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Scott R Plotkin - One of the best experts on this subject based on the ideXlab platform.

  • multicenter prospective phase ii and biomarker study of high dose bevacizumab as induction therapy in patients with Neurofibromatosis Type 2 and progressive vestibular schwannoma
    Journal of Clinical Oncology, 2019
    Co-Authors: Scott R Plotkin, Alona Muzikansky, D Duda, Jeffrey C Allen, Jaishri O Blakeley, Tena Rosser, Jian Campian, Wade D Clapp, Michael Fisher, James H Tonsgard
    Abstract:

    PURPOSEBevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with Neurofibromatosis Type 2 (NF2) and progressive vestibular schwannomas (...

  • health related quality of life of individuals with Neurofibromatosis Type 2 results from the nf2 natural history study
    Otology & Neurotology, 2016
    Co-Authors: Vanessa L Merker, William H Slattery, Amanda L Bergner, Anamaria Vranceanu, Alona Muzikansky, Scott R Plotkin
    Abstract:

    Objective:To explore health-related quality of life (HRQoL) reported by individuals with Neurofibromatosis Type 2 (NF2) and to assess for correlations between HRQoL and objective measures of disease manifestations.Study Design:Prospective observational study.Setting:Seven international NF2 centers.S

  • bevacizumab treatment for symptomatic spinal ependymomas in Neurofibromatosis Type 2
    Acta Neurologica Scandinavica, 2016
    Co-Authors: Said Farschtschi, Scott R Plotkin, Vanessa L Merker, Christian Hagel, David S Wolf, Martin U Schuhmann, Jashri Blakeley, Victor F Mautner
    Abstract:

    Background Neurofibromatosis Type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas, meningiomas, and spinal ependymomas. There have been anecdotal reports of radiographic response of spinal ependymomas in NF2 patients being treated for progressive vestibular schwannomas with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). Aims The aim of this study was to review the clinical effects of bevacizumab treatment for symptomatic, NF2-associated ependymomas Methods We conducted a retrospective review of all patients with NF2 treated with bevacizumab for symptomatic ependymoma at three NF2 specialty centers. Tumor size was evaluated by linear measurements; radiographic response was defined as >20% reduction in tumor size. We also performed immunohistochemical evaluation of NF2-associated symptomatic ependymomas from five patients, including two from this clinical series. Results Eight patients with NF2 and symptomatic ependymoma were treated with bevacizumab. All patients had subjective clinical improvement with bevacizumab, although only five of eight patients evaluated had radiographic response. All tumors expressed VEGF-R2. Four of five evaluated ependymomas expressed VEGF-R1; one without VEGF-R1 expression was from a patient who showed clinical but not radiographic response. Conclusions Treatment using bevacizumab improved symptoms related to NF2-associated ependymomas, often without concurrent radiographic response. This treatment effect may be related to VEGF-R1 expression in NF2-associated ependymoma.

  • Multiple synchronous sites of origin of vestibular schwannomas in Neurofibromatosis Type 2
    Journal of Medical Genetics, 2015
    Co-Authors: Stavros M. Stivaros, Anat O. Stemmer-rachamimov, Robert Alston, Jennifer O'malley, Martin G. Mccabe, Gillian A Whitfield, Scott R Plotkin, A Quesnel, Joseph B. Nadol, Simon R Freeman
    Abstract:

    BACKGROUND: Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenoType which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve. METHODS: High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve. RESULTS: Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN. DISCUSSION: This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease.

  • natural history of vestibular schwannoma growth and hearing decline in newly diagnosed Neurofibromatosis Type 2 patients
    Otology & Neurotology, 2014
    Co-Authors: Scott R Plotkin, Fred G Barker, Vanessa L Merker, Alona Muzikansky, William H Slattery
    Abstract:

    OBJECTIVE To determine the rate of growth in vestibular schwannomas and the rate of hearing decline in Neurofibromatosis Type 2 (NF2) patients not undergoing active treatment STUDY DESIGN Prospective study. SETTING Data were collected at 10 NF2 centers, including hospital-based, academic, and tertiary care centers. PATIENTS 120 NF2 patients with 200 vestibular schwannomas. OUTCOME MEASURES Hearing decline, defined as a decrease in word recognition score outside the 95% critical difference compared with baseline, and radiographic progression, defined as a 20% or greater increase in tumor volume compared with baseline. RESULTS During a total of 313.4 patient-years of follow-up, the rate of hearing decline was 5% at 1 year, 13% at 2 years, and 16% at 3 years; the rate of tumor progression was 31% at 1 year, 64% at 2 years, and 79% at 3 years. For this cohort, the median time to tumor progression (14 mo) was significantly shorter than the median time to hearing decline (62.0 mo). CONCLUSION These data provide potentially useful information for the design of clinical trials for NF2 vestibular schwannoma.

Gareth D Evans - One of the best experts on this subject based on the ideXlab platform.

  • the response of spinal cord ependymomas to bevacizumab in patients with Neurofibromatosis Type 2
    Journal of Neurosurgery, 2017
    Co-Authors: Katrina A Morris, Martin G. Mccabe, Gareth D Evans, Shazia K Afridi, Dorothy Halliday, Pieter Pretorius, Anke Hensiek, Mark Kellett, Allyson Parry
    Abstract:

    OBJECTIVE People with Neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment. METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11–53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (ra...

  • toxicity profile of bevacizumab in the uk Neurofibromatosis Type 2 cohort
    Journal of Neuro-oncology, 2017
    Co-Authors: Gareth D Evans, Rosalie E Ferner, Dorothy Halliday, Katrina A Morris, John F Golding, Claire Blesing, Karen Foweraker, Raj Jena, Catherine Mcbain
    Abstract:

    Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis Type 2(NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event(CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32female), median age 24.5 years (range 11-66years), were followed for a median of 32.7 months (range 12.0–60.2months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24%) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5%) had proteinuria. Of 36 patients followed for 36 months, 78% were free from hypertension and 86% were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be predictors of development of hypertension with dose of 7.5mg/kg three weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.

  • Neurofibromatosis Type 2 nf2 diagnosis and management
    Handbook of Clinical Neurology, 2013
    Co-Authors: S Lloyd, Gareth D Evans
    Abstract:

    Neurofibromatosis Type 2 (NF2) is an autosomal dominant inherited tumor predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. Affected individuals develop schwannomas typically involving both vestibular nerves leading to hearing loss and eventual deafness. Rehabilitation with brainstem implants and in some cases cochlear implants is improving this outcome. Schwannomas also occur on other cranial nerves, on spinal nerve roots and peripheral nerves, and intracutaneously as plaques. Cranial and spinal meningiomas and spinal ependymomas are other common tumors. Fifty to sixty percent of patients represent de novo mutations and as many as 33% of these are mosaic for the underlying disease causing mutation. Truncating mutations (nonsense, frameshift insertions/deletions) are the most frequent germline events and cause the most severe disease, whilst single and multiple exon deletions are common and are usually associated with milder NF2. Neurological deficits are a major feature of the condition and neurologists have a pivotal role in assigning symptoms to lesions and in managing neuropathies. NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy. Surgery remains the focus of current management although watchful waiting and occasionally radiation treatment have a role. We are seeing the advent of tailored drug therapies aimed at the genetic level and these are likely to provide huge improvements for this devastating, life-limiting condition.

  • clinical presentation immunohistochemistry and electron microscopy indicate Neurofibromatosis Type 2 associated gliomas to be spinal ependymomas
    Neuropathology, 2012
    Co-Authors: Christian Hagel, Scott R Plotkin, Anat Stemmerrachamimov, Gareth D Evans, Cordula Matthies, Martin U Schuhmann, Antje Bornemann, Christoph Nagel, Susan M Huson, Lan Kluwe
    Abstract:

    Neurofibromatosis Type 2 (NF2) is a hereditary tumor syndrome. The hallmark of NF2 is bilateral vestibular schwannoma. In addition, glioma is one of the diagnostic criteria of NF2. In this retrospective study the clinical presentation and histopathological features of 12 spinal gliomas from NF2 patients were assessed. Ten tumors were previously diagnosed as ependymomas and two as astrocytomas. However, upon re-evaluation both astrocytomas expressed epithelial membrane antigen in a dot-like fashion and in one case it was possible to perform electron microscopy revealing junctional complexes and cilia typical for ependymoma. The findings suggest that NF2-associated spinal gliomas are ependymomas. Based on the fact that NF2-associated gliomas are almost exclusively spinal and that no NF2 mutations have been found in sporadic cerebral gliomas, we suggest that "glioma" in the current diagnostic criteria for NF2 should be specified as "spinal ependymoma".

  • consensus recommendations for current treatments and accelerating clinical trials for patients with Neurofibromatosis Type 2
    American Journal of Medical Genetics Part A, 2012
    Co-Authors: Jaishri O Blakeley, Derald E. Brackmann, Oliver C Hanemann, Gareth D Evans, Rosalie E Ferner, Gordon J Harris, Ruihong Chen, Susan M Huson, John R Adler, Abraham Jacob
    Abstract:

    Neurofibromatosis Type 2 (NF2) is a tumor suppressor syndrome characterized by bilateral vestibular schwannomas (VS) which often result in deafness despite aggressive management. Meningiomas, ependymomas, and other cranial nerve and peripheral schwannomas are also commonly found in NF2 and collectively lead to major neurologic morbidity and mortality. Traditionally, the overall survival rate in patients with NF2 is estimated to be 38% at 20 years from diagnosis. Hence, there is a desperate need for new, effective therapies. Recent progress in understanding the molecular basis of NF2 related tumors has aided in the identification of potential therapeutic targets and emerging clinical therapies. In June 2010, representatives of the international NF2 research and clinical community convened under the leadership of Drs. D. Gareth Evans (University of Manchester) and Marco Giovannini (House Research Institute) to review the state of NF2 treatment and clinical trials. This manuscript summarizes the expert opinions about current treatments for NF2 associated tumors and recommendations for advancing therapies emerging from that meeting. The development of effective therapies for NF2 associated tumors has the potential for significant clinical advancement not only for patients with NF2 but for thousands of neuro-oncology patients afflicted with these tumors.

Michel Kalamarides - One of the best experts on this subject based on the ideXlab platform.

  • medical treatment in Neurofibromatosis Type 2 review of the literature and presentation of clinical reports
    Neurochirurgie, 2017
    Co-Authors: Stéphane Goutagny, Michel Kalamarides
    Abstract:

    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.

  • internal auditory canal decompression for hearing maintenance in Neurofibromatosis Type 2 patients
    Neurosurgery, 2016
    Co-Authors: Olivier Sterkers, Matthieu Peyre, Daniele Bernardeschi, Michael Collin, Mustapha Smail, Michel Kalamarides
    Abstract:

    BACKGROUND In Neurofibromatosis Type 2 (NF2), multiple therapeutic options are available to prevent bilateral hearing loss that significantly affects the quality of life of patients. OBJECTIVE To evaluate the morbidity and functional results of internal auditory canal (IAC) decompression in NF2 patients with an only hearing ear. METHODS Twenty-one NF2 patients operated on for IAC decompression in a 3-year period with a minimum follow-up of 1 year were included in this retrospective study. They presented unilateral deafness due to previous contralateral vestibular schwannoma removal in 16 patients or contralateral hearing loss due to the tumor in 5 patients. Hearing level was of class A (American Academy of Otolaryngology-Head and Neck Surgery classification) in 7 patients, B in 8 patients, C in 1 patient, and D in 5 patients. Pure-tone average and speech discrimination score evaluations were performed at 6 days, 1 year, and during the follow-up. Eight patients had postoperative chemotherapy. RESULTS No case of facial nerve palsy was observed. In the early postoperative period; all patients maintained the hearing class of the preoperative period. At 1-year follow-up, all but 3 patients maintained their hearing scores; at last follow-up (mean follow-up, 23 ± 8 months; range, 12-44 months), hearing classes remained stable with only 1 patient worsening from class B to C and 1 patient improving from class D to B. CONCLUSION Decompression of IAC seems to be a useful procedure for hearing maintenance in NF2 patients, with very low morbidity. Ideal timing and association with chemotherapy should be evaluated in the future. ABBREVIATIONS FN, facial nerveIAC, internal auditory canalNF2, Neurofibromatosis Type 2PTA, pure tone averageSDS, speech discrimination scoreVS, vestibular schwannoma.

  • phase ii study of mtorc1 inhibition by everolimus in Neurofibromatosis Type 2 patients with growing vestibular schwannomas
    Journal of Neuro-oncology, 2015
    Co-Authors: Stéphane Goutagny, Marco Giovannini, Olivier Sterkers, Daniele Bernardeschi, Beatrice Larroque, Eric Raymond, Marina Espositofarese, Stephanie Trunet, Christian Mawrin, Michel Kalamarides
    Abstract:

    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.

  • conservative management of bilateral vestibular schwannomas in Neurofibromatosis Type 2 patients hearing and tumor growth results
    Neurosurgery, 2013
    Co-Authors: Matthieu Peyre, Stéphane Goutagny, Olivier Sterkers, Alpha Bah, Daniele Bernardeschi, Beatrice Larroque, Michel Kalamarides
    Abstract:

    BACKGROUND As new treatment modalities develop for the management of vestibular schwannomas (VS) in patients with Neurofibromatosis Type 2, it remains crucial to ascertain the natural history of the disease. OBJECTIVE To determine the relationship between hearing and tumor growth in patients undergoing conservative VS management. METHODS Patients harboring bilateral VS with at least 1 year of radiological follow-up were selected. Conservative management was proposed based on the small tumor size and/or serviceable hearing at presentation. Tumor size was calculated by using the 2-component box model and reported as mean tumor diameter. Hearing was evaluated by using pure-tone average and the American Academy of Otololaryngologists and Head and Neck Surgery classification. RESULTS Forty-six patients harboring 92 VS were included. The mean clinical and radiological follow-up times were 6.0 and 4.2 years, respectively. The mean tumor diameter was 13 mm at presentation and 20 mm at the end of follow-up. Mean tumor growth rate was 1.8 mm/year. During follow-up, 17 patients (37%) underwent surgery for VS. Surgery-free rate for VS was 88% at 5 years. The number of patients with at least 1 serviceable ear was 39 (85%) at presentation and 34 (74%) at the end of follow-up, including 22 (66%) with binaural serviceable hearing maintained. There was no statistical correlation between tumor growth rate and preservation of serviceable hearing. Tumor growth rates and age at presentation were inversely correlated. CONCLUSION This study illustrates the high variability among Neurofibromatosis Type 2 patients regarding hearing status and VS growth rate and justifies the choice of initial conservative management in selected cases. ABBREVIATIONS : AAO-HNS, American Academy of Otololaryngologists and Head and Neck Surgery classificationMTD, mean tumor diameterNF2, Neurofibromatosis Type 2PTA, pure-tone averageSDS, speech discrimination scoreVS, vestibular schwannomas.

  • long term follow up of 287 meningiomas in Neurofibromatosis Type 2 patients clinical radiological and molecular features
    Neuro-oncology, 2012
    Co-Authors: Stéphane Goutagny, Alexis Bozorg Grayeli, Olivier Sterkers, Alpha Bah, Dominique Henin, Beatrice Parfait, Michel Kalamarides
    Abstract:

    Decision-making criteria for optimal management of meningiomas in Neurofibromatosis Type 2 (NF2) patients is hampered by lack of robust data, particularly long-term natural history. Seventy-four NF2 patients harboring 287 cranial meningiomas followed up for a mean period of 110.2 months were studied retrospectively. The median number of meningiomas per patient was 3. The mean maximum diameter of meningiomas at diagnosis was 14.3 mm, with a mean annual growth rate of 1.5 mm. Sixty-six percent of tumors showed no or minimal growth. In a subgroup of patients with 3D MRI, 7.3% of meningiomas (28% of patients) had a volumetric growth rate 20% or more per year. Twenty-five de novo meningiomas appeared during the follow-up (8.7%) and demonstrated a higher growth rate than other meningiomas (6.6 mm/year). Fifty-six meningiomas (23%) in 34 NF2 patients (45.9%) were operated on during the follow-up period. Among symptomatic resected meningiomas, grades II and III tumors were found in 29% and 6% of cases, respectively, with a remarkable intratumor histological heterogeneity. Single nucleotide polymorphism array analysis of 22 meningioma samples in 14 NF2 patients showed increasing chromosome instability with increasing grade, the most frequent losses being on 22q, 1p, 18q, and 6p. This study provides clues to improve tailored treatment of meningiomas: de novo and brain edema-associated meningiomas require active treatment. Future clinical trials in NF2 need to focus specifically on meningiomas as the primary endpoint and should include patients with meningiomas growing 20% or more per year in order to assess new treatments.

Mia Maccollin - One of the best experts on this subject based on the ideXlab platform.

  • spinal ependymomas in Neurofibromatosis Type 2 a retrospective analysis of 55 patients
    Journal of Neurosurgery, 2011
    Co-Authors: Scott R Plotkin, Mia Maccollin, Caroline C Odonnell, William T Curry, Catherine Bove, Fabio P Nunes
    Abstract:

    Object The aim of this paper was to define the clinical characteristics of spinal ependymomas associated with Neurofibromatosis Type 2 (NF2). Methods The authors retrospectively reviewed the clinical records of patients with NF2 who had imaging findings consistent with ependymomas and were seen at Massachusetts General Hospital between 1994 and 2007. Clinical characteristics of these patients were obtained from hospital records, imaging studies, surgical reports, and pathology reports. Mutational analysis of the NF2 gene was performed in 37 of 44 unrelated patients. Results Fifty-five patients met inclusion criteria for the study. The median age at diagnosis of NF2 was 21 years; the median time after diagnosis until identification of ependymomas was 5 years. Multiple ependymomas were present in 58% of patients. The most common site of involvement was the cervical cord or cervicomedullary junction (86% of imaging studies), followed by the thoracic and lumbar cords (62% and 8%, respectively). The majority o...

  • ocular pathologic findings of Neurofibromatosis Type 2
    Archives of Ophthalmology, 2007
    Co-Authors: Margaret Mclaughlin, Susan M Pepin, Mia Maccollin, Pitipol Choopong, Simmons Lessell
    Abstract:

    Objective To gain insight into the pathogenesis of Neurofibromatosis Type 2 (NF2) by investigating the ocular manifestations of this disease. Methods Using standard histologic techniques, immunohistochemistry, and electron microscopy, we described the ocular pathologic findings of a 34-year-old woman who died from complications of NF2. Results We identified 3 Types of NF2-associated lesions: juvenile posterior subcapsular cataracts, epiretinal membranes, and an intrascleral schwannoma. Conclusions Our analysis indicated that dysplastic lens cells accumulate just anterior to the posterior lens capsule in juvenile posterior subcapsular cataracts and that dysplastic Muller cells may be a major component of NF2-associated epiretinal membranes. Clinical Relevance Our findings suggest that a subset of glial cells with epithelial features (Schwann cells, ependymal cells, and Muller cells) may be particularly sensitive to loss of the NF2 gene. Understanding the molecular basis for this sensitivity may lead to novel strategies for treating NF2.

  • unilateral vestibular schwannoma with other Neurofibromatosis Type 2 related tumors clinical and molecular study of a unique phenoType
    Journal of Neurosurgery, 2006
    Co-Authors: Manish K Aghi, Fred G Barker, Victorfelix Mautner, Lan Kluwe, Micah T Webster, Lee B Jacoby, Robert G Ojemann, Mia Maccollin
    Abstract:

    Object Although the manifestations of Neurofibromatosis Type 2 (NF2) vary, the hallmark is bilateral vestibular schwannomas (VSs). The authors studied the clinical course and genetic basis of unilateral VSs associated with other NF2-related tumors. Methods Forty-four adults presenting with unilateral VSs and other NF2-related tumors were identified. A comprehensive review of patient records and cranial imaging was conducted. Molecular analysis of the NF2 locus was performed in available tumors and paired blood specimens. Patient age at symptomatic onset ranged from 11 to 63 years (mean 32 years). Twenty-two patients (50%) presented with eighth cranial nerve dysfunction. Twenty-six presented with multiple lesions. Thirty-eight harbored other intracranial tumors and 27 had spinal tumors, with most lesions situated ipsilateral to the VS. No patient had a relative with NF2, although two of 63 offspring had isolated NF2-related findings. A contralateral VS developed in four patients 3 to 46 years after the sym...

  • Type of mutation in the Neurofibromatosis Type 2 gene nf2 frequently determines severity of disease
    American Journal of Human Genetics, 1996
    Co-Authors: M H Ruttledge, Mia Maccollin, Anne Andermann, C M Phelan, J O Claudio, Feiyu Han, N Chretien, S Rangaratnam, P Short, Dilys M Parry
    Abstract:

    Abstract The gene predisposing to Neurofibromatosis Type 2 (NF2) on human chromosome 22 has revealed a wide variety of different mutations in NF2 individuals. These patients display a marked variability in clinical presentation, ranging from very severe disease with numerous tumors at a young age to a relatively mild condition much later in life. To investigate whether this phenotypic heterogeneity is determined by the Type of mutation in NF2, we have collected clinical information on 111 NF2 cases from 73 different families on whom we have performed mutation screening in this gene. Sixty-seven individuals (56.2%) from 41 of these kindreds revealed 36 different putative disease-causing mutations. These include 26 proposed protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), 6 splice-site mutations, 2 missense mutations, 1 base substitution in the 3' UTR of the NF2 cDNA, and a single 3-bp in-frame insertion. Seventeen of these mutations are novel, whereas the remaining 19 have been described previously in other NF2 individuals or sporadic tumors. When individuals harboring protein-truncating mutations are compared with cases with single codon alterations, a significant correlation (P < .001) with clinical outcome is observed. Twenty-four of 28 patients with mutations that cause premature truncation of the NF2 protein, schwannomin, present with severe phenoTypes. In contrast, all 16 cases from three families with mutations that affect only a single amino acid have mild NF2. These data provide conclusive evidence that a phenoType/genoType correlation exists for certain NF2 mutations.

Christopher L Moertel - One of the best experts on this subject based on the ideXlab platform.