Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:The management of World Health Organization (WHO) grade 2 meningiomas is complicated by their diverse clinical behaviors. Stereotactic radiosurgery (SRS) can be an effective management option. Literature on SRS dose selection is limited but suggests that a higher dose is better for tumor control. We characterize the predictors of post-SRS outcomes that can help guide planning and management. METHODS:We reviewed a cohort of consecutive patients with pathologically-proven WHO grade 2 meningiomas who underwent SRS at a single institution between 2011 and 2023. RESULTS:Ninety-nine patients (median age 62 years) underwent SRS, 11 of whom received hypofractionated SRS in 5 fractions. Twenty-two patients had received previous irradiation. The median follow-up was 49 months. The median overall survival was 119 months (95% CI 92-NA) with estimated 5- and 10-year survival of 83% and 27%, respectively. The median progression-free survival (PFS) was 40 months (95% CI 32-62), with 3- and 5-year rates at 54% and 35%, respectively. The median locomarginal PFS was 63 months (95% CI 51.8-NA) with 3- and 5-year rates at 65% and 52%. Nine (9%) patients experienced adverse events, 2 Common Terminology Criteria for Adverse Events grade 3 and 7 grade 2, consisting of worsening neurologic deficit from edema. In the single-session cohort, Ki-67 significantly predicted both overall survival and intracranial PFS. Tumors with Ki-67 >10% had 2.17 times the risk of locomarginal progression compared with Ki-67 ≤10% (P = .018) adjusting for covariates. Sex, prescription dose, tumor volume, and location also predicted tumor control. In tumors with Ki-67 >10%, margin dose ≥14 Gy was associated with significantly better tumor control but not for tumors with Ki-67 ≤10%. CONCLUSION/CONCLUSIONS:The management of WHO grade 2 meningiomas requires a multimodality approach. This study demonstrates the value of a targeted SRS approach in patients with limited disease and further establishes predictive biomarkers that can guide planning through a personalized approach.

BACKGROUND:Radioactive iodine therapy (RAI) is a frequently chosen therapy for Graves' disease. The aim of this study was to determine whether RAI for Graves' disease increases the risk of thyroid malignancy. METHODS:A retrospective analysis was performed of all Graves' disease patients who underwent thyroidectomy at a single institution between 2013 and 2022. Comparative analyses were performed with cohorts based on RAI therapy as the primary grouping variable. RESULTS:413 patients were identified, of which 38 received RAI prior to surgery. RAI treated patients were more likely to undergo surgery for known malignancy or indeterminate nodules. RAI patients were also more likely to have malignancies larger than 1 ​cm. Among RAI treated patients, those who developed malignancy were older at the time of Graves' diagnosis and received early RAI therapy. CONCLUSIONS:Use of RAI for treatment of Graves' disease increases the progression of thyroid carcinoma, but not the prevalence. Older age and early RAI therapy may be risk factors for malignancy in RAI treated patients.

OBJECTIVE:Vocal tremor (VT) poses treatment challenges due to uncertain pathophysiology. VT is typically classified into two phenotypes: isolated vocal tremor (iVT) and essential tremor-related voice tremor (ETvt). The impact of phenotypes on upper aerodigestive tract physiology during swallowing remains unclear. Qualitative and quantitative measures were employed to characterize tremor phenotypes and investigate the effects on swallowing physiology. METHODS:Eleven ETvt participants (1 Male, 10 Female; x̄ age = 74) and 8 iVT participants (1 Male, 7 Female; x̄ age = 71) swallowed 20 mL boluses in cued and uncued conditions under standardized fluoroscopic visualization. Sustained/a/productions were captured to assess the rate and extent of fundamental frequency (F0) modulation. Penetration and Aspiration Scale (PAS) scores were obtained and swallowing biomechanics were captured using Swallowtail™ software. Participants also completed the Swallowing Quality of Life (SWAL-QOL) questionnaire. RESULTS:Hypopharyngeal transit was faster in both VT phenotypes compared with Swallowtail™ normative reference data. Total pharyngeal transit times, however, were only faster in patients with iVT, relative to reference data. No significant differences were observed on the SWAL-QOL or PAS between tremor phenotypes. SWAL-QOL scores revealed that these patients rarely reported dysphagia symptoms. CONCLUSIONS:Subtle differences in swallowing patterns were observed across VT phenotypes, possibly related to adaptive mechanisms resulting in quicker pharyngeal bolus transit. Most patients did not report swallowing issues or dysphagia symptoms. This study is foundational for larger studies on this challenging population. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 134:4599-4603, 2024.

OBJECTIVES/UNASSIGNED:Acute post-thyroidectomy bilateral vocal cord paresis or paralysis (BVCP) is often managed with observation, botulinum toxin injection or tracheostomy. However, only a few cases discuss obstructive sleep apnea (OSA) in the context of BVCP with limited exploration of home sleep test (HST) and continuous positive airway pressure (CPAP) as post-operative assessment and management tools. This study suggests CPAP as a less invasive approach while awaiting vocal cord recovery. METHODS/UNASSIGNED:A retrospective chart review was conducted on 2 female patients who presented with dyspnea and sleep-disordered breathing (SDB) symptoms post-thyroidectomy. Both patients underwent laryngoscopy and HSTs, followed by CPAP prescription. RESULTS/UNASSIGNED:), aged 66 and 77 respectively, presented with post-surgery dyspnea and SDB symptoms. Laryngoscopy revealed left vocal cord paresis and right vocal cord paralysis in both cases. Although tracheostomy could provide definitive treatment, both cases were deferred for non-invasive options, which led to HST, confirming moderate OSA (PAT-derived apnea-hypopnea index (pAHI): 18/hour and 27.1/hour) leading to CPAP recommendation. In Case 2, 5 weeks of CPAP use resulted in dramatic improvements in her sleep quality, with continued benefits at 3-month follow-up. CONCLUSION/UNASSIGNED:These cases underscore the value of considering sleep studies and CPAP as adjunctive tools in acute post-thyroidectomy BVCP management while awaiting vocal motion recovery. This report also further supports that BVCP sufficiently narrows the glottic airway, predisposing patients to OSA.

Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions.

OBJECTIVES/OBJECTIVE:Vocal fold scar remains a therapeutic challenge. Vocal fold fibroblasts (VFFs) secrete extracellular matrix (ECM), and transforming growth factor-beta 1 (TGF-β1)-mediated fibroblast to myofibroblast differentiation is central to the development of fibrosis. The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels, and activation of TRP ankyrin 1 (TRPA1) channel has been shown to have antifibrotic effects through TGF-β1/Smad signaling in various organs. This study aimed to elucidate expression of TRPA1 and the impact of TRPA1 activation on TGF-β1/Smad signaling in VFFs. METHODS: M) for 4 or 24 h. Trpa1, Smad3, Smad7, Col1a1, Acta2, and Has1 mRNA expression were quantified via qPCR. RESULTS:TRPA1 was expressed in cultured VFFs and the lamina propria. TGF-β1 administration significantly increased Trpa1 compared to control. AITC alone did not alter Smad3, Smad7, Acta2, or ECM related genes. However, the combination of AITC and TGF-β1 significantly increased Smad3 and decreased Smad7 and Acta2 compared to TGF-β1 alone; A-967079 significantly reduced this response. CONCLUSIONS:VFFs expressed TRPA1, and the activation of TRPA1 regulated TGF-β1/Smad signaling in VFFs. These findings provide preliminary insights into potential anti-fibrotic mechanisms of TRPA1 activation through TGF-β1/Smad signaling in VFFs. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2024.

BACKGROUND:Preoperative review of computed tomography (CT) imaging assists with endoscopic sinus surgery (ESS) planning, where trainees may benefit from a systematic approach. We have previously developed an optimized preoperative checklist for sinus CT imaging using an iterative modified Delphi method. OBJECTIVE:In this study, we assess the utility of an optimized preoperative checklist for residents performing ESS. METHODS:Resident sinus CT scan education consisted of a preintervention questionnaire, an 18-min video outlining the optimized preoperative checklist, and a delayed postintervention questionnaire; these were distributed via Qualtrics to otolaryngology residents across 5 training programs in the NY metro area. The preintervention questionnaire contained 25 survey questions and a 225-point quiz on sinus CT anatomy; the delayed postintervention questionnaire contained the same 25 survey questions and a second, distinct 225-point quiz. RESULTS: < .001). Resident habitual utilization of a systematic preoperative CT imaging checklist increased significantly from 21.6% to 72.9% as a result of the curriculum intervention. CONCLUSION/CONCLUSIONS:We find that an educational program centered on an iteratively optimized preoperative checklist for ESS improves the ability of trainees to identify critical sinus CT structures. Further integration of checklists and educational curricula may enhance rhinology education efforts and improve surgical anatomy competency.

Humans can remember specific events without acting on them and can influence which memories are retrieved based on internal goals. However, current animal models of memory typically present sensory cues to trigger retrieval and assess retrieval based on action ^1-5 . As a result, it is difficult to determine whether measured patterns of neural activity relate to the cue(s), the retrieved memory, or the behavior. We therefore asked whether we could develop a paradigm to isolate retrieval-related neural activity in animals without retrieval cues or the requirement of a behavioral report. To do this, we focused on hippocampal "place cells." These cells primarily emit spiking patterns that represent the animal's current location (local representations), but they can also generate representations of previously visited locations distant from the animal's current location (remote representations) ^6-13 . It is not known whether animals can deliberately engage specific remote representations, and if so, whether this engagement would occur during specific brain states. So, we used a closed-loop neurofeedback system to reward expression of remote representations that corresponded to uncued, experimenter-selected locations, and found that rats could increase the prevalence of these specific remote representations over time; thus, demonstrating memory retrieval modulated by internal goals in an animal model. These representations occurred predominately during periods of immobility but outside of hippocampal sharp-wave ripple (SWR) ^13-15 events. This paradigm enables future direct studies of memory retrieval mechanisms in the healthy brain and in models of neurological disorders.

Acoustic vocoders play a key role in simulating the speech information available to cochlear implant (CI) users. Traditionally, the intelligibility of vocoder CI simulations is assessed through speech recognition experiments with normally-hearing subjects, a process that can be time-consuming, costly, and subject to individual variability. As an alternative approach, we utilized an advanced deep learning speech recognition model to investigate the intelligibility of CI simulations. We evaluated model's performance on vocoder-processed words and sentences with varying vocoder parameters. The number of vocoder bands, frequency range, and envelope dynamic range were adjusted to simulate sound processing settings in CI devices. Additionally, we manipulated the low-cutoff frequency and intensity quantization of vocoder envelopes to simulate psychophysical temporal and intensity resolutions in CI patients. The results were evaluated within the context of the audio analysis performed in the model. Interestingly, the deep learning model, despite not being originally designed to mimic human speech processing, exhibited a human-like response to alterations in vocoder parameters, resembling existing human subject results. This approach offers significant time and cost savings compared to testing human subjects, and eliminates learning and fatigue effects during testing. Our findings demonstrate the potential of speech recognition models in facilitating auditory research.

Legumain is a cysteine protease broadly associated with inflammation. It has been reported to cleave and activate protease-activated receptor 2 to provoke pain associated with oral cancer. Outside of gastric and colon cancer, little has been reported on the roles of legumain within the gastrointestinal tract. Using a legumain-selective activity-based probe, LE28, we report that legumain is activated within colonocytes and macrophages of the murine colon, and that it is upregulated in models of acute experimental colitis. We demonstrated that loss of legumain activity in colonocytes, either through pharmacological inhibition or gene deletion, had no impact on epithelial permeability in vitro. Moreover, legumain inhibition or deletion had no obvious impacts on symptoms or histological features associated with dextran sulfate sodium-induced colitis, suggesting its proteolytic activity is dispensable for colitis initiation. To gain insight into potential functions of legumain within the colon, we performed field asymmetric waveform ion mobility spectrometry-facilitated quantitative proteomics and N-terminomics analyses on naïve and inflamed colon tissue from wild-type and legumain-deficient mice. We identified 16 altered cleavage sites with an asparaginyl endopeptidase signature that may be direct substrates of legumain and a further 16 cleavage sites that may be indirectly mediated by legumain. We also analyzed changes in protein abundance and proteolytic events broadly associated with colitis in the gut, which permitted comparison to recent analyses on mucosal biopsies from patients with inflammatory bowel disease. Collectively, these results shed light on potential functions of legumain and highlight its potential roles in the transition from inflammation to colorectal cancer.