Faculty Bibliography

Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing^1-6. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers⁷, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.

BACKGROUND AND PURPOSE:Most multinodular and vacuolating neuronal tumors (MVNTs) are diagnosed and followed radiologically without any change across time. There are no surveillance guidelines or quantitative volumetric assessments of these tumors. We evaluated MVNT volumes during long follow-up periods using segmentation tools with the aim of quantitative assessment. MATERIALS AND METHODS:All patients with MVNTs in a brain MR imaging report in our system were reviewed. Patients with only 1 brain MR imaging or in whom MVNT was not clearly the most likely diagnosis were excluded. All MVNTs were manually segmented. For all follow-up examinations, absolute and percentage volume change from immediately prior and initial examinations were calculated. RESULTS:= .67), respectively. CONCLUSIONS:MVNT segmentation across follow-up brain MR imaging examinations did not demonstrate significant volume differences, suggesting that these tumors do not enlarge with time. Hence, frequent surveillance imaging of newly diagnosed MVNTs may not be necessary.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Glucocorticoids (GC)s are commonly employed to treat vocal fold (VF) pathologies. However, VF atrophy has been associated with intracordal GC injections. Dexamethasone-induced skeletal muscle atrophy is well-documented in other tissues and believed to be mediated by increased muscle proteolysis via upregulation of Muscle Ring Finger (MuRF)-1 and Atrogin-1. Mechanisms of dexamethasone-mediated VF atrophy have not been described. This pilot study employed in vitro and in vivo models to investigate the effects of dexamethasone on VF epithelium, thyroarytenoid (TA) muscle, and TA-derived myoblasts. We hypothesized that dexamethasone will increase atrophy-associated gene expression in TA muscle and myoblasts and decrease TA muscle fiber size and epithelial thickness. STUDY DESIGN/METHODS:In vitro, pre-clinical. METHODS:TA myoblasts were isolated from a female Sprague-Dawley rat and treated with 1 μM dexamethasone for 24-h. In vivo, 15 New Zealand white rabbits were randomly assigned to three treatment groups: (1) bilateral intracordal injection of 40 μL dexamethasone (10 mg/ml; n = 5), (2) volume-matched saline (n = 5), and (3) untreated controls (n = 5). Larynges were harvested 7-days post-injection. Across in vivo and in vitro experimentation, MuRF-1 and Atrogin-1 mRNA expression were measured via RT-qPCR. TA muscle fiber cross-sectional area (CSA) and epithelial thickness were also quantified in vivo. RESULTS:Dexamethasone increased MuRF-1 gene expression in TA myoblasts. Dexamethasone injection, however, did not alter atrophy-associated gene expression, TA CSA, or epithelial thickness in vivo. CONCLUSION/CONCLUSIONS:Dexamethasone increased atrogene expression in TA myoblasts, providing foundational insight into GC induced atrophic gene transcription. Repeated dexamethasone injections may be required to elicit atrophy in vivo. LEVEL OF EVIDENCE/METHODS:N/A Laryngoscope, 2022.

OBJECTIVES/OBJECTIVE:Effective treatments for vocal fold fibrosis remain elusive. Tamoxifen (TAM) is a selective estrogen receptor modulator and was recently reported to have antifibrotic actions. We hypothesized that TAM inhibits vocal fold fibrosis via altered transforming growth factor beta 1 (TGF-β1) signaling. Both in vitro and in vivo approaches were employed to address this hypothesis. METHODS: M) ± TGF-β1 (10 ng/ml) to quantify cell proliferation. The effects of TAM on genes related to fibrosis were quantified via quantitative real-time polymerase chain reaction. In vivo, rat vocal folds were unilaterally injured, and TAM was administered by oral gavage from pre-injury day 5 to post-injury day 7. The rats were randomized into two groups: 0 mg/kg/day (sham) and 50 mg/kg/day (TAM). Histological changes were examined on day 56 to assess tissue architecture. RESULTS: M) + TGF-β1, however, significantly increased Smad7 and Has3 expression and decreased Col1a1 and Acta2 expression compared to TGF-β1 alone. In vivo, TAM significantly increased lamina propria area, hyaluronic acid concentration, and reduced collagen deposition compared to sham treatment. CONCLUSIONS:TAM has antifibrotic potential via the regulation of TGF-β1/Smad signaling in vocal fold injury. These findings provide foundational data to develop innovative therapeutic options for vocal fold fibrosis. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2022.

OBJECTIVES:Immune-checkpoint inhibitors (ICI) are being utilized with increasing frequency and may be linked to neurologic and audiovestibular toxicities. This report aimed to describe a case of ICI-induced sensorineural hearing loss ultimately requiring bilateral cochlear implantation. METHODS:A 42-year-old female with stage IV metastatic melanoma of the perianal skin was treated with ipilimumab (blocker of cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) and nivolumab (anti-programmed cell death protein 1 [PD1]). After 21 weeks of therapy, she developed sudden vertigo and bilateral hearing loss. A full workup including MRI and lumbar puncture ruled out intracranial parenchymal metastases, leptomeningeal metastases, stroke and intracranial infection. ICI-associated aseptic meningoencephalitis was therefore diagnosed. The patient received systemic steroids as well as intratympanic steroids, which temporarily improved hearing, but eventually developed permanent, bilateral profound sensorineural hearing loss. RESULTS:The patient received bilateral cochlear implants and has demonstrated good performance one year after implantation. DISCUSSION:ICI are being increasingly used to treat a variety of advanced malignancies. This is the first report of bilateral cochlear implants in the context of profound hearing loss after an immunotherapy induced meningoencephalitis. CONCLUSION:ICI carries the risk of potential ototoxicity, including profound SNHL as depicted in our case. Cochlear implantation proved to be beneficial and may be considered in patients with ICI-related hearing loss.

Office-based procedures can be a fulfilling part of the facial plastic practice with the right tools, personnel, and preparation. Equipping the clinic for office-based procedures has several unique considerations that ultimately impact its success. It is important to strategize preemptively regarding what treatments will be offered and the respective equipment that will allow the safe, cost-effective, and high-quality delivery of those treatments. Most procedures in the office-based setting are cosmetic in nature and there are often overlapping treatment modalities that target similar outcomes. Patient selection and counseling is a crucial step in preparing for office-based procedures in the effort to maximize patient satisfaction. Nearly all the most common facial plastic procedures can be delivered in the office-based based setting under local anesthesia and moderate sedation, depending on the expertise of the surgeon. To enable these and other categories of treatments, there are certain expensive pieces of technology that one might consider for their office-based practice and other fundamental supplies that are necessary for almost all practices. Though the initial investment in equipment can be costly, this article also discusses more affordable alternatives or third-party sales of devices and equipment. The field of facial plastic surgery is very dynamic and having both peer and mentorship networks is invaluable in navigating some of the financial decisions discussed herein. This article also briefly covers personnel, training, and accreditation considerations.

PURPOSE/OBJECTIVE:Patients with EGFR-mutated NSCLC represent a unique subset of lung cancer patients with distinct clinical and molecular characteristics. Previous studies have shown a higher incidence of brain metastases (BM) in this subgroup of patients, and neurologic death has been reported to be as high as 40% and correlates with leptomeningeal disease (LMD). METHODS:Between 2012 and 2021, a retrospective review of our prospective registry identified 606 patients with BM from NSCLC, with 170 patients having an EGFR mutation. Demographic, clinical, radiographic, and treatment characteristics were correlated to the incidence of LMD and survival. RESULTS:LMD was identified in 22.3% of patients (n = 38) at a median follow-up of 19 (2-98) months from initial SRS. Multivariate regression analysis showed targeted therapy and a cumulative number of metastases as significant predictors of LMD (p = 0.034, HR = 0.44), (p = .04, HR = 1.02). The median survival time after SRS of the 170 patients was 24 months (CI 95% 19.1-28.1). In a multivariate Cox regression analysis, RPA, exon 19 deletion, and osimertinib treatment were significant predictors of overall survival. The cumulative incidence of neurological death at 2 and 4 years post initial stereotactic radiosurgery (SRS) was 8% and 11%, respectively, and correlated with LMD. CONCLUSION/CONCLUSIONS:The study shows that current-generation targeted therapy for EGFR-mutated NSCLC patients may prevent the development and progression of LMD, leading to improved survival outcomes. Nevertheless, LMD is associated with poor outcomes and neurologic death, making innovative strategies to treat LMD essential.

BACKGROUND:We created a clinical virtual reality application for vestibular rehabilitation. Our app targets contextual sensory integration (C.S.I.) where patients are immersed in safe, increasingly challenging environments while practicing various tasks (e.g., turning, walking). The purpose of this pilot study was to establish the feasibility of a randomized controlled trial comparing C.S.I. training to traditional vestibular rehabilitation. METHODS:Thirty patients with vestibular dysfunction completed the Dizziness Handicap Inventory (DHI), Activities-Specific Balance Confidence Scale (ABC), Visual Vertigo Analog Scale (VVAS), Functional Gait Assessment (FGA), Timed-Up-and-Go (TUG), and Four-Square Step Test (FSST). Following initial assessment, the patients were randomized into 8 weeks (once per week in clinic + home exercise program) of traditional vestibular rehabilitation or C.S.I. training. Six patients had to stop participation due to the covid-19 pandemic, 6 dropped out for other reasons (3 from each group). Ten patients in the traditional group and 8 in the C.S.I group completed the study. We applied an intention to treat analysis. RESULTS:Following intervention, we observed a significant main effect of time with no main effect of group or group by time interaction for the DHI (mean difference - 18.703, 95% CI [-28.235, -9.172], p = 0.0002), ABC (8.556, [0.938, 16.174], p = 0.028), VVAS, (-13.603, [-25.634, -1.573], p = 0.027) and the FGA (6.405, [4.474, 8.335], p < 0.0001). No changes were observed for TUG and FSST. CONCLUSION:Patients' symptoms and function improved following either vestibular rehabilitation method. C.S.I training appeared comparable but not superior to traditional rehabilitation. TRIAL REGISTRATION:This study (NCT04268745) was registered on clincaltrials.gov and can be found at https://clinicaltrials.gov/ct2/show/NCT04268745 .

OBJECTIVE/UNASSIGNED:To report our institutional experience in diagnosing and surveilling patients with infantile subglottic hemangioma (SGH) using in-office flexible fiberoptic laryngoscopy (FFL) with video technology, without requiring operative endoscopy in the era of propranolol use. METHODS/UNASSIGNED:A retrospective case series was conducted on 4 children diagnosed with SGH between 2016 and 2022 at our institution. RESULTS/UNASSIGNED:Awake FFL with video technology provided adequate visualization of SGH lesions for diagnosis, without any complications. Serial examinations of the airway were performed in the outpatient setting and each SGH gradually regressed, with marked improvement in respiratory symptoms within 48 hours of oral propranolol initiation. CONCLUSION/UNASSIGNED:Our findings showed that in select patients, FFL with video technology can successfully identify SGH lesions without general anesthesia exposure. FFL may be used as a low-risk screening tool for propranolol therapy initiation in some patients, but operative endoscopy should remain the gold standard procedure for others. By utilizing FFL in this manner, it is possible to diagnose SGH lesions and start propranolol therapy without exposing all patients to the risks of operative endoscopy.

BACKGROUND:Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS:Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS:Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS:Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.