Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas

Neurofibromatosis type 2 (NF2) is a genetic disorder with bilateral vestibular schwannomas (VS) as the most frequent manifestation. Merlin, the NF2 tumor suppressor, was identified as a negative regulator of mammalian target of rapamycin complex 1. Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of NF2-schwannomas. We conducted a prospective single-institution open-label phase II study to evaluate the effects of everolimus in ten NF2 patients with progressive VS. Drug activity was monitored every 3 months. Everolimus was administered orally for 12 months and, if the decrease in tumor volume was >20 % from baseline, treatment was continued for 12 additional months. Other patients stopped when completed 12 months of everolimus but were allowed to resume treatment when VS volume was >20 % during 1 year follow-up. Nine patients were evaluable. Safety was evaluated using CTCAE 3.0 criteria. After 12 months of everolimus, no reduction in volume ≥20 % was observed. Four patients had progressive disease, and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment. In these patients, tumor growth resumed within 3-6 months after treatment discontinuation. Everolimus was then reintroduced and VS decreased by a median 6.8 % at 24 months. Time to tumor progression increased threefold from 4.2 months before treatment to > 12 months. Hearing was stable under treatment. The safety of everolimus was manageable. Although the primary endpoint was not reached, further studies are required to confirm the potential for stabilization of everolimus

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS

Modélisation de la tumorigenèse méningée chez la souris récapitulant les altérations génétiques des méningiomes humains

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Identification des altérations génétiques impliquées dans la tumorigénèse méningée chez l'homme

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Apport de l'imagerie par résonance magnétique et de la ponction neurochirurgicale dans le diagnostic et la prise en charge des abcès cérébraux de l'adulte

Le diagnostic positif d abcès cérébral est souvent difficile et le traitement antibiotique reste le plus souvent empirique, expliquant en partie une morbimortalité élevée. L épidémiologie est marquée par l augmentation du nombre de patients immunodéprimés et la diminution des abcès secondaires à des infections ORL ou dentaires. L'obtention d'un diagnostic microbiologique rapide est donc primordial. Les nouvelles stratégies diagnostiques et thérapeutiques récemment développées: les séquences de diffusion en IRM, permettant de différencier abcès et tumeur, et la ponction neurochirurgicale à visée diagnostique pourraient permettre d'atteindre cet objectif. Nous avons évalué ces nouvelles stratégies de prise en charge dans une cohorte rétrospective de 21 patients. L IRM de diffusion a permis d affirmer le diagnostic d abcès chez 11/11 malades et leur prise en charge plus rapide. La ponction a permis le diagnostic microbiologique dans 19/19 cas, même chez les 5 malades déjà sous antibiotiques. Plus de 50% des malades, dont tous les immunodéprimés et la moitié des malades ayant une infection dentaire, étaient infectés avec des germes autres que ceux ciblés par l antibiothérapie empirique. Aucun sous-groupe de patients ne semble donc pouvoir être traité empiriquement au risque d échecs. Devant les changements épidémiologiques récents, un diagnostic positif rapide et le diagnostic microbiologique sont indispensables à la prise en charge des abcès cérébraux à pyogènes. La réalisation d une IRM de diffusion suivie d une ponction diagnostique systématique est une stratégie fiable et rentable pour obtenir un diagnostic bactériologique avant toute antibiothérapie.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Mouse Models in Meningioma Research: A Systematic Review

International audienceMeningiomas are the most frequent primitive central nervous system tumors found in adults. Mouse models of cancer have been instrumental in understanding disease mechanisms and establishing preclinical drug testing. Various mouse models of meningioma have been developed over time, evolving in light of new discoveries in our comprehension of meningioma biology and with improvements in genetic engineering techniques. We reviewed all mouse models of meningioma described in the literature, including xenograft models (orthotopic or heterotopic) with human cell lines or patient derived tumors, and genetically engineered mouse models (GEMMs). Xenograft models provided useful tools for preclinical testing of a huge range of innovative drugs and therapeutic options, which are summarized in this review. GEMMs offer the possibility of mimicking human meningiomas at the histological, anatomical, and genetic level and have been invaluable in enabling tumorigenesis mechanisms, including initiation and progression, to be dissected. Currently, researchers have a range of different mouse models that can be used depending on the scientific question to be answered

How to radiologically identify a spontaneous regression of sporadic vestibular schwannoma?

International audienceBACKGROUND: The natural history of sporadic vestibular schwannoma is unpredictable, with tumors growing, non-growing and even showing spontaneous regression in some rare cases.OBJECTIVE: This retrospective study aims to describe the radiologic signs characterizing and identifying the shrinking vestibular schwannoma.METHODS: Involution was considered to have occurred if tumor size had decreased by 2 mm or more on its largest diameter. All magnetic resonance imaging scans were reviewed for tumor size, internal auditory meatus size, and tumor characteristics. Volumetric measurements were performed on the first and last scan. Audiometric data were collected at the first and last visit.RESULTS: Fourteen patients with a confirmed spontaneous regression were included, with a mean follow-up of 5 ± 2.6 years. The mean shrinkage rate was 0.9 ± 0.59 mm/year on 2D measurements, and 0.2 ± 0.17 cm3/year on volumetric measurements, with a relative shrinkage of 40 ± 16.9%. Two remarkable radiologic features were observed: First, a festooned aspect, defined by multiple curves in the tumor outline, noticed in 12 cases (86%); second, the appearance of cerebrospinal fluid filling the internal auditory meatus, associated with an enlargement of the internal auditory meatus compared to the contralateral side, and observed in 10 out of 13 cases with internal auditory meatus invasion (77%). Those two aspects were associated in 64% of cases.CONCLUSION: These two newly reported radiologic features could help neurosurgeons, oto-neurosurgeons and neuroradiologists to identify a spontaneous vestibular schwannoma involution at first visit. This could allow any treatment to be postponed, monitoring to be more widely spaced, and patients to be reassured

Les méningiomes : mise au point sur les connaissances actuelles

International audienceMeningiomas are the most frequent among intracranial tumors, and represent more than 30% of primitive central nervous system neoplasms. Arising from the meninges, they are generally benign lesions and can be treated by either radio-clinical follow-up or surgical resection with excellent outcome. However, more than 20% of meningiomas harbor atypical or malignant features and represent challenges for both prognostic evaluation and therapeutic strategy. The discovery of the genetic and epigenetic landscapes of meningiomas enabled the identification of new prognostic markers and potential therapeutic targets for refractory meningiomas. This review summarizes current epidemiology, histological and molecular characteristics, diagnosis and treatments for meningiomas, and highlights the close relationship between the development of meningiomas and hormonal intake, as illustrated by recent recommendations of the "Agence Nationale de Securité du Medicament", the French national drug safety agency.Les méningiomes sont les tumeurs intracrâniennes les plus fréquentes, représentant plus d’un tiers des tumeurs primitives du système nerveux central. Développés au dépens des méninges, ils sont généralement histologiquement bénins et bénéficient d’un suivi radioclinique par IRM ou d’un traitement par exérèse chirurgicale avec de bons résultats. Cependant, 20 % d’entre eux se présentent sous la forme de tumeurs plus agressives représentant un défi à la fois pour l’évaluation du pronostic et pour le choix des traitements. Les avancées dans la caractérisation moléculaire et génétique des méningiomes ont permis d’appréhender de nouveaux facteurs pronostiques et de découvrir de potentielles cibles pour des traitements ciblés dans les formes réfractaires à la chirurgie et à la radiothérapie. Cette mise au point synthétise les connaissances épidémiologiques, moléculaires et histologiques, et les modalités de diagnostic et de traitement des méningiomes, ainsi que le lien entre les progestatifs et les méningiomes à la lumière des recommandations récentes de l’Agence nationale de sécurité du médicament