Reported Hearing Outcome Measures Following Stereotactic Radiosurgery for Vestibular Schwannoma: A Scoping Review.

Background Evidence on hearing outcome measures when assessing hearing preservation following stereotactic radiosurgery (SRS) for adults with vestibular schwannoma (VS) has not previously been collated in a structured review. Objective The objective of the present study was to perform a scoping review of the evidence regarding the choice of hearing outcomes and other methodological characteristics following SRS for adults with VS. Methods The protocol was registered in the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses extension guidelines for scoping reviews. A systematic search of five online databases revealed 1,591 studies, 247 of which met the inclusion criteria. Results The majority of studies ( n = 213, 86%) were retrospective cohort or case series with the remainder ( n = 34, 14%) prospective cohort. Pure-tone audiometry and speech intelligibility were included in 222 (90%) and 158 (64%) studies, respectively, often summarized within a classification scheme and lacking procedural details. Fifty-nine (24%) studies included self-report measures. The median duration of follow-up, when reported, was 43 months (interquartile range: 29, 4-150). Conclusion Evidence on hearing disability after SRS for VS is based on low-quality studies which are inherently susceptible to bias. This review has highlighted an urgent need for a randomized controlled trial assessing hearing outcomes in patients with VS managed with radiosurgery or radiological observation. Similarly, consensus and coproduction of a core outcome set to determine relevant hearing and communication outcome domains is required. This will ensure that patient priorities, including communication abilities in the presence of background noise and reduced participation restrictions, are addressed.

Improved Recovery after Vestibular Schwannoma Excision with Intratympanic Gentamicin Prehabilitation.

OBJECTIVE: Translabyrinthine excision of a vestibular schwannoma is associated with acute vestibular failure. Preoperative intratympanic gentamicin (ITG) injections can improve objective balance function after surgery but its clinical benefits remain to be established. METHODS: Adult patients undergoing translabyrinthine removal of a vestibular schwannoma between January 2014 and February 2018 underwent preoperative vestibular function testing. Patients were divided in to 3 groups, those with vestibular function (VF) who received ITG injections, those with VF but did not receive ITG and those with no VF. Groups were compared according to degree of vertigo, length of stay, time to unassisted mobilization, and postoperative anti-emetic consumption. RESULTS: Forty six patients had ITG injections (Group 1), 7 had residual VF but refused treatment (Group 2), 21 had no VF (Group 3). Group 1 had a significant improvement in vertigo over time whereas groups 2 and 3 did not. There was a statistically significant 70% decrease in time to independent mobilization between Group 1 and other groups and a 19% decrease in length of stay in Group 1 compared to other groups although this did not reach statistical significance. Two patients had injection-related complications. Group 1 used less anti-emetics than other groups but this was not statistically significant. CONCLUSION: Preoperative intratympanic gentamicin injection with vestibular rehabilitation exercises is associated with less postoperative vertigo and earlier postoperative mobilization. There was reduced duration of hospitalization and decreased consumption of anti-emetic but not significantly so possibly because of low numbers of patients in the no treatment group. LEVEL OF EVIDENCE: 2 Laryngoscope, 2024.

Changes in audiovestibular handicap following treatment of vestibular schwannomas.

OBJECTIVE: This study aimed to assess degree of audiovestibular handicap in patients with vestibular schwannoma. METHODS: Audiovestibular handicap was assessed using the Hearing Handicap Inventory, Tinnitus Handicap Inventory and Dizziness Handicap Inventory. Patients completed questionnaires at presentation and at least one year following treatment with microsurgery, stereotactic radiosurgery or observation. Changes in audiovestibular handicap and factors affecting audiovestibular handicap were assessed. RESULTS: All handicap scores increased at follow up, but not significantly. The Tinnitus Handicap Inventory and Dizziness Handicap Inventory scores predicted tinnitus and dizziness respectively. The Hearing Handicap Inventory was not predictive of hearing loss. Age predicted Tinnitus Handicap Inventory score and microsurgery was associated with a deterioration in Dizziness Handicap Inventory score. CONCLUSION: Audiovestibular handicap is common in patients with vestibular schwannoma, with 75 per cent having some degree of handicap in at least one inventory. The overall burden of handicap was, however, low. The increased audiovestibular handicap over time was not statistically significant, irrespective of treatment modality.

Rationale for the Development of a Novel Clinical Grading Scale for Postoperative Facial Nerve Function: Results of a Multidisciplinary International Working Group.

OBJECTIVE: The objective of the current study was to present the results of an international working group survey identifying perceived limitations of existing facial nerve grading scales to inform the development of a novel grading scale for assessing early postoperative facial paralysis that incorporates regional scoring and is anchored in recovery prognosis and risk of associated complications. STUDY DESIGN: Survey. SETTING: A working group of 48 multidisciplinary clinicians with expertise in skull base, cerebellopontine angle, temporal bone, or parotid gland surgery. RESULTS: House-Brackmann grade is the most widely used system to assess facial nerve function among working group members (81%), although more than half (54%) agreed that the system they currently use does not adequately estimate the risk of associated complications, such as corneal injury, and confidence in interrater and intrarater reliability is generally low. Simplicity was ranked as the most important attribute of a novel postoperative facial nerve grading system to increase the likelihood of adoption, followed by reliability and accuracy. There was widespread consensus (91%) that the eye is the most critical facial region to focus on in the early postoperative setting. CONCLUSIONS: Members were invited to submit proposed grading systems in alignment with the objectives of the working group for subsequent validation. From these data, we plan to develop a simple, clinically anchored, and reproducible staging system with regional scoring for assessing early postoperative facial nerve function after surgery of the skull base, cerebellopontine angle, temporal bone, or parotid gland.

Changes in antimicrobial resistance in acute otitis media and otitis externa.

OBJECTIVES: Acute otitis media (AOM) and otitis externa (OE) are common ear infections which may warrant antibiotic therapy. For many infections, there is a rise in antimicrobial resistance, which is associated with treatment failure, morbidity, prolonged hospitalisation and mortality. This study aimed to identify longitudinal changes in microbiology and antimicrobial resistance in aural swabs taken from patients with AOM or OE. DESIGN: Retrospective observational analysis. SETTING: Aural samples processed at Manchester Medical Microbiology Partnership Laboratories between January 2008 and December 2018 were analysed to record organism isolated and antimicrobial sensitivity. PARTICIPANTS: Individual aural swabs from 7200 patients. MAIN OUTCOME MEASURES: Changes in the incidence of organisms and antimicrobial resistance between two time periods (2008-2012 and 2013-2018) were compared using the chi-squared test (alpha = 0.05). RESULTS: From 7200 swabs, 2879 (40%) were from children. The most frequently isolated organisms were Staphylococcus aureus (25%), Pseudomonas aeruginosa (24.4%), yeast (9.1%), mixed anaerobes (7.9%) and Haemophilus influenzae (6.1%). In children aged 0-4 years, H. influenzae had particularly high incidence (25%). Overall, the incidence of P. aeruginosa decreased significantly with time (p = 0.05). Isolates displaying resistance to one or more antimicrobial agents increased significantly in number in the second time period for P. aeruginosa (p = 0.04) and H. influenzae (p = 0.03). There was increased resistance to amoxicillin for P. aeruginosa (p = 0.01) and to erythromycin for H. influenzae (p < 0.01). CONCLUSION: Variations in type and frequency of organisms with increasing age likely result from differences in the preponderance of AOM compared to OE in children versus adults. We found increasing antimicrobial resistance for two organisms commonly isolated from AOM and OE infections, suggesting that aspects of current UK treatment practices and national recommendations may need to be revised.

Radiation treatment of benign tumors in NF2-related-schwannomatosis: A national study of 266 irradiated patients showing a significant increase in malignancy/malignant progression.

Background: Radiation treatment of benign tumors in tumor predisposition syndromes is controversial, but short-term studies from treatment centers suggest safety despite apparent radiation-associated malignancy being reported. We determined whether radiation treatment in NF2-related schwannomatosis patients is associated with increased rates of subsequent malignancy (M)/malignant progression (MP). Methods: All UK patients with NF2 were eligible if they had a clinical/molecular diagnosis. Cases were NF2 patients treated with radiation for benign tumors. Controls were matched for treatment location with surgical/medical treatments based on age and year of treatment. Prospective data collection began in 1990 with addition of retrospective cases in 1969. Kaplan-Meier analysis was performed for malignancy incidence and survival. Outcomes were central nervous system (CNS) M/MP (2cm annualized diameter growth) and survival from index tumor treatment. Results: In total, 1345 NF2 patients, 266 (133-Male) underwent radiation treatments between 1969 and 2021 with median first radiotherapy age of 32.9 (IQR = 22.4-46.0). Nine subsequent CNS malignancies/MPs were identified in cases with only 4 in 1079 untreated (P < .001). Lifetime and 20-year CNS M/MP was ~6% in all irradiated patients-(4.9% for vestibular schwannomas [VS] radiotherapy) versus <1% in the non-irradiated population (P < .001/.01). Controls were well matched for age at NF2 diagnosis and treatment (Males = 133%-50%) and had no M/MP in the CNS post-index tumor treatment (P = .0016). Thirty-year survival from index tumor treatment was 45.62% (95% CI = 34.0-56.5) for cases and 66.4% (57.3-74.0) for controls (P = .02), but was nonsignificantly worse for VS radiotherapy. Conclusion: NF2 patients should not be offered radiotherapy as first-line treatment of benign tumors and should be given a frank discussion of the potential 5% excess absolute risk of M/MP.

The experience of auditory implant recipients undergoing magnetic resonance imaging: Factors associated with pain.

OBJECTIVE: Many patients with cochlear implants (CI) and auditory brainstem implants (ABI) require magnetic resonance imaging (MRI) following implantation. This study explores the patient experience of MRI, identifying factors associated with pain, and the effect of interventions designed to enhance comfort and safety. METHODS: A prospective observational case series from a tertiary referral unit. Tight head bandaging ± local anaesthetic injection (devices with non-MRI-compatible magnets) or observation alone (implants with MRI-compatible magnets) were employed for 1.5 T MRI of consecutive adult patients with CI or ABI without magnet removal. Pain was recorded via visual analogue scale (1 = no pain, 5 = extreme pain) at three time points; (1) baseline, (2) head bandage applied (3) during scanning. Patient age, device type, body area imaged and total scan time were recorded as variables, alongside adverse events. RESULTS: Data were collected for 227 MRI scans (34 patients with ABI, 32 with CI). In patients managed with bandaging, pain score after bandaging but prior to scanning (median 2.2) did not differ from pain during scanning (2.1), but both were significantly higher than baseline (1.4, both P ≤ 0.001). Scanning areas other than the head/cervical spine was associated with higher pain scores (P = 0.036). Pain during MRI differed between different manufacturers implants (P ≤ 0.001). Adverse events occurred in 8/227 scans (3.5%), none occurring with devices containing an MRI-compatible magnet. CONCLUSION: MRI scanning with auditory implant magnets in situ is safe and well tolerated by patients.

Intraoperative diagnosis of facial schwannomas: a multicenter summation of clinical experience, preoperative avoidance, and intraoperative management protocol.

OBJECTIVE: Preoperative differentiation of facial nerve schwannoma (FNS) from vestibular schwannoma (VS) can be challenging, and failure to differentiate between these two pathologies can result in potentially avoidable facial nerve injury. This study presents the combined experience of two high-volume centers in the management of intraoperatively diagnosed FNSs. The authors highlight clinical and imaging features that can distinguish FNS from VS and provide an algorithm to help manage intraoperatively diagnosed FNS. METHODS: Operative records of 1484 presumed sporadic VS resections between January 2012 and December 2021 were reviewed, and patients with intraoperatively diagnosed FNSs were identified. Clinical data and preoperative imaging were retrospectively reviewed for features suggestive of FNS, and factors associated with good postoperative facial nerve function (House-Brackmann [HB] grade ≤ 2) were identified. A preoperative imaging protocol for suspected VS and recommendations for surgical decision-making following an intraoperative FNS diagnosis were created. RESULTS: Nineteen patients (1.3%) with FNSs were identified. All patients had normal facial motor function preoperatively. In 12 patients (63%), preoperative imaging demonstrated no features suggestive of FNS, with the remainder showing subtle enhancement of the geniculate/labyrinthine facial segment, widening/erosion of the fallopian canal, or multiple tumor nodules in retrospect. Eleven (57.9%) of the 19 patients underwent a retrosigmoid craniotomy, and in the remaining patients, a translabyrinthine (n = 6) or transotic (n = 2) approach was used. Following FNS diagnosis, 6 (32%) of the tumors underwent gross-total resection (GTR) and cable nerve grafting, 6 (32%) underwent subtotal resection (STR) and bony decompression of the meatal facial nerve segment, and 7 (36%) underwent bony decompression only. All patients undergoing subtotal debulking or bony decompression exhibited normal postoperative facial function (HB grade I). At the last clinical follow-up, patients who underwent GTR with a facial nerve graft had HB grade III (3 of 6 patients) or IV facial function. Tumor recurrence/regrowth occurred in 3 patients (16%), all of whom had been treated with either bony decompression or STR. CONCLUSIONS: Intraoperative diagnosis of an FNS during a presumed VS resection is rare, but its incidence can be reduced further by maintaining a high index of suspicion and undertaking further imaging in patients with atypical clinical or imaging features. If an intraoperative diagnosis does occur, conservative surgical management with bony decompression of the facial nerve only is recommended, unless there is significant mass effect on surrounding structures.

Increased Circulating Chemokines and Macrophage Recruitment in Growing Vestibular Schwannomas.

BACKGROUND: There is evidence that macrophage infiltration in the tumor microenvironment promotes vestibular schwannoma (VS) growth. Efficacy of bevacizumab in NF2-associated VS demonstrates the value of therapies targeting the microvascular tumor microenvironment, and tumor-associated macrophages (TAMs) may represent another druggable target. OBJECTIVE: To characterize the relationship between growth, TAM infiltration, and circulating monocyte chemokines in a large cohort of patients with VS. METHODS: Immunostaining for Iba1 (macrophages), CD31 (endothelium), and fibrinogen (permeability) was performed on 101 growing and 19 static sporadic VS. The concentrations of monocyte-specific chemokines were measured in the plasma of 50 patients with growing VS and 25 patients with static VS. RESULTS: The Iba1 + cell count was significantly higher in growing as compared with static VS (592 vs 226/×20 HPF, P =<0.001). Similarly, the CD31 + % surface area was higher in growing VS (2.19% vs 1.32%, P = .01). There was a positive correlation between TAM infiltration and VS growth rate, which persisted after controlling for the effect of tumor volume (aR2 = 0.263, P =<0.001). The plasma concentrations of several monocytic chemokines were higher in patients with growing rather than static VS. CONCLUSION: There is a strong positive correlation between TAM infiltration and volumetric growth of VS, and this relationship is independent of tumor size. There is a colinear relationship between TAM infiltration and tumor vascularity, implying that inflammation and angiogenesis are interlinked in VS. Chemokines known to induce monocyte chemotaxis are found in higher concentrations in patients with growing VS, suggestive of a potential pathophysiological mechanism.

Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21.

Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants. To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.

Multiple Meningiomas as a Criterion for the Diagnosis of Neurofibromatosis Type 2 and Other Tumor Predisposition Syndromes.

BACKGROUND: Bilateral vestibular schwannomas (VS) are pathognomonic of neurofibromatosis type 2 (NF2), but the diagnostic criteria also include unilateral VS (UVS) in combination with multiple meningiomas (MM) and other schwannomas, as well as MM without VS. OBJECTIVE: To investigate the diagnostic value of these criteria and establish the presence of other genetic conditions in patients presenting in this manner. METHODS: The Manchester International NF2 database was accessed to obtain information on patients presenting with a UVS and MM or ≥2 nonintradermal schwannomas (NIDS). We gathered data on patients diagnosed with NF2 due to MM without VS and on patients presenting with MM without meeting NF2 criteria. Analysis was performed for pathogenic variants (PVs) in NF2, SMARCE1, SMARCB1, and LZTR1. RESULTS: A total of 31 of 131 patients presenting with a UVS and MM had a nonrefuted diagnosis of NF2 after molecular studies, in comparison with 85 of 96 patients presenting with UVS and ≥2 NIDS (P ≤ .00001). Fifty percent of patients presenting with a UVS and ≥2 NIDS with NF2 developed bilateral VS, compared with only 26% of those who presented with a UVS and MM (P = .0046). In total, 11 of 152 patients presenting with MM without fulfilling NF2 criteria were found to have a PV in SMARCE1, and 7 of 152 were confirmed to have mosaic NF2. CONCLUSION: Patients presenting with UVS and MM are significantly more likely to have a nonrefuted diagnosis of NF2 than patients presenting with UVS and ≥2 NIDS, but significantly less likely to develop bilateral VS. Seven percent of those presenting with MM without meeting NF2 criteria had PV in SMARCE1, and 5% had mosaic NF2.

Cochlear Implantation in Neurofibromatosis Type 2: Experience From the UK Neurofibromatosis Type 2 Service.

OBJECTIVE: To review the outcomes of cochlear implants (CI) in patients with neurofibromatosis type 2 (NF2) in a large cohort, and identify factors associated with poor hearing benefit. STUDY DESIGN: Fifteen-year retrospective national observational case series. SETTING: United Kingdom regional NF2 multidisciplinary teams. PATIENTS: Consecutive patients with NF2 receiving a CI. INTERVENTIONS: CI for hearing rehabilitation. MAIN OUTCOME MEASURES: 1) Audiometric performance at 9 to 12 months after implantation using City University of New York (CUNY) sentence recognition score, and Bamford- Kowal-Bench (BKB) word recognition score in quiet (BKBq), and in noise (BKBn). 2) CI use at most recent review. RESULTS: Sixty four consecutive patients, median age 43 years, were included. Nine to 12 months mean audiometric scores were: CUNY 60.9%, BKBq 45.8%, BKBn 41.6%. There was no difference in audiometric outcomes between VS treatment modalities. At most recent review (median 3.6 years from implantation), 84.9% with device in situ/available data were full or part-time users. Between 9 and 12 months and most recent review there was an interval reduction in mean audiometric scores: CUNY -12.9%, BKBq -3.3%, BKBn -4.9%. Larger tumor size and shorter duration of profound hearing loss were the only variables associated with poorer audiometric scores. Tumor growth at the time of surgery was the only variable associated with CI non-use. Individual patient response was highly variable. CONCLUSIONS: CI can provide significant and sustained auditory benefits to patients with NF2 independent of tumor treatment modality, with the majority of those implanted becoming at least part-time users. Larger datasets are required to reliably assess the role of independent variables.

Beyond Antoni: A Surgeon's Guide to the Vestibular Schwannoma Microenvironment.

Introduction Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has highlighted the complex nature of the inflammatory microenvironment in these tumors. Methods A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic. Results The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo . Conclusion Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.

The utility of the exoscope compared to the operating microscope in simulated temporal bone surgery.

OBJECTIVE: To objectively assess the utility of an exoscope during simulated otological surgery. DESIGN: Cohort study. SETTING: Tertiary referral otolaryngology centre. PARTICIPANTS: Seven experienced otologists undertook simulated temporal bone surgery on plastic temporal bones using the Zeiss Kinevo microscope with both a microscope and exoscope facility. OUTCOME MEASURES: The utility of microscope and exoscope was compared using a Likert scale from 1 to 10 with and without PPE. Attributes assessed included image quality, depth perception, adequacy of view, exoscope positioning, surgeon comfort, surgeon safety and adequacy of image and protection for assistants and observers. RESULTS: The exoscope in 3D mode performed as well as or better than the microscope for image quality, field of view and manoeuvrability. It outperformed the microscope for compatibility with PPE, surgeon comfort and assistant/observer experience. It scored almost as highly as the microscope for depth perception. CONCLUSION: There is likely to be a learning curve but this initial assessment of the exoscope shows significant potential as an alternative to the operating microscope in otological surgery but with the advantage of allowing the use of appropriate PPE and better ergonomics for both surgeon and assistant/observer.

Detection of early changes in the post-radiosurgery vestibular schwannoma microenvironment using multinuclear MRI.

Stereotactic radiosurgery (SRS) is an established, effective therapy against vestibular schwannoma (VS). The mechanisms of tumour response are, however, unknown and in this study we sought to evaluate changes in the irradiated VS tumour microenvironment through a multinuclear MRI approach. Five patients with growing sporadic VS underwent a multi-timepoint comprehensive MRI protocol, which included diffusion tensor imaging (DTI), dynamic contrast-enhanced (DCE) MRI and a spiral 23Na-MRI acquisition for total sodium concentration (TSC) quantification. Post-treatment voxelwise changes in TSC, DTI metrics and DCE-MRI derived microvascular biomarkers (Ktrans, ve and vp) were evaluated and compared against pre-treatment values. Changes in tumour TSC and microvascular parameters were observable as early as 2 weeks post-treatment, preceding changes in structural imaging. At 6 months post-treatment there were significant voxelwise increases in tumour TSC (p < 0.001) and mean diffusivity (p < 0.001, repeated-measures ANOVA) with marked decreases in tumour microvascular parameters (p < 0.001, repeated-measures ANOVA). This study presents the first in vivo evaluation of alterations in the VS tumour microenvironment following SRS, demonstrating that changes in tumour sodium homeostasis and microvascular parameters can be imaged as early as 2 weeks following treatment. Future studies should seek to investigate these clinically relevant MRI metrics as early biomarkers of SRS response.

Sporadic vestibular schwannoma: a molecular testing summary.

OBJECTIVES: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis. METHODS: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups. RESULTS: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants. CONCLUSIONS: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

National, Virtual Otolaryngology Training Day in the United Kingdom During the COVID-19 Pandemic: Results of a Pilot Survey.

The COVID-19 pandemic has forced an unprecedented worldwide change in our daily lives, particularly in healthcare. In response to the lockdown measure it has brought on, some deaneries cancelled planned teaching days, while others had delivered remote smaller scale teaching sessions electronically. Due to significant regional variation, the National Association of Program Directors in ENT (NAPDENT) set up a national educational program, matched to the Intercollegiate Surgical Curriculum Program. This is delivered virtually and for free. This pilot survey evaluates participants' learning experience of the first NAPDENT National Otology Training Day, which was held on 20 April 2020 via Zoom. This is a pilot survey evaluating the first online, national educational program delivered by the NAPDENT in the United Kingdom. In the times of the COVID-19 pandemic, our program has rapidly learnt from this initial experience and continues to build on lessons learnt for future editions. It is feasible to augment the national ENT curriculum with a collaborative, online teaching program. Regional buy-in is required to make this work. This modality allows for access to subject experts across the country. Synchronous delivery allows for participant interaction, while an online repository allows for asynchronous viewing when work or personal commitments do not allow live attendance. The key to participant engagement is adequate structure, appropriate breaks and opportunities for interaction. Even once the COVID-19 pandemic has passed, this teaching modality will remain as an opportunity to educate ENT surgeons of the future.

Disease course of neurofibromatosis type 2: a 30-year follow-up study of 353 patients seen at a single institution.

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

The microenvironment in sporadic and neurofibromatosis type II-related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study.

OBJECTIVE: Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)-related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach. METHODS: Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI-derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence. RESULTS: Imaging data demonstrated that DCE-MRI-derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p < 0.001), ve (p ≤ 0.004), and tumoral free water content (p ≤ 0.003) increased with increasing tumor size and pretreatment tumor growth rate. Regression analysis demonstrated that with the exception of mean diffusivity (p < 0.001), NF2 status had no statistically significant effect on any of the imaging parameters or the observed relationship between the imaging parameters and tumor size (p > 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages. CONCLUSIONS: The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups.