Auditory brainstem implants for hearing rehabilitation in NF2-schwannomatosis: A systematic review and single-arm meta-analysis.

BACKGROUND: NF2-schwannomatosis (NF2) is an autosomal dominant disorder prone to hearing loss. Auditory brainstem implants (ABIs) offer a promising solution for hearing rehabilitation in NF2. OBJECTIVE: To synthesize existing literature on ABI implantation in NF2, focusing on audiological outcomes and ABI-related complications. METHODS: The systematic review followed PRISMA guidelines and was registered in the PROSPERO database (CRD42022362155). Relevant studies were identified by searching PubMed, EMBASE, CENTRAL, CMB, and CNKI from inception to August 2023. Data on environmental sound discrimination, open-set discrimination, closed-set discrimination, and ABI-related complications were extracted and subjected to meta-analysis. Publication bias was evaluated using funnel plots and Egger's test. RESULTS: Thirty-three studies were included. The pooled estimate was 58% (95% CI 49-66%) for environmental sound discrimination and 55% (95% CI 40-69%) for closed-set discrimination. Regarding open-set discrimination, the pooled estimates were 30% (95% CI 19-42%) for sound only, 46% (95% CI 37-54%) for lip-reading only, and 63% (95% CI 55-70%) for sound plus lip-reading. The pooled occurrence of ABI-related complications was 33% (95% CI 15-52%). CONCLUSION: This meta-analysis underscores the effectiveness and safety of ABIs in NF2, providing valuable insights for evidence-based decision-making and hearing rehabilitation strategies.

The impact of mental health on health-related quality of life in patients with NF2-related Schwannomatosis.

NF2-related schwannomatosis (NF2-SWN) is a rare genetic disorder and is associated with progressive morbidities. This study aimed to investigate the relationship between NF2-SWN disease severity, health-related Quality of Life (QoL), and mental health aspects of patients. Standardised questionnaires assessing mental health problems (symptoms of depression, anxiety, and somatic burden), psychological factors (resilience, loneliness, and personality functioning), and health-related QoL were administered to 97 patients with NF2-SWN. The results of these questionnaires were compared with physician-rated disease severity. Questionnaires were completed by 77 patients. Physician-rated disease severity scores were available for 55 patients. NF2-SWN patients showed a high prevalence of clinically relevant symptoms of depression (30%), anxiety (16%), and somatic burden (32%). Almost all variables showed moderate to high correlations with NF2-SWN-related QoL. NF2-SWN-related QoL was associated with physician-reported disease severity (r = 0.614). In the stepwise hierarchical linear regression analysis, a significant model with four predictors (disease severity type, depression symptoms, personality functioning, and gender) explained 64% of the variance in NF2-SWN-related QoL. Our results showed a strong association between NF2-SWN-related QoL and depression symptoms. Moreover, personality functioning is an important influencing factor, representing a modifiable construct that can be targeted by prevention programs or psychotherapy.

[Neurofibromatosis type 2 in the otorhinolaryngological practice]. / Neirofibromatoz 2-go tipa v praktike vracha-otorinolaringologa.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disease (frequency 1 in 25-90 000) characterized by the formation of tumors of the central nervous system due to a mutation in the NF2 gene on chromosome 22q12. Bilateral vestibular schwannomas are recognized as absolute diagnostic criteria of NF2 and occur in 95% of patients, are accompanied by hearing impairment, manifest at the age of 18-24 years. Skin manifestations can precede vestibular schwannomas for several years and predict the course of the disease: neurofibromas, cafe-au-lait macules, hypopigmented spots, recently described mesh capillary malformations. Despite the benign nature of schwannomas, they can lead to hearing loss, vestibular dysfunction, facial nerve paralysis, gait disorders, pain and convulsions, there is a risk of early death from compression of the brain stem. The probability of progressive hearing loss is partly determined by the type of mutation. We described a clinical case of NF2 in a 21-year-old patient with bilateral vestibular schwannomas without hearing loss, whose skin examination by ENT specialist revealed this disease. The importance of the presented observation is that the doctor should assume neurofibromatosis type 2 in a young patient with bilateral vestibular schwannomas. It is necessary to undertake a further examination of this patient, including: skin examination for the identification of characteristic neurofibromas and cafe-au-lait macules, consultation with an ophthalmologist, neurologist, MRI of the brain and spinal cord with contrast, genetic analysis - for timely initiation of therapy that prevents hearing loss and vestibular disorders.

Patient-reported measures of tinnitus for individuals with neurofibromatosis type 2-related schwannomatosis: Recommendations for clinical trials.

BACKGROUND: Neurofibromatosis type 2-related schwannomatosis is a genetic disease characterized by the development of bilateral vestibular schwannomas, ependymomas, meningiomas, and cataracts. Mild to profound hearing loss and tinnitus are common symptoms reported by individuals with neurofibromatosis type 2. While tinnitus is known to have a significant and negative impact on the quality of life of individuals from the general population, the impact on individuals with neurofibromatosis type 2 is unknown. Consensus regarding the selection of suitable patient-reported outcome measures for assessment could advance further research into tinnitus in neurofibromatosis type 2 patients. The purpose of this work is to achieve a consensus recommendation by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration for patient-reported outcome measures used to evaluate quality of life in the domain of tinnitus for neurofibromatosis type 2 clinical trials. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis Patient-Reported Outcomes Communication Subgroup systematically evaluated patient-reported outcome measures of quality of life in the domain of tinnitus for individuals with neurofibromatosis type 2 using previously published Response Evaluation in Neurofibromatosis and Schwannomatosis rating procedures. Of the 19 identified patient-reported outcome measures, 3 measures were excluded because they were not validated as an outcome measure or could not have been used as a single outcome measure for a clinical trial. Sixteen published patient-reported outcome measures for the domain of tinnitus were scored and compared on their participant characteristics, item content, psychometric properties, and feasibility for use in clinical trials. RESULTS: The Tinnitus Functional Index was identified as the most highly rated measure for the assessment of tinnitus in populations with neurofibromatosis type 2, due to strengths in the areas of item content, psychometric properties, feasibility, and available scores. DISCUSSION: Response Evaluation in Neurofibromatosis and Schwannomatosis currently recommends the Tinnitus Functional Index for the assessment of tinnitus in neurofibromatosis type 2 clinical trials.

Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis.

Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

Imaging as an early biomarker to predict sensitivity to everolimus for progressive NF2-related vestibular schwannoma.

PURPOSE: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory. METHODS: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL). RESULTS: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores. CONCLUSIONS: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

Characteristics of MicroRNA Expression Depending on the Presence or Absence of Meningioma in Patients with Neurofibromatosis Type 2: A Secondary Analysis.

Meningioma is the second most frequent tumor in patients with neurofibromatosis type 2 (NF2). The presence of meningioma is believed to be a negative prognostic marker in these patients. However, the molecular mechanisms involved in the tumorigenesis of NF2-associated meningioma are not well characterized. Epigenetic regulation, including microRNAs (miRNAs), may be involved in the development of different tumor types in patients with NF2. The objective of this study is to explore the different characteristics of serum miRNA expression depending on the presence or absence of meningioma in patients with NF2. Nine patients with NF2 who were treated at the Department of Neurosurgery, Hiroshima University Hospital, were included. Total RNA (including small RNAs) was extracted from serum samples for the preparation of a small RNA library for next-generation sequencing analysis. Differentially expressed miRNAs (DEMs) were analyzed using the DESeq2 package to compare the characteristic miRNA expression profiles of patients with and without meningioma. In small RNA sequencing analysis, out of a total of 1,879 miRNAs registered in the database, the expressions of 657 miRNAs were observed. In DEM analysis, the expressions of four miRNAs, namely, hsa-miR-664b, hsa-miR-7706, hsa-miR-590, and hsa-miR-6513, were downregulated in patients with NF2 with meningioma compared with patients with NF2 without meningioma. Hsa-miR-193a was identified as the only upregulated miRNA in patients with NF2 with meningioma. In conclusion, we identified different circulating miRNA expression characteristics depending on the presence or absence of meningioma in patients with NF2.

Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance.

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Neurofibromatosis Type II and Facial Paralysis: Clinical Evaluation and Management.

BACKGROUND: Facial paralysis secondary to neurofibromatosis type 2 (NF2) presents the reconstructive surgeon with unique challenges because of its pathognomonic feature of bilateral acoustic neuromas, involvement of multiple cranial nerves, use of antineoplastic agents, and management. Facial reanimation literature on managing this patient population is scant. METHODS: A comprehensive literature review was performed. All patients with NF2-related facial paralysis who presented in the past 13 years were reviewed retrospectively for type and degree of paralysis, NF2 sequelae, number of cranial nerves involved, interventional modalities, and surgical notes. RESULTS: Twelve patients with NF2-related facial paralysis were identified. All patients presented after resection of vestibular schwannoma. Mean duration of weakness before surgical intervention was 8 months. On presentation, one patient had bilateral facial weakness, 11 had multiple cranial nerve involvement, and seven were treated with antineoplastic agents. Two patients underwent gracilis free functional muscle transfer, five underwent masseteric-to-facial nerve transfer (of whom two were dually innervated with a crossfacial nerve graft), and one patient underwent depressor anguli oris myectomy. Trigeminal schwannomas did not affect reconstructive outcomes if trigeminal nerve motor function on clinical examination was normal. In addition, antineoplastic agents such as bevacizumab and temsirolimus did not affect outcomes if stopped in the perioperative period. CONCLUSIONS: Effectively managing patients with NF2-related facial paralysis necessitates understanding the progressive and systemic nature of the disease, bilateral facial nerve and multiple cranial nerve involvement, and common antineoplastic treatments. Neither antineoplastic agents nor trigeminal nerve schwannomas associated with normal examination affected outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Recommendations for the collection and annotation of biosamples for analysis of biomarkers in neurofibromatosis and schwannomatosis clinical trials.

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.

Sporadic vestibular schwannoma in a pediatric population: a case series.

PURPOSE: To describe the characteristics, management, and outcomes of pediatric patients with sporadic vestibular schwannoma (sVS). METHODS: This was a case series at a tertiary care center. Patients were identified through a research repository and chart review. Interventions were microsurgery, stereotactic radiosurgery (SRS), and observation. Outcome measures were tumor control, facial nerve function, and hearing. RESULTS: Eight patients over 2006-2022 fulfilled inclusion criteria (unilateral VS without genetic or clinical evidence of neurofibromatosis type 2 (NF2); age ≤ 21) with a mean age of 17 years (14-20). Average greatest tumor length in the internal auditory canal was 9.7 mm (4.0-16.1). Average greatest tumor dimension (4/8 tumors) in the cerebellopontine angle was 19.1 mm (11.3-26.8). Primary treatment was microsurgery in five (62.5%) patients, observation in two (25%), and SRS in one (12.5%). Four (80%) surgical patients had gross total resections, and one (20%) had regrowth post-near total resection and underwent SRS. One observed patient and the primary SRS patient have remained radiographically stable for 3.5 and 7 years, respectively. The other observed patient required surgery for tumor growth after 12 months of observation. Two surgical patients had poor facial nerve outcomes. All post-procedural patients developed anacusis. Mean follow-up was 3 years (0.5-7). CONCLUSIONS: We describe one of the largest reported cohorts of pediatric sVS in the USA. Diligent exclusion of NF2 is critical. Given the high likelihood of eventually requiring intervention and known adverse effects of SRS, microsurgery remains the preferred treatment. However, observation can be considered in select situations.

Perspectives of adults with neurofibromatosis regarding the design of psychosocial trials: Results from an anonymous online survey.

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.

Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials.

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.

Comparing Speech Recognition Outcomes Between Cochlear Implants and Auditory Brainstem Implants in Patients With NF2-Related Schwannomatosis.

OBJECTIVE: To compare cochlear implant (CI) and auditory brainstem implant (ABI) performance in patients with NF2-related schwannomatosis (NF2). STUDY DESIGN: Historical cohort. SETTING: Tertiary academic center. PATIENTS: A total of 58 devices among 48 patients were studied, including 27 ABIs implanted from 1997 to 2022 and 31 CIs implanted from 2003 to 2022. Three patients had bilateral ABIs, three had bilateral CIs, three had an ABI on one side and a CI on the other, one had a CI that was later replaced with an ipsilateral ABI, and one had an ABI and CI concurrently on the same side. INTERVENTIONS: CI or ABI ipsilateral to vestibular schwannoma. MAIN OUTCOME MEASURES: Open-set speech perception, consonant-nucleus-consonant word scores, and AzBio sentence in quiet scores. RESULTS: Among all patients, 27 (47%) achieved open-set speech perception, with 35 (61%) daily users at a median of 24 months (interquartile range [IQR], 12-87 mo) after implantation. Comparing outcomes, CIs significantly outperformed ABIs; 24 (77%) CIs achieved open-set speech perception compared with 3 (12%) ABIs, with median consonant-nucleus-consonant and AzBio scores of 31% (IQR, 0-52%) and 57% (IQR, 5-83%), respectively, for CIs, compared with 0% (IQR, 0-0%) and 0% (IQR, 0-0%), respectively, for ABIs. Patients with ABIs were younger at diagnosis and at implantation, had larger tumors, and were more likely to have postoperative facial paresis. CONCLUSION: Many patients with NF2-associated vestibular schwannoma achieved auditory benefit with either a CI or an ABI; however, outcomes were significantly better in those patients who were able to receive a CI. When disease and anatomy permit, hearing rehabilitation with a CI should be considered over an ABI in these patients. Tumor management strategies that increase the ability to successfully use CIs should be strongly considered given the high risk of losing bilateral functional acoustic hearing in this population.

Long-term outcomes of stereotactic radiosurgery for intracranial schwannoma in neurofibromatosis type 2: a genetic analysis perspective.

PURPOSE: Neurofibromatosis type 2 (NF2) is intractable because of multiple tumors involving the nervous system and is clinically diverse and genotype-dependent. Stereotactic radiosurgery (SRS) for NF2-associated schwannomas remains controversial. We aimed to investigate the association between radiosurgical outcomes and mutation types in NF2-associated schwannomas. METHODS: This single-institute retrospective study included consecutive NF2 patients with intracranial schwannomas treated with SRS. The patients' types of germline mutations ("Truncating," "Large deletion," "Splice site," "Missense," and "Mosaic") and Halliday's genetic severity scores were examined, and the associations with progression-free rate (PFR) and overall survival (OS) were analyzed. RESULTS: The study enrolled 14 patients with NF2 with 22 associated intracranial schwannomas (median follow-up, 102 months).　The PFRs in the entire cohort were 95% at 5 years and 90% at 10-20 years. The PFRs tended to be worse in patients with truncating mutation exons 2-13 than in those with other mutation types (91% at 5 years and 82% at 10-20 years vs. 100% at 10-20 years, P = 0.140). The OSs were 89% for patients aged 40 years and 74% for those aged 60 years in the entire cohort and significantly lower in genetic severity group 3 than in the other groups (100% vs. 50% for those aged 35 years; P = 0.016). CONCLUSION: SRS achieved excellent PFR for NF2-associated intracranial schwannomas in the mild (group 2A) and moderate (group 2B) groups. SRS necessitates careful consideration for the severe group (group 3), especially in cases with NF2 truncating mutation exons 2-13.

Identification of hub genes and drug candidates for NF2-related vestibular schwannoma by bioinformatics tools.

Neurofibromatosis type 2 (NF2)-related vestibular schwannoma (NF2-VS) is a rare genetic disorder that results in bilateral acoustic neuromas. However, the exact pathogenesis of the disease is still unclear. This study aims to use bioinformatics analyses to identify potential hub genes and therapeutic. We retrieved the mRNA expression profiles (GSE108524 and GSE141801) of NF2-VS from the database, and selected the leading 25% genes with the most variance across samples for weighted correlation network analysis. Subsequently, we conducted gene ontology term and Kyoto Encyclopedia of Genes and Genomes signaling network enrichment analyses. The STRING database was employed for protein-protein interaction (PPI) axis construction. The mRNA-miRNA modulatory network was generated via the miRTarBase database. Differentially expressed genes (DEGs) were identified via the R package "limma" in both datasets, and hub genes were screened via intersection of common DEGs, candidate hub genes from the PPI axis, and candidate hub genes from the key module. Finally, common DEGs were uploaded onto the connectivity map database to determine drug candidates. Based on our observations, the blue module exhibited the most significant relation to NF2-VS, and it included the NF2 gene. Using enrichment analysis, we demonstrated that the blue modules were intricately linked to modulations of cell proliferation, migration, adhesion, junction, and actin skeleton. Overall, 356 common DEGs were screened in both datasets, and 33 genes carrying a degree > 15 were chosen as candidate hub genes in the PPI axis. Subsequently, 4 genes, namely, GLUL, CAV1, MYH11, and CCND1 were recognized as real hub genes. In addition, 10 drugs with enrichment scores < -0.7 were identified as drug candidates. Our conclusions offered a novel insight into the potential underlying mechanisms behind NF2-VS. These findings may facilitate the identification of novel therapeutic targets in the future.

Resiliency outcomes after participation in an asynchronous web-based platform for adults with neurofibromatosis: The NF-Web study.

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.

Extraordinary Speech and Language Outcomes After Auditory Brainstem Implantation: Guidance From a Case Study.

PURPOSE: Large individual differences and poor speech recognition outcomes are routinely observed in most patients who have received auditory brainstem implants (ABIs). A case report of an ABI recipient with exceptionally good speech recognition outcomes presents an opportunity to better understand the core information processing mechanisms that underlie variability and individual differences in outcomes. METHOD: A case study is reported of an adult ABI recipient (ID-006) with postlingually acquired, Neurofibromatosis Type 2 (NF2)-related hearing loss who displayed exceptional postoperative speech recognition scores. A novel battery of assessment measures was used to evaluate ID-006's auditory, cognitive, and linguistic information processing skills. RESULTS: Seventeen years following ABI activation, ID-006 scored 77.6% correct on the AzBio Sentences in quiet. On auditory processing tasks, ID-006 scored higher on tasks with meaningful sentences and much lower on tasks that relied exclusively on audibility. ID-006 also demonstrated exceptionally strong abilities on several cognitive and linguistic information processing tasks. CONCLUSIONS: Results from a novel battery of information processing tests suggest that ID-006 relies extensively on top-down predictive processing and cognitive control strategies to efficiently encode and process auditory information provided by his ABI. Results suggest that current measures of outcomes and benefits should be expanded beyond conventional speech recognition measures to include more sensitive and robust measures of speech recognition as well as neurocognitive measures such as executive function, working memory, and lexical access.

Bilateral intracochlear schwannomas: histopathological confirmation and outcomes following tumour removal and cochlear implantation with lateral wall electrodes.

Intracochlear schwannomas (ICS) are very rare benign tumours of the inner ear. We present histopathological proof of the extremely rare bilateral occurrence of intracochlear schwannomas with negative blood genetic testing for neurofibromatosis type 2 (NF2). Bilateral schwannomas are typically associated with the condition NF2 and this case is presumed to have either mosaicism for NF2 or sporadic development of bilateral tumours. For progressive bilateral tumour growth and associated profound hearing loss, surgical intervention via partial cochleoectomy, tumour removal, preservation of the modiolus, and simultaneous cochlear implantation with lateral wall electrode carrier with basal double electrode contacts was performed. The right side was operated on first with a 14-month gap between each side. The hearing in aided speech recognition for consonant-nucleus-consonant (CNC) phonemes in quiet improved from 57% to 83% 12 months after bilateral cochlear implantation (CI). Bilateral intracochlear schwannomas in non-NF2 patients are extremely rare but should be considered in cases of progressive bilateral hearing loss. Successful tumour removal and cochlear implantation utilizing a lateral wall electrode is possible and can achieve good hearing outcomes.