Disparities in Sporadic Vestibular Schwannoma Initial Presentation Between a Public Safety Net Hospital and Tertiary Academic Medical Center at the Same Zip Code 2010 to 2020.

INTRODUCTION: Treatment of vestibular schwannoma (VS) has been extensively studied, but a gap in knowledge exists demonstrating how racial and socioeconomic status influence VS presentation. Our institution has a unique setting with a public safety net hospital (PSNH) and tertiary academic medical center (TAMC) in the same zip code, which we study to evaluate initial VS presentation disparities in patient populations presenting to these hospital settings. METHODS: Retrospective chart review was performed of all adult patients (n = 531) presenting 2010 to 2020 for initial VS evaluation at TAMC (n = 462) and PSNH (n = 69). Ethnicity, insurance, maximum tumor size, audiometry, initial treatment recommendation, treatment received, and follow up were recorded and statistical analysis performed to determine differences. RESULTS: Average age at diagnosis (51.7 ± 13.6 TAMC vs 52.3 ± 12.4 PSNH) and gender (58.4% TAMC vs 52.2% PSNH female) were similar. Patients' insurance (TAMC 75.9% privately insured vs PSNH 82% Medicaid) and racial/ethnic profiles (TAMC 67.7% White and 10.0% Hispanic/Latinx, vs PSNH 4.8% White but 59.7% Hispanic/Latinx) were significantly different. Tumor size was larger at PSNH (20.2 ± 13.3 mm) than TAMC (16.6 ± 10.0 mm). Hearing was more impaired at PSNH than TAMC (mean pure tone average 58.3 dB vs 43.9 dB, word recognition scores 52.3% vs 68.2%, respectively). Initial treatment recommendations and treatment received may include more than 1 modality. TAMC patients were offered 66.7% surgery, 31.2% observation, and 5.2% radiation, while PSNH patients offered 50.7% observation, 49.3% surgery, and 8.7% radiation. TAMC patients received 62.9% surgery, 32.5% observation, and 5.3% radiation, while PSNH patients received 36.2% surgery, 59.4% observation, and 14.5% radiation. Follow up and treatment at the same facility was not significantly different between hospitals. CONCLUSIONS: Hearing was worse and tumor size larger in patients presenting to PSNH. Despite worse hearing status and larger tumor size, the majority of PSNH patients were initially offered observation, compared to TAMC where most patients were initially offered surgery.

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

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

Nummular and Side-locked Headaches for the Otolaryngologist.

Side-locked headaches are a common symptom having a wide-ranging differential. Unchanging in laterality, these headaches can represent neuralgias, trigeminal autonomic cephalgias, ophthalmologic disorders, otolaryngologic and craniofacial disorders, vascular disorders, and malignancy. In rarer situations, they have presented secondary to neurosurgical or dermatologic considerations. Loss of cranial nerves and visual changes warrant additional evaluation.

Idiopathic Intracranial Hypertension: Implications for the Otolaryngologist.

Idiopathic intracranial hypertension (IIH) is a triad of headaches, visual changes, and papilledema in the absence of a secondary cause for elevated intracranial pressure. There is an association with obesity, and the incidence is rising in parallel with the obesity epidemic. Sometimes these patients present to an otolaryngologist with complaints like tinnitus, dizziness, hearing loss, and otorrhea or rhinorrhea from cerebrospinal fluid leak. IIH diagnosis in conjunction with neurology and ophthalmology, including neuroimaging and lumbar puncture with opening pressure, is key to managing of this condition. Otolaryngologists should recognize IIH as a possible diagnosis and initiate appropriate referrals and treatment.

Trends in Hearing Protection Use With Occupational Noise Exposure in the United States 1999 to 2016.

OBJECTIVE: Determine hearing protection use in relation to occupational noise exposure, tinnitus, and audiometry-measured hearing loss in the United States from 1999 to 2016. STUDY DESIGN: Cross-sectional study utilizing US National Health and Nutritional Examination Survey (NHANES) 1999 to 2016 with occupation, reported occupational noise exposure, hearing protection use, tinnitus, and audiometry-measured hearing loss data. Subgroup analysis divided data into two cohorts early 2000s and 2010s. SETTING: Population-based study using NHANES database capturing representative sample of US population. PARTICIPANTS: Individuals with complete data 1999 to 2004 (n = 10,347) and 2011 to 2012 with 2015 to 2016 (n = 9,383). INTERVENTIONS: Participants self-reported occupational noise exposure lasting more than 4 h/d for more than 3 months. Self-reported hearing protective device uses and tinnitus frequency. Audiometric hearing loss objectively measured. MAIN OUTCOME MEASURES: Hearing protection use. Secondary measures included self-reported bothersome tinnitus and audiometrically measured hearing loss. RESULTS: Across occupations, reported occupational noise exposure was higher in 2010s [32%, 95% CI: 29.6-34.6%] than 2000s [12.5%, 95% CI: 11.2-13.9%], while hearing protection use remained low in 2000s [41.3%, 95% CI: 37.8-44.8%] and 2010s [32.8%, 95% CI: 29.8-35.8%]. Less hearing protection use was associated with absence of bothersome tinnitus. Factors associated with increased hearing protection use were younger age, male sex, college education or higher, and white race in a multivariate model. CONCLUSIONS: Reported occupational noise exposure appeared to increase from 2000s to 2010s yet hearing protection use remained stable at low use rate. As noise exposure is a major risk factor for hearing loss, significant education and reinforcement of appropriate hearing protection use for workplace noise exposures is necessary to preserve workers' hearing.

Contributions of Contemporary Human Temporal Bone Histopathology to Clinical Otology.

Contemporary techniques have greatly enhanced the contributions of human temporal bone (HTB) histopathology to our understanding of the mechanisms of human otologic disease and disease treatment. Herein, we review some of the most salient contributions of this research to disease management. The field of HTB histopathology is challenged by limited resources as applies to trained investigators, infrastructure, and well-equipped laboratories. This research provides insights into clinical otology that cannot be obtained by any other means. Measures should be taken to preserve and extend the contributions of HTB research.

Cochlear implant histopathology.

The microscopic examination of fifty-five serially sectioned implanted temporal bones has provided insight into what is being stimulated; and the changes that are the result of the insertion and presence of the implant. The ganglion cell bodies (neurons) are structures being stimulated (two laboratories have reported an inverse relationship of the number of neurons and performance). Insertion through the round window, verses a cochleostomy, produces the least fibrosis and new bone. Fibrosis and new bone do not affect the implant function unless they form in the scala vestibuli in the region of the ductus reuniens, and, block it; and produce cochlear hydrops resulting in a delayed low tone loss of hearing in hybrid implants. Animal models cannot be applied to humans because of the difference in size and myelination of the neurons.

Activation of PDGFR and EGFR promotes the acquisition of a stem cell-like phenotype in schwannomas.

OBJECTIVES: Vestibular schwannomas (VS) are benign tumors that arise from unregulated growth of Schwann cells. Both benign and malignant tumors are believed to contain tumor stem cells that are hypothesized to originate from dysregulation of tumor suppressors and oncogenes. We aimed to determine if schwannoma cells express stem cell genes and markers and if activation of the proto-oncogenes epidermal growth factor receptor and platelet-derived growth factor receptor would regulate the stem cell properties of these cells. METHODS: Immunohistochemical staining was used to determine the expression of stem cell genes in archived VS tissue, immunofluorescence was used to investigate the expression in cell lines, and Western blot analysis was used to measure PDGFR expression in vestibular schwannoma tissue. Upon activation of PDGFR or EGFR in schwannoma cell lines using specific ligands, flow cytometry was used to quantify the side population (SP), stem cell genes were measured using quantitative PCR, and tumorsphere-forming ability was determined. RESULTS: Stem cell genes are expressed in vestibular schwannoma tissue and schwannoma cell lines. Activation of both EGFR and PDGFR resulted in increase in the induction of the expression of the stem cell genes Oct-4 and Nanog and marked increase in tumorsphere-forming ability, but only PDGFR activation resulted in an increase in the side population in JS1 cells. CONCLUSION: Dysregulation of EGFR and PDGFR promotes the acquisition of a stem cell-like phenotype in schwannnoma cells that may be critical in vestibular schwannoma tumorigenesis.

ErbB expression, activation, and inhibition with lapatinib and tyrphostin (AG825) in human vestibular schwannomas.

BACKGROUND: Pharmacologic agents targeted against the ErbB family, or the intracellular pathways that mediate their effects, could slow clinical progression of vestibular schwannoma (VS) in patients where other modalities carry a high risk-to-benefit ratio. OBJECTIVE: Determine the identity of the predominant ErbB dimer partners in VS tumors and assess the effects of targeted inhibition of the ErbB molecules on VS growth and proliferation, as well as apoptosis. SETTING: Academic tertiary referral center. METHODS: Coimmunoprecipitation and Western blotting of VS tissue, in vitro BrdU assays of proliferation in the presence of lapatinib and tyrphostin (AG825) using primary VS cultures, and annexin V cell death assays and cell cycle assays using propidium iodide staining were performed on HEI193 cell line derived from an neurofibromatosis type 2-associated VS. RESULTS: Activated ErbB family receptor heterodimers in VS contain predominantly epidermal growth factor receptor (EGFR) and ErbB2. A robust, dose-dependent inhibition of VS growth and proliferation with the dual EGFR/ErbB2 inhibitor, lapatinib, was demonstrated. Lapatinib also inhibited EGF-induced VS proliferation. The selective ErbB2 inhibitor, AG825, inhibited growth to a lesser extent. HEI193 demonstrated apoptosis after lapatinib treatment. CONCLUSION: Dual EGFR and ErbB2 inhibition with lapatinib or combination therapy may provide therapeutic benefit in VS treatment, but further studies are necessary.

Comparative case series of exostoses and osteomas of the internal auditory canal.

Exostoses and osteomas are benign bony lesions of the auditory canal. Although common in the external auditory canal, they are rare and difficult to distinguish in the internal auditory canal (IAC). In this literature review and case presentation, we define radiologic and histologic criteria to differentiate exostoses from osteomas of the IAC. Two patients with exostoses and 1 patient with an osteoma of the IAC are described here. Patient 1 presented with disabling vertigo and was found to have bilateral exostoses with nerve impingement on the right. After removal of the right-sided exostoses via retrosigmoid craniotomy, the patient had complete resolution of her symptoms over 1 year. Patient 2 presented with bilateral pulsatile tinnitus and vertigo and was found to have bilateral IAC exostoses. Patient 3 presented with hearing loss and tinnitus, and a unilateral IAC osteoma was ultimately discovered. Because of the mild nature of their symptoms, patients 2 and 3 were managed without surgery. We show that IAC osteomas can be differentiated from exostoses by radiographic evidence of bone marrow in high-resolution computed tomography scans, or by the presence of fibrovascular channels on histologic analysis. Management of these rare entities is customized on the basis of patient symptoms.

Potential role of imatinib mesylate (Gleevec, STI-571) in the treatment of vestibular schwannoma.

HYPOTHESIS: To determine the expression of the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and c-Kit in vestibular schwannoma (VS) and to determine the potential role of imatinib mesylate (Gleevec) in regulating the growth and cell death of this tumor. BACKGROUND: Protein tyrosine kinases are transmembrane tyrosine kinase receptors that transduce signals from inside and outside the cell and function as relay points for signaling pathways. They have a key role in numerous processes that affect cell proliferation, tumorigenesis, cancer invasion, metastasis, and modulation of apoptosis. A few of these kinases have been demonstrated to be overexpressed and dysregulated in many carcinomas, sarcomas, and benign tumors. METHODS: Immunohistochemical staining was used to investigate the expression of PDGFR and c-Kit in archived acoustic neuroma tissue. Clinical data including size of tumors, age, sex, and symptoms were correlated with kinase expression, whereas Western blot analysis and immunofluorescence were performed to demonstrate the expression and localization of PDGFR and c-Kit in HEI193, an immortalized VS cell line. Clonogenic survival assays were performed to assess proliferation inhibition by Gleevec. Gleevec's effect on the cell cycle profile also was investigated via flow cytometry analysis. RESULTS: Expression of PDGFR in the formalin-fixed VS tumor tissue was observed in 23 (67.5%) of the 34 samples. C-kit was expressed in 18 (52.9%) of the 34 samples. Western blot analysis demonstrates positive expression of c-Kit and PDGFR-Q in HEI193 and a primary VS culture. Western blot analysis showed downregulation of phospho-c-kit and phospho-PDGFR-Q with 5 and 10 uM Gleevec. Immunofluorescent staining of this cell line also reveals that PDGFR-ß is localized primarily in the cytoplasm, whereas c-Kit is both nuclear and cytoplasmic. Cell cycle analysis of HEI193 96 hours after incubation with Gleevec indicates a dose-dependent increase in G1 from 61.6% to 70.7% and 74% at 5 and 10 uM of Gleevec, respectively. Colony formation assays demonstrate dose-dependent growth inhibition by Gleevec, in the HEI193 cell line as well as in a VS cell culture derived from a fresh tumor. CONCLUSION: The expression of PDGFR-Q and c-Kit in VS tissue may indicate novel molecular targets involved in the development of this tumor. Direct inhibition of these molecules by Gleevec may have relevant therapeutic applications.

EGF and bFGF promote invasion that is modulated by PI3/Akt kinase and Erk in vestibular schwannoma.

OBJECTIVES: Vestibular schwannomas (VSs) are slow-growing benign tumors but, on rare occasion, can invade adjacent cranial nerves, causing significant morbidity, especially in association with neurofibromatosis 2 (NF2). We aimed to determine the role of the growth factors EGF, bFGF, and the hormone, Epo, in promoting such invasive behavior in VS, as well as their mechanisms of action. METHODS: Immunohistochemical staining showed expression of EGFR, bFGF, Epo, EpoR in archived VS tissue. Western blots and immunofluorescence showed expression of EGFR, EpoR and FGF in HEI-193, an immortalized cell line derived from human NF2-related VS. Matrigel invasion assays were used to study the effect of Epo, FGF and bFGF on invasive behavior in HEI-193. Western blotting showed levels of phospho-Akt and phospho-Erk in HEI-193 upon addition of growth factors plus PI3K or MEK inhibitors. Quantitative RT-PCR was performed to determine the expression of MMP2 and MMP9 after treatment with growth factors. RESULTS: EGFR, bFGF, Epo and EpoR were expressed in VS tissue and HEI193. Addition of EGF and bFGF increased cellular invasion by 10 and 3.5-fold, respectively. Epo had minimal effect on invasion. Results indicated that Erk is involved in bFGF but not EGF-induced invasion, while Akt is involved in both pathways. EGF treatment moderately induced MMP9, but is unlikely to account for the observed invasion. CONCLUSION: Activation of EGFR and FGFR may promote invasive behavior in VS through ERK and Akt signaling pathways. Further investigation will be necessary to elucidate their potential as useful targets in the treatment of VS.

Estrogen receptor expression in sporadic vestibular schwannomas.

HYPOTHESIS: We hypothesize that vestibular schwannomas (VSs) exhibit up-regulation of estrogen receptor (ER) at the protein level compared with control great auricular nerve (GAN). BACKGROUND: It has been reported in the literature that VS occur more commonly in women and tend to be larger and more vascular in women, and growth rate can accelerate during pregnancy. The literature contains widely divergent results on ER expression in VS, however, varying from no detectable levels to detection of ER in all samples. METHODS: Sixteen sporadic VS specimens were immediately snap-frozen after microsurgical excision and analyzed for phosphorylated and total levels of ERα with Western blot analysis. ERα expression levels were normalized to actin; then, relative expression to GAN was determined. RESULTS: All VS specimens exhibited expression of both phosphorylated and total ERα. Total ERα expression in VS is equivalent to or slightly up-regulated compared with GAN. VS specimens exhibited more pronounced up-regulation of phosphorylated (i.e., activated) levels of ERα compared with GAN. CONCLUSION: We have demonstrated that ERα expression in VS is equivalent to GAN. The phosphorylated form of the receptor is up-regulated compared with GAN, however, indicating a higher level of ERα activation in sporadic VS compared with normal nerve. Further investigation into antiestrogen therapy for VS is warranted.

Merlin knockdown in human Schwann cells: clues to vestibular schwannoma tumorigenesis.

HYPOTHESIS: To investigate the early events in molecular progression toward schwannoma tumorigenesis, we developed an in vitro model of human Schwann cell tumorigenesis by merlin knockdown. BACKGROUND: Neurofibromatosis 2 (NF2)-related and sporadic vestibular schwannoma (VS) exhibit loss of functional merlin (schwannomin). After loss of merlin expression in the Schwann cell, the initial steps toward VS tumorigenesis are unknown. Merlin, a putative tumor suppressor protein, interacts with many cellular proteins, regulating their function. Among these are receptor tyrosine kinases, including the epidermal growth factor receptor family B (ErbB) family receptors epidermal growth factor receptor and ErbB2. Functional merlin interacts with and internalizes these growth factor receptors, silencing their proliferation and survival signaling. Deregulation of CD44, the cell adhesion/signaling molecule and cancer stem cell marker, has also been implicated in VS tumorigenesis. METHODS: Merlin knockdown was performed using small interfering RNA transfection into human Schwann cell primary cultures. Knockdown was confirmed by real-time quantitative PCR, immunofluorescence, and Western analysis. Expression profiles of ErbB, merlin, and the stem cell markers nestin and CD44 were examined in knockdowns. Proliferation rate was assessed with bromodeoxyuridine incorporation, and radiation sensitivity was assessed using the Annexin assay in knockdowns versus controls. RESULTS: Merlin knockdowns demonstrated increased proliferation rate, upregulation of epidermal growth factor receptor, ErbB2, and ErbB3, CD44, and nestin. Short-term merlin depletion had no effect on gamma irradiation sensitivity compared with controls. CONCLUSION: Merlin depletion results in deregulation of ErbB receptor signaling, promotes a dedifferentiated state, and increases Schwann cell proliferation, suggesting critical steps toward schwannoma tumorigenesis.

Laterality of exostosis in surfers due to evaporative cooling effect.

OBJECTIVES: 1. To correlate exostosis severity with ear canal evaporative cooling. 2. To assess hearing and complications after canalplasty. STUDY DESIGN: Retrospective chart review. SUBJECTS AND METHOD: A retrospective chart review from 1990 to 2007 at a university tertiary referral center. RESULTS: Surfers from the west coast of the United States were twice as likely to have severe exostoses in the right ear compared with the left. Evaporative cooling from a predominant northerly wind direction during the coldest water temperature months in this region may contribute to this lateral bias because surfers on this coast spend most of their time facing west. Few postoperative complications were identified. No cases of facial nerve injury or entry into the temporomandibular joint occurred. Differences in preoperative versus postoperative pure-tone hearing thresholds were not significant. CONCLUSION: Exostosis severity seems to correspond to the ear that is more exposed to the predominant coastal wind. We propose that evaporative cooling in a cold water environment contributes to greater progression of exostoses in the ear with more exposure to the predominant wind. Exostosis removal using the postauricular approach carries a low complication rate.