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1.
Dev Cell ; 49(3): 425-443.e9, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31063758

RESUMO

Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome neurofibromatosis type 2 (NF2), as well as various sporadic cancers including kidney cancer. Multiple Merlin/NF2 effector pathways including the Hippo-YAP/TAZ pathway have been identified. However, the molecular mechanisms underpinning the growth and survival of NF2-mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors. Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and reactive oxygen species (ROS) buildup, resulting in oxidative-stress-induced cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPAC-dependent activation of RAF-MEK-ERK signaling as a resistance mechanism to YAP/TAZ inhibition. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms a positive correlation of a YAP/TAZ signature with glycolysis and inverse correlations with oxidative phosphorylation and lysosomal gene expression, supporting the clinical relevance of our findings.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Neurofibromina 2/deficiência , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Glicólise , Xenoenxertos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos SCID , Neurofibromatose 2/genética , Neurofibromatose 2/metabolismo , Neurofibromatose 2/patologia , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Fosforilação Oxidativa , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética
2.
Brain Nerve ; 71(4): 368-372, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-30988223

RESUMO

A large number of genetic neurological disorders are accompanied by dermatological manifestations. Among them, neurofibromatosis 1 (NF1, Recklinghausen disease) is characterized by pigmented macules, such as café au lait macules, freckling and numerous neurofibromas. Neurological complications are also seen in NF1 and it is important to conduct appropriate imaging studies for a correct diagnosis. In this report, I will discuss the differential diagnosis of dermatological manifestations of NF1 compared to those of other neurological disorders, such as Legius syndrome or NF2.


Assuntos
Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Manchas Café com Leite/patologia , Diagnóstico Diferencial , Humanos , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/patologia
3.
J Cancer Res Clin Oncol ; 145(2): 523-533, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30603902

RESUMO

PURPOSE: There is no targeted drug therapy for NF2 patients, and surgery or radiosurgery is not always effective. Therefore, the exploration of new therapeutic pathways is urgently needed. METHODS: We analyzed the expression of cytokines in the serum of NF2 patients and determined the percentage of HLA-DR-CD33+CD11b+ cells in blood and NF2-associated schwannomas. Furthermore, we analyzed the role of HLA-DR-CD33+CD11b+ cells in inhibiting T-cell proliferation, cytokine production, and transforming growth factor expression. RESULTS: NF2 patients are in an immunosuppressed state with elevated IL-10 and TGF-ß expression in plasma and the lymphocytes from NF2 patients secrete less IFN-γ and CD3+ T cells proliferate slower than normal healthy donors. HLA-DR-CD33+CD11b+ cells frequency significantly increased in the PBMCs and infiltrated in the tumor, these cells express higher iNOS, NOX2 and TGF-ß, and induce TGF-ß secretion to inhibit CD8+ T-cell proliferation, and induce T-cell transformation to a CD4+CD25+Foxp3+ regulatory T cells phenotype. NF2-associated schwannoma cells induced monocytes transformation into an HLA-DR-CD33+CD11b+ phenotype, and surgical removal of the tumor reduced the percentage of these cells. CONCLUSIONS: HLA-DR-CD33+CD11b+ cells may represent a population of MDSCs in NF2 patients. Dissecting the mechanisms behind these suppressive mechanisms will be helpful for the design of effective immunotherapeutic protocols and likely provide a new effective treatment for NF2 patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Imunossupressores , Células Supressoras Mieloides/imunologia , Neurofibromatose 2/imunologia , Linfócitos T/imunologia , Adulto , Estudos de Casos e Controles , Proliferação de Células , Citocinas/metabolismo , Feminino , Seguimentos , Humanos , Ativação Linfocitária , Masculino , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Neurofibromatose 2/metabolismo , Neurofibromatose 2/patologia , Prognóstico , Linfócitos T/metabolismo , Linfócitos T/patologia
4.
Nat Protoc ; 14(2): 541-555, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30617350

RESUMO

Neurofibromatosis type II (NF2) is a disease that lacks effective therapies. NF2 is characterized by bilateral vestibular schwannomas (VSs) that cause progressive and debilitating hearing loss, leading to social isolation and increased rates of depression. A major limitation in NF2 basic and translational research is the lack of animal models that allow the full spectrum of research into the biology and molecular mechanisms of NF2 tumor progression, as well as the effects on neurological function. In this protocol, we describe how to inject schwannoma cells into the mouse brain cerebellopontine angle (CPA) region. We also describe how to apply state-of-the-art intravital imaging and hearing assessment techniques to study tumor growth and hearing loss. In addition, ataxia, angiogenesis, and tumor-stroma interaction assays can be applied, and the model can be used to test the efficacy of novel therapeutic approaches. By studying the disease from every angle, this model offers the potential to unravel the basic biological underpinnings of NF2 and to develop novel therapeutics to control this devastating disease. Our protocol can be adapted to study other diseases within the CPA, including meningiomas, lipomas, vascular malformations, hemangiomas, epidermoid cysts, cerebellar astrocytomas, and metastatic lesions. The entire surgical procedure takes ~45 min per mouse and allows for subsequent longitudinal imaging, as well as neurological and hearing assessment, for up to 2 months.


Assuntos
Ângulo Cerebelopontino/patologia , Diagnóstico por Imagem/métodos , Modelos Animais de Doenças , Perda Auditiva/patologia , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Animais , Linhagem Celular Tumoral , Ângulo Cerebelopontino/metabolismo , Ângulo Cerebelopontino/cirurgia , Expressão Gênica , Genes Reporter , Audição/fisiologia , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Testes Auditivos , Humanos , Injeções Intraventriculares , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Knockout , Neurofibromatose 2/genética , Neurofibromatose 2/fisiopatologia , Neurofibromina 2/deficiência , Neurofibromina 2/genética , Neuroma Acústico/genética , Neuroma Acústico/fisiopatologia , Técnicas Estereotáxicas
5.
Hum Mol Genet ; 28(4): 572-583, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30335132

RESUMO

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.


Assuntos
Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Comunicação Autócrina/genética , Carcinogênese/genética , Caspase 1/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Humanos , Camundongos , Terapia de Alvo Molecular , NF-kappa B/genética , Neurilemoma/complicações , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/complicações , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas c-met/genética , Células de Schwann , Transdução de Sinais/genética
6.
Otolaryngol Head Neck Surg ; 160(3): 526-532, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30373466

RESUMO

OBJECTIVE: Bevacizumab for hearing preservation in patients with neurofibromatosis type 2 (NF2) is an emerging practice. We set out to characterize the effectiveness and toxicity of bevacizumab in our patient group. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Seventeen consecutive patients with NF2 received bevacizumab treatment for vestibular schwannomas, including 2 patients treated to maintain cochlear implant performance. Volumetric analysis of serial magnetic resonance imaging scans was used to evaluate radiographic response, and hearing response was evaluated with serial audiograms. Patient-reported outcomes were also assessed, including subjective hearing improvement, changes in tinnitus, vertigo, headaches, ear pain, and improvement in ability to communicate via telephone. RESULTS: A positive radiographic response occurred in 8 of 17 (47%) patients and the median tumor volume change was a tumor decrease of 19%. A positive hearing response was recorded in 5 of 9 (56%) patients. Two patients had a word recognition score improvement over 40%. There was an approximately 40% improvement in patient-reported outcomes. Primary toxicities included hypertension, proteinuria, dysgeusia, and amenorrhea. CONCLUSION: Bevacizumab treatment was followed by hearing improvement in 56% of patients, while decreased tumor volume was noted in 47%. These outcomes agree favorably with prior reported series. There were significant improvements in patient-reported outcomes that have not been described previously.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Perda Auditiva/prevenção & controle , Neurofibromatose 2/complicações , Neuroma Acústico/complicações , Adolescente , Adulto , Estudos de Coortes , Feminino , Perda Auditiva/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/patologia , Neurofibromatose 2/terapia , Neuroma Acústico/patologia , Neuroma Acústico/terapia , Medidas de Resultados Relatados pelo Paciente , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
7.
Pediatr Blood Cancer ; 66(2): e27520, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30408304

RESUMO

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue sarcoma with an unfavorable prognosis and limited therapeutic options. MPNSTs can be sporadic, but are often associated with neurofibromatosis (NF) 1 and usually arise from preexisting neurofibromas. MPNSTs in patients with NF2 have been reported in only exceedingly rare cases, and the mechanisms underlying transformation into an MPNST have not been fully elucidated. Here, we describe the clinicopathological and genomic features of a peripheral nerve sheath tumor (PNST), with a primary diagnosis of a neurofibroma, as it transforms into a high-grade MPNST in the context of NF2.


Assuntos
Neoplasias da Bainha Neural/patologia , Neurofibromatose 2/patologia , Sarcoma/patologia , Transformação Celular Neoplásica/patologia , Criança , Humanos , Masculino , Neoplasias da Bainha Neural/genética , Neurofibromatose 2/genética , Sarcoma/genética
8.
J Neurol Sci ; 392: 130-136, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30056201

RESUMO

Meningioangiomatosis (MA) is a rare, complex and heterogeneous disease of meningovascular proliferation that is found primarily in the leptomeninges and cerebral cortex but can involve subcortical white matter and other brain regions such as the cerebellum and deep gray matter. MA may be found in pediatric or adult populations and may be sporadic or neurofibromatosis-associated. The presentation of MA is highly variable: it may be associated with other neurological diseases; clinically presents on a spectrum from asymptomatic to seizures or focal deficits; radiologically presents with multifocal, tumor-like, or cystic lesions, or may appear normal; and pathologically may have cellular or vascular predominance. In this article, we review the various manifestations of MA including neurofibromatosis-associated MA, multifocal MA, cystic MA, and MA associated with meningioma, other brain tumors, focal cortical dysplasia, neurodegenerative changes, and post-radiation changes. The treatment of MA is also reviewed. While the pathogenesis of MA remains elusive, we discuss the proposed theories such as developmental, dysplastic, hamartomatous or reactive ethology in given variants. It is important for physicians to be aware of MA as more research on this complex entity is needed and timely diagnosis may benefit outcomes in patients with MA.


Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Meníngeas/complicações , Meningioma/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/etiologia , Humanos , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Meningioma/diagnóstico por imagem , Meningioma/patologia , Neurofibromatose 2/complicações , Neurofibromatose 2/diagnóstico por imagem , Neurofibromatose 2/patologia , Neuroimagem , Substância Branca/diagnóstico por imagem
9.
Hum Genet ; 137(6-7): 543-552, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30006736

RESUMO

Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated schwannomatosis versus mosaic NF2 in these patients very difficult.


Assuntos
Genótipo , Mutação em Linhagem Germinativa , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 2/genética , Neurofibrossarcoma/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurilemoma/patologia , Neurofibromatoses/patologia , Neurofibromatose 2/patologia , Neurofibrossarcoma/patologia , Proteína SMARCB1/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética
10.
Tumori ; 104(6): NP17-NP21, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29983103

RESUMO

PURPOSE: To describe a case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2. METHODS: A 44-year-old woman, with a history of neurofibromatosis type 2, presented with chest discomfort and mild dyspnea. She had undergone a recent resection of a large frontal parasagittal benign meningioma. Radiologic examinations showed a large lesion (9×12×9 cm) of the left hemithorax causing a complete atelectasis of left upper lobe. Bronchoscopy did not show any endobronchial alterations, apart from an ab estriseco compression of the left upper bronchial tree. A transthoracic needle biopsy was then performed and microscopic examination revealed a mesenchymal tumor composed of spindle-like cells. RESULTS: A video-assisted thoracoscopic surgery procedure was proposed. The tumor mass appeared to be tenaciously adherent to the parietal pleura in its anterolateral aspect, confirming the radiologic appearance. No invasion of the lung parenchyma or parietal pleural metastases were visible. Therefore, a left posterolateral thoracotomy at the fifth intercostal space was performed and a macroscopic complete resection was carried out. The recovery was uneventful and the patient was discharged on postoperative day 5. The histologic examination revealed a moderate cellular proliferation of spindle-shaped and oval to polygonal cells with frequent Verocay bodies; mitotic figures were rare. The tumor cells were strongly S-100 positive. The microscopic features were consistent with benign intercostal schwannoma. Eight years later, the patient is disease-free and asymptomatic. CONCLUSIONS: An unusual case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2 is described.


Assuntos
Nervos Intercostais/patologia , Neurilemoma/patologia , Neurilemoma/cirurgia , Neurofibromatose 2/patologia , Neurofibromatose 2/cirurgia , Adulto , Feminino , Humanos , Parede Torácica/patologia , Toracotomia/métodos
11.
PLoS One ; 13(6): e0197350, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29897904

RESUMO

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.


Assuntos
Neoplasias Meníngeas/genética , Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/patologia , Camundongos , Morfolinas/farmacologia , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Panobinostat/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Biologia de Sistemas , Transcriptoma/genética
12.
J Int Adv Otol ; 14(1): 85-89, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29764780

RESUMO

The wait and scan policy is being increasingly used as the first measure after the diagnosis of a vestibular schwannoma (VS) using magnetic resonance imaging (MRI). As part of the European Academy of Otology and Neuro-Otology (EAONO) position statement on VS, the frequency of imaging has been studied in the literature. Among 163 studies, 29 fulfilled the inclusion criteria and were scored using the Grading of Recommendations, Assessment, Development, and Evaluation system. Because tumor growth rate during the first 5 years of follow-up is predictive of further growth during the upcoming years, a protocol for wait and scan is useful for centers dealing with this condition. The EAONO proposal is that after the initial diagnosis by MRI, a first new MRI would take place after 6 months, annually for 5 years, and then every other year for 4 years, followed by a lifelong MRI follow-up every 5 years. The first early MRI is to screen for fast-growing tumors, and the lifelong follow-up with tapered intervals is to detect late repeated growth.


Assuntos
Imagem por Ressonância Magnética/normas , Neuroma Acústico/diagnóstico por imagem , Conduta Expectante/métodos , Assistência ao Convalescente/normas , Progressão da Doença , Humanos , Imagem por Ressonância Magnética/métodos , Metanálise como Assunto , Gradação de Tumores , Neurofibromatose 2/diagnóstico por imagem , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Neuroma Acústico/radioterapia , Neuroma Acústico/cirurgia , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Estudos Retrospectivos
13.
J Neurosurg Pediatr ; 21(5): 456-459, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29473815

RESUMO

OBJECTIVE The relationship between a tethered cord (TC) and neurofibromatosis type 1 (NF1) and NF2 is not known. The purpose of this study was to define the incidence of TC in pediatric neurosurgical patients who present with NF. METHODS The authors performed a single-institution (tertiary care pediatric hospital) 10-year retrospective analysis of patients who were diagnosed with or who underwent surgery for a TC and/or NF. Clinical and radiological characteristics were analyzed, as was histopathology. RESULTS A total of 424 patients underwent surgery for a TC during the study period, and 67 patients with NF were seen in the pediatric neurosurgery clinic. Of these 67 patients, 9 (13%) were diagnosed with a TC, and filum lysis surgery was recommended. Among the 9 patients with NF recommended for TC-release surgery, 4 (44%) were female, the mean age was 8 years (range 4-14 years), the conus position ranged from L1-2 to L-3, and 3 (33%) had a filum lipoma, defined as high signal intensity on T1-weighted MR images. All 9 of these patients presented with neuromotor, skeletal, voiding, and/or pain-related symptoms. Histopathological examination consistently revealed dense fibroconnective tissue and blood vessels. CONCLUSIONS Despite the lack of any known pathophysiological relationship between NF and TC, the incidence of a symptomatic TC in patients with NF1 and NF2 who presented for any reason to this tertiary care pediatric neurosurgery clinic was 13%. Counseling patients and families regarding TC symptomatology might be indicated in this patient population.


Assuntos
Defeitos do Tubo Neural/etiologia , Neurofibromatose 1/complicações , Neurofibromatose 2/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Defeitos do Tubo Neural/patologia , Defeitos do Tubo Neural/cirurgia , Neurofibromatose 1/patologia , Neurofibromatose 2/patologia , Procedimentos Neurocirúrgicos/métodos , Estudos Retrospectivos , Centros de Atenção Terciária
14.
Otol Neurotol ; 39(3): 357-364, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29342057

RESUMO

OBJECTIVE: To characterize the audiometric natural progression in patient-ears with small volume (<1,000 mm), treatment-naïve cochleovestibular schwannomas (CVSs) in Neurofibromatosis Type 2 (NF2). STUDY DESIGN: Prospective, longitudinal cohort study. SETTING: Quaternary medical research institute. PATIENTS: One hundred eleven ears in 71 NF2 patients with small, treatment-naïve CVSs observed from July 2006 to July 2016. INTERVENTION: Serial audiometric testing, including pure tone audiometry, speech audiometry, and magnetic resonance imaging (MRI). OUTCOME MEASURES: Four-frequency pure tone average (4f-PTA) of 0.5, 1, 2, and 4 kHz and word recognition score (WRS) were recorded. Their changes were compared with MRI changes in CVS volume over time. Times to significant hearing loss (10 dB loss in 4f-PTA) and WRS based on 95% critical difference were measured. RESULTS: Linear regression analysis showed a significant correlation with baseline hearing level (4f-PTA) and internal auditory canal (IAC) tumor volume to annual hearing decrease rate (AHDR) (p = 0.003, p = 0.0004). Hearing level at baseline and tumor volume correlate with AHDR while tumor volume growth rate does not. Two-way analysis of variance found significant differences in AHDR, risk of significant hearing loss, and risk of critical difference in WRS based on baseline hearing level (abnormal or normal) and IAC tumor volume (greater or less than 200 mm). CONCLUSION: Subjects with normal baseline hearing and small IAC tumor component had a low AHDR and low risk of significant hearing loss and may warrant conservative management while the presence of baseline hearing loss and large IAC volume resulted in higher ADHR and greater risk for further hearing loss and may benefit from early treatment interventions.


Assuntos
Perda Auditiva/etiologia , Neurofibromatose 2/complicações , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Progressão da Doença , Orelha Interna/patologia , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroma Acústico/etiologia , Estudos Prospectivos , Adulto Jovem
15.
Neurosurgery ; 83(1): 38-42, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973692

RESUMO

BACKGROUND: The published literature suggests that malignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in neurofibromatosis type 2 (NF2). A recent review based on incidence data in North America showed that 1 per 1000 cerebellopontine angle nerve sheath tumors were malignant. OBJECTIVE: To determine whether MPNST occurred spontaneously in NF2 by reviewing our NF2 database. METHODS: The prospective database consists of 1253 patients with NF2. One thousand and nine are known to be alive at last follow-up. The presence and laterality/pathology of vestibular schwannoma at diagnosis and last follow-up was sought. RESULTS: There were no cases of spontaneous MPNST with 2114 proven (n = 1150) and presumed benign (n = 964) vestibular schwannomas found. Two patients had developed MPNST (1 presumed) after having previously undergone stereotactic radiosurgery for a vestibular schwannoma. CONCLUSION: In this series, and from the literature, malignant transformation of a vestibular schwannoma was not a feature of NF2 in the unirradiated patient. NF2 patients should not be told that they have an increased risk of malignant change in a vestibular schwannoma unless they undergo radiation treatment. However, very much larger datasets are required before it can be determined whether there is any association between NF2 and MPNST in the unirradiated patient.


Assuntos
Neoplasias da Bainha Neural/epidemiologia , Neurofibromatose 2/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Bases de Dados Genéticas , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias da Bainha Neural/genética , Neurofibromatose 2/patologia , Neuroma Acústico/genética , Neuroma Acústico/patologia , Estudos Prospectivos , Adulto Jovem
16.
J Neurooncol ; 136(3): 605-611, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29188529

RESUMO

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.


Assuntos
Tratamento Conservador , Ependimoma/terapia , Neurofibromatose 2/terapia , Procedimentos Neurocirúrgicos , Neoplasias da Medula Espinal/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Ependimoma/complicações , Ependimoma/patologia , Seguimentos , Humanos , Pessoa de Meia-Idade , Neurofibromatose 2/complicações , Neurofibromatose 2/patologia , Complicações Pós-Operatórias , Estudos Retrospectivos , Neoplasias da Medula Espinal/complicações , Neoplasias da Medula Espinal/patologia , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
17.
Br J Ophthalmol ; 102(8): 1147-1153, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29146762

RESUMO

PURPOSE: To study the natural history, clinical and radiological characteristics of primary paediatric optic nerve sheath meningioma (PPONSM). METHODS: Retrospective study of eight paediatric patients who were treated between 1994 and 2016 at the University Hospital Zurich, Switzerland and the Royal Adelaide Hospital, Australia. Clinical records and imaging studies were reviewed. RESULTS: The mean age at presentation was 11 years (range: 6-17 years). There were six female patients and two male patients. 2/8 patients had associated neurofibromatosis type 2. Patients were followed up for 71-297 months (mean 156±70 months). 6/8 patients were observed through the course of their disease and 2/8 patients were treated with radiotherapy. 2/8 patients who were observed had minimal change in vision and did not experience tumour growth after long-term follow-up. CONCLUSIONS: This is the largest PPONSM case series with long-term data on patients treated conservatively. We highlight that a small subset of these tumours are indolent and can be managed using observation alone.


Assuntos
Imagem por Ressonância Magnética , Meningioma/diagnóstico por imagem , Neurofibromatose 2/diagnóstico por imagem , Neoplasias do Nervo Óptico/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adolescente , Criança , Feminino , Seguimentos , Humanos , Masculino , Meningioma/patologia , Meningioma/radioterapia , Neurofibromatose 2/patologia , Neurofibromatose 2/radioterapia , Neoplasias do Nervo Óptico/patologia , Neoplasias do Nervo Óptico/radioterapia , Estudos Retrospectivos , Acuidade Visual , Campos Visuais
18.
Neurochirurgie ; 64(5): 364-369, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26071178

RESUMO

INTRODUCTION: Neurofibromatosis type 2 is characterized by the presence of bilateral vestibular schwannomas. However, other nervous system tumors may also occur. Therefore, the management of NF2 patients is complex and requires a multidisciplinary discussion in a specialized center. MATERIALS AND METHODS: All recent articles concerning tumors other than vestibular schwannoma in NF2 disease were reviewed, using PubMed databases. RESULTS: Intracranial meningiomas occur in 50% of NF2 patients, and are often multiple. Surgery remains the main treatment and should be performed in cases of growing tumors. The role of antiangiogenic therapy is currently under evaluation and the role of radiosurgery still remains to be defined in NF2 disease. Spinal tumors occur in about half of NF2 patients. Surgery should be discussed when radiological tumor progression is demonstrated, even if spinal tumors are asymptomatic, in order to preserve neurological function and good quality of life. As regards lower cranial nerve schwannomas, radiosurgery appears to be a more appropriate treatment for growing tumor with a small volume in order to avoid post-operative complications, especially swallowing disorders. Facial nerve schwannomas may appear, on MRI, like vestibular schwannomas. The diagnosis should be suspected when the facial palsy is an early symptom during cerebello-pontine tumor progression. Trigeminal schwannomas are frequent in NF2 disease and fortunately they are often asymptomatic. Among major neurofibromatosis types, peripheral nerve sheath schwannomas are only present in patients with NF2 disease and schwannomatosis. Surgical resection is required when the cutaneous schwannomas is painful or when tumor progression is observed and causes symptoms. CONCLUSION: Tumors other than vestibular schwannoma are also associated with a poor prognosis in NF2 patients. Surgery remains the main treatment in most cases. Each treatment decision in NF2 disease requires a complete evaluation of all cranial and spinal locations of the disease in order to establish surgical priorities and strategies.


Assuntos
Neurofibromatoses/cirurgia , Neurofibromatose 2/patologia , Neurofibromatose 2/cirurgia , Neoplasias da Coluna Vertebral/cirurgia , Progressão da Doença , Humanos , Imagem por Ressonância Magnética/métodos , Meningioma/diagnóstico , Meningioma/cirurgia , Neurilemoma/diagnóstico , Neurilemoma/cirurgia , Neurofibromatoses/diagnóstico , Neurofibromatose 2/diagnóstico , Complicações Pós-Operatórias/cirurgia , Radiocirurgia/métodos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento
19.
Clin Genet ; 93(1): 187-190, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28737257

RESUMO

A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as 3 small (<2 cm) meningiomas, which according to the Manchester consensus diagnostic criteria for neurofibromatosis 2 (NF2) is sufficient for a clinical diagnosis. Analysis of blood revealed a mosaic PIK3CA c.2740G>A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome. Genetic analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p.Arg262Ter) and loss of a portion of 22q, including NF2, SMARCB1, and LZTR1 genes. These results suggest that the patient has 2 different mosaic disorders, NF2 and PIK3CA-related overgrowth. The PIK3CA mutation was also present in the VS. Confirmation of the clinical diagnosis of mosaic NF2 in this patient has implications for monitoring and highlights the possibility of co-occurrence of mosaicism for multiple rare disorders in a single patient.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Mutação , Neuroma Acústico/genética , Adulto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia , Mosaicismo , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Doenças Raras/genética , Doenças Raras/patologia
20.
Neurol Res ; 39(12): 1086-1093, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28934903

RESUMO

Objective To study the function and potential mechanism of RAC1 inhibitors in NF2-associated schwannoma. Methods In this study, we the downregulation of RAC1 activity and tumor cell phenotypes by RAC1 inhibitor NSC23766 in vitro. And we further validated the anti-proliferation effect by this RAC1 inhibitor in subcutaneous xenograft tumor model and sciatic nerve model. Results Pharmacological inhibition of RAC1 could significantly inhibit the proliferation of both RT4 cells and human NF2-associated primary schwannoma cells by inducing apoptosis. Pharmacological inhibition of RAC1 effectively reduced Rac1 activity and down-regulated the pathway downstream of Rac. Moreover, pharmacological inhibition of RAC1 showed a potential antitumor effect, with low toxicity in vivo. Conclusion RAC1 inhibitors may play a therapeutic role in patients with schwannoma.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Neurilemoma/metabolismo , Neurofibromatose 2/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Aminoquinolinas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Neoplasias do Sistema Nervoso Periférico/tratamento farmacológico , Neoplasias do Sistema Nervoso Periférico/metabolismo , Neoplasias do Sistema Nervoso Periférico/patologia , Pirimidinas/farmacologia , Distribuição Aleatória , Ratos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
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