BACKGROUND: For patients with neurofibromatosis type 2 (NF2), maintaining an independent state of living is important. The present study aimed to examine the loss of social independence (i.e., a status that patients can work and go to school) and its contributing factors in patients with NF2 using data from a national registry in Japan.
METHODS: This longitudinal study used a registry database containing information on patients with NF2 who had submitted initial claims to receive medical expense subsidies between 2004 and 2010. Patients with \"employed,\" \"studying,\" and \"housekeeping\" categories were classified as \"socially independent.\" Patients who were socially independent at baseline were followed-up for up to nine years. The primary outcome of the present study was the loss of social independence during the follow-up period, which was defined as the change in status from being socially independent to socially dependent. First, we examined longitudinal associations between demographic variables and neurological symptoms at baseline and the loss of social independence. Second, we examined whether the occurrence of neurological symptoms is associated with a loss of social independence in patients.
RESULTS: A total of 156 patients were included in the present study. During the follow-up period, 37 (23.7%) patients experienced a loss of social independence. In the first analysis, the multivariate logistic regression model showed that the loss of social independence was significantly more frequent among patients with spinal dysfunction than among patients without. In the second analysis, logistic regression analyses showed that neurological symptoms, including bilateral hearing loss, facial nerve palsy, cerebellar dysfunction, decreased facial sensation, speech dysfunction (dysphagia/dysarthria and aphasia), double vision, blindness, hemiparesis, and seizures, were significantly associated with loss of social independence.
CONCLUSIONS: The occurrence of various neurological symptoms of NF2 can hinder social independence in the long term. Medical service providers need to observe patients while considering the risks, and provide appropriate support to address neurological symptoms that can restrict social independence, as this will lead to maintaining social engagement.

OBJECTIVE: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant syndrome associated primarily with bilateral vestibular schwannomas (VSs). Conventional surgical or radiosurgical treatments for VS in NF2 usually result in high risks of hearing loss and facial nerve impairment, while there is no validated medical option to date. This single-institution phase II study evaluated the efficacy and safety of icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with NF2 and progressive VS.
METHODS: Icotinib was administered daily at 375 mg orally in a continuous 28-day course for up to 12 courses. The primary endpoint of the study was radiographic response assessed by brain MRI using 3D volumetric tumor analysis and defined as a ≥ 20% decrease in VS volume. Hearing function was evaluated as a secondary endpoint, with response defined as a statistically significant increase in word recognition scores.
RESULTS: Ten eligible patients with a mean age of 23.8 years were enrolled. One patient (10%) with bilateral tumors experienced an objective radiographic response (-23.58% and -22.01%). Three (43%) of 7 patients met the hearing response criteria. At 12 months, the estimated progression-free survival was 82.0% (95% CI 42.3%-95.5%) for volumetric progression and 69.2% (95% CI 37.3%-87.2%) for hearing progression. Common mild to moderate adverse events included rash (90%), diarrhea (50%), myalgia (20%), and nausea/gastrointestinal pain (20%).
CONCLUSIONS: Icotinib carries minor toxicity and is associated with radiographic and hearing responses in patients with NF2 and progressive VS.

Objective  Meningiomas are the second most common tumors in neurofibromatosis type 2 (NF-2). Microsurgery is challenging in NF-2 patients presenting with skull base meningiomas due to the intrinsic risks and need for multiple interventions over time. We analyzed treatment outcomes and complications after primary Gamma Knife radiosurgery (GKRS) to delineate its role in the management of these tumors. Methods  An international multicenter retrospective study approved by the International Radiosurgery Research Foundation was performed. NF-2 patients with at least one growing and/or symptomatic skull base meningioma and 6-month follow-up after primary GKRS were included. Clinical and radiosurgical parameters were recorded for analysis. Results  In total, 22 NF-2 patients with 54 skull base meningiomas receiving GKRS as primary treatment met inclusion criteria. Median age at GKRS was 38 years (10-79 years). Most lesions were located in the posterior fossa (55.6%). Actuarial progression free survival (PFS) rates were 98.1% at 2 years and 90.0% at 5 and 10 years. The median follow-up time after initial GKRS was 5.0 years (0.6-25.5 years). Tumor volume at GKRS was a predictor of tumor control. Lesions >5.5 cc presented higher chances to progress after radiosurgery ( p  = 0.043). Three patients (13.64%) developed adverse radiation effects. No malignant transformation or death due to meningioma or radiosurgery was reported. Conclusions  GKRS is effective and safe in the management of skull base meningiomas in NF-2 patients. Tumor volume deserve greater relevance during clinical decision-making regarding the most appropriate time to treat. GKRS offers a minimally invasive approach of particular interest in this specific group of patients.

The objective of this study was to explore serum microRNA (miRNA) profile characteristic of patients with neurofibromatosis type 2 (NF2), including both sporadic and familial cases, by comprehensive analysis of miRNA expression using next-generation sequencing.
Nine patients with NF2 were included in this study. In addition, 7 patients with unilateral acoustic neuroma without a family history of NF2 were invited to participate as the control cohort in the study. Total RNA including the small RNAs was extracted from serum. We comprehensively analyzed the expression of miRNAs using next-generation sequencing, and differentially expressed miRNAs (DEMs) were analyzed. Biological implications of DEMs were analyzed by Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis.
Distinctive miRNA profiles (16 miRNAs were significantly downregulated, and 4 miRNAs were significantly upregulated) were observed in the comparison between all patients with NF2 and controls. In the NF2 subgroup analysis, 23 miRNAs (including hsa-miR-let7b, hsa-miR-let7c, and hsa-miR-200a) and 7 miRNAs (including hsa-miR-193b) were identified as specifically downregulated miRNAs in sporadic NF2 and familial NF2, respectively. Moreover, hsa-miR-193a and hsa-miR-504 were identified as specifically upregulated miRNAs in sporadic NF2 and familial NF2, respectively. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis showed that identified DEMs were mainly enriched in gene silencing by miRNA, miRNAs in cancer, and regulation of angiogenesis.
We were able to identify distinctive miRNA profiles in the serum of patients with NF2, including both sporadic and familial cases, by comprehensive miRNA expression analysis using miRNA sequencing.

OBJECTIVE: The management of neurofibromatosis type 2 (NF2)-associated meningiomas is challenging. The role of Gamma Knife radiosurgery (GKRS) in the treatment of these tumors remains to be fully defined. In this study, the authors aimed to examine the role of GKRS in the treatment of NF2-associated meningiomas and to evaluate the outcomes and complications after treatment.
METHODS: Seven international medical centers contributed data for this retrospective cohort. Tumor progression was defined as a ≥ 20% increase from the baseline value. The clinical features, treatment details, outcomes, and complications were studied. The median follow-up was 8.5 years (range 0.6-25.5 years) from the time of initial GKRS. Shared frailty Cox regression was used for analysis.
RESULTS: A total of 204 meningiomas in 39 patients treated with GKRS were analyzed. Cox regression analysis showed that increasing the maximum dose (p = 0.02; HR 12.2, 95% CI 1.287-116.7) and a lower number of meningiomas at presentation (p = 0.03; HR 0.9, 95% CI 0.821-0.990) were predictive of better tumor control in both univariable and multivariable settings. Age at onset, sex, margin dose, location, and presence of neurological deficit were not predictive of tumor progression. The cumulative 10-year progression-free survival was 94.8%. Radiation-induced adverse effects were noted in 4 patients (10%); these were transient and managed medically. No post-GKRS malignant transformation was noted in 287 person-years of follow-up.
CONCLUSIONS: GKRS achieved effective tumor control with a low and generally acceptable rate of complications in NF2-associated meningiomas. There did not appear to be an appreciable risk of post-GKRS-induced malignancy in patients with NF2-treated meningiomas.

Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor\'s growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab\'s efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.

Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity.
This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD.
Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached).
Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors.
NCT01129193, registered 5/24/2010.

Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design.
A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death.
Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting <16 and >40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004).
Understanding disease course improves prognostication, allowing for better-informed decisions about care.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare, progressive and incurable genetic disorder associated with progressive hearing loss and eventual deafness. As a group, patients with NF report high levels of stress and depressive symptoms. However, no studies have explored improvement in these symptoms after psychosocial interventions. We have previously shown that a mind-body program tailored to adults with NF2 who are deaf (the Relaxation Response and Resiliency Program for Deaf NF2, d3RP-NF2) improves quality of life and resiliency over and above a Health Enhancement program when both are delivered via live-video and assisted by Communication Access Realtime Translation (CART). Here we tested the effects of the programs on depression and perceived stress.
METHODS: Forty-five patients with NF2 and significant hearing loss were randomized to the d3RP-NF2 or Health-Enhancement program and completed measures of depression (PHQ-9) and perceived stress (PSS-10) at baseline, post-intervention, and six-month follow-up.
RESULTS: Patients randomized to the d3RP-NF2 program, but not to the control condition, experienced significant decreases on both measures from baseline to post-test, which were maintained at follow-up (within group tests). However, improvements following the d3RP-NF2 program was not significantly higher than those observed in the control group (between group tests).
CONCLUSIONS: Results provide the first evidence of improvement in symptoms of depression and perceived stress among deaf patients living with NF2 who participate in a virtual mind-body program.

There is no dedicated study on outcome after meningioma surgery in neurofibromatosis type 2 (NF2) patients.
We processed the French Système National des Données de Santé (SNDS) database using an algorithm combining the type of surgical procedure and the International Classification of Diseases to retrieve cases of meningioma operated in NF2 patients between 2007 and 2017. Descriptive and survival analyses were performed.
This nationwide study found 184 patients who were operated on for 315 meningiomas over a 10-year period. 57.6 % were female, median age at first surgery was 40 years IQR[24.8-50.2] and 10.9 % were under 18 years. Cranial convexity (23.4 %) and posterior skull base (16.8 %) were the most common locations. 89.7 % of the tumours were benign and 3.3 % malignant. 16.3 % of the patient received radiotherapy and 13.6 % stereotactic radiosurgery. Median follow-up was 6.3 years, IQR[5.3-7]. At data collection, 28 patients were dead (15.2 %) and median age at death was 41.7 years, IQR [32.7-50.4]. 5 patients died within the year of meningioma surgery. OS rates at 5 and 10 years were: 87.8 %, 95 %CI[82.6-93.3] and 73.2 %, 95 %CI[63.7-84.1] respectively. In univariable Cox regression analysis, Mortality-Related Morbidity Index (MRMI) (HR = 1.57, 95 %CI[1.3-1.9], p < 0.001) Expenditure-Related Morbidity Index (HR1.16, 95 %CI[1.09-1.24], p < 0.001), a malignant meningioma (HR=8.15, 95 %CI[2.78-23.85], p < 0.001), and a diagnosis of deafness or vestibular schwannoma (HR=2.52, 95 %CI[1.02-6.23], p = 0.0447), were associated to the outcome. In multivariable analysis, solely the MRMI and a malignant meningioma remained significant predictors of reduce OS.
Using this unique database, we found that outcome of NF2 patients after meningioma surgery is impaired, especially for those with significant co-morbidities and affected by a malignant meningioma.