Chris Halpin

Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2

BACKGROUND Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. METHODS We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. RESULTS VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. CONCLUSIONS VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.

Oral steroid treatment of sudden sensorineural Hearing loss: A ten year Retrospective analysis

Objective To describe ten years of experience with Sudden Sensorineural Hearing Loss and compare the outcomes with and without treatment with oral corticosteroids. Study Design Retrospective review of medical records. Setting Large specialty hospital, Department of Otolaryngology. Patients Patients presenting with sudden onset (72 hours) unilateral sensorineural hearing loss, with no evidence of Ménières Disease, acoustic injury, retrocochlear disease, and other specifiable disorders. Interventions The majority of patients received a standard course of oral corticosteroids (Prednisone 60mg and taper). A smaller group declined treatment. Main Outcome Measures Recovery of hearing sensitivity was measured using standard audiometry and reported as change in Pure Tone Average. Word recognition scores were also analyzed. Results When severe-to-profound cases are analyzed, a significant improvement (p < .01) in Pure Tone Average is seen in cases treated with steroids versus those untreated. When milder cases are included, a statistical floor effect prevents differentiation of these groups. Word recognition scores were significantly improved (p < .05) in the treated group. Conclusions Application of steroid medication significantly improves the recovery outcomes in cases of Severe Sudden Sensorineural Hearing Loss.

Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients.

Objective Early studies suggest that bevacizumab treatment can result in tumor shrinkage and hearing improvement for some patients with neurofibromatosis type 2 (NF2). The aim of this study was to report extended follow-up in a larger cohort of similarly treated patients. Study Design Retrospective study. Setting Tertiary referral center Patients Thirty-one consecutive NF2 patients who received bevacizumab for progressive vestibular schwannomas. Main Outcome Measure Hearing improvement, defined as an improvement in word recognition score above the 95% critical difference compared with baseline, and radiographic response, defined as a 20% or greater decrease in tumor volume compared with baseline. Results The median age was 26 years (range, 12–73 yr). The median volumetric tumor growth rate before treatment was 64% per year. At the time of analysis, the median duration of treatment was 14 months (range, 6–41 mo) with a total of 47 patient-years of follow-up. A hearing response occurred in 57% (13/23) of evaluable patients and a radiographic response in 55% (17/31) of target vestibular schwannomas. The median time to response was 3 months for both end points. The only clinical or radiographic feature at baseline that correlated with change in tumor volume at 3 months was the mean apparent diffusion coefficient value, a radiologic marker of edema (p = 0.036). Ninety percent of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years; 88% of patients had stable or decreased tumor size after 1 year of treatment and 54% at 3 years. Overall, treatment was well tolerated. Conclusion Bevacizumab treatment was followed by hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas in NF2 patients. Stable or improved hearing was retained in the majority of patients.

Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients.

Objective: In vitro treatment of Nf2-deficient cells with epidermal growth factor receptor (EGFR) inhibitors can reduce cellular proliferation. We sought to determine the activity of erlotinib for progressive vestibular schwannoma (VS) associated with neurofibromatosis 2 (NF2). Study Design: Retrospective case review. Setting: Tertiary referral center. Patients: Eleven NF2 patients with progressive VS who were poor candidates for standard therapy. Intervention: Erlotinib 150 mg daily. Main Outcome Measures: A radiographic response was defined as ≥ 20% decrease in tumor volume compared with baseline. A hearing response was defined as a statistically significant increase in word recognition score (WRS) compared with baseline; a minor hearing response was defined as a 10 dB improvement in pure-tone average with stable WRS. Results: Before treatment, the median and mean annual volumetric growth rate for 11 index VS were 26% and 46%, respectively. Among 10 evaluable patients, the median time-to-tumor progression was 9.2 months. Three patients with stable disease experienced maximum tumor shrinkage of 4%, 13%, and 14%. Nine patients underwent audiologic evaluations. One experienced a transient hearing response, 2 experienced minor hearing responses, 3 remained stable, and 2 developed progressive hearing loss. The median time-to-progressive hearing loss was 9.2 months and to either tumor growth or progressive hearing loss was 7.1 months. Adverse treatment effects included mild-to-moderate rash, diarrhea, and hair thinning, with 2 episodes of grade 3 toxicity. Conclusion: Erlotinib treatment was not associated with radiographic or hearing responses in NF2 patients with progressive VS. Because a subset of patients experienced prolonged stable disease, time-to-progression may be more appropriate than radiographic or hearing response for anti-EGFR agents in NF2-associated VS.

Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy.

Background A 48-year-old man presented to a neurologist with complaints of bilateral hearing loss and tinnitus. The patient was a member of a large family affected by neurofibromatosis type 2 and first noted hearing loss 10 years before presentation.Investigations Medical and neurological examination, MRI scan of the brain and spinal cord, pure-tone audiometry, NU–6 monosyllabic word test with phoneme scoring, City University of New York topic-related sentences test, noise/voice test of minimal auditory capability battery.Diagnosis Progressive neurofibromatosis-type-2-related vestibular schwannomas.Management Annual cranial MRI and audiology, surgical resection of right vestibular schwannoma, high-power behind-the-ear hearing aid, erlotinib therapy for progressive left vestibular schwannoma.

Using audiometric thresholds and word recognition in a treatment study.

Objectives: First, to examine a possible limit on significant results imposed by a progressive floor effect for hearing threshold improvement in a treatment study. This floor effect for hearing recovery suggests that if inclusion criteria are not set sufficiently high, the superiority of a treatment group may not be detectable. Second, to examine the outcomes when using two different types of criteria for significant change in a subjects word recognition score. Methods: Several single-number criteria (e.g., 15 percentage points) are compared with the 95% (p = 0.05) criteria from the binomial critical difference table for monosyllables. Critical differences for binomial variables change depending on whether the starting value lies in the middle (near 50% correct) or at either extreme of the range of scores (0 or 100%). Different judgments of significant word recognition improvement (or decrease) using binomial versus single-value criteria are presented. Data Source: A recent treatment study of sudden sensorineural hearing loss (n = 318) is used to illustrate these effects. Conclusion: First, there is a progressive floor effect of presenting severity that covaries with the outcome measure hearing threshold recovery. In some designs, this may act to constrain the ability to detect a significant difference. Second, in the example data set, the use of single-value criteria for significant within-subject change in word recognition (e.g., 15 percentage points) introduced a miscategorization error rate of approximately 9% when compared with the result of the binomial 95% critical difference table.

The impact of dexamethasone on hearing loss in experimental pneumococcal meningitis.

Bacterial meningitis, particularly that resulting from Streptococcus pneumoniae, is a common cause of acquired profound sensorineural deafness in children. The pathogenesis of meningogenic hearing loss has been investigated in an experimental rabbit model. In this study significant deafness was documented within the first 15 hours of infection. Initiation of antibiotic therapy at this time diminished the severity of hearing loss in most animals. The addition of dexamethasone to antibiotic therapy prevented the development of profound deafness. These results suggest this model will be useful in developing antiinflammatory strategies to improve the outcome of bacterial meningitis.

Clinical implications of a damaged cochlea : Pure tone thresholds vs information-carrying capacity

The pure tone audiogram is an accurate measure of auditory threshold as a function of stimulus frequency. However, it does not provide the complete picture in patients with sensorineural hearing loss (SNHL) because it is not a direct measure of damage to the cochlear epithelium or of the associated limits on information-carrying capacity that restrict word recognition. Diagnostic use of the audiogram leads to the error of viewing SNHL as “dB of hearing loss,” which may seem reversible by gain. Cochlear disorders, on the other hand, often give rise to abnormal thresholds because regions are damaged and may best be thought of more in terms of intractable sensory limitations, comparable to vision loss in retinal disease. We argue that word recognition testing at low vs high presentation levels provides a quantification of the cochleas information-carrying capacity and is a useful predictor of word recognition limits with hearing aids.

Autosomal-Dominant Progressive Sensorineural Hearing Loss in a Large North American Family

Forty-nine members of a family with autosomal-dominant progressive sensorineural hearing loss were evaluated by audiologists, otologists, and geneticists. The results presented here show a nonsyndr...

Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2–Associated Vestibular Schwannomas

PURPOSE Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. PATIENTS AND METHODS Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. RESULTS Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell-derived factor 1α (P = .037 and .025, respectively). CONCLUSION Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.