Dispersed DNA variants underlie hearing loss in South Florida's minority population.

BACKGROUND: We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations. RESULTS: The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients. CONCLUSION: This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses.

Theoretical Evaluation and Experimental Validation of Localized Therapeutic Hypothermia Application to Preserve Residual Hearing After Cochlear Implantation.

OBJECTIVES: Cochlear implantation surgery has been shown to result in trauma to inner ear sensory structures, resulting in loss of residual hearing. Localized therapeutic hypothermia has been shown in clinical care to be a neuroprotective intervention. Previously, we have shown in an experimental model that localized hypothermia protects cochlear hair cells and residual hearing function against surgical and cochlear implantation trauma. Using experimental temperature measurements carried out in human cadaver temporal bones and a finite element model of the inner ear, the present study examined the temperature distribution of a custom-designed hypothermia delivery system in the human inner ear organs. DESIGN: The efficacy of the hypothermia probe and resulting heat distribution across human cochlea and surrounding tissues were modeled in three-dimensional in COMSOL. The geometry and dimensions of inner ear and temporal bones were derived from computed tomographic and magnetic resonance imaging images. Model predictions were compared with experimental observations from five human temporal bones. RESULTS: In both the modeling and experimental studies, the cochlear temperature was lowered by 4 to 6 °C on the round window from a baseline of 37 °C within 16 to 18 minutes. The model simulations showed uniformly distributed cooling across the cochlea. This study provides insight for design, operation, and protocols for efficacious delivery of mild therapeutic hypothermia to the human cochlea that may significantly benefit patients undergoing surgical cochlear implantation by preserving residual hearing. CONCLUSION: There was a close correlation between the results of the numerical simulations and experimental observations in this study. Our custom-designed system is capable of effectively providing mild therapeutic hypothermia locally to the human cochlea. When combined with results from in vivo animal experiments, the present study suggests that the application of localized therapeutic hypothermia may hold potential for patients with an aim to preserve residual hearing after cochlear implantation.

Transcranial Attenuation in Patients with Single-Sided Deafness.

Transcranial attenuation (TA) of bone-conducted sound has a high degree of variability by frequency and subject, which may play a role in the objective benefit of individuals with single-sided deafness (SSD) treated with a bone-anchored implant (BAI). This study sought to determine whether TA is predictive of benefit in individuals with SSD who receive a BAI. Adult, English-speaking patients with unilateral profound sensorineural hearing loss who underwent a BAI evaluation were included for study. Absolute TA values were consistent with previously published reports. Regression analysis indicated no correlation between TA values and aided speech-in-noise performance for any combined or individual frequencies. Measures of TA do not provide predictive value in determining behavioral outcomes in the SSD population. Specifically, low TA does not suggest improved outcomes with a BAI.

Atypical radiographic features of skull base cholesterol granuloma.

Cholesterol granulomas (CGs) are the most common benign lesions of the petrous apex (PA) and have distinct computed tomography (CT) and magnetic resonance imaging (MRI) characteristics. On CT, CGs of the PA (PACG) present as expansile lesions with erosion of bony trabeculae. MRI shows a hyperintense lesion on T1-and T2-weighted images and do not enhance with gadolinium. The objective is to describe the radiographic features of CGs of the skull base that do not arise from the PA. This study is a retrospective review. Three patients were operated on for suspected recurrent endolymphatic sac tumor, intracranial cholesteatoma, and recurrent sphenoid wing meningioma based on CT and MRI findings. Pathology results were consistent with CG in all three cases. All patients had bone erosion on CT. These skull base CGs did not demonstrate similar MRI features. These lesions were hyperintense, iso-to-hyperintense, and hypointense on T1-weighted MRI, respectively. These CGs were hyperintense in two cases and iso-to-hyperintense in one case on T2-weighted MRI. These lesions either demonstrated central or rim enhancement after gadolinium administration. Skull base CGs that do not arise from the PA demonstrate a broad spectrum of radiographic characteristics on MRI that are not typical of PACG.

Middle fossa vestibular neurectomy for refractory vertigo: less is more.

OBJECTIVE: This study aimed to evaluate outcomes of the middle fossa (MF) superior vestibular neurectomy in unilateral Ménière's disease. PATIENTS AND METHODS: Case series with preoperative and postoperative analysis of the 1995 American Academy of Otolaryngology hearing stage and vertigo class, gait instability, and results of vestibular-evoked myogenic potentials (VEMP). RESULTS: Four out of the 5 patients had total vertigo control (class A) and 1 had near total control (class B) by the last visit (mean follow-up, 23.6 months). There were no changes in hearing thresholds and hearing stage. Four patients had resolution of their gait instability by 2 months after surgery. Postoperative VEMP responses were preserved in all 3 patients with positive VEMP preoperatively. CONCLUSION: This is the first report of the anatomical and functional preservation of the inferior vestibular nerve in vestibular neurectomy for the treatment of refractory vertigo in unilateral Ménière's disease, with VEMP testing before and after vestibular neurectomy. The modified technique limits the surgical dissection and may help avoid complications such as postoperative hearing loss and persistent gait instability. This approach is indicated when other more conservative measures have failed, and patient selection is paramount to avoid long-term complications.

Speech Discrimination Outcomes in Adult Cochlear Implant Recipients by Primary Language and Bilingual Hispanic Patients.

OBJECTIVE: Compare cochlear implant (CI) outcomes in English speakers, Spanish speakers, and bilingual Hispanics. STUDY DESIGN: Retrospective review. SETTING: Academic tertiary care center. METHODS: Eighty-five postlingually deafened adults unilaterally implanted between January 2014 and December 2018 were stratified by primary language. Primary outcomes were: (1) English consonant-nucleus-consonant and Spanish bisyllables word tests in quiet, and (2) English AzBio and Latin American Hearing In Noise Test (LA-HINT) sentence tests in quiet and in noise at multiple time-intervals postactivation. RESULTS: In the respective languages, primary Spanish speakers (n = 24), and English speakers (n = 61) experienced the greatest increases in average scores for word and sentence tests in quiet during the first 6 months postactivation, with gradual increases in average scores over time. English speakers performed significantly worse on AzBio tests in noise, compared to quiet, while the addition of noise did not significantly affect average LA-HINT scores in Spanish speakers across multiple time intervals. An early ceiling effect was also demonstrated for LA-HINT. Although not significant, bilingual Hispanics (n = 12) had lower average AzBio in quiet scores than English speakers and higher average LA-HINT in quiet scores than the Spanish speakers across multiple time intervals. CONCLUSION: English and Spanish CI users experienced the greatest increases in speech understanding in quiet the first few months after implant activation. An early ceiling effect is demonstrated with LA-HINT, indicating LA-HINT is not appropriate for evaluating longitudinal CI outcomes in Spanish speakers. Bilingual Hispanics represent a unique group, and further investigations are necessary to understand speech perception patterns in both languages and develop the best CI test strategies for these individuals.

Functional Hearing Preservation in Cochlear Implantation: The Miami Cocktail Effect.

OBJECTIVE: To investigate if pharmacological treatment with prednisone and L-N-acetylcysteine (STE + NAC) influence functional hearing preservation in cochlear implant (CI) surgery. STUDY DESIGNS: Preimplantation and postimplantation longitudinal case-control study. SETTING: Tertiary referral center. PATIENTS: Pediatric and adult recipients of CI with preimplantation functional hearing defined as an average of air-conducted thresholds at 125, 250, and 500 Hz (low-frequency pure-tone average [LFPTA]) <80 dB. INTERVENTIONS: Preimplantation and postimplantation audiometry. Weight-adjusted oral prednisone and L-N-acetylcysteine starting 2 days before surgery (Miami cocktail). Prednisone was continued for 3 days and L-N-acetylcysteine for 12 days after surgery, respectively. Cochlear implantation with conventional length electrodes. MAIN OUTCOME MEASURES: Proportion of patients with LFPTA <80 dB, and LFPTA change at 1-year postimplantation. RESULTS: All 61 patients received intratympanic and intravenous dexamethasone intraoperatively, with 41 patients receiving STE + NAC and 20 patients not receiving STE + NAC. At 1-year postimplantation, the proportion of functional hearing preservation was 83% in the STE + NAC group compared with 55% of subjects who did not receive STE + NAC ( p = 0.0302). The median LFPTA change for STE + NAC-treated and not treated subjects was 8.33 dB (mean, 13.82 ± 17.4 dB) and 18.34 dB (mean, 26.5 ± 23.4 dB), respectively ( p = 0.0401, Wilcoxon rank test). Perioperative STE + NAC treatment resulted in 10 dB of LFPTA better hearing than when not receiving this treatment. Better low-frequency preimplantation hearing thresholds were predictive of postimplantation functional hearing. No serious side effects were reported. CONCLUSION: Perioperative STE + NAC, "The Miami Cocktail," was safe and superior to intraoperative steroids alone in functional hearing preservation 1-year after cochlear implantation.

Amplitude Parameters Are Predictive of Hearing Preservation in a Randomized Controlled Trial of Intracochlear Electrocochleography During Cochlear Implant Surgery.

OBJECTIVE: To prospectively evaluate the association between hearing preservation after cochlear implantation (CI) and intracochlear electrocochleography (ECochG) amplitude parameters. STUDY DESIGN: Multi-institutional, prospective randomized clinical trial. SETTING: Ten high-volume, tertiary care CI centers. PATIENTS: Adults (n = 87) with sensorineural hearing loss meeting CI criteria (2018-2021) with audiometric thresholds of ≤80 dB HL at 500 Hz. METHODS: Participants were randomized to CI surgery with or without audible ECochG monitoring. Electrode arrays were inserted to the full-depth marker. Hearing preservation was determined by comparing pre-CI, unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to LF-PTA at CI activation. Three ECochG amplitude parameters were analyzed: 1) insertion track patterns, 2) magnitude of ECochG amplitude change, and 3) total number of ECochG amplitude drops. RESULTS: The Type CC insertion track pattern, representing corrected drops in ECochG amplitude, was seen in 76% of cases with ECochG "on," compared with 24% of cases with ECochG "off" (p = 0.003). The magnitude of ECochG signal drop was significantly correlated with the amount of LF-PTA change pre-CI and post-CI (p < 0.05). The mean number of amplitude drops during electrode insertion was significantly correlated with change in LF-PTA at activation and 3 months post-CI (p ≤ 0.01). CONCLUSIONS: ECochG amplitude parameters during CI surgery have important prognostic utility. Higher incidence of Type CC in ECochG "on" suggests that monitoring may be useful for surgeons in order to recover the ECochG signal and preventing potentially traumatic electrode-cochlear interactions.

Genotype-phenotype associations in paragangliomas of the temporal bone in a multi-ethnic cohort.

BACKGROUND: Temporal bone paragangliomas are rare tumours with variable presentation that can be hereditary. Identification of clinical and genetic factors of aggressive tumour behaviour is important. OBJECTIVE: To determine the underlying genetic mutations and genotype/phenotype correlations in a multi-ethnic population of South Florida with sporadic temporal bone paragangliomas. METHODS: In a cohort of glomus tympanicum (GT) and glomus jugulare (GJ) cases, we assessed the frequency of pathogenic single nucleotide variants, insertions, deletions, and duplications in coding exons of genes that have been associated with paragangliomas (SDHB, SDHC, SDHD, SDHA, SDHAF2, RET, NF1, VHL, TMEM127, and MAX). RESULTS: None of the 12 GT cases had mutations. Among 13 GJ cases, we identified four mutation carriers (31%); two in SDHC, one in SDHB, and one in SDHD. All patients with pathogenic mutations were of Hispanic ethnicity, presented at a younger age (mean 27.5 versus 52.11 years), and with more advanced disease when compared to mutation-negative GJ cases.Conclusions and Significance: Mutations in the SDH genes are found in 31% of sporadic GJ. SDH-associated GJ had advanced disease and a 50% risk of metastasis. Our data supports emerging recommendations for genetic screening in all populations with GJ tumours as the genetic status informs management.

Single Fraction and Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, and Reduced Viability of Merlin-Deficient Schwann Cells.

BACKGROUND: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). METHODS: Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. RESULTS: Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. CONCLUSIONS: Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.

Cytokine Profiling of Cyst Fluid and Tumor-Associated Macrophages in Cystic Vestibular Schwannoma.

BACKGROUND: The vestibular schwannoma (VS) secretome can initiate monocyte recruitment and macrophage polarization to M1 (proinflammatory) and/or M2 (protumorigenic) phenotypes, which in turn secrete additional cytokines that contribute to the tumor microenvironment. Profiling cyst fluid and cerebrospinal fluid (CSF) in cystic VS provides a unique opportunity to understand mechanisms that may contribute to tumor progression and cyst formation. HYPOTHESIS: Cystic VSs secrete high levels of cytokines into cyst fluid and express abundant M1 and M2 macrophages. METHODS: Tumor, CSF, and cyst fluid were prospectively collected from 10 cystic VS patients. Eighty cytokines were measured in fluid samples using cytokine arrays and compared with normal CSF from normal donors. Immunofluorescence was performed for CD80 + M1 and CD163 + M2 macrophage markers. Demographic, audiometric, and radiographic information was obtained through retrospective chart review. RESULTS: Cyst fluid expressed more osteopontin and monocyte chemotactic protein-1 (MCP-1; p < 0.0001), when compared with normal CSF. Cyst fluid also expressed more protein ( p = 0.0020), particularly MCP-1 ( p < 0.0001), than paired CSF from the same subjects. MCP-1 expression in cyst fluid correlated with CD80 + staining in VS tissue ( r = 0.8852; p = 0.0015) but not CD163 + staining. CONCLUSION: Cyst fluid from cystic VS harbored high levels of osteopontin and MCP-1, which are cytokines important in monocyte recruitment and macrophage polarization. MCP-1 may have a significant role in molding the tumor microenvironment, by polarizing monocytes to CD80 + M1 macrophages in cystic VS. Further investigations into the role of cytokines and macrophages in VS may lead to new avenues for therapeutic intervention.

Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.

Ethnic disparity in skin complications following bone-anchored hearing aid implantation.

OBJECTIVES: Sound processor loading after implantation of a bone-anchored hearing aid is often delayed by skin-site complications. This study examined the frequency of skin-site complications in various ethnic groups and determined factors that may lead to higher rates of skin-site complications resulting in delayed processor loading. METHODS: Adult, English-speaking patients who underwent implantation of a bone-anchored hearing aid between 2007 and 2010 were reviewed. Demographic data including ethnicity, tobacco use, diabetes mellitus, immunosuppression, and long-term steroid use were determined. Major and minor skin-site complications and the time to processor loading were recorded. RESULTS: The mean time to processor loading was 9.5 weeks, and the mean follow-up time was 23 months. There were no cases of osseointegration failure. African American patients had a significantly higher rate of major skin-site complications (p < 0.005) and a longer time to processor loading (mean, 17.6 weeks; p < 0.05) than the other ethnic groups. There was no significant difference in minor skin complication rates. There was no correlation between diabetes mellitus, long-term immunosuppression, or tobacco use and skin-site complications. CONCLUSIONS: Skin complications can delay processor loading following implantation of a bone-anchored hearing aid. There is a higher rate of major skin-site complications in African American patients, and these often delay processor loading. The risk of skin-site complications is not correlated with smoking, diabetes mellitus, or immunosuppression. An increased risk of skin-site complications is an important consideration for preoperative counseling.

Comparison of Speech Test Outcomes After Cochlear Implantation in Patients With and Without Asymmetric Hearing Loss.

OBJECTIVES: Determine whether asymmetric hearing loss (AHL) affects postoperative speech outcomes in cochlear implant (CI) patients. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care hospital. PATIENTS: Adult English-speaking patients with unilateral CIs implanted between 2014 and 2018 were stratified into NonAHL and AHL groups based on preoperative AzBio scores in quiet from the nonimplanted ear (0-50% vs. 51-100%, respectively). INTERVENTIONS: CI surgery in the poorer performing ear. MAIN OUTCOME MEASURES: Postoperative consonant-nucleusconsonant (CNC) word and AzBio sentence test scores in quiet and/or noise at +5 dB signal-to-noise ratio (SNR). RESULTS: Of 512 patients, 33 non-AHL and 27 AHL patients were included. Average ages were 65.6 and 63.6 years, respectively. As expected, preoperative AzBio scores in quiet from the nonimplanted ear were higher in the AHL group (95% confidence interval [95%CI]: 66.4-76.4%) than the non-AHL group at baseline (95%CI: 12.3-23.6%). In both cohorts, AzBio scores in quiet from the implanted ear improved from baseline, with 24-month scores (95%CI: 73.8 - 84.9%) being higher than preoperative scores (95%CI: 13.2-23.1%). There were also significant differences in AzBio scores in quiet between cohorts overall (p  = 0.0120) on mixed model analysis, with the AHL group performing ∼6.4% better than the non-AHL group; however, differences were not significant when scores were stratified by time. In addition, there were no significant differences in CNC in quiet and AzBio scores in noise at +5 dB SNR between cohorts (p  = 0.1786 and p  = 0.6215, respectively). CONCLUSIONS: After CI, patients with AHL can achieve scores on word and sentence tests at least comparable to traditional CI candidates, supporting the expansion of CI candidacy to include patients with AHL.

Effect of AR42 in Primary Vestibular Schwannoma Cells and a Xenograft Model of Vestibular Schwannoma.

HYPOTHESIS: AR42, a histone deacetylase (HDAC) inhibitor, reduces viability of primary vestibular schwannoma (VS) cells and delays tumor progression and hearing loss (HL) in a xenograft model of VS. BACKGROUND: The impact of HDAC expression on AR42 response in primary VS cells is unknown, as well as the effects of AR42 on VS-associated HL and imbalance. METHODS: Primary human VS cells (n = 7) were treated with AR42 (0-3.0 µM), and viability assays were conducted. Immunohistochemistry and western blotting for phosphorylated-HDAC2 (pHDAC2) were performed on tumor chunks. Pharmacokinetic studies were conducted in Fischer rats using mass spectrometry. Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats and treated with vehicle (n=7) or AR42 (25 mg/kg/day for 4weeks; n=12). Tumor bioluminescence imaging, auditory brainstem response (ABR), and rotarod tests were conducted to 6weeks. Final tumor weight and toxicities were measured. RESULTS: AR42 caused dose-dependent reductions in viability of VS cells. Tumors with higher pHDAC2:HDAC2 ratios had greater reductions in viability with AR42. On pharmacokinetic studies, AR42 reached peak levels in nerve ~24 hours after oral administration. Although AR42-treated rats demonstrated mean ABR threshold shifts ~10 to 20 dB lower than controls, this did not persist nor reach significance. When compared to controls, AR42 did not affect tumor bioluminescence, tumor weight, and rotarod measurements. CONCLUSIONS: Response of primary VS cells to AR42 may be influenced by pHDAC2 expression in tumor. Although AR42 may delay HL in our xenograft model, it did not halt tumor growth or vestibular dysfunction. Further investigations are warranted to evaluate the AR42 effectiveness in NF2-associated VS.

Merlin-Deficient Schwann Cells Are More Susceptible to Radiation Injury than Normal Schwann Cells In Vitro.

Objectives Vestibular schwannomas (VS) are intracranial tumors, which are caused by NF2 gene mutations that lead to loss of merlin protein. A treatment for VS is stereotactic radiosurgery, a form of radiation. To better understand the radiobiology of VS and radiation toxicity to adjacent structures, our main objectives were (1) investigate effects of single fraction (SF) radiation on viability, cytotoxicity, and apoptosis in normal Schwann cells (SCs) and merlin-deficient Schwann cells (MD-SCs) in vitro, and (2) analyze expression of double strand DNA breaks (γ-H2AX) and DNA repair protein Rad51 following irradiation. Study Design This is a basic science study. Setting This study is conducted in a research laboratory. Participants Patients did not participate in this study. Main Outcome Measures In irradiated normal SCs and MD-SCs (0-18 Gy), we measured (1) viability, cytotoxicity, and apoptosis using cell-based assays, and (2) percentage of cells with γ-H2AX and Rad51 on immunofluorescence. Results A high percentage of irradiated MD-SCs expressed γ-H2AX, which may explain the dose-dependent losses in viability in rodent and human cell lines. In comparison, the viabilities of normal SCs were only compromised at higher doses of radiation (>12 Gy, human SCs), which may be related to less Rad51 repair. There were no further reductions in viability in human MD-SCs beyond 9 Gy, suggesting that <9 Gy may be insufficient to initiate maximal tumor control. Conclusion The MD-SCs are more susceptible to radiation than normal SCs, in part through differential expression of γ-H2AX and Rad51. Understanding the radiobiology of MD-SCs and normal SCs is important for optimizing radiation protocols to maximize tumor control while limiting radiation toxicity in VS patients.

RAD51 Inhibitor and Radiation Toxicity in Vestibular Schwannoma.

OBJECTIVE: To describe the RAD51 response (DNA repair) to radiation-induced DNA damage in patient-derived vestibular schwannoma (VS) cells and investigate the utility of RAD51 inhibitor (RI-1) in enhancing radiation toxicity. STUDY DESIGN: Basic and translational science. SETTING: Tertiary academic facility. METHODS: VS tumors (n = 10) were cultured on 96-well plates and 16-well slides, exposed to radiation (0, 6, 12, or 18 Gy), and treated with RI-1 (0, 5, or 10 µM). Immunofluorescence was performed at 6 hours for γ-H2AX (DNA damage marker), RAD51 (DNA repair protein), and p21 (cell cycle arrest protein). Viability assays were performed at 96 hours, and capillary Western blotting was utilized to determine RAD51 expression in naïve VS tumors (n = 5). RESULTS: VS tumors expressed RAD51. In cultured VS cells, radiation initiated dose-dependent increases in γ-H2AX and p21 expression. VS cells upregulated RAD51 to repair DNA damage following radiation. Addition of RI-1 reduced RAD51 expression in a dose-dependent manner and was associated with increased γ-H2AX levels and decreased viability in a majority of cultured VS tumors. CONCLUSION: VS may evade radiation injury by entering cell cycle arrest and upregulating RAD51-dependent repair of radiation-induced double-stranded breaks in DNA. Although there was variability in responses among individual primary VS cells, RAD51 inhibition with RI-1 reduced RAD51-dependent DNA repair to enhance radiation toxicity in VS cells. Further investigations are warranted to understand the mechanisms of radiation resistance in VS and determine whether RI-1 is an effective radiosensitizer in patients with VS.

Safety and Facial Nerve Outcomes of Intracisternal Papaverine Irrigation for Vestibular Schwannoma Resection.

BACKGROUND: Papaverine, a vasodilator approved for use by the U.S. Food and Drug Administration, has shown efficacy in treating vasospasm in cardiology, urology, and nephrology. The vasodilatory effect of papaverine is also hoped to protect the facial nerve from ischemic damage and nerve manipulation during vestibular schwannoma surgery. Our institution uses intracisternal papaverine irrigation during vestibular schwannoma resection to protect the facial nerve in patients with neuromonitoring changes. Our objective was to investigate the safety and facial nerve outcomes of intracisternal papaverine irrigation during vestibular schwannoma resection. METHODS: We retrospectively reviewed patients who underwent resection of vestibular schwannoma at our institution between 2008 and 2021. Patients received papaverine if the intraoperative facial nerve stimulation threshold increased above 0.05 mA. Postoperative outcomes were compared with control patients who did not receive papaverine. RESULTS: A total of 283 cases were included in our analysis. Patients who received papaverine (n = 60) had lower immediate postoperative House-Brackmann (HB) grades than did control individuals (mean, 1.54 vs. 1.95; P = 0.029) and a lower likelihood of immediate postoperative HB grade >1 (odds ratio, 0.514; P = 0.039). At long-term follow-up, there was no significant difference in HB grade. Papaverine use was not associated with increased rates of perioperative complications (P = 0.24). CONCLUSIONS: The off-label use of intracisternal papaverine irrigation during vestibular schwannoma resection can certainly be used safely for select cases. It is associated with improved immediate postoperative facial nerve outcomes, similar long-term facial nerve outcomes, and no significant increase in complications.

Microsurgical Management of Vestibular Schwannoma (Acoustic Neuroma): Facial Nerve Outcomes, Radiographic Analysis, Complications, and Long-Term Follow-Up in a Series of 420 Surgeries.

OBJECTIVE: The purpose of this study is to retrospectively evaluate the clinical and surgical outcomes of a large surgical series of vestibular schwannoma from North America over 20 years. METHODS: After institutional review board approval a retrospective review of the senior author's personal case logs to identify patients who had operations for vestibular schwannoma was performed. The clinical notes, operative record, preoperative and postoperative imagings, and long-term clinical follow-up notes were evaluated. RESULTS: A total of 415 patients who underwent 420 surgeries were identified from the years 1998-2021. The average length of follow-up was 3 years and 9 months. Overall, at last follow-up the rate of "good" facial nerve outcomes (House-Brackmann [HB] score I and II) was 86% and "poor" facial nerve outcomes (HB III-VI) was 14%. The amount of cerebellopontine angle extension (P = 0.023), tumor volume (P = 0.015), facial nerve consistency (P < 0.001), preoperative HB score (P < 0.001), and FN stimulation threshold at the end of the procedure (P < 0.001) were correlated to facial nerve function at the last follow-up. CONCLUSIONS: This study represents one of the largest recently reported surgical series of vestibular schwannoma in North American literature with available long term follow-up. Facial nerve outcomes correlated with cerebellopontine angle extension, tumor volume, facial nerve stimulation threshold, facial nerve consistency, preoperative facial nerve function, and history of a prior resection. Tumor recurrence remains significantly higher after subtotal resection. We believe the data supports a continuation of a strategy of general intent of gross total resection, greatly modifiable by intraoperative findings and judgment.

Can Electrocochleography Help Preserve Hearing After Cochlear Implantation With Full Electrode Insertion?

OBJECTIVES: To evaluate the utility of intracochlear electrocochleography (ECochG) monitoring during cochlear implant (CI) surgery on postoperative hearing preservation. STUDY DESIGN: Prospective, randomized clinical trial. SETTING: Ten high-volume, tertiary care CI centers. PATIENTS: Adult patients with sensorineural hearing loss meeting the CI criteria who selected an Advanced Bionics CI. METHODS: Patients were randomized to CI surgery either with audible ECochG monitoring available to the surgeon during electrode insertion or without ECochG monitoring. Hearing preservation was determined by comparing preoperative unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to postoperative LF-PTA at CI activation. Pre- and post-CI computed tomography was used to determine electrode scalar location and electrode translocation. RESULTS: Eighty-five adult CI candidates were enrolled. The mean (standard deviation [SD]) unaided preoperative LF-PTA across the sample was 54 (17) dB HL. For the whole sample, hearing preservation was "good" (i.e., LF-PTA change 0-15 dB) in 34.5%, "fair" (i.e., LF-PTA change >15-29 dB) in 22.5%, and "poor" (i.e., LF-PTA change ≥30 dB) in 43%. For patients randomized to ECochG "on," mean (SD) LF-PTA change was 27 (20) dB compared with 27 (23) dB for patients randomized to ECochG "off" ( p = 0.89). Seven percent of patients, all of whom were randomized to ECochG off, showed electrode translocation from the scala tympani into the scala vestibuli. CONCLUSIONS: Although intracochlear ECochG during CI surgery has important prognostic utility, our data did not show significantly better hearing preservation in patients randomized to ECochG "on" compared with ECochG "off."