At-Risk Phenotype of Neurofibromatose-1 Patients: A Multicentre Case-Control Study

<p>Abstract</p> <p>Objectives</p> <p>To assess associations between subcutaneous neurofibromas (SC-NFs) and internal neurofibromas in patients with neurofibromatosis type 1 (NF-1) and to determine whether the association between SC-NFs and peripheral neuropathy was ascribable to internal neurofibromas.</p> <p>Patients and methods</p> <p>Prospective multicentre case-control study. Between 2005 and 2008, 110 NF-1 adults having two or more SC-NFs were individually matched for age, sex and hospital with 110 controls who had no SC-NF. Patients underwent standardized MRI of the spinal cord, nerve roots and sciatic nerves and an electrophysiological study. Analyses used adjusted multinomial logistic regression (ORa) to estimate the risk of the presence of internal neurofibromas or peripheral neuropathies associated with patients presented 2 to 9 SC-NFs, at least 10 SC-NFs as compared to patients without any (referential category).</p> <p>Results</p> <p>Cases had a mean age of 41 (± 13) years; 85 (80%) had two to nine SC-NFs and 21 (19%) at least ten SC-NFs. SC-NFs were more strongly associated with internal neurofibromas in patients with ten or more SC-NFs than in patients with fewer NF-SCs (e.g., sciatic nerve, aOR = 29.1 [8.5 to 100] vs. 4.3 [2.1 to 9.0]). The association with SC-NFs was stronger for diffuse, intradural, and > 3 cm internal neurofibromas than with other internal neurofibromas. Axonal neuropathy with slowed conduction velocities (SCV) was more strongly associated with having at least ten SC-NFs (aOR = 29.9, 5.5 to 162.3) than with having fewer SC-NFs (aOR = 4.4, 0.9 to 22.0). Bivariate analyses showed that the association between axonal neuropathy with SCV and sciatic neurofibromas was mediated by the association between SC-NFs and sciatic neurofibromas.</p> <p>Conclusion</p> <p>The at-risk phenotype of NF-1 patients (i.e. NF-1 patients with SC-NFs) is ascribable to associations linking SC-NFs to internal neurofibromas at risk for malignant transformation and to axonal neuropathies with slowed conduction velocities. Axonal neuropathies with SCV are particularly common in patients with at least ten SC-NFs.</p> <p>Registration details</p> <p>ORPHA86301</p

End-User Modelling

National audienceno abstrac

Dégénérescence carcinomateuse des ulcères vasculaires de jambe (à propos de 78 cas - revue de la littérature )

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocPARIS-Bib. Serv.Santé Armées (751055204) / SudocSudocFranceF

Approche de métamodélisation pour la simulation et la vérification de modèle (application à l'ingénierie des procédés)

Nous proposons dans cette thèse une démarche permettant de décrire un DSML et les outils nécessaires à l'exécution, la vérification et la validation des modèles. La démarche que nous proposons offre une architecture générique de la syntaxe abstraite du DSML pour capturer les informations nécessaires à l'exécution d'un modèle et définir les propriétés temporelles qui doivent être vérifiées. Nous nous appuyons sur cette architecture pour expliciter la sémantique de référence et l'implanter. Plus particulièrement, nous étudions les moyens : - d'exprimer et de valider la définition d'une traduction vers un domaine formel dans le but de réutiliser des outils de model-checking. - de compléter la syntaxe abstraite par le comportement; et profiter d'outils génériques pour pouvoir simuler les modèles construits. Enfin, de manière à valider les différentes sémantiques implantées vis-à-vis de la sémantique de référence, nous proposons un cadre formel de métamodélisation.We propose in this thesis a specific taxonomy of the mechanisms to express a DSML execution semantics. Then, we replace these different mechanisms within a comprehensive approach to describe a DSML and the tools required for model execution, verification and validation. The proposed approach provides a rigorous and generic architecture for DSML abstract syntax to capture the information required for model execution. We rely on this generic architecture to explain the reference semantics and to implement it. More specifically, we are studying the ways : - to express and validate the definition of a translation into a formal domain in order to re-use model-checker. - to complete the abstract syntax with the definition of the behaviour and to take advantage of generic tools to simulate the built models. Finally, to validate the equivalence of the different semantics implemented according to the reference semantics, we also propose a formal metamodeling framework.TOULOUSE-ENSEEIHT (315552331) / SudocSudocFranceF

Schwannomatose : aspects cliniques, génétiques et thérapeutiques (à propos de 32 cas et revue de la littérature)

La schwannomatose est une sorte de neurofibromatose, de reconnaissance récente, caractérisée par la présence de schwannomes multiples sans autre stigmate de NF1 ou NF. Cette étude rétrospective propose de préciser les caractéristiques cliniques, génétiques et thérapeutique de la schwannomatose. Entre 1986 et 2009, 32 patients ont été pris en charge pour des schwannomes multiples sans atteinte vestibulaire. Les informations cliniques, les éléments histologiques et thérapeutiques ont été relevés de manière rétrospective et séquençage du gène INI1 a été pratiqué. Résultats 32 patients, 16 hommes et 16 femmes, ont été inclus. L'âge médian de début de la maladie était de 29 ans. L'apparition d'une tumeur et/ou la survenue d'une douleur étaient les symptômes inauguraux prédominants. La présence de tâches café au lait était notée dans 41% des cas. La localisation prédominante des schwannomes était sous-cutanée. L'atteinte vestibulaire était constamment absente. La proportion de formes familiales était de 15,6%. Le gène INI1 était non muté chez les 12 patients sporadiques analysés, alors que 4 individus d'une même famille étaient porteurs d'une substitution A>T sur l'intron 4. La schwannomatose se présente comme une identité distincte des neurofibromatoses de type 1 et 2. En effet, la révélation de la maladie est plus tardive, l'élément cutané caractéristique est le schwannome sous-cutané même si l'on note une surfréquence de tâches café au lait. Surtout, l'atteinte vestibulaire est constamment absente, mais une surveillance attentive est nécessaire avant 30 ans afin de ne pas méconnaître une NF2 latente. L'association à des ménigiomes est possible, mais dans une moindre mesure que dans la NF2. Le risque de dégénérescence maligne des schwannomes est non négligeable. Les formes familiales sont minoritaires, une anomalie du gène INI1 étant alors mise en évidence dans 68% des cas. La schwannomatose représente la troisième forme de neurofibromatose, caractérisée par la survenue de schwannomes multiples sans atteint vestibulaire. Son pronostic est favorable, la seule complication grave étant le risque de survenue d'un schwannosarcome.ST ETIENNE-BU Médecine (422182102) / SudocSudocFranceF

Hospitalisation costs of metastatic melanoma in France; the MELISSA study (MELanoma In hoSpital coSts Assessment)

Abstract Background Management of metastatic melanoma is changing rapidly following the introduction of innovative effective therapies, with consequences for the allocation of healthcare resources. The objective of this study was to assess hospitalisation costs of metastatic melanoma in France from 2011 to 2013 from the perspective of the government payer. Methods The population studied corresponded to all adults with metastatic melanoma hospitalised in France between 1st January 2011 and 31st December 2013 who required chemotherapy, immunotherapy or radiotherapy due to tumour progression and unresectable Stage III or Stage IV melanoma. Metastatic melanoma was identified by ICD-10 codes documented in the hospital patient discharge records. For each patient, hospital stays were stratified into a pre- or post- progression health state using proxy variables for the RECIST criteria. All healthcare expenditure documented in the French national hospital claims system database and incurred between the index hospitalisation (or change of progression state) and the end of follow-up were analysed. For the principal analysis, valuation of healthcare resource consumption was performed using official national hospitalisation tariffs. Any expensive therapy administered during the stay was documented from a linked database of expensive drugs (FICHCOMP). Results Seventy-eight thousand seven hundred fifty hospital stays by 10,337 patients with metastatic melanoma were identified over the three-year study period. Annual per capita costs of hospitalisation were € 5046 in the pre-progression stage and € 19,006 in the post-progression stage. Hospitalisations attributed to adverse drug reactions to chemotherapy or immunotherapy were observed in 27% of patients. Annual per capita costs of these hospitalisations related to adverse drug reactions were € 3762 in the pre-progression stage and € 5523 in the post-progression stage. Conclusions Hospitalisation costs related to metastatic melanoma rise substantially as the disease progresses. Treatment strategies which slow down disease progression would be expected to reduce costs of hospitalisation for metastatic melanoma, although they may also entail significant acquisition costs. This will entail organisational changes of resource allocation for the treatment of metastatic melanoma in hospitals

Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966.

International audienceNeurofibromatosis type 1 is a relatively common genetic disease, with a prevalence ranging between 1/3000 and 1/6000 people worldwide. The disease affects multiple systems with cutaneous, neurologic, and orthopedic as major manifestations which lead to significant morbidity or mortality. Indeed, NF1 patients are at an increased risk of malignancy and have a life expectancy about 10-15 years shorter than the general population. The mainstay of management of NF1 is a patient-centered longitudinal care with age-specific monitoring of clinical manifestations, aiming at the early recognition and symptomatic treatment of complications as they occur. Protocole national de diagnostic et de soins (PNDS) are mandatory French clinical practice guidelines for rare diseases required by the French national plan for rare diseases. Their purpose is to provide health care professionals with guidance regarding the optimal diagnostic and therapeutic management of patients affected with a rare disease; and thus, harmonizing their management nationwide. PNDS are usually developed through a critical literature review and a multidisciplinary expert consensus. The purpose of this article is to present the French guidelines on NF1, making them even more available to the international medical community. We further dwelled on the emerging new evidence that might have therapeutic potential or a strong impact on NF1 management in the coming feature. Given the complexity of the disease, the management of children and adults with NF1 entails the full complement healthcare providers and communication among the various specialties

Utility of 18F-FDG PET with a Semi-Quantitative Index in the Detection of Sarcomatous Transformation in Patients with Neurofibromatosis Type 1

International audienceBackground: Malignant peripheral nerve sheath tumors (MPNSTs) are a serious complications of neurofibromatosis type 1 associated with poor prognosis and deeper lesions can be difficult to diagnose. 18-FDG PET improves the detection of malignancies. However, the criteria for malignancy, notably the SUVmax threshold, are not standardized. Therefore, the aim of the study was to evaluate a semi-quantitative index for the reproducible detection of MPNST with FDG PET.Methods: It is a multicenter retrospective study conducted between 2000 to 2012. All patients with NF1 referred for suspected MPNST underwent PET. Since SUVmax was not available until 2004 in our centers, we had to settle for the semi-quantitative method used at that time, the uptake ratio between the tumor and the normal liver (T/L ratio) with 1.5 as the cut-off for malignancy. When dedicated PET with SUVmax became available, the semi-quantitative analysis of PET images remained, along with SUVmax.Results: 113 patients with 145 tumors were included. PET assessment revealed 65 suspected lesions with T/L >1.5 and among these, 40 were MPNSTs. 80 tumors were classified as non-suspicious, and 79 were benign. The 1.5 T/L cut-off had a negative predictive value (NPV) of 98,8% and a positive predictive value of 61,5%. The positive likelihood ratio (LR) was 4,059, the negative LR was 0,032 with 97% sensitivity and 76% specificity.Conclusions: This study, which is among the largest published, confirms the utility of PET for detecting NF1-associated MPNSTs. A semi-quantitative index, the T/L ratio with a cut-off of 1.5, allowed sensitive and specific differentiation of malignant from benign tumors better than SUVmax. When T/L was 1.5, there was a strong suspicion of malignancy. This semi-quantitative analytical method is as simple as SUVmax, but is more sensitive, more reproducible and non-user-dependen

Absence of efficacy of everolimus in neurofibromatosis 1-related plexiform neurofibromas: results from a phase 2a trial

International audienc