30 results on '"V. Heidelberger"'
Search Results
2. Efficacité du rechallenge dans le mélanome avancé, chez des patients ayant répondu à une première immunothérapie : une étude nationale multicentrique rétrospective
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A. Hennemann, C. Nardin, K. Diallo, E. Funck-Brentano, E. Puzenat, V. Heidelberger, G. Jeudy, M. Samimi, C. Lesage, L. Boussemart, L. Peuvrel, S. Mansard, F. Brunet Possenti, E. Gerard, A. Seris, T. Jouary, M. Saint-Jean, M. Puyraveau, P. Saiag, and F. Aubin
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Ocean Engineering ,Safety, Risk, Reliability and Quality - Published
- 2022
3. Intérêt du cétuximab dans le carcinome épidermoïde évolué ou métastatique en échec des anti-PD-1
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F. Blanchet, B. Villette, C. Bejar, V. Heidelberger, O. Briard, I. Scheer, A. Louzoun, M. Boutouil, F. Toukal, F. Caux, and E. Maubec
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Ocean Engineering ,Safety, Risk, Reliability and Quality - Published
- 2022
4. Traitement en vie réelle par cémiplimab des carcinomes épidermoïdes avancés en rémission complète et facteurs prédictifs d’une réponse rapide
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K. Khelef, E. Maubec, G. Jeudy, B. Bonniaud, A. Pham-Ledard, F. Herms, F. Aubin, N. Beneton, M. Dinulescu, A. Jannic, A.B. Modeste-Duval, E. Archier, C. Berthin, F. Grange, J.P. Arnault, A. Palladini, V. Heidelberger, M. Moncourier, S. Mansard, F. Brunet Possenti, F. Skowron, J. Sanchez, R. Triller, M. Pracht, M. Dumas, P. Combe, O. Lauche, L. Mortier, C. Bedane, and S. Dalac
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Ocean Engineering ,Safety, Risk, Reliability and Quality - Published
- 2022
5. Colite microscopique à collagène induite par le lansoprazole chez une patiente traitée par immunothérapie pour un mélanome métastatique
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J. Emile, B. Villette, C. Bejar, V. Heidelberger, M. Boutouil, F. Toukal, F. Caux, and E. Maubec
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Ocean Engineering ,Safety, Risk, Reliability and Quality - Published
- 2022
6. Hypoacousie induite par les anti-PD-1 associée à une réaction granulomateuse
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C. Zumelzu, L. Goldfarb, Frédéric Caux, Eve Maubec, V. Heidelberger, M. Aljundi, I. Lazaridou, M. Popescu, and Liliane Laroche
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Dermatology - Abstract
Introduction Les toxicites des immunotherapies a type d’hypoacousie sont exceptionnelles. Nous rapportons une observation d’hypoacousie induite par un anti-PD-1 associee a une reaction granulomateuse. Observation Une patiente de 69 ans, aux antecedents d’embolie pulmonaire, d’hypertension arterielle et de carcinome epidermoide bien differencie du plancher buccal traite chirurgicalement simultanement a une seconde rechute ganglionnaire iliaque inoperable d’un melanome de type SSM du mollet gauche de stade initial T1aN0M0 de statut moleculaire BRAF WT, NRAS mute, debutait un traitement par nivolumab 480 mg mensuel en 1re ligne. Il n’y avait aucune fixation en dehors de l’atteinte iliaque sur le PET-scan de baseline. La premiere evaluation sous nivolumab montrait une tres bonne reponse partielle metabolique mais l’apparition d’un hypermetabolisme mediastinal et parotidien faisait avant tout evoquer une reaction granulomateuse induite par les anti-PD-1. Deux jours apres la 4e injection d’anti-PD-1, la patiente presentait une hypoacousie unilaterale spontanement resolutive. Lors de la 6e injection, l’hypoacousie recidivait, associee a une otalgie droite intense ainsi qu’a une fievre a 40 °C. Une infection etait ecartee. Apres une corticotherapie breve a 1 mg/kg/jour, l’otalgie disparaissait et l’hypoacousie s’attenuait progressivement mais persistait ; l’anti-PD-1 etait poursuivi avec une premedication systematique par corticotherapie orale les 48 h avant la perfusion et le jour du traitement. L’evaluation a 1 an de traitement montre le maintien d’une tres bonne reponse partielle sous nivolumab et la reaction granulomateuse connue persistante. L’hypoacousie etait stable dans le temps. Discussion Notre observation suggere que la reaction granulomateuse induite par les anti-PD-1 pourrait etre a l’origine d’au moins une partie des hypoacousies survenant sous anti-PD-1. En effet, les reactions granulomateuses peuvent etre a l’origine d’hypoacousies, leur survenue simultanee suggerant un lien de causalite. Dans les 2 cas publies d’hypoacousie, l’un sous ipilimumab, le second sous nivolumab, l’hypothese que les melanocytes de l’oreille interne pourraient etre la cible d’un processus auto-immun en cas de melanome a ete proposee mais le mecanisme exact reste inconnu. Conclusion Il est possible qu’une reaction granulomateuse induite par les anti-PD-1 soit a l’origine de l’hypoacousie dans cette observation. Le maintien de l’anti-PD-1 a ete possible chez cette patiente grâce a l’introduction d’une corticotherapie ponctuelle. Il serait interessant de proposer un TEP scanner aux patients presentant une hypoacousie sous anti-PD-1 afin de rechercher une granulomatose associee dont l’aspect scintigraphique est typique.
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- 2019
7. Essai de phase 2 multicentrique évaluant le pembrolizumab dans la maladie de Kaposi classique ou endémique
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Vincent Allain, L. Toullec, V. Heidelberger, Guislaine Carcelain, L. Da Meda, Matthieu Resche-Rigon, Stéphane Dalle, J. Le Goff, Sophie Caillat-Zucman, Samia Mourah, C. Lebbé, Marisa Battistella, M. Renaud, and Julie Delyon
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Dermatology - Abstract
Introduction Alors que le traitement de la maladie de Kaposi (MK) iatrogenique et epidemique est relativement bien codifie, reposant avant tout sur une restauration des fonctions immunitaires, le traitement optimal de la MK classique/endemique reste a definir. Les patients avec atteinte cutanee etendue ou viscerale sont traites generalement par interferon ou chimiotherapie, mais la tolerance peut etre mediocre chez des sujets souvent âges, et les remissions a long terme sont rares. Les anti-PD1 ont fait preuve d’une efficacite spectaculaire dans de nombreux cancers dont le carcinome de Merkel, une tumeur viro-induite comme la MK, notamment mediee par l’immunogenicite des antigenes associes au virus. Compte tenu de l’implication du virus HHV8 dans la MK et de la bonne tolerance des anti-PD1 chez les sujets âges, les anti-PD1 apparaissent comme une option therapeutique interessante. Materiel et methodes Nous avons conduit un essai de phase 2 multicentrique incluant les patients atteints de MK classique/endemique avec atteinte cutanee etendue, evolutive, avec indication a un traitement systemique. Les patients etaient traites par pembrolizumab 200 mg/3 semaines IV pendant 6 mois. La reponse tumorale etait evaluee par une mesure clinique des lesions cibles (nombre, taille, infiltration, couleur) suivant les criteres ACTG pour definir la meilleure reponse dans les 6 mois (critere principal). Une probabilite de reponse > 30 % suivant le plan de Simon en 2 etapes permettait de conclure a l’efficacite. Resultats Dix-sept patients ont ete inclus (47 % et 53 % de MK classique et endemique), dont 6 avec une atteinte ganglionnaire associee. Une majorite (12, 71 %) avait deja recu de la chimiotherapie. Avec une mediane de suivi de 25 semaines, 2 patients etaient en reponse complete, 10 en reponse partielle, et 5 en stabilite comme meilleure reponse. Onze patients ont eu ≥ 1 effet secondaire lie au traitement dont 1 de grade 3 (œdeme aigu pulmonaire, OAP). Deux patients ont arrete prematurement pour toxicite (un OAP grade 3 sans myocardite et une pancreatite aigue grade 2, traites symptomatiquement, reversibles). Sur les biopsies initiales, l’absence d’expression de PDL1 sur les cellules tumorales et immunes etait associee a la non reponse au pembrolizumab. Le score de divergence entre alleles du HLA de classe 1 a ete mesure chez chaque patient, et etait significativement plus faible chez les 5 patients non repondeurs (p = 0,031). Discussion Dans ce premier essai clinique evaluant l’efficacite d’un anti-PD1 dans la MK classique/endemique, le pembrolizumab etait efficace (taux de reponse de 71 %) et la tolerance acceptable. Si confirmes, ces resultats suggerent que les anti-PD1 pourraient rapidement devenir un traitement systemique de premier plan dans cette indication.
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- 2020
8. 1077MO PD1 blockade with pembrolizumab in classic and endemic Kaposi sarcoma: A multicenter phase II study
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L. Da Meda, M. Renaud, Marisa Battistella, Julie Delyon, Guislaine Carcelain, Samia Mourah, Matthieu Resche-Rigon, V. Heidelberger, Sophie Caillat-Zucman, Vincent Allain, L. Toullec, J. Le Goff, Stéphane Dalle, and C. Lebbé
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Phases of clinical research ,Medicine ,Hematology ,Sarcoma ,Pembrolizumab ,business ,medicine.disease ,Blockade - Published
- 2020
9. Première étude en « vie réelle » comparant le pembrolizumab et le nivolumab dans le traitement du mélanome métastatique
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V. Seta, Selim Aractingi, V. Heidelberger, Nathalie Franck, F. Kurihara, Nora Kramkimel, Johan Chanal, Sarah Guégan, Nicolas Dupin, C. Isnard, M.-F. Avril, and C. Lheure
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Dermatology - Abstract
Introduction Deux anticorps anti-PD1 peuvent etre prescrits en France en 1re ligne pour le melanome metastatique avec ou sans mutation BRAF : le pembrolizumab (P) et le nivolumab (N). Aucune etude ne les a compares directement. L’objectif etait ici de comparer leur efficacite et leur tolerance. Patients et methodes Etude retrospective observationnelle monocentrique ayant inclus tous les patients (pts) avec un melanome metastatique (stade IIIc non operable ou IV) ayant recu au moins 1 perfusion en 1re ligne de P ou N initie entre mai 2015 et mars 2017. Les donnees analysees etaient : caracteristiques des pts et des melanomes, tolerance, reponse au traitement (evaluee par scanner et/ou PET scanner tous les 3 mois), survie sans progression (PFS), survie mediane (OS). Les outils statistiques etaient : test exact de Fisher, methode de Kaplan-Meier et test du Log-Rank. Resultats Vingt-neuf pts ont ete traites par P et 21 par N, d’âge median respectif de 73 et 71 ans, en bon etat general (PS0/1 : P93 % vs N86 %). Une elevation des LDH (P38 % vs N33 %) et la presence de metastases cerebrales (P21 % vs N14 %) etaient plus frequentes dans le groupe P (NS). Des effets indesirables (tous grades) sont survenus chez 38 % des pts traites par P et 43 % par N (p = 0,72), dont respectivement 7 (24 %) et 5 (23,8 %) de grade 3–4 (NS), responsables de, respectivement 4 et 2 hospitalisations (NS) et 4 et 2 arrets de traitement (NS). Le seul deces lie au traitement a ete dans le groupe N (toxicite cardio-renale). Au moment de l’analyse (mai 2018 ; suivi median = 17,5 mois), 13 pts de chaque groupe etaient en vie dont 2 dans chaque groupe encore traites par anti-PD1, le taux de reponse (RC + RP) etait de 55,2 % sous P et 66,7 % sous N (p = 0,56) et le taux de controle de la maladie (RC + RP + SD) respectivement de 75 % et 71,4 % (p = 0,54). La PFS mediane etait de 8 mois, l’OS mediane non atteinte, sans difference significative entre les 2 groupes ( Fig. 1 ). Discussion Sur le plan de la tolerance et de la reponse au traitement, il n’y a pas de difference significative entre P et N. Nos resultats pour chaque molecule sont proches de ceux des etudes publiees, avec, cependant, plus d’effets secondaires de grades 3–4 et une PFS mediane moins bonne, ce qui peut s’expliquer par le fait qu’il s’agit d’une etude en « vie reelle » avec des pts plus fragiles (plus âges, taux eleve de LDH, metastases cerebrales). Par ailleurs, bien que ce ne soit pas statistiquement significatif, il semble, tout de meme, dans notre etude, que la PFS et l’OS soient moins bonnes avec le P d’apres la Fig. 1 ; cela pourrait peut-etre se confirmer avec un plus grand nombre de pts. Conclusion Actuellement, le choix entre le P et le N est laisse a la decision du prescripteur. Notre etude ne montre pas de difference significative entre les 2 en termes de tolerance et d’efficacite ; une etude prospective randomisee semble necessaire afin de confirmer ces resultats et nous aider dans notre pratique quotidienne.
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- 2018
10. Efficacité des anti-TNFα sur les atteintes cutanées de la sarcoïdose : étude multicentrique de 46 cas
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M. Mahevas, Frédéric Caux, Anne-Bénédicte Duval-Modeste, O. Chosidow, Diane Bouvry, S. Oro, Sébastien Debarbieux, Groupe sarcoïdose francophone, Pascal Sève, Pascal Joly, Emmanuel Delaporte, V. Heidelberger, Alicia Marquet, Jean-Benoît Monfort, Didier Bessis, Laurence Fardet, and Dominique Valeyre
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Dermatology - Abstract
Introduction Le traitement des formes etendues/affichantes de sarcoidose cutanee est mal codifie. Plusieurs etudes de faible effectif ont montre l’interet des anti-TNFα dans les formes refractaires. Nous rapportons les resultats d’une etude multicentrique francaise. Materiel et methodes Le Groupe sarcoidose francophone a mis en place en 2014 un registre (STAT) qui repertorie de facon retrospective ou prospective les sarcoidoses traitees par anti-TNFα pour en preciser l’efficacite et la tolerance. Les patients avec une atteinte cutanee (± viscerale), de gravite cotee par le score ePOST en 6 points (de minime a tres severe) ont ete extraits. Si disponibles, les photos ont ete revues. La reponse aux anti-TNF etait evaluee par le medecin en charge du patient : reponse complete (RC), partielle (RP), stabilite et progression. Resultats Parmi les 140 patients inclus entre 7/2014 et 5/2016 dans 18 services de pneumologie, medecine interne ou dermatologie, 46 avaient une atteinte cutanee a la mise sous anti-TNFα. Les caracteristiques cliniques et les traitements anterieurs sont dans le tableau 1. L’indication des anti-TNFα etait exclusivement cutanee chez 21 patients (groupe 1) et viscerale ± cutanee chez 25 (groupe 2). La semiologie cutanee est detaillee dans le Tableau 2. Le lupus pernio etait le plus frequent (44 %). L’atteinte du visage etait plus frequente dans le groupe 1 (90 vs 60 %, p = 0,009). L’anti-TNFα prescrit en 1e ligne etait l’infliximab dans 87 % des cas (5 mg/kg/6–8 sem). Les autres recevaient de l’adalimumab. L’anti-TNF etait associe a de la prednisone dans 28 cas (moyenne 17,5 mg/j) et/ou un immunosuppresseur (IS) dans 32 cas (methotrexate n = 27). Apres un suivi median de 45 mois, la reponse aux anti-TNFα etait : dans le groupe 1 de 62 % (IC95 42–83 %) dont 7 RC et 6 RP ; dans le groupe 2 de 76 % (IC95 59–93 %) sur l’organe cible, dont 2 RC et 17 RP, et de 68 % sur la peau, dont 5 RC et 12 RP. Dans les 2 groupes, la baisse du score ePOST cutane et l’epargne cortisonique etaient significatives. Le delai median jusqu’a meilleure reponse etait de 6 mois (1,5–23 mois). Le traitement de 1e ligne etait arrete chez 30 patients (65 %), pour echec (n = 11), remission (n = 6), echappement (n = 3) ou evenement indesirable (n = 10). Le taux de rechute etait alors de 54 % apres un delai median de 14 mois (2–27 mois), avec bonne reponse a la reprise du meme anti-TNFα. Vingt-deux episodes infectieux sont survenus chez 15 patients (33 %), dont 5 responsables d’arret de traitement. Discussion Dans notre serie, le taux de reponse cutanee etait globalement de 66 %, mais les rechutes frequentes a l’arret. Des complications infectieuses survenaient chez un tiers des patients mais beaucoup avaient une corticotherapie ou un IS concomitant. Le caractere volontaire de l’inclusion dans STAT doit cependant rendre prudentes nos conclusions. Conclusion Les anti-TNFα sont un traitement efficace mais suspensif des atteintes cutanees graves de sarcoidose.
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- 2016
11. La sarcopénie associée à un IMC>25kg/m2 est prédictive de toxicité sévère précoce sous anti-PD1 chez les patients atteints de mélanome
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Selim Aractingi, V. Heidelberger, François Goldwasser, O. Huillard, J. Arrondeau, Nathalie Franck, P. Boudou-Rouquette, J. Alexandre, Nicolas Dupin, Benoit Blanchet, Nora Kramkimel, Johan Chanal, and K. Leroy
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Gynecology ,medicine.medical_specialty ,business.industry ,medicine ,Dermatology ,business ,Anti pd1 - Abstract
Introduction Bien que moins frequents qu’avec les anti-CTLA4, des effets secondaires graves peuvent survenir sous anti-PD1. Ces traitements etant prescrits en mg/kg, les patients ayant une composition corporelle anormale et un volume de distribution reduit pourraient etre surexposes. Cette etude a pour but d’evaluer si la sarcopenie associee a un indice de masse corporelle (IMC) eleve est un facteur de risque de toxicite sous anti-PD1. Materiel et methodes Les dossiers des patients du service de dermatologie de l’hopital Cochin ayant recu des anti-PD1 pour un melanome ont ete revus retrospectivement. Une toxicite severe precoce etait definie comme toute toxicite survenant dans les 3 premiers mois de traitement faisant interrompre l’anti-PD1 de maniere definitive ou temporaire. Pour chaque patient etaient notes l’âge, le sexe, le type de melanome, le statut BRAF, les traitements anterieurs, l’IMC et l’index de muscle squelettique (calcule avec la masse musculaire mesuree en L3 sur le scanner de debut du traitement). Les patients ayant un index inferieur a la mediane de la population etudiee de meme sexe etaient definis comme sarcopeniques. Resultats Sur les 81 patients traites par anti-PD1 entre aout 2014 et fevrier 2016, 71 ont ete inclus (33 femmes, âge median 65 ans [22–91 ans]). Soixante-huit pour cent des patients ont recu du pembrolizumab (2 mg/kg/3 semaines), 32 % du nivolumab (3 mg/kg/2 semaines). Trente-six pour cent etaient naifs de traitement. Trente-neuf pour cent des melanomes etaient des SSM et 30 % etaient mutes BRAF V600. Quarante-deux (59 %) des patients avaient un IMC > 25 kg/m 2 et 10 (14 %) combinaient une sarcopenie et un IMC > 25. Onze patients (15 %) ont presente une toxicite severe precoce : 1 pneumonie, 1 nephrite, 1 polymyosite, 2 hepatites, 1 uveite, 3 cytopenies et 2 polyarthrites. Tous les patients ont ete traites par corticotherapie. Il n’y a pas eu de deces toxique. Soixante-douze pour cent de ces toxicites sont survenues apres la 1 re ou la 2 e perfusion. L’anti-PD1 a ete definitivement arrete chez 9 patients et repris chez 2. Ces effets secondaires graves sont survenus plus souvent chez les sarcopeniques avec un IMC > 25 kg/m 2 (40 % [ n = 4]) que chez les autres patients (11 % [ n = 7]), p = 0,04. Les patients ayant presente une toxicite severe avaient un taux de reponse objective de 40 % soit comparable au reste de la population dans cette etude. La sarcopenie n’etait pas predictive d’une meilleure reponse aux anti-PD1. Discussion La sarcopenie est un facteur de risque de toxicite demontre pour de nombreux anticancereux. La survenue precoce des effets secondaires dans cette etude renforce l’hypothese d’une surexposition. Une etude prospective avec des dosages sanguins des anti-PD1 est en cours pour confirmer ces resultats. Conclusion Les patients sarcopeniques avec un IMC > 25 kg/m 2 ont presente, dans cette etude, significativement plus de toxicite severe precoce sous anti-PD1, suggerant une surexposition. Une attention particuliere doit leur etre portee.
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- 2016
12. Une histoire naturelle lente est associée à un meilleur taux de réponse aux anti-PD1 dans le mélanome
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Nathalie Franck, Nicolas Dupin, Benoit Blanchet, Johan Chanal, K. Leroy, Selim Aractingi, V. Heidelberger, J. Arrondeau, J. Alexandre, Nora Kramkimel, O. Huillard, J. Mullaert, P. Boudou-Rouquette, and François Goldwasser
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Dermatology - Abstract
Introduction Le taux de reponse objective aux anti-PD1 est de 40 % dans le melanome. Les facteurs predictifs de reponse sont encore mal connus. Nous avons etudie l’association entre la rapidite d’evolution de la maladie et le type de dissemination (lymphatique ou hematogene) et la reponse aux anti-PD1. Materiel et methodes Les dossiers des patients de dermatologie de l’hopital Cochin ayant recu des anti-PD1 pour un melanome metastatique ont ete revus retrospectivement. Etaient etudies : l’âge, le sexe, le type de melanome primitif, le statut BRAF, les traitements anterieurs, la reponse objective (RO) (reponse complete ou partielle selon les criteres RECIST 1.1), le type de dissemination (lymphatique defini comme l’existence de metastases ganglionnaires exclusives ou la survenue d’une metastase ganglionnaire avant celle d’une metastase viscerale et hematogene le reste). Les patients avec un stade N2c (metastases en transit isolees) ont ete exclus. Nous avons egalement etudie le temps de passage ganglionnaire defini comme le delai entre 1 e metastase ganglionnaire et 1 e metastase viscerale et le delai de traitement defini comme le temps entre le diagnostic du melanome et l’initiation des anti-PD1. Les patients n’ayant recu qu’une perfusion d’anti-PD1 ont ete exclus. Resultats Sur les 79 patients traites par anti-PD1 entre aout 2014 et fevrier 2016, 65 ont ete inclus (31 femmes, âge median 65 ans [21–90 ans]). Le traitement etait toujours introduit pour progression de la maladie. Soixante treize pour cent des patients ont recu du pembrolizumab (2 mg/kg/3 semaines), 27 % du nivolumab (3 mg/kg/2 semaines). Trente-six pour cent des patients etaient naifs de traitement. Quarante-trois pour cent des melanomes etaient des SSM. Vingt-huit pour cent des melanomes etaient porteurs d’une mutation BRAF V600. Vingt-cinq pour cent des patients avaient des metastases cerebrales. Le taux de RO dans la cohorte etait de 42 %. La dissemination etait lymphatique chez 23 patients (37 %), hematogene chez 39 (63 %) et 3 stades N2c exclus. Il n’y avait pas d’association significative entre le type de dissemination et la reponse. Le temps de passage ganglionnaire moyen etait de 26 mois (2 a 132 mois). Un temps de passage ganglionnaire superieur a 4 ans etait associe a une meilleure reponse au traitement (0 % chez les non-repondeurs et 33 % chez les repondeurs, p = 0,03). Le delai de traitement moyen etait de 71 mois (2 a 409 mois) et etait statistiquement associe a la reponse : delai moyen de 99 mois chez les repondeurs et de 53 mois chez les non-repondeurs ( p = 0,01). Discussion L’evolutivite des melanomes est difficile a prendre en compte dans les essais et seule la LDH de debut de traitement est utilisee. Les valeurs elevees sont predictives de mauvaise reponse aux anti-PD1. Nous proposons avec le temps de passage ganglionnaire et le delai entre le diagnostic initial du melanome et l’introduction des anti-PD1 des mesures indirectes de l’evolutivite des melanomes. Conclusion Les melanomes d’evolution lente repondent mieux aux anti-PD1.
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- 2016
13. Slow natural history predicts higher response rate to nivolumab and pembrolizumab in advanced melanoma patients
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Johan Chanal, Selim Aractingi, V. Heidelberger, N. Franck, F. Goldwasser, P. Boudou Rouquette, Nicolas Dupin, Jérôme Alexandre, Benoit Blanchet, Olivier Huillard, Jennifer Arrondeau, Nora Kramkimel, and J. Mullaert
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0301 basic medicine ,Oncology ,Response rate (survey) ,medicine.medical_specialty ,business.industry ,Hematology ,Pembrolizumab ,Natural history ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Nivolumab ,business ,Advanced melanoma - Published
- 2016
14. Sarcopenia associated with a body mass index (BMI) > 25 kg/m2 predicts severe acute toxicity of nivolumab and pembrolizumab in melanoma patients
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Selim Aractingi, V. Heidelberger, Jérôme Alexandre, Nicolas Dupin, Benoit Blanchet, Jennifer Arrondeau, Johan Chanal, N. Franck, P. Boudou Rouquette, F. Goldwasser, Olivier Huillard, and Nora Kramkimel
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Oncology ,medicine.medical_specialty ,business.industry ,Melanoma ,Hematology ,Pembrolizumab ,medicine.disease ,Acute toxicity ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Sarcopenia ,Internal medicine ,medicine ,Nivolumab ,business ,Body mass index ,030217 neurology & neurosurgery - Published
- 2016
15. GALACTIC WINDS DRIVEN BY ISOTROPIC AND ANISOTROPIC COSMIC-RAY DIFFUSION IN DISK GALAXIES
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Springel, V. [Heidelberger Institut für Theoretische Studien, Schloss-Wolfsbrunnenweg 35, D-69118 Heidelberg (Germany)]
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- 2016
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16. Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée).
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Rousset P, Nardin C, Maubec E, Heidelberger V, Picard A, Troin L, Gerard E, Kramkimel N, Steff-Naud M, Quéreux G, Gaudy-Marqueste C, Lesage C, Mignard C, Jeudy G, Jouary T, Saint-Jean M, Baroudjian B, Archier E, Mortier L, Lebbe C, and Montaudié H
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- Humans, Male, Female, Aged, Retrospective Studies, Middle Aged, Aged, 80 and over, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Skin Neoplasms mortality, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, France, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors pharmacology, Antibodies, Monoclonal, Humanized, Quinolines therapeutic use, Quinolines adverse effects, Melanoma drug therapy, Melanoma pathology, Melanoma mortality, Phenylurea Compounds therapeutic use, Phenylurea Compounds adverse effects
- Abstract
Background: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population., Materials and Methods: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR)., Results: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred., Conclusion: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies., (© The Author(s) 2024. Published by Oxford University Press.)
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- 2024
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17. Neurological toxicities of targeted therapies in melanoma: a multicenter national observational study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).
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Hazard M, Duval F, Dutriaux C, Beylot-Barry M, Pham-Ledard A, Quereux G, Amini-Adle M, Heidelberger V, Aubin F, Saint-Jean M, Nardin C, Abed S, Leccia MT, Mansard S, Prey S, Khammari A, Dréno B, and Gérard E
- Subjects
- Humans, Antineoplastic Combined Chemotherapy Protocols, Melanoma drug therapy, Lung Neoplasms drug therapy, Skin Neoplasms drug therapy
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- 2024
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18. Duration of treatment with cemiplimab in advanced cutaneous squamous cell carcinoma in complete response: Real-life study.
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Khelef K, Maubec E, Jeudy G, Bonniaud B, Pham-Ledard A, Herms F, Aubin F, Beneton N, Dinulescu M, Jannic A, Duval-Modeste A, Archier E, Berthin C, Grange F, Arnault J, Heidelberger V, Moncourier M, Mansard S, Brunet-Possenti F, Triller R, Pracht M, Dumas M, Lauche O, Mortier L, Bedane C, and Dalac Rat S
- Subjects
- Humans, Antibodies, Monoclonal, Humanized therapeutic use, Duration of Therapy, Treatment Outcome, Time Factors, Carcinoma, Squamous Cell drug therapy, Skin Neoplasms drug therapy, Antineoplastic Agents therapeutic use
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- 2024
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19. Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).
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Nardin C, Hennemann A, Diallo K, Funck-Brentano E, Puzenat E, Heidelberger V, Jeudy G, Samimi M, Lesage C, Boussemart L, Peuvrel L, Rouanet J, Brunet-Possenti F, Gerard E, Seris A, Jouary T, Saint-Jean M, Puyraveau M, Saiag P, and Aubin F
- Abstract
Background: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature., Patients and Methods: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes., Results: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab ( n = 44, 52%), nivolumab ( n = 35, 41%), ipilimumab ( n = 2, 2%), or ipilimumab plus nivolumab ( n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge ( p = 0.035) and shorter PFS ( p = 0.016)., Conclusion: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.
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- 2023
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20. Lobular panniculitis and diffuse osteonecrosis occurring during anti-MEK and anti-BRAF combination therapy for metastatic melanoma.
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Tzoumpa S, Villette B, Tieng AC, Bejar C, Rousset L, Heidelberger V, Playe M, Desbene C, Khalifa B, N'Guessan-Koffi C, Braun T, Le Jeune S, Caux F, and Maubec E
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- 2023
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21. PD-1 blockade with pembrolizumab in classic or endemic Kaposi's sarcoma: a multicentre, single-arm, phase 2 study.
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Delyon J, Biard L, Renaud M, Resche-Rigon M, Le Goff J, Dalle S, Heidelberger V, Da Meda L, Toullec L, Carcelain G, Mourah S, Caillat-Zucman S, Allain V, Battistella M, and Lebbe C
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Programmed Cell Death 1 Receptor, Prospective Studies, Sarcoma, Kaposi drug therapy, Sarcoma, Kaposi etiology
- Abstract
Background: Although the treatment of iatrogenic and HIV-related Kaposi sarcoma is well defined and mostly based on restoring immune function, the treatment of classic and endemic Kaposi sarcoma is less well established. Chemotherapy or interferon α is used for patients with extensive cutaneous or visceral Kaposi sarcoma, but tolerance might be poor and long-term remission is rare. We aimed to evaluate the activity of pembrolizumab in classic and endemic Kaposi sarcoma with cutaneous extension requiring systemic treatment., Methods: We did a multicentre, single-arm, proof-of-concept, phase 2 trial in adults aged 18 years or older with histologically proven classic or endemic Kaposi's sarcoma with progressive cutaneous extension requiring systemic treatment and an Eastern Cooperative Oncology Group performance status of 0-1 in three hospitals in France. The patients were treated with 200 mg pembrolizumab intravenously every 3 weeks for 6 months (eight cycles) or until severe toxicity. The primary endpoint was the best overall response rate within the 6-month timeframe, defined by the occurrence of a complete response or partial response and assessed by an investigator using the modified AIDS Clinical Trial Group (ACTG) criteria. Three or more responses among a total 17 patients were needed for the primary endpoint to be met, using a Simon's two-stage optimal design assuming a 30% response rate as desirable. For this final study analysis, all patients were included following the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03469804, and is closed to new participants., Findings: 30 patients were screened for eligibility and 17 patients (eight [47%] with classic and nine [53%] with endemic Kaposi's sarcoma) were enrolled between July 2, 2018, and Dec 16, 2019. The median follow-up was 20·4 months (IQR 18·1-24·1). Two (12%) patients had a complete response, ten (59%) had a partial response, and five (29%) had stable disease as the best response within the 6-month treatment timeframe, with a best overall response rate of 71% (95% CI 44-90), meeting the predefined primary outcome (ie, exceeding a response rate of 30%). Treatment-related adverse events occurred in 13 (76%) of 17 patients, including two grade 3 adverse events (one [6%] acute cardiac decompensation and one [6%] granulomatous reaction). Treatment was prematurely discontinued in two (12%) patients due to grade 3 acute reversible cardiac decompensation and grade 2 pancreatitis, and one other patient had a grade 3 granulomatous reaction in mediastinal lymph nodes requiring steroids and methotrexate treatment. There were no serious adverse events or treatment-related deaths., Interpretation: In this prospective trial, which to our knowledge is the first to assess the role of PD-1 blockade in patients with classic and endemic Kaposi's sarcoma, pembrolizumab showed promising anti-tumour activity with an acceptable safety profile. If this result is supported by further studies, treatment with anti-PD-1 could be part of the therapeutic armamentarium for patients with classic and endemic Kaposi's sarcoma., Funding: MSD France., Competing Interests: Declarations of interests JD reports support for travel or accommodation from Pierre Fabre and Roche; research funding from Merck Sharpe and Dohme and Amgen; and honoraria from Bristol Myers Squibb. SD reports institutional research grants from and travel costs covered by Bristol Myers Squibb and Merck Sharpe and Dohme. VH reports support for attending meetings from Merck Sharpe and Dohme. SM reports a consulting role for and research funding from Novartis, Bristol Myers Squibb, Biocartis, and Roche. VA reports support for attending meetings from Bediagenomics. MB reports board member fees from Bristol Myers Squibb; travel expenses from Roche; research grants from Takeda; expert consultancy for Innate Pharma and Kyowa Kirin; and speaker board fees from Kyowa Kirin. CL reports research funding from Roche and Bristol Myers Squibb; consulting fees from Bristol Myers Squibb, Merck Sharpe and Dohme, Novartis, Amgen, Roche, Merck Serono, Sanofi, and Pierre Fabre; honoraria from Roche, Bristol Myers Squibb, Novartis, Amgen, Merck Sharpe and Dohme, Pierre Fabre, Pfizer, and Incyte; fees for speaker's bureau from Roche, Bristol Myers Squibb, Novartis, Amgen, and Merck Sharpe and Dohme; support for attending meetings from Bristol Myers Squibb, Merck Sharpe and Dohme, Novartis, Sanofi, and Pierre Fabre; and fees from Avantis Medical Systems. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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22. Treatment strategies and safety of rechallenge in the setting of immune checkpoint inhibitors-related myositis: a national multicentre study.
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Weill A, Delyon J, Descamps V, Deschamps L, Dinulescu M, Dupuy A, Célérier P, Nardin C, Aubin F, Le Corre Y, Heidelberger V, Maubec E, Malissen N, Longvert C, Machet L, Gounant V, Brosseau S, Bonniaud B, Jeudy G, Psimaras D, Doucet L, Lebbe C, Zalcman G, De Masson A, Baroudjian B, Leonard-Louis S, Hervier B, and Brunet-Possenti F
- Subjects
- Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Retreatment, Retrospective Studies, Treatment Outcome, Immune Checkpoint Inhibitors therapeutic use, Myositis drug therapy, Practice Guidelines as Topic
- Abstract
Objectives: The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyse the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICIs) rechallenge., Methods: We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analysed in both groups. The modalities and outcomes of ICI rechallenge were reviewed., Results: Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favourable evolution, including one irM-related death, and required heavy immunosuppression. ICIs were safely reintroduced in nine patients presenting a moderate (n = 6) or a severe (n = 3) irM., Conclusion: Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favour of a safe reintroduction of ICI following symptom resolution and creatin kinase (CK) normalization in moderate and severe forms of irM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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23. Cemiplimab for Locally Advanced and Metastatic Cutaneous Squamous-Cell Carcinomas: Real-Life Experience from the French CAREPI Study Group.
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Hober C, Fredeau L, Pham-Ledard A, Boubaya M, Herms F, Celerier P, Aubin F, Beneton N, Dinulescu M, Jannic A, Meyer N, Duval-Modeste AB, Cesaire L, Neidhardt ÈM, Archier É, Dréno B, Lesage C, Berthin C, Kramkimel N, Grange F, de Quatrebarbes J, Stoebner PE, Poulalhon N, Arnault JP, Abed S, Bonniaud B, Darras S, Heidelberger V, Devaux S, Moncourier M, Misery L, Mansard S, Etienne M, Brunet-Possenti F, Jacobzone C, Lesbazeilles R, Skowron F, Sanchez J, Catala S, Samimi M, Tazi Y, Spaeth D, Gaudy-Marqueste C, Collard O, Triller R, Pracht M, Dumas M, Peuvrel L, Combe P, Lauche O, Guillet P, Reguerre Y, Kupfer-Bessaguet I, Solub D, Schoeffler A, Bedane C, Quéreux G, Dalac S, Mortier L, and Maubec È
- Abstract
Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%; partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS < 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.
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- 2021
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24. Carpal Tunnel Syndrome: A New Adverse Effect of Immune Checkpoint Inhibitors, 11 Cases.
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Lechevalier D, Denis D, Le Corre Y, Heidelberger V, Brunet-Possenti F, Longvert C, Piot JM, Maillard H, and Beneton N
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- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Retrospective Studies, Carpal Tunnel Syndrome chemically induced, Immune Checkpoint Inhibitors adverse effects
- Abstract
This study aims at reporting 11 cases of carpal tunnel syndrome (CTS) occurring in patients on immunotherapy. The increasing use of immune checkpoint inhibitors in oncodermatology is associated with the appearance of immunologic adverse effects linked to nonspecific stimulation of the immune system. CTS has not been reported in this context. A retrospective multicenter review was performed on CTSs occurring on immunotherapy and confirmed with electroneuromyography. Data were collated from patients' files. Most of the time, CTS was severe, bilateral, with a motor deficit and confirmed axonal damage on electroneuromyography. In 4 cases, it was associated with rheumatological adverse effects (arthralgia/inflammatory synovitis). The most effective treatment appeared to be general corticosteroid therapy, even at low doses (<15 mg/d), or surgery. An imputability of the CTS of these patients to immunotherapy was considered due to the unusual intensity of the symptoms and the absence of other predisposing factors (diabetes and dysthyroidism well-controlled). Its combination with other immunologic adverse effects and the efficacy of general corticosteroid therapy suggests an immunologic origin. CTS is probably an immunologic adverse effect of immunotherapy. It is often severe or misleading in presentation and affects quality of life. The recognition of this adverse effect should make it possible to provide patients with appropriate care., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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25. Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma.
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Balakirouchenane D, Guégan S, Csajka C, Jouinot A, Heidelberger V, Puszkiel A, Zehou O, Khoudour N, Courlet P, Kramkimel N, Lheure C, Franck N, Huillard O, Arrondeau J, Vidal M, Goldwasser F, Maubec E, Dupin N, Aractingi S, Guidi M, and Blanchet B
- Abstract
Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances ( p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC
OHD /AUCDAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); p = 0.023 and 10.61 (2.34-48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); p = 0.032 and HR = 1.23 (1.35-10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUCOHD /AUCDAB deserves more investigation in a larger cohort of MM patients.- Published
- 2020
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26. Late onset of nivolumab-induced severe gastroduodenitis and cholangitis in a patient with stage IV melanoma.
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Cǎlugǎreanu A, Rompteaux P, Bohelay G, Goldfarb L, Barrau V, Cucherousset N, Heidelberger V, Nault JC, Ziol M, Caux F, and Maubec E
- Subjects
- Adult, Antineoplastic Agents, Immunological adverse effects, Cholangitis etiology, Disease Progression, Duodenitis etiology, Female, Gastritis etiology, Humans, Melanoma diagnosis, Neoplasm Metastasis, Neoplasm Staging, Nivolumab adverse effects, Positron-Emission Tomography, Remission Induction, Skin Neoplasms diagnosis, Antineoplastic Agents, Immunological therapeutic use, Cholangitis diagnosis, Drug-Related Side Effects and Adverse Reactions diagnosis, Duodenitis diagnosis, Gastritis diagnosis, Immunotherapy adverse effects, Melanoma drug therapy, Nivolumab therapeutic use, Skin Neoplasms drug therapy
- Abstract
Antiprogramed cell death-1 protein agents represent a therapeutic approach based on stimulating the host's immune response through blockade of immune checkpoints, inhibitory pathways that dampen the physiological peripheral T-cell immune response and are essential for maintaining self-tolerance. We describe the late onset of severe gastroduodenitis and cholangitis in a nivolumab-treated, metastatic melanoma patient in complete remission. Positron-emission tomography with computed tomography scans showed diffuse fluorodeoxyglucose (FDG) uptake in the stomach preceding upper digestive tract symptoms. Hence, positron-emission tomography with computed tomography might as well be a useful tool for early diagnosis of subclinical gastric toxicity as recently shown for colitis. Furthermore, physicians must be aware and remain vigilant to antiprogramed cell death-1 protein-related digestive toxicity that may appear very late during treatment.
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- 2019
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27. Clinical parameters associated with anti-programmed death-1 (PD-1) inhibitors-induced tumor response in melanoma patients.
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Heidelberger V, Goldwasser F, Kramkimel N, Jouinot A, Franck N, Arrondeau J, Guégan S, Mansuet-Lupo A, Alexandre J, Damotte D, Avril MF, Dupin N, and Aractingi S
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized administration & dosage, Brain Neoplasms drug therapy, Female, Follow-Up Studies, Humans, Lymphatic Metastasis, Male, Melanoma drug therapy, Middle Aged, Neoplasm Invasiveness, Neoplasm Recurrence, Local drug therapy, Nivolumab, Prognosis, Retrospective Studies, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms secondary, Melanoma pathology, Neoplasm Recurrence, Local pathology, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Background The identification of the melanoma patients sensitive to anti-PD-1 inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an urgent need. We hypothesized that the natural history of the disease might partly reflect the immune state of the patients. Methods We analyzed our cohort of melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our institution. Objective response was defined as a complete or partial response according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients, the overall response rate was 43%. Median time from diagnosis to anti-PD-1 initiation was longer among responders than non-responders (64 months vs. 35 months, p = 0.02). The response rate was 10% in patients starting anti-PD-1 within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status (PS) 0 was also associated with enhanced tumor response: 70% of responders were PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type BRAF status were significant predictors of progression free survival. Conclusion A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical features might reflect a potentially intact immune system of the host.
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- 2017
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28. Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients.
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Heidelberger V, Goldwasser F, Kramkimel N, Jouinot A, Huillard O, Boudou-Rouquette P, Chanal J, Arrondeau J, Franck N, Alexandre J, Blanchet B, Leroy K, Avril MF, Dupin N, and Aractingi S
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Female, Humans, Male, Middle Aged, Nivolumab, Retrospective Studies, Young Adult, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Melanoma drug therapy, Overweight drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Sarcopenia drug therapy
- Abstract
Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m
2 ) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m2 and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m2 . For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m2 ; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.- Published
- 2017
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29. Erratum to: Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients.
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Heidelberger V, Goldwasser F, Kramkimel N, Jouinot A, Huillard O, Boudou-Rouquette P, Chanal J, Arrondeau J, Franck N, Alexandre J, Blanchet B, Leroy K, Avril MF, Dupin N, and Aractingi S
- Published
- 2017
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30. Efficacy and Tolerance of Anti-Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases.
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Heidelberger V, Ingen-Housz-Oro S, Marquet A, Mahevas M, Bessis D, Bouillet L, Caux F, Chapelon-Abric C, Debarbieux S, Delaporte E, Duval-Modeste AB, Fain O, Joly P, Marchand-Adam S, Monfort JB, Noël N, Passeron T, Ruivard M, Sarrot-Reynauld F, Verrot D, Bouvry D, Fardet L, Chosidow O, Sève P, and Valeyre D
- Subjects
- Adolescent, Adult, Aged, Databases, Factual, Dermatologic Agents adverse effects, Dermatologic Agents pharmacology, Female, Follow-Up Studies, France, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents pharmacology, Immunosuppressive Agents therapeutic use, Infliximab adverse effects, Infliximab pharmacology, Infliximab therapeutic use, Male, Middle Aged, Recurrence, Sarcoidosis pathology, Skin Diseases pathology, Treatment Outcome, Young Adult, Dermatologic Agents therapeutic use, Sarcoidosis drug therapy, Skin Diseases drug therapy, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Importance: Evidence for the long-term efficacy and safety of anti-tumor necrosis factor α agents (anti-TNF) in treating cutaneous sarcoidosis is lacking., Objective: To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis in a large observational study., Design, Setting, and Participants: STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multicenter observational database that receives data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments. Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016. We extracted data for patients with skin involvement at anti-TNF initiation., Main Outcomes and Measures: Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop ≥2 points from baseline but >1 at last follow-up)., Results: Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93%). Most patients received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were women. The OCRR was 24% after 3 months, 46% after 6 months, and 79% after 12 months. Steroid sparing was significant. Treatment was discontinued because of adverse events in 11 patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate was 44% 18 months after discontinuation of treatment. Relapses during treatment occurred in 35% of cases, mostly during anti-TNF or concomitant treatment tapering., Conclusions and Relevance: Anti-TNF agents are effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered.
- Published
- 2017
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