Faculty Bibliography

Acoustic coordinated reset (CR) therapy based on neuromodulation and neuroplasticity principles has been proposed for the treatment of tonal tinnitus. The original therapy involved periodic delivery of randomly ordered sequences of four low-level tones centered around the frequency of a tone that matched the tinnitus pitch, f_T, with fixed ratios relative to f_T and delivered several hours/day over several weeks. Here we transform the original CR tone selection method to a more perceptually-relevant equivalent rectangular bandwidth (ERB) frequency scale, the ERB_N-number scale. Specifically, we provide a mathematical model that enables calculation of CR tones that accounts for f_T- and hearing loss-related ERB widening and ERB overlaps and gaps of CR tone alignments. Further, the model ensures symmetric CR tone alignments based on modelling studies that indicate the effect is optimal if the CR stimuli are symmetrically spaced relative to the tinnitus-related population of abnormally synchronized cortical neurons to activate the adjacent sub-populations. We also present experimentally testable ERB-based CR tone alignment strategies and explain how to use the ERB-based model in experiments, clinical studies, other types of tinnitus sound treatment such as tailor-made notch music training and limitations of our approach.

OBJECTIVES/OBJECTIVE:To determine the accuracy of a modern navigation system in temporal bone surgery. While routine in other specialties, navigation has had limited use in the temporal bone due to issues of accuracy, perceived impracticality, and value. STUDY DESIGN/METHODS:Prospective observational study. SETTING/METHODS:Temporal bone laboratory. SUBJECTS AND METHODS/METHODS:Eighteen cadaveric specimens were dissected after rigid fiducials were implanted and computed tomography scans were obtained. Target registration and target localization errors were then measured at various points. RESULTS:The mean overall target registration error was 0.48 ± 0.29 mm. The mean target localization error was 0.54 mm at the sinodural angle, 0.48 mm at the lateral semicircular canal, 0.55 mm at the round window, 0.39 mm at the oval window, and 0.52 mm at the second genu of the facial nerve. CONCLUSION/CONCLUSIONS:A modern navigation system demonstrated submillimeter accuracy for all points of interest. Its use in clinical as well as training settings has yet to be fully elucidated.

Neutrophil elastase is a serine protease that has been implicated in the pathogenesis of inflammatory bowel disease. Due to post-translational control of its activation and high expression of its inhibitors in the gut, measurements of total expression poorly reflect the pool of active, functional neutrophil elastase. Fluorogenic substrate probes have been used to measure neutrophil elastase activity, though these tools lack specificity and traceability. PK105 is a recently described fluorescent activity-based probe, which binds to neutrophil elastase in an activity-dependent manner. The irreversible nature of this probe allows for accurate identification of its targets in complex protein mixtures. We describe the reactivity profile of PK105b, a new analogue of PK105, against recombinant serine proteases and in tissue extracts from healthy mice and from models of inflammation induced by oral cancer and Legionella pneumophila infection. We apply PK105b to measure neutrophil elastase activation in an acute model of experimental colitis. Neutrophil elastase activity is detected in inflamed, but not healthy, colons. We corroborate this finding in mucosal biopsies from patients with ulcerative colitis. Thus, PK105b facilitates detection of neutrophil elastase activity in tissue lysates, and we have applied it to demonstrate that this protease is unequivocally activated during colitis.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in patients with ET/PV previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC) 111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET/PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rate ORR (CR / PR) at 12 months was 69.2% (43.1% / 26.2%) in ET, and 60% (22%/38%) in PV patients. CR rates were higher in CALR mutated ET patients (56.5% vs. 28.0%, p= 0.01) as compared to subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction (VAF) was -6% (range -84%-47%) in patients achieving a CR versus +4% (range -18%-56%) in patients with PR/non-response (NR). Therapy was associated with a significant rate of adverse events (AE), most were manageable, and PEG discontinuation due to AEs occurred only in 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET/PV who were previously refractory and/or intolerant to HU. (ClinicalTrials.gov Identifier: NCT01259856).

OBJECTIVES/OBJECTIVE:To quantify the effect that time to initiation of treatment after diagnosis has on the outcomes of patients with head and neck squamous cell carcinoma (HNSCC). METHODS:This is a single institution retrospective analysis of 633 HNSCC patients treated from 2004 to 2017. Clinical information was abstracted from the medical records. Patients were divided into quartiles based on the time to treatment initiation (0-27 days, 28-41 days, 42-60 days, and >60 days). Kaplan-Meier overall survival (OS) curves and multivariate cox proportional hazard ratios were determined for time to treatment quartiles. RESULTS:Differences in Kaplan-Meier estimates for OS based on treatment time quartiles were statistically significantly (p = 0.02), and multivariate Cox Proportional hazard ratios for OS revealed that patients in the 42-60 day treatment time group had better OS (hazard ratio = 0.55) compared to patients treated >days after diagnosis (p < 0.01). CONCLUSIONS:For our study population, increased time to initiation of treatment did not impact overall survival. These results may help to alleviate patient anxiety while allowing time for useful interventions such as smoking cessation, nutritional counseling, and others that can affect clinical outcomes.

PURPOSE/OBJECTIVE:To determine the risk factors for unanticipated readmission, prolonged index admission, and discharge to a facility after vestibular schwannoma surgery. MATERIALS AND METHODS/METHODS:Retrospective cohort study of those undergoing surgery for vestibular schwannoma in the Nationwide Readmissions Database (2013-2014). Main outcome measures included readmission rate, length of stay, discharge destination. RESULTS:There were 4585 cases identified. The overall unanticipated readmission rate was 8.1%, and 9.1% had a prolonged length of stay (PLOS) of ≥7 days. Mean and median LOS were 4.63 and 4.00 days, respectively, and >90% of patients were discharged after 7 days. Disposition to a facility occurred in 6.7% of cases. Teaching hospitals were protective against unintended readmission (odds ratio [OR] 0.44, p < .001). Major functional loss was associated with PLOS (OR 12.55, p < .001). High volume centers were associated with decreased risk of PLOS (OR 0.46, p < .001) and facility discharge (OR 0.68, p < .001). The most common readmission diagnoses included "other nervous system complications" (n = 128), cerebrospinal fluid leak (n = 71), "other postoperative infection" (n = 61), and meningitis (n = 59). CONCLUSIONS:Unanticipated readmission and prolonged LOS following vestibular schwannoma surgery are common, with varied sociodemographic, hospital, and patient factors independently associated with each. Further studies are needed to investigate targeted interventions aimed at minimizing readmission and prolonged LOS using the factors outlined above.

BACKGROUND:Intraosseous petrous apex schwannomas are an exceedingly rare entity; little is known about their epidemiology, natural history, and post-operative outcomes. CASE DESCRIPTION/METHODS:Here, we present the fourth known case of a primary intraosseous schwannoma of the petrous apex: a 68-year-old woman presenting with diplopia, facial numbness, progressive intermittent vertigo, tinnitus, diminished hearing, and ataxia. She underwent a transtemporal approach for subtotal resection of the tumor with subsequent stereotactic radiosurgery. CONCLUSIONS:Our two-year follow-up demonstrates slow growth and success of multimodal management in the treatment of these tumors. We review the three prior reports of petrous apex schwannomas, and identify unifying radiographic and clinical characteristics in order to aid in future diagnostic considerations of lesions of the petrous apex.

The BRAF-V600E mutation is found in 15-20% of pediatric low grade gliomas (PLGG) and result in worse outcome and higher risk of transformation to high grade gliomas (PHGG). Although ongoing trials are assessing the role of BRAF inhibitors (BRAFi) in these children, data are still limited. We aimed to report overall response rates and predictors of outcome in childhood BRAF-V600E gliomas. We collected clinical, imaging and molecular information of patients treated with BRAFi outside trials from centers participating in the PLGG taskforce. Response was calculated by RANO criteria and follow up data were collected for all patients. Sixty-six patients were treated with BRAFi (55 PLGG and 11 PHGG); median follow-up time was 1.5 years (0.1-5y). In PLGG, objective response (tumor reduction of >25%) was observed in 77% compared to 15% in a cohort treated with conventional chemotherapy (pCDKN2A deletion was not associated with lack of response, while specifc enhancing patterns correlated strongly with response to BRAFi. Two-year PFS for the BRAF-V600E PLGG was 74% vs 47% for BRAFi vs chemotherapy, respectively (p=0.02). Our data reveal rapid, dramatic and sustained response of BRAF-V600E PLGG to BRAFi. These are in contrast to BRAF-V600E PHGG and non-enhancing PLGG. Additional molecular analyses are being performed to identify poor responders and emerging mechanisms of resistance in these tumors