Mutation de KIT et de PDGFRA dans le mélanome (série de 107 patients)

Introduction : Les mélanomes sont des tumeurs diverses sur le plan moléculaire. Il a été démontré une corrélation entre les différents sous-types anatomo-cliniques de mélanome, les altérations moléculaires somatiques et l association à une exposition solaire ponctuelle ou chronique. En effet, les mutations de BRAF sont présentes dans 50 à 60% des SSM, alors qu elles sont plus rares dans les mélanomes de types acro-lentigineux, muqueux et les Dubreuilh où en revanche les mutations de KIT sont parfois retrouvées.Méthode : Nous avons recherché les mutations de KIT et de PDGFRA sur les tumeurs de 107 patients atteint d un mélanome : 45 acro-lentigineux, 42 muqueux dont 23 de la sphère ORL, 11 vaginaux et 8 anaux, 6 Dubreuilh et 14 sans primitif retrouvé. Résultats :Nous avons mis en évidence quatre mutations de KIT (4,8%) sur les 84 résultats contributifs et deux mutations du même exon de PDGFRA (1,3%) sur les 80 contributifs. Trois mutations sur des mélanomes acraux (KITL576P, KITY553C et PDGFRAP567S/G569R) et deux mutations sur des mélanomes vaginaux(KITL576P et KITD820V).Sur trois patients traités par thérapie ciblée anti-KIT, nous avons eu une réponse partielle pendant cinq mois sous dasatinib, une stabilité de deux mois sous imatinib et un patient dont les métastases cérébrales ont rapidement progressé sous imatinib.Conclusion : Notre travail confirme l existence de mutations de KIT et de PDGFRA dans certains sous-types de mélanomes. Même si nous avons trouvé un pourcentage de mutations plus faible que dans des publications antérieures, notre série est particulière car nous avons identifié trois nouvelles mutations dans le mélanome : KITY553C, KITD820V et PDGFRAP567S/G569R.Aujourd hui, même si nous disposons encore de peu de données sur l efficacité des inhibiteurs de KIT dans le mélanome, plusieurs cas cliniques anecdotiques et résultats préliminaires d essais de phases précoces sont très encourageants, faisant espérer que le succès thérapeutique de ces thérapies dans les GIST puisse se transposer dans les mélanomes avec anomalie moléculaire de KIT ou PDGFRA.Introduction: They are many different types of melanomas from the molecular point of view. Correlations between the anatomic site the somatic molecular events and the type of sun exposure has been demonstrated. Indeed, BRAF mutations are prevalent in 50-60% of the SSM, and much less frequent in the acral and mucosal types as well as in the melanoma occurring on chronically sun-exposed skin, where KIT mutations are sometimes found. Method: We studied the frequency of KIT and PDGFRA mutations in 107 primary acral (45), mucosal (42) as well as lentigo malignant melanomas (6) and melanomas with unknown primary (14).Results: KIT mutation were found in 4 melanomas (4.8%) of the 84 cases in which amplifiable DNA was obtained and PDGFRA mutation in one melanoma (1.3%) of the 80 cases. There were three mutations in acral melanomas (KITL576P, KITY553C and PDGFRAP567S/G569R) and two mutations in vaginal melanoma (KITL576P and KITD820V). Three patients have been treated with targeted anti-kit agents. One patient achieved partial response lasting five months with dasatinib, one patient achieved stable disease for two months with imatinib and one patient died from rapidly progressing CNS metastases under imatinib therapy.Conclusion:Our work confirm the existence of KIT and PDGFRA mutations in certain melanoma subtypes and our series is unique because we have identified three new somatic melanoma mutations: KITY553C, KITD820V and PDGFRAP567S/G569R.To date, only anecdotal reports of melanoma patients with KIT mutations and early data from phase II trials are available, but these data are so encouraging that the hope that therapeutic successes in GIST may translate to melanomas with KIT or PDGFRA alterations seems justified.PARIS12-CRETEIL BU Médecine (940282101) / SudocSudocFranceF

Impact of dermatologic adverse events induced by targeted therapies on quality of life

Background: Investigations about the impact of dermatologic adverse events on quality of life in the context of targeted therapies are quite recent and results vary in some dimensions. This article aims to summarize the existing data and to clarify needs in terms of clinical management and future research. Methods: A literature review was done with Pubmed, Medline, Scopus and PsycInfo databases and it combined the empirical studies published in English and in French over the past ten years. Results and conclusions: Dermatologic adverse events globally have a low to moderate impact on quality of life, mainly in the physical and emotional domains. Reasons for inter-individual variations in adjustment and long-term impact are still not well known. Making quality of life assessments systematic, making early referrals of patients to dermatology consultations and giving more attention to individual experience were identified as measures that could help prevent deterioration in quality of life.SCOPUS: re.jinfo:eu-repo/semantics/publishe

The Frontal Sharp Transient in Newborns: An Endogenous Neurobiomarker Concomitant to the Physiological and Critical Transitional Period around Delivery?

International audienceThe frontal sharp transient (FST) consists of transient electrical activity recorded around the transitional period from the in to ex utero environment. Although its positive predictive value is assumed, nothing is known about its functionality or origin. The objectives were (i) to define its characteristics and (ii) to develop functional hypothesis. The 128-channels high-resolution electroencephalograms of 20 healthy newborns (37.1-41.6~weeks) were studied. The morphological and time-frequency characteristics of 418 FSTs were analyzed. The source localization of the FSTs was obtained using a finite element head model (5 layers and fontanels) and various source localization methods (distributed and dipolar). The characteristics (duration, slopes, and amplitude) and the localization of FSTs were not modulated by the huge developmental neuronal processes that occur during the very last period of gestation. The sources were located beneath the ventral median part of the frontal lobe around the interhemispheric fissure, suggesting that the olfactory bulbs and orbitofrontal cortex, essential in olfaction and the mother-infant attachment relationship, are likely candidates for the generation of FSTs. FSTs may contribute to the implementation of the functionalities of brain structures involved in the higher-order processing necessary for survival ahead of delivery, with a genetic fingerprint

Automatic patient-level recognition of four Plasmodium species on thin blood smear by a real-time detection transformer (RT-DETR) object detection algorithm: a proof-of-concept and evaluation

International audienceMalaria remains a global health problem, with 247 million cases and 619,000 deaths in 2021. Diagnosis of Plasmodium species is important for administering the appropriate treatment. The gold-standard diagnosis for accurate species identification remains the thin blood smear. Nevertheless, this method is time-consuming and requires highly skilled and trained microscopists. To overcome these issues, new diagnostic tools based on deep learning are emerging. This study aimed to evaluate the performances of a real-time detection transformer (RT-DETR) object detection algorithm to discriminate Plasmodium species on thin blood smear images. The algorithm was trained and validated on a data set consisting in 24,720 images from 475 thin blood smears corresponding to 2,002,597 labels. Performances were calculated with a test data set of 4,508 images from 170 smears corresponding to 358,825 labels coming from six French university hospitals. At the patient level, the RT-DETR algorithm exhibited an overall accuracy of 79.4% (135/170) with a recall of 74% (40/54) and 81.9% (95/116) for negative and positive smears, respectively. Among Plasmodium-positive smears, the global accuracy was 82.7% (91/110) with a recall of 90% (38/42), 81.8% (18/22), and 76.1% (35/46) for P. falciparum, P. malariae, and P. ovale/vivax, respectively. The RT-DETR model achieved a World Health Organization (WHO) competence level 2 for species identification. Besides, the RT-DETR algorithm may be run in real-time on low-cost devices such as a smartphone and could be suitable for deployment in low-resource setting areas lacking microscopy experts.IMPORTANCEMalaria remains a global health problem, with 247 million cases and 619,000 deaths in 2021. Diagnosis of Plasmodium species is important for administering the appropriate treatment. The gold-standard diagnosis for accurate species identification remains the thin blood smear. Nevertheless, this method is time-consuming and requires highly skilled and trained microscopists. To overcome these issues, new diagnostic tools based on deep learning are emerging. This study aimed to evaluate the performances of a real-time detection transformer (RT-DETR) object detection algorithm to discriminate Plasmodium species on thin blood smear images. Performances were calculated with a test data set of 4,508 images from 170 smears coming from six French university hospitals. The RT-DETR model achieved a World Health Organization (WHO) competence level 2 for species identification. Besides, the RT-DETR algorithm may be run in real-time on low-cost devices and could be suitable for deployment in low-resource setting areas

An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells

International audienceCancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Here we show that a subpopulation of BRAFV600 mutant melanoma cells that tolerates exposure to BRAF and MEK inhibitors undergoes a reversible remodelling of mRNA translation that evolves in parallel with drug sensitivity. Although this process is associated with a global reduction in protein synthesis, a subset of mRNAs undergoes an increased efficiency in translation. Inhibiting the eIF4A RNA helicase, a component of the eIF4F translation initiation complex, abrogates this selectively increased translation and is lethal to persister cells. Translation remodelling in persister cells coincides with an increased N6-methyladenosine modification in the 5'-untranslated region of some highly translated mRNAs. Combination of eIF4A inhibitor with BRAF and MEK inhibitors effectively inhibits the emergence of persister cells and may represent a new therapeutic strategy to prevent acquired drug resistance