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1.
J Neurooncol ; 143(3): 505-513, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31049826

RESUMO

PURPOSE: To test the feasibility, acceptability, and preliminary efficacy of a mind-body program for patients with neurofibromatosis 2 (NF2) who are deaf or have significant hearing loss (d3RP-NF2) against an attention placebo control (dHEP-NF2) in a single-blind randomized control trial. Both were delivered using Communication Access Real-Time Translation and live group videoconferencing. METHODS: Forty-five adults with NF2 were randomized. Co-primary outcomes were physical quality of life (QoL) and psychological QoL and secondary outcomes were social QoL and environmental QoL, all measured with the World Health Organization Quality of Life Abbreviated Instrument (WHOQOL-BREF). Assessments were conducted at baseline, post-treatment, and six-month follow-up. RESULTS: Forty-one participants (91%) completed the intervention, and 29 (64%) completed the six-month follow up. Participants in the d3RP-NF2 showed significantly greater improvements from baseline to post-treatment on physical QoL (14.79, 95% CI 5.41-24.18; p ≤ 0.001), psychological QoL (18.77, 95% CI 7.09-30.44, p ≤ 0.001), and environmental QoL (13.25, 95% CI 1.10-25.39, p = 0.03) compared to the dHEP-NF2. Social QoL also significantly increased in the d3RP-NF2 (16.32, 95% CI 6.66-25.97, p = 0.001), but improvement was not beyond the dHEP-NF2. Gains in QoL were clinically meaningful and maintained at the 6-month follow-up for d3RP-NF2 participants across all QoL domains. There were more treatment responders in the d3RP-NF2 compared to the dHEP-NF2. CONCLUSIONS: The d3RP-NF2 was well accepted, highly feasible, and resulted in sustained improvements in QoL in patients with NF2 who are deaf or have significant hearing loss.


Assuntos
Surdez/complicações , Perda Auditiva/complicações , Terapias Mente-Corpo/métodos , Neurofibromatose 2/terapia , Psicoterapia de Grupo/métodos , Qualidade de Vida , Videoconferência , Atividades Cotidianas , Adulto , Idoso , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/etiologia , Prognóstico , Método Simples-Cego , Inquéritos e Questionários , Telemedicina , Adulto Jovem
3.
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
4.
BMC Health Serv Res ; 18(1): 668, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157837

RESUMO

BACKGROUND: Our primary aim was to assess the ability of a non-profit foundation-sponsored clinic network to facilitate access to specialized care for patients with neurofibromatoses (NF), a group of neurogenetic disorders including NF1, NF2, and schwannomatosis (SWN). Our secondary aim was to identify how our findings in NF could be applied more broadly to other rare diseases. METHODS: We retrospectively reviewed aggregate data on patient volume reported by specialty NF clinics in a nonprofit network from 2008 to 2015. We classified clinics as high or low volume for disease type (NF1 and NF2/schwannomatosis) and pediatric/adult care. We compared clinic-level data to self-reported patient-level data from a large online patient registry. RESULTS: Between 2008 and 2015, the number of certified NF clinics grew from 32 to 50, and annual patient volume rose from 6776 to 10,245 patients (13% of the total estimated U.S. NF patient population). For patient registry participants (n = 4476), the median driving distance to the nearest network clinic was 51.3 miles. Driving distances to reach high-volume centers were elevated for adults compared to children (295.8 vs. 67.9 miles), and schwannomatosis and NF2 patients compared to NF1 patients (310.9 vs. 368.1 vs. 161.7 miles). Of registry participants reporting their location of care (n = 2271), only 43.2% received care in a network specialty clinic, with especially low rates of attendance in the Southwest and Far West. CONCLUSIONS: While the number of certified NF clinics and volume of patients seen in these clinics has increased, many NF patients still do not attend specialty clinics and/or travel a significant distance for care. Geographic access to care is more limited for adults, patients with rarer conditions, and patients in the Western U.S. Potential measures to improve access to specialty care for people living with NF and other rare diseases are discussed.


Assuntos
Assistência Ambulatorial/normas , Acesso aos Serviços de Saúde/normas , Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/terapia , Neurofibromatose 2/terapia , Doenças Raras/terapia , Neoplasias Cutâneas/terapia , Adolescente , Adulto , Distribuição por Idade , Idoso , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Condução de Veículo/estatística & dados numéricos , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Organizações sem Fins Lucrativos , Características de Residência/estatística & dados numéricos , Estudos Retrospectivos , Autorrelato , Viagem/estatística & dados numéricos , Estados Unidos , Adulto Jovem
5.
Neurochirurgie ; 64(5): 381-385, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29754738

RESUMO

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.


Assuntos
Assistência ao Convalescente/psicologia , Neurofibromatose 2/terapia , Neuroma Acústico/terapia , Resultado do Tratamento , Implantes Auditivos de Tronco Encefálico/psicologia , Humanos , Neurofibromatose 2/psicologia , Neuroma Acústico/psicologia , Qualidade de Vida
6.
Adv Otorhinolaryngol ; 81: 93-104, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29794459

RESUMO

Bilateral vestibular schwannomas are almost pathognomonic of neurofibromatosis type 2 (NF2). As a result of these tumors, hearing loss is the presenting symptom in 60% of adults and 30% of children with NF2. It is often bilateral. The best means of preserving hearing in patients with NF2 is conservative management. Even so at least 28% of patients have progression of hearing loss following diagnosis. The likelihood of progression of hearing loss is, at least in part, determined by the type of mutation. Treatment of vestibular schwannomas often has a detrimental effect on hearing. Only 41% of patients having stereotactic radiosurgery maintain their hearing at 5 years. Treatment with bevacizumab maintains medium-term hearing in 38% and improves it in 48%. Surgery to remove vestibular schwannomas invariably leads to complete loss of ipsilateral hearing, although in a very limited number of patients hearing preservation surgery may be possible. For those that lose their hearing but have an intact cochlear nerve, for example, conservative management, radiotherapy treatment or cochlear nerve preserving surgery, cochlear implantation has been shown to be an effective option although outcomes are not as good as traditional implant candidates (mean sentence testing scores in quiet: stable untreated tumors 69%; radiotherapy treated tumors 49%; cochlear nerve preserving surgery ∼40%). For those that do not have a functional cochlear nerve, auditory brainstem implantation (ABI) is an option. The non-user rate in this group is 13%. The mean sentence score in users with ABI alone is 12%. ABI therefore acts, in most cases, as an aid to lip reading and rarely provides open set speech discrimination.


Assuntos
Auxiliares de Audição , Perda Auditiva/etiologia , Perda Auditiva/reabilitação , Neurofibromatose 2/complicações , Perda Auditiva/diagnóstico , Humanos , Neurofibromatose 2/terapia
7.
Am J Med Genet A ; 176(5): 1258-1269, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29681099

RESUMO

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.


Assuntos
Neurilemoma/diagnóstico , Neurilemoma/etiologia , Neurofibromatoses/diagnóstico , Neurofibromatoses/etiologia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/etiologia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/etiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Animais , Gerenciamento Clínico , Modelos Animais de Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Técnicas de Diagnóstico Molecular , Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/terapia , Neurofibromatose 2/terapia , Neoplasias Cutâneas/terapia , Pesquisa Médica Translacional
8.
Expert Rev Neurother ; 18(1): 29-39, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29088993

RESUMO

INTRODUCTION: Vestibular schwannomas (VS) account for approximately 85% of tumors in the cerebello-pontine angle, with a lifetime incidence of approximately 1 in 1000. Most are sporadic, with approximately 5% related to the tumor predisposition syndrome Neurofibromatosis Type 2 (NF2). The mainstays of management strategies are: observation, surgery, radiosurgery/radiotherapy and, for patients with NF2 and rapidly growing tumors or deteriorating neurologic function the targeted therapy bevacizumab. While morbidity and mortality rates related to treatment of VS have improved dramatically over the last decades, there are still significant improvements that could be made, in particular with regards to long-term facial nerve and hearing outcomes. Areas covered: The epidemiology and diagnosis of VS are discussed, followed by the different management strategies and outcomes of those for both sporadic and NF2 related tumors. An extensive literature review has been performed to inform this review article using PubMed and Google Scholar. Expert commentary: The future direction of VS management lies in obtaining longer-term follow-up data for patients with treated VS, and in improved understanding of cellular pathways and targeted therapies.


Assuntos
Neurilemoma/diagnóstico , Neurilemoma/terapia , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/terapia , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Transtornos da Audição , Humanos , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia , Complicações Pós-Operatórias , Radiocirurgia , Radioterapia , Resultado do Tratamento
9.
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
10.
J Med Genet ; 54(10): 657-664, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28848060

RESUMO

​BACKGROUND: The clinical severity of disease in neurofibromatosis type 2 (NF2) is variable. Patients affected with a constitutional truncating NF2 mutation have severe disease, while missense mutations or mosaic mutations present with a milder attenuated phenotype. Genotype-derived natural history data are important to inform discussions on prognosis and management. METHODS: We have assessed NF2 clinical phenotype in 142 patients in relation to the UK NF2 Genetic Severity Score to validate its use as a clinical and research tool. RESULTS: The Genetic Severity Score showed significant correlations across 10 measures, including mean age at diagnosis, proportion of patients with bilateral vestibular schwannomas, presence of intracranial meningioma, spinal meningioma and spinal schwannoma, NF2 eye features, hearing grade, age at first radiotherapy, age at first surgery and age starting bevacizumab. In addition there was moderate but significant correlation with age at loss of useful hearing, and weak but significant correlations for mean age at death, quality of life, last optimum Speech Discrimination Score and total number of major interventions. Patients with severe disease presented at a younger age had a higher disease burden and greater requirement of intervention than patients with mild and moderate disease. CONCLUSIONS: This study validates the UK NF2 Genetic Severity Score to stratify patients with NF2 for both clinical use and natural history studies.


Assuntos
Neurofibromatose 2/genética , Neurofibromatose 2/fisiopatologia , Fatores Etários , Feminino , Genes da Neurofibromatose 2 , Perda Auditiva , Humanos , Masculino , Mutação , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia , Fenótipo , Qualidade de Vida , Índice de Gravidade de Doença
11.
J Neurooncol ; 135(1): 47-56, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28735458

RESUMO

Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 -/-) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2.


Assuntos
Antineoplásicos/farmacologia , Neurilemoma/terapia , Neurofibromatose 2/terapia , Neoplasias do Sistema Nervoso Periférico/terapia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia , Everolimo/farmacologia , Lapatinib , Camundongos , Camundongos Nus , Camundongos Transgênicos , Modelos Estatísticos , Transplante de Neoplasias , Neurilemoma/patologia , Neurofibromatose 2/patologia , Neoplasias do Sistema Nervoso Periférico/patologia , Nervo Isquiático , Fatores de Tempo
12.
Am J Med Genet A ; 173(6): 1714-1721, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28436162

RESUMO

The Annual Children's Tumor Foundation International Neurofibromatosis Meeting is the premier venue for connecting discovery, translational and clinical scientists who are focused on neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis (SWN). The meeting also features rare tumors such as glioma, meningioma, sarcoma, and neuroblastoma that occur both within these syndromes and spontaneously; associated with somatic mutations in NF1, NF2, and SWN. The meeting addresses both state of the field for current clinical care as well as emerging preclinical models fueling discovery of new therapeutic targets and discovery science initiatives investigating mechanisms of tumorigenesis. Importantly, this conference is a forum for presenting work in progress and bringing together all stakeholders in the scientific community. A highlight of the conference was the involvement of scientists from the pharmaceutical industry who presented growing efforts for rare disease therapeutic development in general and specifically, in pediatric patients with rare tumor syndromes. Another highlight was the focus on new investigators who presented new data about biomarker discovery, tumor pathogenesis, and diagnostic tools for NF1, NF2, and SWN. This report summarizes the themes of the meeting and a synthesis of the scientific discoveries presented at the conference in order to make the larger research community aware of progress in the neurofibromatoses.


Assuntos
Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/terapia , Neurofibromatose 2/terapia , Neoplasias Cutâneas/terapia , Criança , Humanos , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 1/genética , Neurofibromatose 2/genética , Pediatria/tendências , Neoplasias Cutâneas/genética
13.
Clin Otolaryngol ; 42(6): 1329-1337, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28371358

RESUMO

BACKGROUND: It is common for patients with neurofibromatosis type 2 to develop bilateral profound hearing loss hearing loss, and this is one of the main determinants of quality of life in this patient group. OBJECTIVES: The aim of this systematic review was to review the current literature regarding hearing outcomes of treatments for vestibular schwannomas in neurofibromatosis type 2 including conservative and medical management, radiotherapy, hearing preservation surgery and auditory implantation in order to determine the most effective way of preserving or rehabilitating hearing. SEARCH STRATEGY: A MESH search in PubMed using search terms (('Neurofibromatosis 2' [Mesh]) AND 'Neuroma, Acoustic'[Mesh]) AND 'Hearing Loss' [Mesh] was performed. A search using keywords was also performed. Studies with adequate hearing outcome data were included. With the exception of the cochlear implant studies (cohort size was very small), case studies were excluded. EVALUATION METHOD: The GRADE system was used to assess quality of publication. Formal statistical analysis of data was not performed because of very heterogenous data reporting. RESULTS: Conservative management offers the best chance of hearing preservation in stable tumours. The use of bevacizumab probably improves the likelihood of hearing preservation in growing tumours in the short term and is probably more effective than hearing preservation surgery and radiotherapy in preserving hearing. Of the hearing preservation interventions, hearing preservation surgery probably offers better hearing preservation rates than radiotherapy for small tumours but recurrence rates for hearing preservation surgery were high. For patients with profound hearing loss, cochlear implantation provides significantly better auditory outcomes than auditory brainstem implantation. Patients with untreated stable tumours are likely to achieve the best outcomes from cochlear implantation. Those who have had their tumours treated with surgery or radiotherapy do not gain as much benefit from cochlear implantation than those with untreated tumours. CONCLUSIONS: This review summarises the current literature related to hearing preservation/rehabilitation in patients with NF2. Whilst it provides indicative data, the quality of the data was low and should be interpreted with care. It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision-making is determined by many factors, not just the need to preserve hearing.


Assuntos
Perda Auditiva/etiologia , Perda Auditiva/terapia , Neurofibromatose 2/complicações , Perda Auditiva/diagnóstico , Humanos , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia
14.
J Child Neurol ; 32(1): 9-22, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27655473

RESUMO

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder (incidence 1:33 000-40 000) characterized by formation of central nervous system tumors, due to mutation in the NF2 gene on chromosome 22q12. Vestibular schwannomas are the hallmark lesion, affecting 95% of individuals and typically occur bilaterally. Schwannomas commonly occur on other nerves intracranially and in the spinal compartment, along with meningiomas, ependymomas, and gliomas. Although histologically benign, tumors are associated with significant morbidity due to multiple problems including hearing and vision loss, gait abnormalities, paralysis, pain, and seizures. Risk of early mortality from brainstem compression and other complications is significant. Severity of disease is higher when NF2 presents during childhood. Children have a more variable presentation, which can be associated with significant delays in recognition of the condition. Careful examination of the skin and eyes can identify important clinical signs of NF2 during childhood, allowing timely initiation of disease-specific surveillance and treatment. Monitoring for complications comprises clinical evaluation, along with functional testing including audiology and serial neuroimaging, which together inform decisions regarding treatment. Evidence for disease-specific medical treatment options is increasing, nevertheless most patients will benefit from multimodal treatment including surgery during their lifetime. Patient enrolment in international natural history and treatment trials offers the best opportunity to accelerate our understanding of the complications and optimal treatment of NF2, with a view to improving outcomes for all affected individuals.


Assuntos
Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia , Criança , Humanos , Neurofibromatose 2/complicações , Neurofibromatose 2/genética
15.
Acta Otorhinolaryngol Ital ; 36(5): 345-367, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27958595

RESUMO

Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.


Assuntos
Terapia Biológica , Neurofibromatose 2/terapia , Criança , Humanos , Neurofibromatose 2/complicações , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética
16.
Semin Oncol ; 43(3): 401-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27178695

RESUMO

Skin findings are a rare but important aspect of the evaluation and management of patients with tumors of the nervous system. Skin findings have the highest prevalence in genetic tumor syndromes termed neuro-genodermatoses, which include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and tuberous sclerosis. Skin changes are observed in patients with non-syndromic nervous system malignancy, often as a result of pharmacotherapy. The skin may also manifest findings in paraneoplastic conditions that affect the nervous system, providing an early indication of underlying neoplasm, including dermatomyosistis, neuropathic itch, and brachioradial pruritus. In this article, we review the major cutaneous findings in patients with tumors of the brain, spine, and peripheral nervous system focusing on (1) cutaneous manifestations of genetic and sporadic primary nervous system tumor syndromes, and (2) paraneoplastic neurological syndromes with prominent cutaneous features.


Assuntos
Neoplasias de Tecido Nervoso/patologia , Síndromes Paraneoplásicas/patologia , Esclerose Tuberosa/patologia , Dermatomiosite/etiologia , Dermatomiosite/patologia , Humanos , Neoplasias de Tecido Nervoso/terapia , Neurofibromatose 1/patologia , Neurofibromatose 1/terapia , Neurofibromatose 2/patologia , Neurofibromatose 2/terapia , Esclerose Tuberosa/terapia
17.
Neuro Oncol ; 18(5): 624-38, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26851632

RESUMO

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are tumor-suppressor syndromes. Each syndrome is an orphan disease; however, the tumors that arise within them represent the most common tumors of the nervous system worldwide. Systematic investigation of the pathways impacted by the loss of function of neurofibromin (encoded byNF1) and merlin (encoded byNF2) have led to therapeutic advances for patients with NF1 and NF2. In the syndrome of SWN, the genetic landscape is more complex, with 2 known causative genes (SMARCB1andLZTR1) accounting for up to 50% of familial SWN patients. The understanding of the molecular underpinnings of these syndromes is developing rapidly and offers more therapeutic options for the patients. In addition, common sporadic cancers harbor somatic alterations inNF1(ie, glioblastoma, breast cancer, melanoma),NF2(ie, meningioma, mesothelioma) andSMARCB1(ie, atypical teratoid/rhabdoid tumors) such that advances in management of syndromic tumors may benefit patients both with and without germline mutations. In this review, we discuss the clinical and genetic features of NF1, NF2 and SWN, the therapeutic advances for the tumors that arise within these syndromes and the interaction between these rare tumor syndromes and the common tumors that share these mutations.


Assuntos
Oncologia/tendências , Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/terapia , Neurofibromatose 2/terapia , Neoplasias Cutâneas/terapia , Humanos , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 1/genética , Neurofibromatose 2/genética , Neoplasias Cutâneas/genética
18.
Semin Pediatr Neurol ; 22(4): 240-58, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26706012

RESUMO

Neurofibromatosis type 2 (NF2; MIM # 101000) is an autosomal dominant disorder characterized by the development of vestibular schwannomas (VSs); schwannomas of other cranial, spinal, and cutaneous nerves; cranial and spinal meningiomas or other central nervous system tumors (eg, ependymomas and astrocytomas) or both. Additional features include eye (eg, early onset cataracts, optic nerve sheath meningiomas, retinal or pigment epithelial hamartomas or both, and epithelial retinal membranes) and skin abnormalities (eg, flat dermal [NF2 plaques] or spherical subcutaneous nodular schwannomas or both, and few, atypical café-au-lait spots). Clinically, children with NF2 fall into 2 main groups: (1) congenital NF2 with bilateral VSs detected as early as the first days to months of life, which can be stable or asymptomatic for 1-2 decades and suddenly progress; and (2) severe prepubertal (Wishart type) NF2 with multiple (and rapidly progressive) central nervous system tumors other-than-VS, which usually presents first, years before VSs, both associated with more marked skin and eye involvement (vs the classical mild adult [Gardner type] NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature). Individuals manifesting unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localized to a part of the peripheral nervous system have mosaic or segmental NF2; individuals developing multiple nonVS, nonintradermal cranial, spinal, and peripheral schwannomas (histologically proven) have schwannomatosis (SWNTS). NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin proteins; mosaic or segmental NF2 is because of mosaic phenomena for the NF2 gene, whereas SWNTS is caused by germline and possibly mosaic mutations either in the SMARCB1 gene (SWNTS1; MIM # 162091) or the LZTR1 gene (SWNTS2; MIM # 615670), both falling within the 22q region. Data driven from in vitro and animal studies on the merlin pathway allowed biologically targeted treatment strategies (employing Lapatinib, Erlotinib, Everolimus, Picropodophyllin, OSU.03012, Imatinib, Sorafenib, and Bevacizumab) aimed at multiple tumor shrinkage or regression or both and tumor arrest of progression with functional improvement.


Assuntos
Neurofibromatose 2/diagnóstico , Neurofibromatose 2/terapia , Animais , Humanos , Neurofibromatose 2/genética , Neurofibromatose 2/patologia
19.
Artigo em Chinês | MEDLINE | ID: mdl-26596021

RESUMO

Neurofibromatosis type 2 (NF2) is a dominantly inherited genetic condition. Bilateral vestibular schwannoma, which are benign tumors, composed of neoplastic Schwann cells that arise from the eighth cranial nerve, are the hallmark of NF2. Standard approaches for treatment of growing vestibular schwannoma include observation, surgical removal and radiation therapy. Molecular targeted therapies also present great prosperity in recent years. In this review, we summarize the latest progresses on the treatment of NF2-associated vestibular schwannoma.


Assuntos
Neurofibromatose 2/terapia , Neuroma Acústico/terapia , Humanos , Terapia de Alvo Molecular , Neurofibromatose 2/radioterapia , Neurofibromatose 2/cirurgia , Neuroma Acústico/radioterapia , Neuroma Acústico/cirurgia
20.
World Neurosurg ; 84(4): 1062-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26087434

RESUMO

OBJECTIVE: Treatment of meningiomas in neurofibromatosis type II (NF2) patients is challenging because the natural history of these tumors is unclear. More insight in tumor growth and factors predicting growth may contribute to a better clinical management. In this study, growth characteristics of supratentorial NF-related meningiomas were examined and the association between tumor growth rate and location was evaluated. METHODS: In all NF2 patients followed up at the VU University Medical Center, who underwent a minimum of 3 consecutive scans, tumor volumes were assessed by using 3D volumetric measurement (Brainlab, Feldkirchen, Germany). Growth patterns were visually analyzed. To assess the association between tumor growth rate and tumor location, the meningiomas were divided in 3 groups on the basis of their location: skull base, convexity, and "other." Univariable and multivariable logistic regression models were built. RESULTS: Twenty-one patients (13 females) with a mean (standard deviation) follow-up period of 5.55 (2.48) years and a total of 210 meningiomas were included in the analyses. Tumors followed different growth patterns and did not increase in size simultaneously within 1 patient. Skull base meningiomas had a significantly higher absolute growth rate compared with convexity (ß = 0.91, 95% confidence interval [CI] 0.08-1.73) and "other" (ß = 1.07, 95% CI 0.27-1.86) and a significantly higher relative growth rate on both linear and geometric growth rate compared with "other" (ß = 90.73, 95% CI 5.50-175.95 and ß = 18.63, 95% CI 2.94-34.31, respectively) on multivariable logistic regression. CONCLUSION: Within a single patient, NF2-related meningiomas follow different growth patterns. Skull base meningiomas grow faster compared with other locations. Yearly magnetic resonance imaging scans and timely treatment of skull base meningiomas should be considered.


Assuntos
Imagem Tridimensional/métodos , Meningioma/patologia , Neurofibromatose 2/patologia , Neuroimagem/métodos , Adulto , Progressão da Doença , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Meningioma/cirurgia , Meningioma/terapia , Neurofibromatose 2/cirurgia , Neurofibromatose 2/terapia , Procedimentos Neurocirúrgicos/métodos , Base do Crânio/patologia , Base do Crânio/cirurgia
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