RESUMO
NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.
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Neurilemoma , Neurofibromatoses , Neurofibromina 2 , Neoplasias Cutâneas , Humanos , Neurofibromatoses/terapia , Neurofibromatoses/genética , Neurofibromatoses/metabolismo , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Neurilemoma/genética , Neurilemoma/terapia , Neurilemoma/metabolismo , Neurilemoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Animais , Neurofibromatose 2/genética , Neurofibromatose 2/terapia , Neurofibromatose 2/metabolismo , Mutação , Transdução de Sinais , Terapia de Alvo MolecularRESUMO
The neurofibromatoses (NFs) are a set of incurable genetic disorders that predispose individuals to nervous system tumors. Although many patients experience anxiety and depression, there is little research on psychosocial interventions in this population. The present study examined the effects of a mind-body intervention on depression and anxiety in adults with NF. This is a secondary analysis of the Relaxation Response Resiliency Program for NF (3RP-NF), an 8-week virtual group intervention that teaches mind-body skills (e.g., relaxation, mindfulness) to improve quality of life. Participants were randomized to 3RP-NF or the Health Enhancement Program for NF (HEP-NF) consisting of health informational sessions and discussion. We evaluated depression (PHQ-9) and anxiety (GAD-7) at posttreatment, 6 months, and 12 months. Both groups improved in depression and anxiety between baseline and posttest, 6 months, and 12 months. The 3RP-NF group showed greater improvements in depression scores from baseline to 6 months compared with HEP-NF and with lower rates of clinically significant depressive symptoms. There were no between-group differences for anxiety. Both interventions reduced distress and anxiety symptoms for individuals with NF. The 3RP-NF group may be better at sustaining these improvements. Given the rare nature of NF, group connection may facilitate reduced distress.
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Ansiedade , Depressão , Terapias Mente-Corpo , Neurofibromatoses , Qualidade de Vida , Humanos , Feminino , Masculino , Depressão/terapia , Depressão/psicologia , Adulto , Ansiedade/terapia , Neurofibromatoses/psicologia , Neurofibromatoses/terapia , Terapias Mente-Corpo/métodos , Pessoa de Meia-Idade , Atenção Plena/métodosRESUMO
INTRODUCTION: Neurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enables study of low-incidence disease. The implementation of a common data model would further enhance biomarker discovery by enabling effective concatenation of data from multiple studies. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis biomarker working group reviewed published data on emerging trends in neurofibromatosis 1 and schwannomatosis biomarker research and developed recommendations in a series of consensus meetings. RESULTS: Liquid biopsy has emerged as a promising assay for neurofibromatosis 1/schwannomatosis biomarker discovery and validation. In addition, we review recommendations for a range of biomarkers in clinical trials, neurofibromatosis 1/schwannomatosis-specific data annotations, and common data models for data integration. CONCLUSION: These Response Evaluation in Neurofibromatosis and Schwannomatosis consensus guidelines are intended to provide best practices for the inclusion of biomarker studies in neurofibromatosis 1/schwannomatosis clinical trials, data, and sample annotation and to lay a framework for data harmonization and concatenation between trials.
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Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Neoplasias Cutâneas , Humanos , Neurofibromatose 1/diagnóstico , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/patologia , Neurofibromatoses/diagnóstico , Neurofibromatoses/terapia , Neurofibromatoses/patologia , BiomarcadoresRESUMO
Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.
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Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neoplasias Cutâneas , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/terapia , Densidade Óssea/fisiologia , Estudos Prospectivos , Neurofibromatoses/complicações , Neurofibromatoses/terapiaRESUMO
Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.
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Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Neoplasias Cutâneas , Animais , Humanos , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Neurofibromatoses/genética , Neurofibromatoses/terapia , Neurofibromatoses/diagnóstico , Neurilemoma/genética , Neurilemoma/terapia , Neurilemoma/diagnósticoRESUMO
BACKGROUND/AIMS: Individuals with neurofibromatosis, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2)-related schwannomatosis (SWN), and other forms of SWN, often experience disease manifestations and mental health difficulties for which psychosocial interventions may help. An anonymous online survey of adults with neurofibromatosis assessed their physical, social, and emotional well-being and preferences about psychosocial interventions to inform clinical trial design. METHODS: Neurofibromatosis clinical researchers and patient representatives from the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration developed the survey. Eligibility criteria included age ≥ 18 years, self-reported diagnosis of NF1, NF2, or SWN, and ability to read and understand English. The online survey was distributed internationally by the Neurofibromatosis Registry and other neurofibromatosis foundations from June to August 2020. RESULTS: Surveys were completed by 630 adults (18-81 years of age; M = 45.5) with NF1 (78%), NF2 (14%), and SWN (8%) who were mostly White, not Hispanic/Latino, female, and from the United States. The majority (91%) reported that their neurofibromatosis symptoms had at least some impact on daily life. In the total sample, 51% endorsed a mental health diagnosis, and 27% without a diagnosis believed they had an undiagnosed mental health condition. Participants indicated that neurofibromatosis affected their emotional (44%), physical (38%), and social (35%) functioning to a high degree. Few reported ever having participated in a drug (6%) or psychosocial (7%) clinical trial, yet 68% reported they "probably" or "definitely" would want to participate in a psychosocial trial if it targeted a relevant concern. Top treatment targets were anxiety, healthier lifestyle, and daily stress. Top barriers to participating in psychosocial trials were distance to clinic, costs, and time commitment. Respondents preferred interventions delivered by clinicians via individual sessions or a combination of group and individual sessions, with limited in-person and mostly remote participation. There were no significant group differences by neurofibromatosis type in willingness to participate in psychosocial trials (p = 0.27). Regarding interest in intervention targets, adults with SWN were more likely to prefer psychosocial trials for pain support compared to those with NF1 (p < 0.001) and NF2 (p < 0.001). CONCLUSION: This study conducted the largest survey assessing physical symptoms, mental health needs, and preferences for psychosocial trials in adults with neurofibromatosis. Results indicate a high prevalence of disease manifestations, psychosocial difficulties, and untreated mental health problems in adults with neurofibromatosis and a high degree of willingness to participate in psychosocial clinical trials. Patient preferences should be considered when designing and implementing psychosocial interventions to develop the most feasible and meaningful studies.
Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Neoplasias Cutâneas , Adulto , Feminino , Humanos , Estados Unidos , Adolescente , Neurofibromatoses/terapia , Neurofibromatoses/diagnóstico , Neurofibromatoses/psicologia , Neurilemoma/diagnóstico , Neurilemoma/psicologia , Neurilemoma/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/psicologia , Neoplasias Cutâneas/terapia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/psicologia , Neurofibromatose 2/terapia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/psicologia , Neurofibromatose 1/terapia , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Neurofibromatosis (NF) is chronic neurogenetic condition that increases risk for poor quality of life, depression, and anxiety. Given the lack of biomedical treatments, we developed the "Relaxation Response Resiliency for NF" (3RP-NF) program to improve psychosocial outcomes among adults with NF. OBJECTIVE: To move toward effectiveness testing, we must understand mechanisms that explained treatment effects. We tested whether our hypothesized mechanisms of change-mindfulness, coping, and optimism-mediated improvements in quality of life, depression, and anxiety among adults in the 3RP-NF program (N = 114; ages 18-70; 72.80% female; 81.58% White). METHODS: We conducted mixed-effects models to assess whether these mechanisms uniquely mediated outcomes. RESULTS: Improvements in quality of life were most explained by coping, (b = 0.97, SE = 0.28, CI [0.45, 1.56]), followed by mindfulness (b = 0.46, SE = 0.17, CI [0.15, 0.82]) and optimism (b = 0.39, SE = 0.12, CI [0.17, 0.65]). Improvements in depression and anxiety were most explained by mindfulness (b = -1.52, SE = 0.38, CI [-2.32, -0.85], CSIE = -0.26; b = -1.29, SE = 0.35, CI [-2.04, -0.67], CSIE = -0.23), followed by optimism (b = 0.39, SE = 0.12, CI [0.17, 0.65]; b = -0.49, SE = 0.20, CI [-0.91, -0.13]), but were not explained by coping (b = 0.22, SE = 0.43, CI [-0.62, 1.07]; b = 0.06, SE = 0.46, CI [-0.84, 0.97]), respectively. CONCLUSIONS: Targeting mindfulness, coping, and optimism in psychosocial interventions may be a promising way to improve the lives of adults with NF.
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Atenção Plena , Neurofibromatoses , Resiliência Psicológica , Adulto , Humanos , Feminino , Masculino , Qualidade de Vida , Neurofibromatoses/psicologia , Neurofibromatoses/terapia , Capacidades de Enfrentamento , Ansiedade/terapia , Depressão/terapiaRESUMO
BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.
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Neurilemoma , Neurofibroma Plexiforme , Neurofibromatoses , Neurofibromatose 1 , Neoplasias Cutâneas , Criança , Humanos , Idoso , Neurofibromatose 1/complicações , Neurofibromatose 1/tratamento farmacológico , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/diagnóstico , Neurofibroma Plexiforme/patologia , Qualidade de Vida , Neurofibromatoses/complicações , Neurofibromatoses/terapiaRESUMO
The purpose of this study was to analyze secondary resiliency and user experience outcomes from a novel, 8-week website-based mind-body intervention (NF-Web) for adults (18+) with neurofibromatosis (NF1, NF2, and schwannomatosis), a genetic, neurocutaneous disorder characterized by nerve sheath tumors of the central and peripheral nervous system. The study design was a secondary data analysis of a single-arm, early feasibility pilot study (September 2020-May 2021) for adults with NF (N = 28). Across participants, the mean age was 46 (SD = 13.67) and included 22 females and 6 males. Participants completed baseline and posttest assessments (t-tests), as well as exit interviews (exploratory rapid data analysis). Results demonstrated that participation was associated with pre-to-post improvements in gratitude, coping, and mindfulness (p < .05). Exit interviews indicated participant enjoyment and that many would recommend NF-Web to a friend. Participants found the website easy to navigate and enjoyed NF-Web's video format. Many found transcripts useful if they had hearing differences or if English was their second language. NF-Web demonstrated initial signals of improvement in resiliency outcomes and positive user experience. Future pilot RCTs will explore these changes by NF type.
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Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Resiliência Psicológica , Masculino , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Neurofibromatoses/terapia , InternetRESUMO
Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.
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Neurofibroma Plexiforme , Neurofibromatoses , Neurofibromatose 1 , Neoplasias do Sistema Nervoso Periférico , Adulto , Humanos , Criança , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/terapia , Fator A de Crescimento do Endotélio Vascular , Neurofibromatoses/complicações , Neurofibromatoses/terapia , Neurofibromatoses/diagnóstico , Neurofibromatose 1/complicações , Neurofibromatose 1/terapia , Predisposição Genética para Doença , Inibidores de Proteínas Quinases/uso terapêutico , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
Schwannomatoses is a new classification unit for all the hereditary diseases caused by chromosome 22 damage followed by multiple benign neoplasms of the peripheral and central nervous system. Schwannomatosis occurs as a result of damage to different genes: NF2, SMARCB1, LZRT1, loss of heterozygosity of the long arm of chromosome 22. Nevertheless, clinical manifestations are similar. Molecular diagnostics not only confirms the diagnosis, but also predicts the course of disease. Thus, the most severe clinical manifestations are observed in patients with violation of semantic sequences and reading frame shift in exons 2-13 of the NF2 gene. A more favorable course with less number of tumors is observed in patients with somatic mosaicism. Stereotactic irradiation and surgery are the main treatment options for schwannomatosis. However, there is evidence of effective targeted therapy with bevacizumab (inhibitor of vascular endothelial growth factor). Bevacizumab is used in patients with bilateral vestibular schwannomas and high risk of hearing loss, as well as for intramedullary tumor growth control.
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Neurilemoma , Neurofibromatoses , Neurofibromatose 2 , Humanos , Bevacizumab , Fator A de Crescimento do Endotélio Vascular , Neurilemoma/genética , Neurilemoma/terapia , Neurofibromatoses/genética , Neurofibromatoses/terapia , Neurofibromatoses/diagnóstico , Neurofibromatose 2/genética , Neurofibromatose 2/terapia , Neurofibromatose 2/diagnósticoRESUMO
PURPOSE OF REVIEW: In 2022, an international consensus recommendation revised the nomenclature for neurofibromatosis type 2 ( NF2 ) and Schwannomatosis (SWN), now grouped under the umbrella term Schwannomatosis, and defined new diagnostic criteria. RECENT FINDINGS: This review describes the molecular criteria for diagnosis of schwannomatosis and the subsequent diagnosis strategy, while setting out the most recent advances in our understanding of the natural history, pathology, molecular biology and treatment of schwannomatosis-associated tumors, including schwannomas, meningiomas and ependymomas. SUMMARY: Somatic mutation screening should become a new standard for the diagnosis of NF2 -, LTZTR1 -, SMARCB1 - and 22q-schwannomatosis to discriminate those conditions. Constitutional events in NF2 -Schwannomatosis have a major influence on disease severity and justifiably motivate ongoing efforts on gene replacement therapy research. On the other hand, underlying mechanisms of disease severity and associated pain remain largely unknown in non- NF2 -SWN and independent of germline mutation. Research efforts therefore focus on pain relief in ongoing trials and the discovery of new molecular mechanisms underlying schwannoma tumorigenesis/pain/neuropathies.
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Neurilemoma , Neurofibromatoses , Neurofibromatose 2 , Neoplasias Cutâneas , Humanos , Neurilemoma/diagnóstico , Neurilemoma/genética , Neurilemoma/terapia , Neurofibromatoses/diagnóstico , Neurofibromatoses/genética , Neurofibromatoses/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromatose 2/terapia , DorRESUMO
PURPOSE: To test the effects of the Relaxation Response Resiliency Program - Neurofibromatosis (3RP-NF), a mind-body resilience program for people with NF, on resilience factors from baseline to post-treatment and 6- and 12-month follow-up. METHODS: This is a secondary analysis of a fully powered randomized clinical trial (RCT) of 3RP-NF and health education control (HEP-NF). We recruited adults with NF1, NF2, or schwannomatosis who reported stress or difficulty coping with NF symptoms. Both conditions received 8 weekly 90-minute group sessions; 3RP-NF focused on building resilience skills. We measured resilience factors via the Measure of Current Status-A (adaptive coping), Cognitive and Affective Mindfulness Scale-Revised (mindfulness), Gratitude Questionnaire-6 (gratitude), Life Orientation Test Optimism Scale (optimism), and Medical Outcomes Study Social Support Survey (perceived social support) at baseline, post-intervention, and 6- and 12-month follow-up. We used linear mixed models with completely unstructured covariance across up to four repeated measurements (baseline, post-treatment, and 6- and 12-month follow-up) to investigate treatment effects on resilience factors. RESULTS: We enrolled 228 individuals (Mage=42.7, SD = 14.6; 74.5% female; 87.7% White; 72.8% NF1, 14.0% NF2, 13.2% schwannomatosis). Within groups, both 3RP-NF and HEP-NF showed statistically significant improvements in all outcomes across timepoints. 3RP-NF showed significantly greater improvement in adaptive coping compared to HEP-NF from baseline to post-intervention and baseline to 6 months (Mdifference= 0.29; 95% CI 0.13-0.46; p < 0.001; Mdifference= 0.25; 95% CI 0.07-0.33; p = 0.005); there were no other between-group differences amongst the remaining resilience factors. CONCLUSION: 3RP-NF showed promise in sustainably improving coping abilities amongst people with NF. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03406208. Registration submitted December 6, 2017, first patient enrolled October 2017.
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Neurilemoma , Neurofibromatoses , Neoplasias Cutâneas , Feminino , Humanos , Adulto , Masculino , Neurofibromatoses/terapia , Neurofibromatoses/psicologia , Adaptação PsicológicaRESUMO
Importance: Neurofibromatoses (NF; NF1, NF2, and schwannomatosis) are hereditary tumor predisposition syndromes with a risk for poor quality of life (QOL) and no evidence-based treatments. Objective: To compare a mind-body skills training program, the Relaxation Response Resiliency Program for NF (3RP-NF), with a health education program (Health Enhancement Program for NF; HEP-NF) for improvement of quality of life among adults with NF. Design, Setting, and Participants: This single-blind, remote randomized clinical trial randomly assigned 228 English-speaking adults with NF from around the world on a 1:1 basis, stratified by NF type, between October 1, 2017, and January 31, 2021, with the last follow-up February 28, 2022. Interventions: Eight 90-minute group virtual sessions of 3RP-NF or HEP-NF. Main Outcomes and Measures: Outcomes were collected at baseline, after treatment, and at 6-month and 1-year follow-up. The primary outcomes were physical health and psychological domain scores of the World Health Organization Quality of Life Brief Version (WHOQOL-BREF). Secondary outcomes were the social relationships and environment domain scores of the WHOQOL-BREF. Scores are reported as transformed domain scores (range, 0-100, with higher scores indicating higher QOL). Analysis was performed on an intention-to-treat basis. Results: Of 371 participants who underwent screening, 228 were randomized (mean [SD] age, 42.7 [14.5] years; 170 women [75%]), and 217 attended 6 or more of 8 sessions and provided posttest data. Participants in both programs improved from baseline to after treatment in primary outcomes of physical health QOL score (3RP-NF, 5.1; 95% CI, 3.2-7.0; P < .001; HEP-NF, 6.4; 95% CI, 4.6-8.3; P < .001) and psychological QOL score (3RP-NF, 8.5; 95% CI, 6.4-10.7; P < .001; HEP-NF, 9.2; 95% CI, 7.1-11.2; P < .001). Participants in the 3RP-NF group showed sustained improvements after treatment to 12 months; posttreatment improvements for the HEP-NF group diminished (between-group difference for physical health QOL score, 4.9; 95% CI, 2.1-7.7; P = .001; effect size [ES] = 0.3; and psychological QOL score, 3.7; 95% CI, 0.2-7.6; P = .06; ES = 0.2). Results were similar for secondary outcomes of social relationships and environmental QOL. There were significant between-group differences from baseline to 12 months in favor of the 3RP-NF for physical health QOL score (3.6; 95% CI, 0.5-6.6; P = .02; ES = 0.2), social relationships QOL score (6.9; 95% CI, 1.2-12.7; P = .02; ES = 0.3), and environmental QOL score (3.5; 95% CI, 0.4-6.5; P = .02; ES = 0.2). Conclusions and Relevance: In this randomized clinical trial of 3RP-NF vs HEP-NF, benefits from 3RP-NF and HEP-NF were comparable after treatment, but at 12 months from baseline, 3RP-NF was superior to HEP-NF on all primary and secondary outcomes. Results support the implementation of 3RP-NF in routine care. Trial Registration: ClinicalTrials.gov Identifier: NCT03406208.
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Neurofibromatoses , Neoplasias Cutâneas , Humanos , Adulto , Feminino , Qualidade de Vida , Método Simples-Cego , Neurofibromatoses/terapia , Neurofibromatoses/psicologia , Terapia de RelaxamentoRESUMO
BACKGROUND & FOCUS: While the Neurofibromatoses have been observed and classified by their phenotypes for several centuries, their great variability constitutes a considerable challenge in diagnostics and therapy selection. This article focuses on highlighting the three most frequent sub-types NF1, NF2 and NF3. METHODS: All three NF types are outlined by the following measures: the history of their clinical detection, the typical appearance, the underlying genetic constitution and its consequences, the official diagnostic criteria, the mandatory diagnostic steps and finally the treatment opportunities and specific risks. RESULTS: About 50% of NF patients have a positive family history and the other 50% are the first symptomatic generations and suffer from new mutations. A considerable (unknown) number of patients do not exhibit a complete genetic NF constitution, but have a so-called mosaic sub-form with only a limited number of cells being genetically affected and prone to tumorous changes. The neurofibromatoses are neuro-cutaneous diseases with manifestations at the skin and nervous system, except for NF 3, where the skin and eyes are never affected. Skin and eye manifestations, especially pigmentation disturbances, mostly started early in childhood and adolescence. The underlying genetic constitutions, on chromosome 17 in NF1 and on chromosome 22 in NF2 and NF3, cause a defect in tumor suppressor genes and lead to excessive proliferation of Schwann cells. Major features are tumors of the peripheral nerves, including cranial and spinal nerves leading to tumors with considerable nerve, brain and spinal cord compression and resulting in pain, sensory and motor deficits. A further variable disease feature may be neuropathy with neuropathic pain, related to tumor formation or even independent of it.Although benign by histopathology and growing rather slowly, those tumors often cause progressive neurological deficit and loss of function. Loss of function may be prevented by adequate timing of therapy such as nerve decompression by microsurgical tumor resection or reduction, medication with immunotherapy or radiotherapy in selected cases. To date it is unknown why some tumors remained silent and stable while others progress and show periods of accelerated growth.As a consequence, NF patients need to be accompanied by a specialized interdisciplinary NF team at long-term, with a clear-cut standardized protocol for clinical and imaging controls along with counseling and support in decision-making.Further, NF patients may suffer from reactive depression due to the danger of losing essential neural functions, such as vision or audition or movement. And especially NF1 patients show characteristics of ADHS and other cognitive compromise in at least 50% of cases. CONCLUSIONS: As the neurofibromatosis belong to the so-called rare diseases, all patients with a suspicion or diagnosis of NF should get the opportunity to present to an interdisciplinary NF Center, mostly situated at University Hospitals, where competent counseling on the individual disease phenotype may be provided. Here the patients will be informed on the necessary diagnostic steps, their frequency as well as on practical steps in case of acute deterioration. Most NF centers are run by neurosurgeons or neurologists or pediatricians, working in a network with geneticists, neuro-radiologists, ophthalmologists, dermatologists, plastic and general surgeons, psychologists, psychiatrists and social work experts. They participate regularly in neuro-oncological tumor and sarcoma tumor boards, skull base tumor centers, comprehensive hearing centers, and deliver all the treatment opportunities provided by certified brain tumor centers, among those the inclusion in special diagnostic and treatment studies or the contact information to patient support groups.
Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromatose 2 , Humanos , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Neurofibromatose 2/terapia , Neurilemoma/genética , Neurilemoma/patologia , Neurilemoma/cirurgia , Neurofibromatoses/diagnóstico , Neurofibromatoses/genética , Neurofibromatoses/terapiaRESUMO
PURPOSE: Neurofibromatosis (NF) is an incurable genetic neurological condition. Psychosocial interventions that promote resiliency are a promising approach to address the high emotional distress and low quality of life (QoL) associated with NF. However, no studies have examined the psychosocial needs of treatment-seeking adults with NF. Our goal was to explore, using data from the largest efficacy trial of a psychosocial intervention for NF, differences in QoL, emotional distress, resiliency, and pain-related outcomes compared to other chronic medical populations and within subtypes (NF1, NF2, schwannomatosis; SCHW). METHODS: Enrolled participants (N = 228) were geographically diverse adults with NF and elevated stress. We performed secondary analysis on baseline measures of QoL, emotional distress, resiliency, and pain-related outcomes. We reported descriptive statistics and normative comparisons to understand the psychosocial characteristics of the overall sample and performed between-group analyses to explore differences within NF type. RESULTS: Our sample endorsed worse QoL, emotional distress, resilience, and pain-related outcomes than similar chronic illness populations. Within NF types, participants with NF1 reported lower QoL and resilience compared to those with NF2. Participants with SCHW reported higher pain intensity than those with NF1. Participants with SCHW reported higher pain interference and lower physical QoL compared to those with NF1 and NF2. CONCLUSIONS: Our findings support the urgent need for psychosocial interventions targeting deficits in QoL, emotional distress, resilience, and pain-related outcomes in adults with NF. We recommend efforts to enhance sample diversity, prepare clinicians to provide high-levels of support, and attune skills training to each NF type. TRIAL REGISTRATION: ClinicalTrials.gov NCT03406208; https://clinicaltrials.gov/ct2/show/NCT03406208 (Archived by WebCite at http://www.webcitation.org/72ZoTDQ6h ).
Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Adulto , Humanos , Neurilemoma/complicações , Neurofibromatoses/psicologia , Neurofibromatoses/terapia , Neurofibromatose 1/psicologia , Neurofibromatose 2/complicações , Dor/complicações , Qualidade de Vida/psicologiaRESUMO
INTRODUCTION: The neurofibromatoses comprise three different genetic conditions causing considerable morbidity and mortality: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). This review summarizes recent and ongoing clinical trials involving patients with neurofibromatoses to better understand the current state of clinical trial research centered around these conditions and inform areas of need. METHODS: A search was conducted using the Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases. Inclusion and exclusion criteria were designed to identify clinical trials focused on patients with NF1, NF2, or SWN completed in or after 2010 and in process as of December 31, 2021. Information was collected using standardized guidelines. RESULTS: A total of 134 clinical trials were included, with 75 (56%) completed and 59 (44%) in process. For completed trials, 74% (n = 56) involved patients with NF1, and of those based on specific tumors (n = 26, 46%), the majority focused on plexiform neurofibromas (PNs) (n = 12, 46%). For ongoing trials, 79% (n = 47) involve patients with NF1, and of those based on specific tumors (n = 29, 61%), the majority are focused on PNs (n = 13, 45%). CONCLUSION: Both recent and ongoing clinical trials have primarily focused on patients with NF1 and the treatment of PNs. This research has led to the first FDA-approved drug for NF1-PN and has changed management of these tumors, allowing for systemic therapy rather than reliance on only a surgical modality. Trials evaluating comorbid psychiatric conditions and quality of life among patients with any of the neurofibromatoses appear less common. These areas may warrant focus in future studies to improve clinical management.
Assuntos
Neurilemoma , Neurofibroma Plexiforme , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Humanos , Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/complicações , Neurofibromatose 1/terapia , Neurofibromatose 2/genética , Qualidade de Vida , Neoplasias CutâneasRESUMO
A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70-85% of familial schwannomatosis and 30-40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12-14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients' psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.