Dermatologic manifestations in paediatric neurofibromatosis type 2: a cross sectional descriptive multicentric study.

BACKGROUND: Neurofibromatosis type 2 (NF2) is characterized by bilateral vestibular schwannoma (VS) more often in adults but a severe paediatric form with multiple neurological tumours is also described. In this population, a early diagnosis is important to prevent the onset of neurological complications but is difficult, particularly without a familial history. Cutaneous manifestations, which may precede VS or neurological tumours by several years, may contribute to an early diagnosis, but specific studies are lacking. The objective of this study was to characterize cutaneous manifestations of NF2 in a paediatric population. RESULTS: This observational, descriptive and multicentric study was conducted from April 2019 to April 2020 in seven academic French hospitals. We included patients ≤ 18 years old who fulfilled the Manchester diagnostic criteria or had a pathogenic mutation identified in the NF2 gene. All patients underwent a dermatological examination guided by a standardized questionnaire. 21 children were included, of whom 20 had at least one skin tumour (mean number 5 ± 4.6 [range 0-15]), which led to a diagnosis in four cases. In the other 17 cases, the diagnosis of NF2 was based on neurosensory complications (n = 10), family screening (n = 4) or ocular signs (n = 3). Before the NF2 diagnosis, 15 children had at least one "undiagnosed" cutaneous tumour that did not lead to a specific management. Patients' dermatological examination also revealed < 6 non specific café au lait macules (n = 15), hypopigmented macules (n = 12) with more than 3 lesions in 4 cases, and purple reticulated macules of the trunk (n = 4). CONCLUSION: Dermatological lesions are frequent and early in children with NF2 but rarely lead to the diagnosis. Cutaneous schwannomas are the most frequent but are often underdiagnosed. Café au lait macules are frequent, but atypical and mostly in small numbers. Multiple hypopigmented macules seem suggestive although inconsistent. The sensitivity of reticulated capillary malformation-like lesions remains to be assessed by further studies.

[Meningiomas: A review of current knowledge]. / Les méningiomes : mise au point sur les connaissances actuelles.

Meningiomas 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.

Neurofibromatosis type 2: Hearing preservation and rehabilitation.

The main manifestation of neurofibromatosis type 2 (NF2) is the development of bilateral vestibular schwannomas (VS). Consequently, one of the most severe functional sequelae is bilateral sensorineural hearing loss, caused by spontaneous tumor progression and/or treatment-related damage (surgery or radiosurgery). Preserving or restoring hearing is still challenging in NF2 no matter the strategy applied to each individual based on the natural history of VS. In this review, the different strategies for hearing preservation or rehabilitation are discussed and illustrated by several cases. A decisional algorithm for NF2 patients with VS is proposed that takes into consideration the tumor size and hearing level.

Psychological follow-up care of neurofibromatosis type 2 patients and their relatives.

Neurofibromatosis type 2 (NF2) confronts patients and their relatives with the dual issue of a progressive disease and disability. Deafness creates a brutal rupture in the patients' course of life, and other disabilities often follow in addition, that further deteriorates their quality of life. Hearing rehabilitation, via a cochlear implant and auditory brainstem implant, attempts to reduce the feeling of isolation and suffering due to communication impairment. A NF2-specific quality of life questionnaire not only helps to evaluate the impact of the disease but it is also useful therapy proposals (treatment, auditory implants). This may contribute to improve the quality of care for patients and their families. Within the multidisciplinary NF2 team, the psychologist offers constant listening of patients, and their suffering at each stage of the disease, that takes into account the life context in which the disease occurs, thus playing a major role in the patient care offered.

Medical treatment in neurofibromatosis type 2. Review of the literature and presentation of clinical reports.

The understanding of the molecular pathways underlying tumor development in neurofibromatosis type 2 (NF2) is increasing. Thus, repositioning drugs, drug therapies that are already clinically available for various cancers, appear potentially promising for NF2 patients. Based on preclinical data from in vitro or animal models, five different treatments have been proposed for selected NF2 cases. Evaluation of bevacizumab, a monoclonal antibody against VEGF has mainly been reported in retrospective studies; it has been reported to induce hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas (VS). In our experience with 16 patients, bevacizumab is associated with an increase of median time to tumor progression of VS from 5.6 months before bevacizumab onset, to more than 29.3 months. The need for intravenous injections and long term adverse events (hypertension, proteinuria, hemorrhage) are the main drawbacks. Lapatinib seemed promising in a single phase II trial with a volumetric response observed in 4/17 patients and a hearing response in 4/13, but is not currently used in clinical practice. Erlotinib has not been associated with radiographic or hearing responses in a phase II trial. Everolimus has been evaluated in 3 phase II trials. Everolimus did not induced tumor shrinkage, but seems to be able to increase time to tumor progression in selected cases. Currently, bevacizumab is the only drug proposed to selected NF2 patients.

Molecular genetics of meningiomas: Building the roadmap towards personalized therapy.

New advances have recently been made in the field of molecular genetics and mouse modeling of meningiomas, opening new perspectives for future treatments. Recent genome-wide genotyping and exome sequencing studies have confirmed the pivotal role of NF2 in meningioma tumorigenesis, concerning roughly half of the tumors, and unraveled new mutations in non-NF2 meningiomas concerning AKT1, SMO, KLF4 and TRAF7. The molecular mechanisms underlying tumorigenesis of high histological grades have been progressively deciphered with the recent discovery of TERT promoter mutations in progressing tumors. A better understanding of the genetics and clinical behavior of high-grade meningiomas is mandatory in order to better design future clinical trials. New genetically engineered mouse models of benign and histologically aggressive meningioma represent a substantial resource for the establishment of relevant pre-clinical trials. By studying the mechanisms underlying these new tumorigenesis pathways and the corresponding mouse models, we should be able to offer personalized chemotherapy to patients with surgery- and radiation-refractory meningiomas in the near future.

Neurofibromatosis type 2 French cohort analysis using a comprehensive NF2 molecular diagnostic strategy.

OBJECTIVE: Neurofibromatosis type 2 (NF2) affects about one in 25,000 to 40,000 people. Most NF2 patients have private loss-of-function mutations scattered along the NF2 gene. Here, we present our NF2 investigation strategy. MATERIAL AND METHODS: We report a comprehensive NF2 mutation analysis of 221 NF2 French patients: 134 unrelated typical NF2 patients fulfilling the Manchester criteria and 87 unrelated patients presenting symptoms that partially fulfilled the Manchester criteria. RESULTS: A NF2 mutation was identified in 56 of the 221 patients, giving a global mutation detection rate of 25%. This rate reached 37% (49/134) for typical NF2 patients fulfilling the Manchester criteria and only 8% (7/87) for patients presenting symptoms suggestive of NF2. Six of these seven patients were under 25 of age. Our approach showed that 77% of NF2 identified variants were detected by coding exons sequencing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements (23% of NF2 identified variants corresponding to complete deletion or partial deletion/duplication of NF2). CONCLUSION: High mutation detection rate can be achieved if well phenotyped NF2 patients are studied with multiple complementary and optimized techniques. NF2 somatic mosaicism detection was improved by frozen tumor samples molecular analysis.

Natural history of vestibular schwannomas and hearing loss in NF2 patients.

CONTEXT AND OBJECTIVE: Bilateral vestibular schwannomas are the hallmark of neurofibromatosis 2 (NF2), occurring in 95% of patients. These tumors are associated with significant morbidity due to hearing loss, tinnitus, imbalance and facial weakness. As radiosurgery and chemotherapy have been recently introduced in the treatment armamentarium in addition to surgery, a thorough evaluation of vestibular schwannoma natural history is mandatory to determine the role and timing of each treatment modality. METHODS: An exhaustive review of the literature was performed using the PubMed database concerning the natural history of tumor growth and hearing loss in NF2 patients with vestibular schwannomas. RESULTS: Although some aspects of vestibular schwannoma natural history remain uncertain (pattern of tumor growth, mean tumor growth rate), factors influencing growth such as age at presentation and paracrine factors are well established. Studies focusing on the natural history of hearing have highlighted different patterns of hearing loss and the possible role of intralabyrinthine tumors. The polyclonality of vestibular schwannomas in NF2 was recently unveiled, giving a new perspective to their growth mechanisms. CONCLUSION: An uniform evaluation of tumor growth using volumetric evaluation and hearing with standard classifications will ensure the use of common endpoints and should improve the quality of clinical trials as well as foster comparison among studies while ensuring more consistency in decision-making.

Spinal ependymomas in NF2: a surgical disease?

The management of spinal cord ependymomas in Neurofibromatosis Type 2 (NF2) has traditionally been conservative, in contrast to the management of sporadic cases; the assumption being that, in the context of NF2, they did not cause morbidity. With modern management and improved outcome of other NF2 tumours, this assumption, and therefore the lack of role for surgery, has been questioned. To compare the outcome of conservative treatment of spinal ependymomas in NF2 with surgical intervention in selected patients. Retrospective review at two NF2 centers, Manchester, UK and Paris/Lille, France. In Manchester patients were managed conservatively. In France surgery was a treatment option. Inclusion in the study was based on tumor length of greater than 1.5 cm. The primary parameter assessed was acquired neurological deficit measured by the Modified McCormick Outcome Score. 24 patients from Manchester and 46 patients from France were analyzed. From Manchester, 27% of these patients deteriorated during the course of follow-up. This effectively represents the natural history of ependymomas in NF2. Of the surgical cases, 23% deteriorated postoperatively, but only 2/18 (11%) of those operated on in the NF2 specialist centers. Comparison of the two specialist centers Manchester/France showed a significantly improved outcome (P = 0.012, χ2 test) in the actively surgical center. Spinal ependymomas produce morbidity. Surgery can prevent or improve this in selected cases but can itself can produce morbidity. Surgery should be considered in growing/symptomatic ependymomas, particularly in the absence of overwhelming tumor load where bevacizumab is the preferred option.

Progestin-associated shift of meningioma mutational landscape.

Background: Meningiomas are the most common primary tumor of the central nervous system. The relationship between meningioma and progestins is frequently mentioned but has not been elucidated. Patients and methods: We identified 40 female patients operated for a meningioma after long-term progestin therapy and performed targeted next generation sequencing to decipher the mutational landscape of hormone-related meningiomas. A published cohort of 530 meningiomas in women was used as a reference population. Results: Compared with the control population of meningiomas in women, progestin-associated meningiomas were more frequently multiple meningiomas [19/40 (48%) versus 25/530 (5%), P < 10-12] and located at the skull base [46/72 (64%) versus 241/481 (50%), P = 0.03]. We found a higher frequency of PIK3CA mutations [14/40 (35%) versus 18/530 (3%), P < 10-8] and TRAF7 mutations [16/40 (40%) versus 140/530 (26%), P < 0.001] and a lower frequency of NF2-related tumors compared with the control population of meningiomas [3/40 (7.5%) versus 169/530 (32%), P < 0.001]. Conclusion: This shift in mutational landscape indicates the vulnerability of certain meningeal cells and mutations to hormone-induced tumorigenesis. While the relationship between PIK3CA mutation frequency and hormone-related cancers such as breast and endometrial cancer is well-known, this hormonally induced mutational shift is a unique feature in molecular oncology.

Surgical treatment of sporadic vestibular schwannoma in a series of 1006 patients.

The management of sporadic vestibular schwannoma (VS) has evolved in the last decades. The aim of this study was to analyse the evolution in surgical outcomes of VSs operated by a neurotological team between 1990 and 2006 by different approaches. A monocentric retrospective review of medical charts of 1006 patients was performed. In order to assess eventual changes and progress, the 17-years period was divided in three periods, each one comprehending 268 VS (1990-1996), 299 VS (1997-2001), and 439 VS (2002-2006). Mean follow-up was 5.9 ± 2.4 years. Overall, complete VS removal was achieved in 99.4% of cases. Mortality rate was 0.3%, meningitis and CSF leaks were observed in 1.2 % and 9 % of the cases, respectively. CSF leakage decreased from 11.6% to 7.1% between the first and last period (p < 0.01) as well as revision surgery from 3.4 % to 0.9 % (p < 0.05). Facial nerve was anatomically preserved in 97.7% of cases. At one year, a good facial nerve function was observed in 85.1% of patients (grade I and II of House-Brackmann grading scale), which ranged between the first and last period from 78.4% to 87.6% (p <0.05). At one year, hearing preservation was obtained in 61.6% of patients, which increased from the first period to the last one from 50.9% to 69.0% (p < 0.05) (class A+B+C from the AAO-HNS classification). Useful hearing (class A+B) was observed in 33.5% of cases overall, with 21.8% and 42% in the first and last period, respectively (p < 0.01). Surgical outcomes of sporadic vestibular schwannoma have improved concerning facial nerve function outcomes, hearing preservation and cerebrospinal fluid (CSF) leaks, mainly due to the neuro-otological team's experience. Functional results after complete microsurgical removal of large VS depend on experience gained on small VS removal.

[A report of three cases and review of auditory brainstem implants in children]. / Implantation auditive du tronc cérébral chez l'enfant. À propos de trois cas.

AIM OF THE STUDY: To present three pediatric cases of auditory brainstem implantation (ABI) and review literature data concerning this topic. PATIENTS: The first two children had a neurofibromatosis type II with bilateral sensorineural deafness; in both cases, the implant was inserted during the surgical removal of a vestibular schwannoma; the third patient had profound deafness due to bilateral cochlear nerve insufficiency associated with inner ear malformation. RESULTS: Two postoperative complications were observed: patient 1 had a persistent fever which required the replacement of the fat graft used to seal the translabyrinthine approach; patient 3 had a CSF leakage requiring additional surgery and lumbar external drainage. In our three patients, the numbers of active electrodes were 6/22 (Cochlear ABI 24M ABI), 11/12 (Medel Opus II ABI) and 11/12 (implant Medel), respectively. Due to additional major surgical procedures and to disappointing functional results of the ABI, patient 1 stopped wearing her implant 18 months after implantation. Nine months after surgery, patient 2 achieved open-set speech recognition and was very satisfied with the implant. Six months after implantation, patient 3 (cochlear nerve deficiency), who was 3.5 years-old at the time, clearly reacted to some environmental sounds but was not yet able to achieve speech recognition. CONCLUSIONS: ABI has now entered the list of treatments that can be proposed in pediatric profound sensorineural deafness. Its major risks of complications are CSF leakage and non-auditory side effects. Its outcomes are worse and less predictable than cochlear implants. Thus, its indications must remain restricted to cases meeting the following conditions: absence of alternative option to restore hearing, patients and parents high level of motivation and realistic expectations.

Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation.

Aggressive variants of meningiomas (WHO grade II and III) represent up to 30% of those tumors that are among the most common primary central nervous system tumors in adults. Currently, there is no effective treatment for grade-II and -III meningiomas, the main treatment remaining surgical excision. Genetic studies have highlighted two main events associated with meningioma progression: an increase of chromosomal instability in tumors with NF2 inactivation and homozygous deletions or point mutations of the CDKN2AB locus. In this study we demonstrated that in mice, in addition to bi-allelic Nf2 inactivation, homozygous and heterozygous Adenovirus Cre-mediated Cdkn2ab deletions lead to increased meningioma frequency (72% and 50%, respectively) with a shorter latency (3.5 and 7.8 months, respectively) compared with control cohorts and induce grade II/III meningioma progression with an incidence of 34% and 28%, respectively. Moreover, Cdkn2ab inactivation in arachnoidal cells was associated with decreased senescence compared with Nf2(-/-) and wild-type arachnoidal cells in vitro. We have established three mouse meningioma cell lines and generated a syngenic orthotopic meningioma mouse model with 50-100% grade-II/III meningiomas after reimplantation. Comparative genomic hybridization of four meningiomas from Cdkn2ab homozygous mice and three cell cultures revealed the absence of unbalanced chromosomal segments in tumors and several chromosome imbalances in cell cultures. In addition, we were able to detect meningiomas by using bioluminescence and to evaluate tumor vascular permeability by dynamic magnetic resonance imaging. These results show that Nf2 and Cdkn2ab cooperate to promote meningioma progression in mice. The short latency of tumor development and the ability to derive grade II/III meningioma cell cultures are key aspects of this model to promote its use in pre-clinical drug testing.

Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes.

Meningiomas are among the most common primary central nervous system tumours in adults. Studies focused on the molecular basis for meningioma development are hampered by a lack of information with regard to the cell of origin for these brain tumours. Herein, we identify a prostaglandin D synthase-positive meningeal precursor as the cell of origin for murine meningioma, and show that neurofibromatosis type 2 (Nf2) inactivation in prostaglandin D2 synthase (PGDS) (+) primordial meningeal cells, before the formation of the three meningeal layers, accounts for the heterogeneity of meningioma histological subtypes. Using a unique PGDSCre strain, we define a critical embryonic and early postnatal developmental window in which biallelic Nf2 inactivation in PGDS (+) progenitor cells results in meningioma formation. Moreover, we identify differentially expressed markers that characterize the two major histological meningioma subtypes both in human and mouse tumours. Collectively, these findings establish the cell of origin for these common brain tumours as well as a susceptible developmental period in which signature genetic mutations culminate in meningioma formation.

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas.

The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cell-to-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and platelet-derived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.

[Creation of self-assessment tools for on-line continuing medical education. Modelization of a training session]. / Création d'outils d'autoévaluation pour une formation médicale continue en ligne. Modélisation à propos d'une formation.

BACKGROUND: For several years, the sessions of continuing medical education organized within the framework of the Société française de neurochirurgie have been recorded on the "campus de neurochirurgie" website, accessible in a form called in "videostreaming" which structures the training session. PURPOSE: Using modern educational methods, how can we transform the scientific productions of our meetings into effective tools for on-line continuing education? METHODS: The article describes the experience gained while creating self-assessment tools starting from the teaching material transmitted by the person in charge of a continuing medical education session, selected and an example for demonstration. RESULTS: We present the various written tools for self-assessment: multiple-choice test and script concordance test (SC). These SC were based partly on a clinical case with various test formats: units of diagnosis, investigation and therapeutics. In connection with the example chosen, we propose a model for constructing on-line continuing medical education sessions, which could be used by persons in charge of such training sessions in neurosurgery and in other specialties. CONCLUSIONS: With the availability of on-line self-assessment tests round-tables videostreaming, this teaching method can be used to fulfil mandatory continuing medical education requirements.