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Neurofibromatosis type 2 (NF2) is a rare disorder that causes vestibular schwannomas (VS), meningiomas and ependymomas. To date, there is no FDA approved drug-based treatment for NF2. We have previously identified that BET inhibition can selectively reduce growth of the NF2-null schwannoma and Schwann cells in vitro and tumorigenesis in vivo and, separately, reported that inhibition of Focal Adhesion Kinase 1 (FAK1) via crizotinib has antiproliferative effects in NF2-null Schwann cells. The current study was aimed at determining whether combined BET and FAK inhibition can synergize and to identify the mechanisms of action. A panel of normal and NF2-null Schwann and schwannoma cell lines were used to characterize the effects of combined BET and FAK inhibition in vitro and in vivo using pharmacological and genetic approaches. The mechanism of action was explored by chromatin immunoprecipitation, ChIP-PCR, western blotting, and functional approaches. We find that combined BET and FAK inhibition are synergistic and inhibit the proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo, by arresting cells in the G1/S and G2/M phases of the cell cycle. Further, we identify the mechanism of action through the downregulation of FAK1 transcription by BET inhibition, which potentiates inhibition of FAK by 100-fold. Our findings suggest that combined targeting of BET and FAK1 may offer a potential therapeutic option for the treatment of NF2-related schwannomas., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Our goal was to develop a 3D tumor slice model, replicating the individual tumor microenvironment and for individual pharmaceutical testing in vestibular schwannomas with and without relation to NF2., Methods: Tissue samples from 16 VS patients (14 sporadic, 2 NF2-related) were prospectively analyzed. Slices of 350 µm thickness were cultured in vitro, and the 3D tumor slice model underwent thorough evaluation for culturing time, microenvironment characteristics, morphology, apoptosis, and proliferation rates. Common drugs - Lapatinib (10 µM), Nilotinib (20 µM), and Bevacizumab (10 µg/ml) - known for their responses in VS were used for treatment. Treatment responses were assessed using CC3 as an apoptosis marker and Ki67 as a proliferation marker. Standard 2D cell culture models of the same tumors served as controls., Results: The 3D tumor slice model accurately mimicked VS ex vivo, maintaining stability for three months. Cell count within the model was approximately tenfold higher than in standard cell culture, and the tumor microenvironment remained stable for 46 days. Pharmacological testing was feasible for up to three weeks, revealing interindividual differences in treatment response to Lapatinib and intraindividual variability in response to Lapatinib and Nilotinib. The observed effects were less pronounced in tumor slices than in standard cell culture, indicating the model's proximity to in vivo tumor biology and enhanced realism. Bevacizumab had limited impact in both models., Conclusion: This study introduces a 3D tumor slice model for sporadic and NF2-related VS, demonstrating stability for up to 3 months, replication of the schwannoma microenvironment, and utility for individualized pharmacological testing., Competing Interests: Declaration of Competing Interest Nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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)., (© 2024. The Author(s).)

Purpose: Patients with vestibular schwannoma undergoing definitive radiotherapy commonly experience hearing loss due to tumor and treatment effects; however, there is limited data evaluating concurrent medication use and other clinicopathologic factors associated with hearing preservation during and after radiotherapy. We performed a retrospective cohort study reviewing consecutive patients from 2004 to 2019 treated with radiotherapy for vestibular schwannoma at our institution., Methods: Ninety four patients with concurrent medications, baseline audiograms, and post-radiotherapy audiograms available were evaluable. We performed chi-squared analyses of the frequency of various clinicopathologic factors and t-tests evaluating the degree of hearing loss based on audiograms., Results: At a median follow-up of 35.7 months (mean: 46.5 months), the baseline pure-tone average (PTA) of the ipsilateral ear worsened from 38.4 to 59.5 dB following completion of radiotherapy (difference: 21.1, 95% CI 17.8-24.4 dB, p < 0.001). 36 patients (38.3%) reported regular use of cyclooxygenase (COX) inhibitors (including acetaminophen and NSAIDs) during radiotherapy. The mean increase in PTA was significantly higher for patients taking COX inhibitors (25.8 dB vs 18.1 dB, p = 0.024) in the ipsilateral ear but not for the contralateral side. COX inhibitor use remained independently associated with worse PTA in the multivariate analysis., Conclusion: COX inhibitor use during definitive radiotherapy is associated with worse hearing loss in the affected ear but not for the contralateral side. This suggests the ototoxic effects of COX inhibitors may influence the effects of radiotherapy. These results could have clinical implications and warrant further investigation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To systematically review and evaluate metformin's potential impact on vestibular schwannoma (VS) growth., Data Sources: PubMed, Cochrane Library, and Embase., Review Methods: A retrospective cohort study was performed on sporadic VS patients undergoing initial observation who had at least two magnetic resonance imaging studies. Patients were stratified by metformin use during the observation period. Primary endpoint was VS growth, defined as at least a 2 mm increase in diameter. Survival free of tumor growth was evaluated between groups. Systematic review and meta-analysis were performed to produce a pooled odds ratio [OR]. Study heterogeneity was assessed and post-hoc power analysis was performed., Results: A total of 123 patients were included, of which 17% were taking metformin. Median patient age was 56.6 years (range, 25.1-84.5). There were no statistically significant differences between the groups. Survival analysis did not demonstrate a statistically significant difference in time to VS growth between groups (hazard ratio = 0.61, 95% confidence interval [CI] = 0.29-1.29). Furthermore, logistic regression analysis did not demonstrate a statistically significant difference between groups in the odds of VS growth (OR = 0.46, 95% CI = 0.17-1.27). Systematic review identified 3 studies. Meta-analysis suggested that metformin reduces the odds of developing VS growth (pooled OR = 0.45, 95% CI = 0.29-0.71). Studies demonstrated low between-study heterogeneity. Power analysis demonstrated a sample size of 220 patients with equal randomization would be required to prospectively identify a true difference with 80% power., Conclusions: Metformin use may reduce the odds of VS growth. A randomized trial would be ideal to identify an unbiased estimate of metformin's effect on VS growth. Laryngoscope, 133:2066-2072, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: The objectives of this study are to (i) estimate the incidence of vestibular schwannoma (VS) among patients in an integrated healthcare system who present for evaluation of sudden sensorineural hearing loss (SSNHL) and (ii) evaluate the efficacy of empiric steroid therapy on audiologic recovery among SSNHL patients ultimately diagnosed with VS., Methods: A retrospective chart review was performed on patients presenting with SSNHL in 2021 at a multicenter integrated healthcare system serving over 4 million members. Patient demographics, audiometric data, VS diagnosis, therapeutic steroid intervention, and data regarding treatment response were recorded. A clinically significant audiometric improvement was defined as (i) an increase of 15% in word recognition score, (ii) a decrease of 15 dB in four-frequency pure-tone average (PTA) using frequencies of 500, 1000, 2000, and 4000 Hz, or (iii) a PTA of <20 dB on follow-up audiogram., Results: Six hundred fifty-eight patients were reviewed, of which 309 (56.0% male; mean, 57.5 years) met the inclusion criteria with audiometric data and magnetic resonance imaging data. Ten patients (70.0% male; mean, 51.3 years) were found to have VS. Of these, five patients received oral steroid therapy alone, and five had combination therapy (oral + intratympanic steroid injections). No patients received intratympanic steroid therapy alone. Median PTA improvement with steroid therapy was 3.1-dB hearing loss, and median word recognition score improvement was 16.5%. Six of 10 patients demonstrated clinically significant audiometric improvement with steroid therapy., Conclusion: This study represents the largest US-based study showcasing the prevalence of VS in patients originally presenting with SSNHL. It also reinforces previous findings that VS does not preclude trials of steroid therapy., Competing Interests: Funding and conflicts of interest: None to disclose. No sources of support or funding., (Copyright © 2023, Otology & Neurotology, Inc.)

Background: Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS)., Methods: Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline., Results: Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events., Conclusions: Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose of Review: Neurofibromatosis 2 (NF2) is an autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas (VS), meningiomas, ependymomas, spinal and peripheral schwannomas, optic gliomas, and juvenile cataracts. Ongoing studies provide new insight into the role of the NF2 gene and merlin in VS tumorigenesis., Recent Findings: As NF2 tumor biology becomes increasingly understood, therapeutics targeting specific molecular pathways have been developed and evaluated in preclinical and clinical studies. NF2-associated VS are a source of significant morbidity with current treatments including surgery, radiation, and observation. Currently, there are no FDA-approved medical therapies for VS, and the development of selective therapeutics is a high priority. This manuscript reviews NF2 tumor biology and current therapeutics undergoing investigation for treatment of patients with VS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Few investigations have been conducted on the clinical characteristics of the differential diagnosis of acoustic neuroma with acute sensorineural hearing loss and idiopathic sudden sensorineural hearing loss. The aim of the study was to investigate the clinical characteristics of the differential diagnoses between acoustic neuroma and idiopathic sudden sensorineural hearing loss., Methods: The medical records of patients with acute sensorineural hearing loss (142 ears), including acoustic neuroma (19 ears) and idiopathic sudden sensorineural hearing loss (123 ears), who underwent audiometric and hematologic examinations and received systemic corticosteroid treatment, were retrospectively reviewed., Results: Hematological examination revealed that the erythrocyte sedimentation rate and fibrinogen values were significantly higher in the idiopathic sudden sensorineural hearing loss group compared to the acoustic neuroma group. Although all patients received corticosteroid treatment, hearing thresholds at the initial examination and 3 months after corticosteroid treatment were significantly higher in the idiopathic sudden sensorineural hearing loss group compared to the acoustic neuroma group at all frequencies. However, hearing recovery was worse in the acoustic neuroma group compared to the idiopathic sudden sensorineural hearing loss group. Furthermore, speech discrimination and short increment sensitivity index tests were not significantly different between the acoustic neuroma and idiopathic sudden sensorineural hearing loss groups., Conclusion: This is the first study to reveal that speech discrimination and short increment sensitivity index tests are not useful for the differential diagnoses between acoustic neuroma and idiopathic sudden sensorineural hearing loss, whereas erythrocyte sedimentation rate and fibrinogen, blood biomarkers of inflammation and blood viscosity, would be considered valuable. Furthermore, acoustic neuroma should be considered in cases where acute sensorineural hearing loss did not recover after corticosteroid treatment, although the initial hearing loss was mild.

Objective: To identify factors associated with prolonged tracheal extubation after vestibular schwannoma resection in patients receiving propofol-remifentanil-based total intravenous anesthesia (TIVA)., Study Design: Single-center retrospective study of vestibular schwannoma resection performed by a single neurosurgeon between July 2018 and September 2021., Setting: Tertiary academic medical center., Patients: Adults receiving TIVA for vestibular schwannoma resection, classified according to extubation time: non-prolonged extubation (<15 min) and prolonged extubation (≥15 min)., Main Outcome Measures: Time from end of surgery to extubation, demographic parameters, intraoperative variables, and familiarity between the anesthesia provider and the neurosurgeon were analyzed. Predictors for prolonged extubation were analyzed via multivariate analysis. The primary outcome was the incidence of prolonged extubation. The secondary outcome was factors associated with prolonged tracheal extubation., Results: A total of 234 cases were analyzed. The median (interquartile range) extubation time was 9.4 minutes (7.2, 12.2 min). Extubation was prolonged in 39 patients (16.7%). Factors predicting prolonged extubation were significant blood loss (odds ratio [OR], 12.8; 95% confidence interval [CI], 2.6-61.7; p = 0.002), intraoperative neuromuscular blocking drug infusion (OR, 6.6; 95% CI, 2.8-15.7; p < 0.001), and lack of familiarity between the anesthesia provider and neurosurgeon (OR, 4.4; 95% CI, 1.5-12.3; p = 0.005)., Conclusion: Significant blood loss, intraoperative neuromuscular blocking drug infusion, and lack of familiarity between anesthesia provider and neurosurgeon were associated with prolonged extubation following TIVA for vestibular schwannoma resection., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

Vestibular schwannoma (VS), one of characteristic tumors of neurofibromatosis type 2 (NF2), is an intracranial tumor that arises from Schwann cells of the vestibular nerve. VS results in hearing loss, tinnitus, dizziness, and even death, but there are currently no FDA-approved drugs for treatment. In this study, we established a high-throughput screening to discover effective compounds that could inhibit the viability of VS cells. Among 1019 natural products from the Korea Chemical Bank screened, we found that celastrol, a pentacyclic triterpene derived from a Tripterygium Wilfordi plant, exerted potent inhibitory effect on the viability of VS cells with an IC 50 value of 0.5  µM. Celastrol (0.5, 1  µM) dose-dependently inhibited the proliferation of primary VS cells derived from VS patients. Celastrol also inhibited the growth, and induced apoptosis of two other VS cell lines (HEI-193 and SC4). Aberrant activation of Wnt/β-catenin signaling has been found in VS isolated from clinically defined NF2 patients. In HEI-193 and SC4 cells, we demonstrated that celastrol (0.1, 0.5 μM) dose-dependently inhibited TOPFlash reporter activity and protein expression of β-catenin, but not mRNA level of β-catenin. Furthermore, celastrol accelerated the degradation of β-catenin by promoting the formation of the β-catenin destruction complex. In nude mice bearing VS cell line SC4 allografts, administration of celastrol (1.25 mg · kg -1  · d -1 , i.p. once every 3 days for 2 weeks) significantly suppressed the tumor growth without showing toxicity. Collectively, this study demonstrates that celastrol can inhibit Wnt/β-catenin signaling by promoting the degradation of β-catenin, consequently inhibiting the growth of VS., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Objective: Vestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene NF2, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5'-triphosphate-competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models., Methods: Treatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (Postn-Cre;Nf2flox/flox). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, Postn-Cre;Nf2flox/flox mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from Postn-Cre;Nf2flox/flox mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees., Results: Treatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated Postn-Cre;Nf2flox/flox mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in Postn-Cre;Nf2flox/flox mice up to 3 months posttreatment., Conclusions: The data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2-associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.

Vestibular schwannoma (VS) is one of the most common types of benign tumors of the central nervous system. At present, the prevailing treatment methods of VS include surgery, stereotactic radiotherapy, and follow-up observation, etc. However, there is still no drug therapy available for treating VS. Although the surgical technique is relatively mature, the complications cannot be completely avoided. Furthermore, both the growth rate of different cases and patients' sensitivity to radiotherapy vary greatly. With the constant progress made in molecular biology research, most of the studies on the growth mechanism of VS focus on the upstream and downstream of neurofibromin 2 ( NF 2) gene and merlin protein, and a number of corresponding targets, including receptor protein tyrosine kinase (RTK), vascular endothelial growth factor receptor (VEGFR), mammalian target of rapamycin complex 1 (mTORC1) and platelet derived growth factor receptor (PDGFR). It has been reported in some studies that quite a few drugs could inhibit the proliferation of VS cells. Most of the studies are still in the stage of in vitro cell experiment and/or animal experiment. A small number of studies have entered phase Ⅰ and phase Ⅱ clinical trials, but have not led to any clinical treatment yet. This paper provides a comprehensive understanding of the current status and the prospects of drug therapies of VS, which is conducive to the development of subsequent research., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Background: Sudden sensorineural hearing loss (SSNHL) has several aetiologies and may be a presenting symptom of vestibular schwannoma (VS)., Objectives: The aim of this study was to investigate the recovery rate after steroid treatment and the prognostic factors of SSNHL with VS., Materials and Methods: This was a retrospective observational study wherein 32 patients with VS who presented with SSNHL were analysed at a tertiary referral centre. Hearing gain and prognostic factors were the main outcome measures for steroid treatment intervention., Results: Among the 1698 patients presenting with SSNHL, VS was found in 43 (2.5%) patients. Eleven cases (34.3%) showed good recovery, with significant improvements in the pure-tone audiometry values. Even though age was a significant factor, there were no associations between steroid response and initial hearing level, presence of vertigo, tumour size, and tumour extension., Conclusions and Significance: Our study showed that hearing recovery of SSNHL does not exclude a VS diagnosis. We suggest that steroid treatment be considered in patients with VS presenting SSNHL.

Intratympanically applied treatments are of increasing interest to the otologic community to treat sudden sensorineural hearing loss or vestibular disorders but also to deliver gene therapy agents, or biologics to the inner ear. Further diversion from the middle ear and perilymph to blood circulation and cerebrospinal fluid via the cochlear aqueduct are one of the limiting factors and so far not understood well enough. In this study, intratympanically applied triamcinolone acetonide was determined in cerebrospinal fluid. Additionally, perilymph was sampled through the round window membrane as well as at the lateral semicircular canal to determine drug levels. Of the twenty-one included patients, triamcinolone acetonide was quantifiable in cerebrospinal fluid in 43% at very low levels (range 0 ng/ml-6.2 ng/ml) which did not correlate with perilymph levels. Drug levels at the two different perilymph sampling sites were within a range of 13.5 ng/ml to 1180.0 ng/ml. Results suggest an equal distribution of triamcinolone acetonide to semicircular canals, which might support the use of triamcinolone acetonide as a treatment option for vestibular pathologies such as Menièrés disease. On the other hand, the distribution to cerebrospinal fluid might be limiting current approaches in gene therapy where a central distribution is unwanted., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Pharmacologic treatment of vestibular schwannomas (VSs) may increase the success of conservative management for small lesions, and offer an alternative to surgery and stereotactic radiotherapy in symptomatic cases in the high-risk population. Agents that have been studied include aspirin (ASA), but the results of the preliminary studies have been conflicting. In this study, we aimed to systematically review the evidence on the effect of ASA intake on tumor growth in patients with VSs., Methods: Pubmed, Cochrane, Scopus, Embase, ClinicalTrials.gov , and Web of Science were searched for studies comparing VS tumor growth in patients with aspirin intake and those without. Random-effect meta-analysis was used to evaluate the outcomes in terms of linear and/or volumetric tumor growth., Results: Four retrospective cohort studies were included in the meta-analysis. No significant difference was found in tumor growth between VS patients with aspirin intake and those without. This result held true for the analysis of linear tumor growth (OR 1.23; 95% CI 0.49, 3.10), volumetric tumor growth (OR 1.41; 95% CI 0.36, 5.59), and both combined (OR 1.02; 95% CI 0.56, 1.86)., Conclusions: Our meta-analysis suggests that there is insufficient evidence to recommend ASA therapy in patients with VSs. High-quality randomized controlled trials are warranted to determine the efficacy of this drug in reducing VS tumor growth., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: The anti-angiogenic agent bevacizumab is currently the only drug used clinically for neurofibromatosis type 2-related vestibular schwannomas (NF2-VS). Though benefits have been demonstrated in several cases, the standardized dosage remains unclear., Objective: Our meta-analysis was performed to systematically and comprehensively investigate the reliability and toxicity of bevacizumab in the treatment of NF2-VS, with particular emphasis on the impact of dosage., Methods: The literature search was conducted for studies providing data on patients treated with bevacizumab for NF2-VS across PubMed, Embase, and Cochrane Library until December 31, 2020. Two reviewers extracted the incidence rate of results independently. Then we calculated and pooled unadjusted incidence rate with 95% CIs for each study. The subgroups analyzed were conducted., Results: Fourteen citations (prospective or retrospective observational cohort studies) were eligible based on data from a total of 247 patients with NF2 and 332 related VSs. The pooled results showed that the radiographic response rate (RRR) was 30% [95% CI (20%-42%)], the hearing response rate (HRR) was 32% [95% CI (21%-45%)]. The incidence of major complications was: hypertension 29% [95% CI (23%-35%)], proteinuria 30% [95% CI (18%-44%)], menstrual disorders 44% [95% CI (16%-73%)], hemorrhage 14% [95% CI (4%-26%)], grade3/4 events 12% [95% CI (4%-22%)]., Conclusions: Nearly one-third of NF2-VS patients may benefit significantly from bevacizumab due to hearing improvement and tumor reduction. Menstrual disorders were the most common adverse events. The high-dose regimen didn't show better efficacy, but results varied considerably according to age., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients ( P = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas., (©2021 American Association for Cancer Research.)

Objective: Recent research demonstrates a potential association between metformin use and reduced sporadic vestibular schwannoma (VS) growth in patients undergoing conservative observation. The current study was designed to elucidate the effect of metformin on tumor growth in sporadic VS using volumetric analyses., Study Design: Retrospective cohort., Setting: Tertiary referral center., Patients: Patients with sporadic VS who elected initial conservative treatment with at least two serial magnetic resonance imaging (MRI) scans were included., Interventions: Metformin use among patients with observed sporadic VS., Main Outcome Measures: Tumor growth, defined as an increase in volume of at least 20% from the initial MRI., Results: A total of 361 patients were evaluated. Thirty-four patients (9%) had a diagnosis of diabetes at baseline. Nineteen patients (5%) were taking metformin at the time of the initial MRI. Metformin use was not significantly associated with a reduced risk of volumetric tumor growth in a univariable analysis in all patients undergoing observation for VS (hazard ratio [HR] 0.75; 95% confidence intervals [CI] 0.40-1.42; p = 0.38) or within the diabetic subset (HR 0.79; 95% CI 0.34-1.83; p = 0.58). Additionally, diabetes status, insulin dependence, hemoglobin A1c value, and metformin dose were not significantly associated with volumetric tumor growth., Conclusion: Despite promising initial results in several previous studies, our data suggest that metformin use does not significantly reduce the risk of volumetric tumor growth in sporadic VS., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2021, Otology & Neurotology, Inc.)

A 2016 published randomized multicenter phase III trial of prophylactic nimodipine treatment in vestibular schwannoma surgery showed only a tendency for higher hearing preservation rates in the treatment group. Gender was not included in statistical analysis at that time. A retrospective analysis of the trial considering gender, preoperative hearing, and nimodipine treatment was performed. The treatment group received parenteral nimodipine from the day before surgery until the seventh postoperative day. The control group was not treated prophylactically. Cochlear nerve function was determined by pure-tone audiometry with speech discrimination preoperatively, during in-patient care, and 1 year after surgery and classified according to the Gardner-Robertson grading scale (GR). Logistic regression analysis showed a statistically significant effect for higher hearing preservation rates (pre- and postoperative GR 1-4) in 40 men comparing the treatment (n = 21) and the control (n = 19) groups (p = 0.028), but not in 54 women comparing 27 women in both groups (p = 0.077). The results were also statistically significant for preservation of postoperative hearing with pre- and postoperative GR 1-3 (p = 0.024). There were no differences in tumor sizes between the treatment and the control groups in men, whereas statistically significant larger tumors were observed in the female treatment group compared with the female control group. Prophylactic nimodipine is safe, and an effect for hearing preservation in 40 men with preoperative hearing ability of GR 1-4 was shown in this retrospective investigation. The imbalance in tumor size with larger tumors in females of the treatment group may falsely suggest a gender-related effect. Further investigations are recommended to clarify whether gender has impact on nimodipine's efficacy.

A 25-year-old man presented with left-sided hearing loss, blurred vision and papilloedema. Imaging revealed a large, left-sided, contrast-enhancing cerebellopontine mass causing obstructive hydrocephalus, consistent with vestibular schwannoma (VS). Following an incomplete resection via retrosigmoid craniotomy at an outside facility, he was referred to our department, and cerebrospinal fluid diversion followed by repeat resection was recommended. A subtotal resection was achieved, and the patient was subsequently treated with adjuvant stereotactic radiosurgery (SRS). Progressive interval growth was observed on serial post-SRS MRI studies; correspondingly, at 31 months after treatment, the patient was initiated on antiprogrammed-death receptor 1 (PD-1) antibody treatment with pembrolizumab. Growth arrest was noted on subsequent serial imaging studies, which have been maintained for a total of 30 months since initiation of a 18-month anti-PD-1 course of therapy. Additional case accumulation and translational study is required to better characterise this therapeutic strategy; however, PD-1/programmed death-ligand 1 inhibition may offer a promising salvage therapy for refractory VS., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Vestibular schwannomas (VSs, also known as acoustic neuromas) are benign intracranial tumors commonly managed with observation, surgery, and radiotherapy. There is currently no approved pharmacotherapy for VS patients, which is why we conducted a detailed search of relevant literature from PubMed and Web of Science to explore recent advances and experiences in drug therapy. VSs feature a long course of disease that requires treatment to have minimal long-term side effects. Conventional chemotherapeutic agents are characterized by neurotoxicity or ototoxicity, poor effect on slow-growing tumors, and may induce new mutations in patients who have lost tumor suppressor function, and therefore are unsuitable for treating VSs. Along with the well-investigated molecular pathophysiology of VS and the increasingly accessible technology such as drug repositioning platform, many molecular targeted inhibitors have been identified and shown certain therapeutic effects in preclinical experiments or clinical trials., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Long et al.)

Objective: Recently, treatment decision making for large vestibular schwannomas (VS) in patients with neurofibromatosis type 2 (NF2) has become increasingly challenging due to the availability of multiple therapeutic options including surgery, bevacizumab (an anti-VEGF), radiosurgery, and observation; and it often remains an arbitrary decision based on local practices without firm recommendations. Our objective is to discuss the multimodal treatment options for Koos IV VS in a national reference center for NF2., Study Design: Single-institution retrospective cohort study., Methods: All NF2 patients with Koos IV VS who visited our center, the National Reference Center for NF2 Rare Disease in Pitié-Salpétrière Hospital of Paris, between January 2016 and December 2018 were included. Clinical charts, radiology, operative reports, and audiograms were reviewed., Results: Among 54 NF2 patients with Koos IV VS (mean maximum extrameatal diameter: 34 mm; range:17-62 mm), 27 were operated on for 28 VS; 21 were treated with bevacizumab; and six were observed. In the surgical group, VS resections were gross total, near-total, subtotal, or partial in 32%, 25%, 32%, and 11%, respectively; and a good (House-Brackmann grades I-II) facial nerve function was achieved in 81.5% at 1 year. Hearing was preserved in 14%, 78%, and 66% of the surgical (n = 7), bevacizumab (n = 9), and observation (n = 3) patients, respectively., Conclusion: All therapeutic options, including surgery and/or bevacizumab and occasionally observation, should be proposed to NF2 patients with large VS in the setting of dedicated centers. A decision-making tree is proposed for Koos IV VS management based on tumor evolution, hearing and clinical status of the patient, and contralateral VS size., Level of Evidence: 4, case series study, historically controlled study Laryngoscope, 131:E98-E107, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

We reviewed our experience in managing of NF2-associated vestibular schwannoma (VS) in children and young adults regarding the effect of surgery and postoperative bevacizumab treatment. A total of 579 volumetric and hearing data sets were analyzed. The effect of surgery on tumor volume and growth rate was investigated in 46 tumors and on hearing function in 39 tumors. Long-term hearing follow-up behavior was compared with 20 non-operated ears in additional 15 patients. Sixteen operated VS were treated with bevacizumab. Mutation analysis of the NF2 gene was performed in 25 patients. Surgery significantly slowed down VS growth rate. Factors associated with a higher growth rate were increasing patient age, tumor volume, and constitutional truncating mutations. Immediately after surgery, functional hearing was maintained in 82% of ears. Deterioration of hearing was associated with initial hearing quality, larger tumor volumes, and larger resection amounts. Average hearing scores were initially better in the group of non-operated VS. Over time, hearing scores in both groups worsened with a similar dynamic. During bevacizumab treatment of residual tumors, four different patterns of growth were observed. Decompression of the internal auditory canal with various degrees of tumor resection decreases the postoperative tumor growth rates. Carefully tailored BAEP-guided surgery does not cause additional hearing deterioration. Secondary bevacizumab treatment showed heterogenous effects both regarding tumor size and hearing preservation. It seems that postoperative tumor residuals, that grow slower, behave differently to bevacizumab than reported for not-operated faster growing VS.

Seventeen children at six institutions with neurofibromatosis type 2 (NF2)-related vestibular schwannomas received bevacizumab. Eight of the 13 patients with initial hearing loss (61%) showed objective hearing improvement within six months of treatment. No patients showed hearing deterioration during therapy; however, only two patients showed objective radiological response. Seven of eight patients had tumor progression or worsening hearing loss upon cessation of treatment. Bevacizumab was well tolerated with no patients discontinuing therapy. Bevacizumab appears to postpone hearing loss in childhood NF2-associated vestibular schwannomas, but responses are not durable, suggesting that either longer maintenance therapy or new strategies are required., (© 2020 Wiley Periodicals, Inc.)

Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by bilateral vestibular schwannomas (VS) that arise from neoplastic Schwann cells (SCs). NF2-associated VSs are often accompanied by meningioma (MN), and the majority of NF2 patients show loss of the NF2 tumor suppressor. mTORC1 and mTORC2-specific serum/glucocorticoid-regulated kinase 1 (SGK1) are constitutively activated in MN with loss of NF2. In a recent high-throughput kinome screen in NF2-null human arachnoidal and meningioma cells, we showed activation of EPH RTKs, c-KIT, and SFK members independent of mTORC1/2 activation. Subsequently, we demonstrated in vitro and in vivo efficacy of combination therapy with the dual mTORC1/2 inhibitor AZD2014 and the multi-kinase inhibitor dasatinib. For these reasons, we investigated activated mTORC1/2 and EPH receptor-mediated signaling in sporadic and NF2-associated VS. Using primary human VS cells and a mouse allograft model of schwannoma, we evaluated the dual mTORC1/2 inhibitor AZD2014 and the tyrosine kinase inhibitor dasatinib as monotherapies and in combination. Escalating dose-response experiments on primary VS cells grown from 15 human tumors show that combination therapy with AZD2014 and dasatinib is more effective at reducing metabolic activity than either drug alone and exhibits a therapeutic effect at a physiologically reasonable concentration (~0.1 µM). In vivo, while AZD2014 and dasatinib each inhibit tumor growth alone, the effect of combination therapy exceeds that of either drug. Co-targeting the mTOR and EPH receptor pathways with these or similar compounds may constitute a novel therapeutic strategy for VS, a condition for which there is no FDA-approved pharmacotherapy.

Objective: Previous work has suggested that metformin may possess antineoplastic properties. This study aims to assess the effect of metformin on the growth of sporadic vestibular schwannomas., Methods: A retrospective cohort study was performed on patients presenting with radiologically confirmed vestibular schwannomas to Stanford medical center between January 1990 and October 2018. Patients who received metformin during the follow-up period were included and were compared with the control group who were not receiving metformin. Tumor progression and hearing loss are primary and secondary outcomes, respectively., Results: A total of 149 patients were analyzed, with 42 patients receiving metformin. The mean age at presentation is 69.6 (±11.7) years. There are 69 (46.3%) females and 80 (53.7%) males and there is no significant age difference between the groups. Tumor size at presentation is similar between both groups, 8 mm (4-13) in control group and 7.5 mm (4-14) in metformin group. The average follow-up period is 34.2 months (18.3-57.8) and 30.3 months (13.6-69.8) in the metformin and control cohorts, respectively, and they are not significantly different. No significant differences between both groups were found in final American Academy of Otolaryngology - Head and Neck Surgery hearing outcome or poor audiogram outcome. Metformin users are significantly less likely to present with tumor growth at final follow-up compared with nonmetformin users (28.6 versus 49.5%, respectively; p = 0.02)., Conclusions: This preliminary result suggests metformin may reduce vestibular schwannoma tumor growth rate and shows potential promise as a novel chemotherapeutic agent. Further studies are needed to validate this finding.

We conducted a feasibility study to investigate the therapeutic effect of bevacizumab on vestibular schwannomas (VS) associated with neurofibromatosis type 2 (NF2) in a sample of Japanese patients. Ten NF2 patients were selected between 2013 and 2018: nine women and one man, with ages ranging from 12 to 45 years (mean: 29.4). Bevacizumab was administered intravenously in 5 mg/kg doses four times, with an inter-dose interval of 2 weeks. Seventeen tumors were followed for 3-72 months (mean: 39). A reduction from baseline tumor volume of at least 20% was considered a therapeutic radiologic response. Maximum reduction in tumor volume was identified in the 3rd month in 11 tumors, and in the 6th month in three tumors. Three tumors did not show any response to bevacizumab. A radiologic response was detected in seven tumors (41%). There was a significantly lower tumor volume mean in the 3rd month in comparison to the baseline for the entire sample. Tumors in patients aged 25 and above showed a significant reduction in volume in the 3rd month and significantly lower tumor-volume-to-baseline ratio than younger patients in both the 3rd and 6th months. The interaction between 'time' and 'age group' factors significantly affected the therapeutic outcome of bevacizumab on tumor volume. This study investigated the therapeutic effects of bevacizumab on NF2-associated vestibular schwannomas in Japanese patients. Bevacizumab appears to be a useful therapeutic choice in NF2 cases to control the growth of VS. Therefore, a randomised control trial to prove this assumption is necessary.

Purpose: Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS., Patients and Methods: Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers., Results: Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma., Conclusion: High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

Background: Individual evidence suggests that the anti-angiogenic agent bevacizumab may control vestibular schwannoma (VS) growth and promote hearing preservation in patients with neurofibromatosis type 2 (NF2). However, such metadata has yet to be consolidated, as well as its side-effect profile yet to be fully understood. Our aim was to pool systematically-identified metadata in the literature and substantiate the clinical efficacy and safety of bevacizumab with respect to radiographic tumor response, hearing, and treatment outcomes., Methods: Searches of seven electronic databases from inception to March 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of outcomes was then extracted and pooled by random-effects meta-analysis of proportions., Results: Eight articles reporting 161 NF2 patients with 196 assessable VS met satisfied all criteria. Radiographic response to bevacizumab was partial regression in 41% (95% CI 31-51%), no change in 47% (95% CI 39-55%), and tumor progression in 7% (95% CI 1-15%). In patients with assessable audiometric data, bevacizumab treatment resulted in hearing improvement in 20% (95% CI 9-33%), stability in 69% (95% CI 51-85%) and additional loss in 6% (95% CI 1-15%) Serious bevacizumab toxicity was observed in 17% (95% CI 10-26%). Subsequent surgical intervention was required in 11% (95% CI 2-20%)., Conclusions: Bevacizumab may arrest both tumor progression and hearing loss in select NF2 patients presenting with VS lesions. However, a considerable proportion of patients are anticipated to experience serious adverse events; correspondingly, judicious use of bevacizumab for symptomatic management of VS in NF2 is recommended.

Objectives: Conflicting research exists surrounding the utility of aspirin to prevent tumor growth in the medical management of vestibular schwannoma (VS). Recent studies demonstrated no association between aspirin and VS growth using linear tumor measurements. Given the heightened sensitivity of volumetric analyses to monitor tumor growth, the current study was conceived with the chief objective of assessing the association between aspirin or other nonsteroidal anti-inflammatory drug (NSAID) use and VS growth using volumetric analyses., Study Design: Retrospective review., Setting: Tertiary referral center., Subjects and Methods: A total of 361 patients totaling 1601 volumetrically analyzed magnetic resonance imaging studies who underwent initial observation since January 1, 2003., Results: In total, 123 (35%) patients took 81 mg aspirin daily, 23 (7%) took 325 mg aspirin daily, and 41 (11%) reported other NSAID use. Among those taking aspirin, 112 (72%) exhibited volumetric tumor growth during observation compared to 33 (80%) among other NSAID users and 137 (67%) among nonaspirin users. Patients taking aspirin or other NSAIDs were significantly older at time of diagnosis (median, 66 vs 56 years; P < .001). Neither aspirin use (hazard ratio [HR], 0.96; P = .73) nor other NSAID use (HR, 1.39; P = .081) was significantly associated with a reduced risk of volumetric tumor growth. These results were similar following age adjustment ( P = .81 and .087, respectively). When separating aspirin users by 81-mg or 325-mg dosing, neither group exhibited a reduced risk of growth ( P = .95 and .73, respectively)., Conclusion: Despite promising initial results, the preponderance of existing literature suggests that aspirin and other NSAID use does not prevent tumor growth in VS.

Objective: There is a common misconception that improvement in sudden sensorineural hearing loss (SSNHL) after treatment with steroid therapy effectively excludes the diagnosis of a vestibular schwannoma (VS) and such cases do not warrant an MRI. Paralleling this, steroids are commonly withheld for SSNHL in patients with an existing diagnosis of VS, believing that this condition is not steroid-responsive. This study seeks to underscore that improvement or recovery of SSNHL with steroid therapy does not exclude the diagnosis of VS and does not preclude the need for magnetic resonance imaging., Methods: A retrospective chart review was performed (2002-2017) of patients with previously untreated sporadic VS who developed SSNHL that improved after steroid treatment. A clinically significant audiometric improvement was defined as an increase of more than or equal to 15% in word recognition score (WRS) and/or decrease of more than or equal to 15 dB in 4-frequency pure-tone average (PTA). To supplement these data, a separate population of patients with incomplete or missing audiometric data, who reported unequivocal subjective improvement in hearing after steroid treatment, were also described to reinforce the study objective. Patient demographics, tumor characteristics, steroid regimen, and data regarding treatment response were recorded., Results: A total of 29 patients (55% women; median age of 47 yr) met inclusion criteria. Fourteen (48%) cases had objective audiometric documentation of SSNHL, while 15 (52%) had either subjective report only or incomplete audiometric data available. Eighteen (62%) had a single event, while 11 (38%) had more than one episode of SSNHL that was treated with steroids. For all patients, the median time between SSNHL and diagnosis of VS was 1.3 months (range, 0.13-148.4 mo). At the time of diagnosis, 15 tumors were purely intracanalicular, while 15 tumors had cerebellopontine angle extension. Of the latter, the median cisternal tumor size was 15.9 mm (range, 5.3-33). Twenty-six (90%) cases received oral steroid therapy alone, two (9%) had intratympanic steroid therapy alone, and one (3%) required combination therapy. The median PTA improvement with steroid therapy was 21 dB HL (range, -10-101.2) and the median WRS improvement was 40% (range, 4-100%)., Conclusion: A therapeutic response to steroid therapy for SSNHL does not exclude the diagnosis of VS. All patients with SSNHL should undergo appropriate diagnostic imaging to prevent delays in diagnosis and potential treatment.

The understanding of the molecular pathways underlying tumor development in neurofibromatosis type 2 (NF2) is increasing. Thus, repositioning drugs, drug therapies that are already clinically available for various cancers, appear potentially promising for NF2 patients. Based on preclinical data from in vitro or animal models, five different treatments have been proposed for selected NF2 cases. Evaluation of bevacizumab, a monoclonal antibody against VEGF has mainly been reported in retrospective studies; it has been reported to induce hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas (VS). In our experience with 16 patients, bevacizumab is associated with an increase of median time to tumor progression of VS from 5.6 months before bevacizumab onset, to more than 29.3 months. The need for intravenous injections and long term adverse events (hypertension, proteinuria, hemorrhage) are the main drawbacks. Lapatinib seemed promising in a single phase II trial with a volumetric response observed in 4/17 patients and a hearing response in 4/13, but is not currently used in clinical practice. Erlotinib has not been associated with radiographic or hearing responses in a phase II trial. Everolimus has been evaluated in 3 phase II trials. Everolimus did not induced tumor shrinkage, but seems to be able to increase time to tumor progression in selected cases. Currently, bevacizumab is the only drug proposed to selected NF2 patients., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: Epidermal growth factor receptors EGFR and ErbB2 are overexpressed in schwannomas and meningiomas. Preclinical and clinical data indicate that lapatinib, an EGFR/ErbB2 inhibitor, has antitumor activity against vestibular schwannomas in neurofibromatosis type 2 (NF2) patients. Its antitumor activity against meningiomas, however, is unknown., Methods: We conducted a retrospective review of patients with NF2 and progressive vestibular schwannomas treated on a phase 2 clinical trial with lapatinib (NCT00973739). We included patients with at least one volumetrically measurable meningioma (> 0.5 cm 3 ) who received at least five 28-day courses of treatment. Patients received lapatinib 1500 mg daily. Meningioma response was assessed using 3-dimensional MRI volumetrics. Progressive meningioma growth and response were defined as + 20 and - 20% change in tumor volume from baseline, respectively. Off-treatment was defined as any period > 5 months without lapatinib., Results: Eight patients (ages: 20-58 years) who met criteria had 17 evaluable meningiomas with a combined volume of 61.35 cc at baseline, 61.17 cc during treatment, and 108.86 cc (+ 77.44% change) off-treatment, p = 0.0033. Median time on-treatment and off-treatment was 15.5 and 16.7 months, respectively. On-treatment mean and median annualized growth rates were 10.67 and 1.32%, respectively. Off-treatment mean and median annualized growth rates were 20.05 and 10.42%, respectively. The best volumetric response was - 26.1% after 23 months on lapatinib. Two tumors increased > 20% volumetrically on-treatment, compared to eight tumors off-treatment., Conclusions: These data suggest that lapatinib may have growth-inhibitory effects on meningiomas in NF2 patients, and support prospective studies of lapatinib for NF2 patients with progressive meningiomas.

Objective: To evaluate the objective and subjective effects of intratympanic gentamicin treatment in patients with small vestibular schwannomas who exhibit intractable vertigo., Patients: Individuals diagnosed with small vestibular schwannomas who exhibited intractable vertigo were retrospectively reviewed., Interventions: Intratympanic gentamicin injection., Main Outcome Measures: Vertigo control., Results: Eight patients were included in the study. All patients achieved complete or substantial control of vertigo attacks while six patients reported residual imbalance. Three patients experienced significant hearing loss during therapy and follow-up. Only one patient showed a drop from Class B to Class C. Caloric tests and vestibular evoked myogenic potentials showed that all patients exhibited impaired peripheral vestibular function before treatment and that unilateral vestibular deafferentation was achieved during follow-up. Dizziness Handicap Inventory scores decreased over time, indicating an increase in the quality of life., Conclusions: Intratympanic gentamicin could provide an efficient approach to control intractable vertigo caused by small vestibular schwannoma. Before treatment, a complete physical examination, hearing level evaluation, vestibular function evaluation, and appropriate patient expectations are indispensable.

Objectives/hypothesis: To determine if aspirin intake is associated with reduced growth of vestibular schwannomas (VS). To determine the prevalence of contraindications to regular aspirin in patients with VS., Study Design: Retrospective, observational case-control study., Methods: The study utilized a postal questionnaire and telephone interviews to determine aspirin exposure. Propensity score matching was used to control for age, sex, and tumor size. Cases were defined as patients with VS proven to have grown on serial magnetic resonance imaging (MRI). Controls were defined as patient with VS stable on serial MRI. Prevalence of regular aspirin use was compared in patients with growing VS versus stable VS. Absolute and relative contraindications to aspirin intake were recorded., Results: Six hundred fifty-three patients with VS were contacted, and responses were received by 67% (220 cases and 217 controls). The mean tumor size was 11.3 mm (9.0 mm and 13.3 mm in controls and cases, respectively). Aspirin exposure was more common in stable VS than growing VS (22.1% vs. 17.3%). However, following matching to control for covariates, aspirin was not found to be associated with VS stability (P = .475). Multiple logistic regression (analysis of variance) found tumor size to be the only factor strongly associated with tumor growth (P < .0001). Ninety-two percent of patients were able to take aspirin, with the majority being at low risk of complications from regular use., Conclusions: This study aimed to examine the relationship between aspirin intake and VS stability. In contrast to previous reports, after controlling for covariates, the findings do not demonstrate an association. Only tumor size at diagnosis appears predictive of risk of VS growth., Level of Evidence: 3b. Laryngoscope, 128:2139-2144, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Ailanthone (AIL) is a quassinoid isolated from the traditional Chinese medicinal herb Ailanthus altissima . The antitumor activities of AIL have been reported in several cancers. The purpose of the present study was to explore the effect of AIL on vestibular schwannomas (VSs). Various concentrations of AIL (0-1 μM) were used to treat human primary VS cells, and then cell viability, proliferation, apoptosis, and autophagy were assessed. Expression of miR-21 in VS cells was altered by miRNA transfection. The functional actions of AIL on miR-21 dysregulated cells were also assessed. AIL significantly reduced the viability of VS cells, and the IC 50 value was 0.48 ± 0.023 μM. In response to 0.6 μM AIL, BrdU + cell rate and cyclin D1 expression were reduced, apoptotic cell rate was increased, caspase 3 and caspase 9 were cleaved, Beclin-1 and LC3-II were accumulated, and p62 was downregulated. miR-21 was lowly expressed in AIL-treated cells, and AIL-induced apoptosis and autophagy were attenuated by miR-21 overexpression. In addition, AIL downregulated Ras and Raf and deactivated MEK, ERK, mTOR, and p70S6K, while the downregulation and deactivation induced by AIL were reversed by miR-21 overexpression. To conclude, AIL inhibited VS cell proliferation and induced apoptosis and autophagy. The antitumor activities of AIL in VS cells were realized possibly via downregulation of miR-21 and blocking the Ras/Raf/MEK/ERK and mTOR pathways.

Objective: Assess patient-reported outcomes (PRO) for hearing and tinnitus relative to clinical hearing assessment in people with neurofibromatosis 2 (NF2) associated hearing loss., Study Design: Prospective, open label, phase-II clinical trial with PRO administered pre-, post-, and after treatment., Setting: Three tertiary referral centers., Patients: Fourteen patients with NF2, median age of 30 years (range, 14-79 yr) and progressive hearing loss (median baseline word recognition score, 60%; range, 13-82%). Half of these patients achieved objective hearing response (word recognition score improved beyond the 95% critical difference versus baseline)., Intervention: Bevacizumab 7.5 mg/kg was administered every 3 weeks for 48 weeks, followed by surveillance for 24 weeks off-drug., Main Outcome Measures: Speech, spatial, and qualities of hearing scale (SSQ) and tinnitus reaction questionnaire (TRQ) to assess hearing difficulties in life situations and tinnitus related distress., Results: Patient-reported speech understanding and auditory quality improved with bevacizumab treatment and were significantly correlated with word recognition scores, but not pure tone threshold average. There was no change in spatial perception after treatment. Reduction in tinnitus distress after treatment with bevacizumab did not reach statistical significance., Conclusion: Participants had reductions in hearing difficulty during treatment with bevacizumab, suggesting that patients subjectively experience hearing-related benefit mirroring clinical hearing assessments. We suspect the lack of significant reduction in tinnitus distress is related to small sample size and low intensity of distress in our sample. These data highlight the usefulness of PRO measures to assess benefits of treatment in the setting of NF2-associated hearing loss.

Research of various diseases of the nervous system has shown that VEGF has direct neuroprotective effects in the central and peripheral nervous systems, and indirect effects on improving neuronal vessel perfusion which leads to nerve protection. In the tumors of the nervous system, VEGF plays a critical role in tumor angiogenesis and tumor progression. The effect of anti-VEGF treatment on nerve protection and function has been recently reported - by normalizing the tumor vasculature, anti-VEGF treatment is able to relieve nerve edema and deliver oxygen more efficiently into the nerve, thus reducing nerve damage and improving nerve function. This review aims to summarize the divergent roles of VEGF in diseases of the nervous system and the recent findings of anti-VEGF therapy in nerve damage/regeneration and function in tumors, specifically, in Neurofibromatosis type 2 associated schwannomas., (Copyright © 2017. Published by Elsevier Inc.)

OBJECTIVE In clinical routines, neuroprotective strategies in neurosurgical interventions are still missing. A pilot study (n = 30) and an analogously performed Phase III trial (n = 112) pointed to a beneficial effect of prophylactic nimodipine and hydroxyethyl starch (HES) in vestibular schwannoma (VS) surgery. Considering the small sample size, the data from both studies were pooled. METHODS The patients in both investigator-initiated studies were assigned to 2 groups. The treatment group (n = 70) received parenteral nimodipine (1-2 mg/hour) and HES (hematocrit 30%-35%) from the day before surgery until the 7th postoperative day. The control group (n = 72) was not treated prophylactically. Facial and cochlear nerve functions were documented preoperatively, during the inpatient care, and 1 year after surgery. RESULTS Pooled raw data were analyzed retrospectively. Intent-to-treat analysis revealed a significantly lower risk for hearing loss (Class D) 12 months after surgery in the treatment group compared with the control group (OR 0.46, 95% CI 0.22-0.97; p = 0.04). After exclusion of patients with preoperative Class D hearing, this effect was more pronounced (OR 0.38, 95% CI 0.17-0.83; p = 0.016). Logistic regression analysis adjusted for tumor size showed a 4 times lower risk for hearing loss in the treatment group compared with the control group (OR 0.25, 95% CI 0.09-0.63; p = 0.003). Facial nerve function was not significantly improved with treatment. Apart from dose-dependent hypotension (p < 0.001), the study medication was well tolerated. CONCLUSIONS Prophylactic nimodipine is safe and may be recommended in VS surgery to preserve hearing. Prophylactic neuroprotective treatment in surgeries in which nerves are at risk seems to be a novel and promising concept. Clinical trial registration no.: DRKS 00000328 ( https://drks-neu.uniklinik-freiburg.de/drks&#95;web/ ).

Background: Except for glucocorticoids there is a lack of neuroprotective medication in neurosurgical interventions., Objective: An overview of clinical trials investigating administration of the calcium antagonist nimodipine and hydroxyethyl starch (HES) in vestibular schwannoma (VS) surgery is given. Basic research is addressed and potential neuroprotective effect mechanisms are discussed, as are perspectives for application of the concept to other types of surgery with a risk postoperative impairment of nerve function., Materials and Methods: A selective PubMed search was performed and all 10 clinical trials corresponding to the search criteria were included., Results: Four trials with an intraoperative start of the medication showed a positive effect for the preservation of facial nerve function and hearing preservation. A pilot study showed superiority of prophylactic treatment over intraoperative application. There were no significant results in a prospective multicenter phase III trial. After 1 year, postoperative facial nerve preservation rates were excellent in both groups. However, the risk of hearing loss was twice as high in the control group. A combined analysis of the phase III trial with its pilot study showed significant results for better hearing preservation rates in the treatment group (probably by increasing the case load)., Conclusion: Prophylactic nimodipine can be recommended in VS surgery in patients with good preoperative hearing. The effect mechanisms of nimodipine and modifications to prophylaxis should be clarified in basic research.

Objective: To investigate whether the use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) impact the growth of vestibular schwannoma (VS)., Study Design: Retrospective case series., Setting: Single academic, tertiary care center., Patients: Patients with VS who underwent at least two magnetic resonance imaging (MRI) studies before intervention., Intervention(s): Serial MRI studies., Main Outcome Measure(s): VS tumor growth, defined as more than or equal to 2 mm increase in the maximum tumor diameter between consecutive MRI studies, or between the first and last available study. Mean growth rate was also calculated, defined as the change in tumor size divided by length of follow-up., Results: A total of 564 VS patients met inclusion criteria, with 234 (41.2%) taking some type of NSAID. Aspirin use was not associated with VS tumor growth, presenting tumor diameter, or mean VS growth rate. Further, aspirin dosage did not impact growth outcomes or presenting tumor diameter. A total of 96 (17.0%) patients took an NSAID other than aspirin. Neither non-aspirin NSAID use nor degree of cyclooxygenase-2 (COX-2) selectivity, including aspirin, was significantly associated with VS tumor growth, presenting tumor diameter, or mean VS growth rate., Conclusions: While previous studies have suggested a relationship between aspirin usage and VS growth, we found no significant association in our series of 564 observed VS. Furthermore, there was no apparent relationship between aspirin dosage, non-aspirin NSAID use, and COX-2 selectivity with VS growth, presenting tumor diameter at presentation, or mean VS growth rate.

Intralabyrinthine schwannoma (ILS) is a rare benign tumor that affects the ends of cochlear and vestibular nerves. In a majority of the cases, it occurs with unilateral progressive sensorineural hearing loss. Less frequent symptoms include tinnitus, imbalance, vertigo, or fullness. The advent of magnetic resonance imaging allows early diagnosis and enables an appropriate therapeutic protocol. This report describes a case of intravestibular schwannoma, with fluctuating hearing loss and intractable vertigo, treated with intratympanic gentamicin. The patient was a 28-year-old woman with intractable vertigo and fluctuating left-side hearing loss caused by left intravestibular schwannoma. Because surgery was temporarily rejected by the patient, a single dose of intratympanic gentamicin was administered. Following this, the patient showed a significant improvement in the symptoms. However, moderate to flat sensorineural hearing loss was also observed. Intratympanic gentamicin infiltration is a valid therapeutic option for patients with ILS, affected by intractable vertigo, when the patient refuses surgery.

Objectives/hypothesis: The development of a simple, reliable, and cost-effective animal model greatly facilitates disease treatment. We aimed to establish a rapid, simple, and reproducible live zebrafish vestibular schwannoma xenograft model for antitumor drug screening., Methods: We optimized each of the following conditions for tumor cell xenografts in zebrafish larvae: larval stage, incubation temperature, and injected cell number. We used NF2-/-mouse Schwann (SC4) cells and generated mCherry fluorescent protein-expressing cells prior to injection into zebrafish larvae. SC4 cells were counted using a fluorescence microscope, suspended in 10% fetal bovine serum, and injected into the center of the yolk sac using a microinjection system. The injected embryos were transferred to E3 medium (for zebrafish embryos), and subsequent tumor formation was observed by fluorescence microscopy over a 5-day period. To validate our model, xenografted embryos were transferred into 6-well plates (5 embryos per well) and treated with everolimus, a known antitumor drug., Results: mCherry fluorescent protein-expressing SC4 cells were successfully grafted into the yolk sacs of zebrafish embryos without any immunosuppressant treatment. At 2 days postinjection, the xenografted cells had grown into tumor masses. The optimal speed of tumor formation depended on the larval stage (30 hpf), incubation temperature (31°C), and injected cell number (200 cells). In preliminary tests, everolimus treatment yielded a > 20% reduction in the number of SC4 cells in the yolk., Conclusion: Our in vivo model has the potential to greatly facilitate vestibular schwannoma treatment because of its speed, simplicity, reproducibility, and amenability to live imaging., Level of Evidence: NA Laryngoscope, 126:E409-E415, 2016., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Vestibular schwannoma (VS) is an intracranial tumor that causes significant morbidity, including hearing loss, tinnitus, dizziness, and possibly even death from brainstem compression. However, FDA-approved pharmacologic treatments for VS do not exist. Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables, such as broccoli, with potent chemoprotective effects in several cell types. Our objective was to determine whether SFN is effective against VS in vitro and in vivo. Human primary VS cells, HEI-193 schwannoma cells, and SC4 Nf2 -/- Schwann cells were used to investigate the inhibitory effects of SFN in vitro. Cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and cell viability and metabolic activity was calculated by MTT assay. Apoptosis was measured by flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and Western blot for cleaved caspases. A mouse model with a murine schwannoma allograft was also used to examine the antitumor activity of SFN. SFN exhibited significant antiproliferative activity in schwannoma cells in vitro, via the inhibition of HDAC activity and the activation of ERK. SFN treatment induced apoptosis and cell cycle arrest at the G2/M phase. SFN also significantly inhibited schwannoma growth in vivo. Our preclinical studies motivate a future prospective clinical study of SFN for the treatment of VS.

Purpose: To describe the natural growth of vestibular schwannoma in patients with neurofibromatosis type 2 and to predict tumor volume evolution in patients treated with bevacizumab and everolimus., Methods: Clinical data, including longitudinal tumor volumes in patients treated by bevacizumab (n = 13), everolimus (n = 7) or both (n = 2), were analyzed by means of mathematical modeling techniques. Together with clinical data, data from the literature were also integrated to account for drugs mechanisms of action., Results: We developed a model of vestibular schwannoma growth that takes into account the effect of vascular endothelial growth factors and mammalian target of rapamycin complex 1 on tumor growth. Behaviors, such as tumor growth rebound following everolimus treatment stops, was correctly described with the model. Preliminary results indicate that the model can be used to predict, based on early tumor volume dynamic, tumor response to variation in treatment dose and regimen., Conclusion: The developed model successfully describes tumor volume growth before and during bevacizumab and/or everolimus treatment. It might constitute a rational tool to predict patients' response to these drugs, thus potentially improving management of this disease.