelerators, exponential amplification of a shot-noise type of radiation in a self-amplified spontaneous emission configuration was recently achieved [2]. However, employing this compact approach for the delivery of temporally coherent pulses in a controlled manner remained a major challenge. Here, we present the experimental demonstration of a laser-plasma accelerator driven free-electron laser in a seeded configuration, where control over the radiation wavelength is accomplished. Furthermore, the appearance of interference fringes, resulting from the interaction between the phase-locked emitted radiation and the seed, confirms longitudinal coherence. Building on our scientific achievements, we anticipate a straightforward scaling to extreme-ultraviolet wavelengths, paving the way towards university-scale free-electron lasers, unique tools for a multitude of applications. [1] Meyer, M. FELs of europe: Whitebook on science with free electron lasers 8–19 (2016). [2] Wang, W. et al. Free-electron lasing at 27 nanometres based on a laser wakefield accelerator.

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• Type de publi. : Article dans une revue
• Date de publi. : 22/11/2022
• Auteurs : Lydie LemoineVirginie AdamXavier GalusPascale SilesAgnès CoulonJeannette Grenier-DesforgesJoseph OrabonaIsabelle KergastelPierre WagnerJulia SalleronPriscillia TostiCécile Huin-SchohnJean-Louis MerlinRémi EtiennePhilippe Henrot
• Organismes : Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Hôpital de la Timone [CHU - APHM] Département cancer environnement (Centre Léon Bérard - Lyon) CHU de Bordeaux Pellegrin [Bordeaux] Centre Hospitalier Bastia Centre Hospitalier Régional Universitaire de Brest Centre Paul Strauss Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Centre de Recherche en Automatique de Nancy Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy]
• Publié dans Frontiers in Psychology le 02/11/2020

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Résumé : Background Surgery is a cornerstone of breast cancer management. Prior to surgery, a wire marker is placed at the site of the tumor, to enable the surgeon to accurately localize the lesion during later surgery. This procedure can generate considerable anxiety for many patients. We investigated the value of conversational hypnosis (CH) in reducing anxiety in patients undergoing preoperative wire placement under radiographic control. Methods Randomized, multicentre study in 7 centers in France. Inclusion criteria were patients aged >18 years with an Eastern Cooperative Oncology Group performance status ≤2, scheduled to undergo preoperative wire placement in one or several breast lesions. Patients were randomized in a 1:1 ratio, stratified by center to undergo preoperative wire placement with or without the use of CH by a radiological technician trained in the CH technique. The primary endpoint was the percentage of patients with an anxiety score ≥ 6 on a visual analog scale ranging from 0 (absence of anxiety) to 10 (maximal anxiety). Secondary endpoints were pain score, perceived duration reported by the patient, technician satisfaction with their relationship with the patient, and ease of marker insertion reported by the radiologist. Semi-structured interviews were performed with patients to assess their perception of the marker placement procedure. Results The trial was prematurely interrupted for futility after a planned interim analysis after accrual of 167 patients, i.e., half the planned sample size. Prior to marker placement, 29.3% ( n = 24) of patients in the control group had an anxiety score ≥ 6, versus 42.3% ( n = 33) in the CH group ( p = 0.08). After marker placement, the change of anxiety score was not significantly different between groups (11.0% ( n = 9) versus 14.3% ( n = 11), p = 0.615). There was no significant difference in any of the secondary endpoints. In the interviews, patients from both groups frequently spoke of a feeling of trust. Conclusion This study failed to show a benefit of conversational hypnosis on anxiety in patients undergoing marker placement prior to surgery for breast cancer. The fact that some caregivers had learned this personalized therapeutic communication technique may have had a positive impact on the whole caregiving team. Trial registration The study was registered with ClinicalTrials.gov (NCT02867644).

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• Type de publi. : Article dans une revue
• Date de publi. : 21/11/2022
• Auteurs : Philippe Boulanger
• Organismes : Sorbonne Université
• Publié dans Revue de Géographie Historique le 27/10/2020

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• Type de publi. : Article dans une revue
• Date de publi. : 20/11/2022
• Auteurs : Ivan AlonsoCristiano AlpigianiBrett AltschulHenrique AraujoGianluigi ArduiniJan ArltLeonardo BadurinaAntun BalazSatvika BandarupallyBarry C Barish Michele BaroneMichele BarsantiSteven BassAngelo BassiBaptiste BattelierCharles F. A. BaynhamQuentin BeaufilsAleksandar BelicJoel BergéJose BernabeuAndrea BertoldiRobert BinghamS. BizeDiego BlasKai BongsPhilippe BouyerCarla BraitenbergChristian BrandClaus BraxmaierAlexandre BressonOliver BuchmuellerDmitry BudkerLuıs BugalhoSergey BurdinLuigi Cacciapuoti Simone CallegariXavier CalmetDavide CalonicoBenjamin CanuelLaurentiu-Ioan CarameteOlivier CarrazDonatella CassettariPratik ChakrabortySwapan ChattopadhyayUpasna ChauhanXuzong ChenYu-Ao ChenMaria Luisa ChiofaloJonathon ColemanRobin CorgierJ. P. CotterA. Michael CruiseYanou CuiGavin DaviesAlbert de RoeckMarcel DemarteauAndrei DereviankoMarco Di ClementeGoran S. DjordjevicSandro DonadiOlivier DorePeter DornanMichael DoserGiannis DrougakisJacob DunninghamSajan EasoJoshua EbyGedminas ElertasJohn EllisDavid EvansPandora ExamiliotiPavel FadeevMattia FanıFarida FassiMarco FattoriMichael A. FedderkeDaniel FeleaChen-Hao FengJorge FerrerasRobert FlackVictor V. FlambaumRene ForsbergMark FromholdNaceur GaaloulBarry M. GarrawayMaria GeorgousiAndrew GeraciKurt GibbleValerie GibsonPatrick GillGian F. GiudiceJon GoldwinOliver GouldOleg GrachovPeter W. GrahamDario GrassoPaul F. GriffinChristine GuerlinMustafa GundoganRatnesh K GuptaMartin HaehneltEkim T. HanımeliLeonie HawkinsAurelien HeesVictoria A. HendersonWaldemar HerrSven HerrmannThomas HirdRichard HobsonVincent HockJason M. HoganBodil HolstMichael HolynskiUlf IsraelssonPeter JeglicPhilippe JetzerGediminas JuzeliunasRainer KaltenbaekJernej F. KamenikAlex KehagiasTeodora KirovaMarton Kiss-TothSebastian KokeShimon KolkowitzGeorgy KornakovTim KovachyMarkus KrutzikMukesh KumarPradeep KumarClaus LammerzahlGreg LandsbergChristophe Le Poncin-LafitteDavid R. LeibrandtThomas LevequeMarek LewickiRui LiAnna LipniackaChristian Lisdat Mia LiuJ. L. Lopez-GonzalezSina LorianiJorma LoukoGiuseppe Gaetano LucianoNathan LundbladSteve MaddoxM. A. MahmoudAzadeh MaleknejadJohn March-RussellDidier MassonnetChristopher MccabeMatthias MeisterTadej MeznarsicSalvatore MicalizioFederica MigliaccioPeter MillingtonMilan MilosevicJeremiah MitchellGavin W. MorleyJurgen MullerEamonn MurphyOzgur E. MustecaplıogluVal OsheaDaniel K. L. OiJudith OlsonDebapriya PalDimitris G. PapazoglouElizabeth PasatembouMauro PaternostroKrzysztof PawlowskiEmanuele PelucchiFranck Pereira dos SantosAchim PetersIgor PikovskiApostolos PilaftsisAlexandra PintoMarco PrevedelliVishnupriya Puthiya-VeettilJohn QuenbyJohann RafelskiErnst M. RaselCornelis RavensbergenMirko ReguzzoniAndrea RichaudIsabelle RiouMarkus RothacherAlbert RouraAndreas RuschhauptDylan O. SabulskyMarianna SafronovaIppocratis D. SaltasLeonardo SalviMuhammed SameedPandey SaurabhStefan SchafferStephan SchillerManuel SchillingVladimir SchkolnikDennis SchlippertPiet O. SchmidtHarald SchnatzJean SchneiderUlrich SchneiderFlorian SchreckChristian SchubertArmin ShayeghiNathaniel SherrillIan ShipseyCarla SignoriniRajeev SinghYeshpal SinghConstantinos SkordisAugusto SmerziCarlos F. SopuertaFiodor SorrentinoParaskevas SphicasYevgeny V. StadnikPetruta StefanescuMarco G. TaralloSilvia TentindoGuglielmo M. TinoJonathan N. TinsleyVincenza TornatorePhilipp TreutleinAndrea TrombettoniYu-Dai TsaiPhilip TuckeyMelissa A UchidaTristan ValenzuelaMathias van Den BosscheVille VaskonenGunjan VermaFlavio VetranoChristian VogtWolf von KlitzingPierre WallerReinhold WalserEric Wille Jason WilliamsPatrick WindpassingerUlric WittrockPeter WolfMarian WoltmannLisa WornerAndre XuerebMohamed YahiaEfe YazganNan YuNassim ZahzamEmmanuel Zambrini CruzeiroMingsheng ZhanXinhao ZouJure ZupanErik Zupanic
• Organismes : DPHY, ONERA, Université Paris Saclay [Châtillon] DPHY, ONERA, Université Paris Saclay [Palaiseau] Laboratoire Photonique, Numérique et Nanosciences Laboratoire national de métrologie et d'essais - Systèmes de Référence Temps-Espace Laboratoire Univers et Théories DPHY, ONERA, Université Paris Saclay [Palaiseau]
• Publié dans European physical journal quantum technology le 03/02/2016

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Résumé : We summarise the discussions at a virtual Community Workshop on Cold Atoms in Space concerning the status of cold atom technologies, the prospective scientific and societal opportunities offered by their deployment in space, and the developments needed before cold atoms could be operated in space. The cold atom technologies discussed include atomic clocks, quantum gravimeters and accelerometers, and atom interferometers. Prospective applications include metrology, geodesy and measurement of terrestrial mass change due to, e.g., climate change, and fundamental science experiments such as tests of the equivalence principle, searches for dark matter, measurements of gravitational waves and tests of quantum mechanics. We review the current status of cold atom technologies and outline the requirements for their space qualification, including the development paths and the corresponding technical milestones, and identifying possible pathfinder missions to pave the way for missions to exploit the full potential of cold atoms in space. Finally, we present a first draft of a possible road-map for achieving these goals, that we propose for discussion by the interested cold atom, Earth Observation, fundamental physics and other prospective scientific user communities, together with ESA and national space and research funding agencies.

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Fichiers liés : s40507-022-00147-w.pdf

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• Type de publi. : Pré-publication, Document de travail
• Date de publi. : 18/11/2022
• Auteurs : Mathieu MévelVirginie PichardMohammed BouzelhaDimitri Alvarez-DortaPierre-Alban LalysNathalie ProvostMarine AllaisAlexandra MendesElodie LandagarayJean‐baptiste DucloyerAnne GalyNicole BrumentGaëlle M LefevreSebastien G. GouinCarolina IsiegasGuylène Le MeurT. CroninCaroline Le GuinerMichel WeberPhilippe P. MoullierEduard AyusoOumeya Adjali
• Organismes : Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Coave Therapeutics Coave Therapeutics Coave Therapeutics Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089

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Résumé : Inherited retinal diseases are a leading and untreatable cause of blindness and are therefore candidate diseases for gene therapy. Recombinant vectors derived from adeno-associated virus (rAAV) are currently the most promising vehicles for in vivo therapeutic gene delivery to the retina. However, there is a need for novel AAV-based vectors with greater efficacy for ophthalmic applications, as underscored by recent reports of dose-related inflammatory responses in clinical trials of rAAV-based ocular gene therapies. Improved therapeutic efficacy of vectors would allow for decreases in the dose delivered, with consequent reductions in immune reactions. Here, we describe the development of new rAAV vectors using bioconjugation chemistry to modify the rAAV capsid, thereby improving the therapeutic index. Covalent coupling of a mannose ligand, via the formation of a thiourea bond, to the amino groups of the rAAV capsid significantly increases vector transduction efficiency of both rat and nonhuman primate retinas. These optimized rAAV vectors have important implications for the treatment of a wide range of retinal diseases.

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Fichiers liés : ManAAV_MainManuscriptHAL.pdf

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• Type de publi. : Rapport
• Date de publi. : 16/11/2022
• Auteurs : Parisa GhodousNicolas FigayChristophe OzcanLéo BesançonJean-Patrick GelasPhilippe ClémentBertrand PeaudecerfEricka Aicha RaharimananiaainaRoland FaureFrédéric FaureYves Le QuerecPierre ValiorgueFrédérique BiennierJulien Bringer
• Organismes : Service Oriented Computing Laboratoire d'InfoRmatique en Image et Systèmes d'information Service Oriented Computing Service Oriented Computing Service Oriented Computing Laboratoire d'InfoRmatique en Image et Systèmes d'information

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• Type de publi. : Article dans une revue
• Date de publi. : 15/11/2022
• Auteurs : Nicolas BoisselFrancoise HuguetThibaut LeguayHunault-Berger MathildeCarlos GrauxYves ChalandonEric DelabesseYosr HicheriPatrice ChevallierMarie BalsatCedric PastoretMartine Escoffre-BarbeFlorence PasquierJean-Pierre MarolleauAnne Thiebaut-BertrandAnne HuynhNathalie DhedinEmilie LemasleCaroline BonmatiSébastien MauryGaëlle GuillermAnna BerceanuUrs SchanzThomas CluzeauPascal TurlurePhilippe RousselotBernard J.M. de PrijckNathalie GrardelMarie BeneMarine LafageNorbert IfrahVeronique LheritierVahid AsnafiEmmanuelle ClappierHerve Dombret
• Organismes : Hopital Saint-Louis [AP-HP] Recherche clinique appliquée à l'hématologie Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH) Institut Universitaire du Cancer de Toulouse - Oncopole Centre Hospitalier Universitaire de Toulouse Centre Hospitalier Universitaire de Bordeaux Centre Hospitalier Universitaire d'Angers CHU UCL Namur Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève] Service Hématologie - IUCT-Oncopole [CHU Toulouse] Institut Paoli-Calmettes Centre Hospitalier Universitaire de Nantes = Nantes University Hospital Centre Hospitalier Lyon Sud [CHU - HCL] Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou] Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou] Dynamique moléculaire de la transformation hématopoïétique Institut Gustave Roussy Département d'hématologie [Gustave Roussy] CHU Amiens-Picardie Centre Hospitalier Universitaire [CHU Grenoble] Institut Universitaire du Cancer de Toulouse - Oncopole Hopital Saint-Louis [AP-HP] Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen Centre Hospitalier Régional Universitaire de Nancy Hôpital Henri Mondor Centre Hospitalier Régional Universitaire de Brest Centre Hospitalier Régional Universitaire de Besançon University hospital of Zurich [Zurich] Centre Hospitalier Universitaire de Nice Université Côte d'Azur CHU Limoges Centre Hospitalier de Versailles André Mignot Centre Hospitalier Universitaire Sart Tilman Centre Hospitalier Régional Universitaire [CHU Lille] Centre Hospitalier Universitaire de Nantes = Nantes University Hospital Hôpital de la Timone [CHU - APHM] Aix Marseille Université CHU d'Angers [Département Urgences] Centre Hospitalier Lyon Sud [CHU - HCL] Coordination du Groupe GRAALL [CH Lyon-Sud] Institut Necker Enfants-Malades Hôpital Necker - Enfants Malades [AP-HP] Hopital Saint-Louis [AP-HP] Recherche clinique appliquée à l'hématologie Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH) Hopital Saint-Louis [AP-HP]
• Publié dans Blood le 28/10/2020

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Résumé : Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time. In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions. Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively. Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001). Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p<0.001), especially in pts aged 18-44y (21 vs 40%, p<0001). Consequently, the rate of pts transplanted in CR1 dropped down from 38 to 23% (p<0.001). The GRAALL-2014 strategy also yielded a significant reduction in CITRM (5 vs 11% at 3 years; p<0.001; Figure 1B) after CR achievement. This reduction was more pronounced in pts aged 45-59y (7 vs 17%, p<0.001 compared to 4 vs 8%, p= 0.02 in 18-44y pts). This was associated with an increased CIR (35% vs 28% at 3 years; p= 0.01), with more late relapses as depicted in Figure 1A. Even if the resulting RFS was similar in both cohorts (59 vs 62% at 3 years; p= 0.77), OS was significantly longer in the GRAALL-2014 (71 vs 64%; p= 0.002) (Figure 1C) likely due to better post-relapse outcomes. When censoring those GRAALL-2014 pts who received nelarabine or blinatumomab in CR1, observations were basically unchanged, even if the difference in CIR was even more marked. Finally, using a 3-month RFS landmark in the 211 GRAALL-2014 pts eligible for HSCT in CR1 based on their poor early MRD response, HSCT significantly prolonged RFS (HR= 0.46 [95% CI, 0.27-0.78]; p= 0.004). Conclusions In adults with Ph-negative ALL enrolled in the GRAALL-2014, age-adapted chemotherapy intensity and MRD-driven indication for HSCT significantly reduced induction and post-remission TRM. This translated into a prolonged OS, indicating that this strategy was safe, despite a higher incidence of late relapses. Newly available salvage options along with HSCT in CR2 might also have played a role.

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• Type de publi. : Article dans une revue
• Date de publi. : 15/11/2022
• Auteurs : Jean ChastreBruno FrançoisMarc BourgeoisApostolos KomnosRicard FerrerGalia RahavNicolas de SchryverAlain LepapeIftihar KoksalCharles-Edouard LuytMiguel Sánchez-GarcíaAntoni TorresPhilippe EggimannDespoina KoulentiThomas HollandOmar AliKathryn ShoemakerPin RenJulien SauserAlexey RuzinDavid TaborAhmad AkhgarYuling WuYu JiangAntonio DigiandomenicoSusan ColbertDrieke VandammeFrank CoenjaertsSurbhi Malhotra-KumarLeen TimbermontAntonio OliverOlivier BarraudTerramika BellamyMarc BontenHerman GoossensColin ReisnerMark EsserHasan JafriMichael JoannidisWalter KlimschaElisabeth de WaeleJacques DevriendtVincent HuberlantPieter DepuydtSam van BoxstaelMladen PericJasminka KopicMichal HanauerTomas HrubyVladimir SramekPetr SvobodaTomas VymazalMartin NovacekDjillali AnnaneJean-Paul MiraBertrand SouweinePierre-François DequinFerhat MezianiFrançois StephanSaadalla NseirSébastien GibotCarole SchwebelGaetan PlantefeveJean-Luc DiehlChristian RichardChristian LamerKada KloucheSamir JaberEpaminondas ZakynthinosGeorgios FilntisisSpyros ZakynthinosAntonia KoutsoukouGeorgios SaroglouCharikleia NikolaouGlykeria VlachogianniIoannis PnevmatikosKonstantinos MandragosIldiko KremerZsolt Dezso RozgonyiZsuzsa MarjanekIgnacio Martin-LoechesPierre SingerVernon van HeerdenYehuda CarmeliPedro PovoaAntonio Alvarez SeoanePedro MouraFilipe GonzalezPaula RamirezAntonio Torres MartiRicard Ferrer RocaLorena OteizaDolores EscuderoEnrique PiacentiniPaula VeraLuis TamayoMiguel Angel Gonzalez GallegoBorja Suberviola CanasIglesias FigueiraRafael LeonVolkan KortenMurat AkovaDuncan WyncollTony WhitehousePhil HopkinsMalcolm SimYoav GolanMarcus ZervosJose VazquezKartikeya CherabuddiGeorge SmulianNadine RouphaelJames WelkerMathew SimsDavid van DuinTodd MccarthyChristopher Polk
• Organismes : Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] Centre Hospitalier Régional Universitaire [Montpellier]
• Publié dans Critical Care le 31/10/2020

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Résumé : Abstract Background Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects. Methods EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee. Results Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% ( n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% ( n = 15/83) of placebo recipients (relative risk reduction [RRR]: − 23.7%; 80% confidence interval [CI] − 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) μg/mL, with 80.6% ( n = 58/72) subjects achieving concentrations > 1.7 μg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups. Conclusions The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.

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Fichiers liés : 2022 Chastre et al., Safety.pdf

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