Faculty Bibliography

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.

Explicit rewards are commonly used to reinforce a behavior, a form of learning that engages the dopaminergic neuromodulatory system. In contrast, skill acquisition can display dramatic improvements from a social learning experience, even though the observer receives no explicit reward. Here, we test whether a dopaminergic signal contributes to social learning in naïve gerbils that are exposed to, and learn from, a skilled demonstrator performing an auditory discrimination task. Following five exposure sessions, naïve observer gerbils were allowed to practice the auditory task and their performance was assessed across days. We first tested the effect of an explicit food reward in the observer's compartment that was yoked to the demonstrator's performance during exposure sessions. Naïve observer gerbils with the yoked reward learned the discrimination task significantly faster, as compared to unrewarded observers. The effect of this explicit reward was abolished by administration of a D1/D5 dopamine receptor antagonist during the exposure sessions. Similarly, the D1/D5 antagonist reduced the rate of learning in unrewarded observers. To test whether a dopaminergic signal was sufficient to enhance social learning, we administered a D1/D5 receptor agonist during the exposure sessions in which no reward was present and found that the rate of learning occurred significantly faster. Finally, a quantitative analysis of vocalizations during the exposure sessions suggests one behavioral strategy that contributes to social learning. Together, these results are consistent with a dopamine-dependent reward signal during social learning.

Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain.

Undiagnosed and untreated obstructive sleep apnea (OSA) is associated with health comorbidities and negatively affects quality of life. Alternative treatments should be considered in patients who are unable to tolerate or benefit from positive airway pressure treatment. When properly indicated, positional devices, oral appliances, airway surgery, and hypoglossal nerve stimulation have been shown to be effective in treating OSA. Hypoglossal nerve stimulation is a successful second-line treatment with low associated morbidity and complication rate.

PURPOSE/OBJECTIVE:The aim of this systematic review is to compare the perioperative characteristics and outcomes of submental artery island flap (SAIF) to free tissue transfer (FTT) in head and neck reconstruction. MATERIALS AND METHODS/METHODS:Screening and data extraction were done with Pubmed, Embase, and Web of Science databases by two independent authors to identify randomized and observational studies that compared patient outcomes for SAIF vs. FTT for reconstruction head and neck cancer ablative surgery. Data were pooled with random-effects meta-analysis to determine pooled difference in means (DM), absolute risk differences, and 95% confidence intervals (CI). Heterogeneity was assessed with the I-squared statistic. RESULTS:(95% CI 6.5 to 38.4). SAIF had a 5% higher incidence of partial flap necrosis than FTT (95% CI, 1 to 10), but all other perioperative complications, including recurrence rate in malignant cases, were statistically comparable. CONCLUSIONS:The SAIF requires less operative time, hospital stay, and has comparable perioperative outcomes to FTT, but the area of flap harvest is significantly smaller. The findings of this study add to the growing body of evidence demonstrating the safety and reliability of SAIF in head and neck reconstruction.

Purpose: This research aimed to perform an overview on adjuvant vaginal brachytherapy (VBT) in stage I to II endometrial carcinoma (EC) according to ESMO-ESGO-ESTRO risk group consensus in China from multi-institutional analysis.Materials and Methods: We retrospectively analyze patients with stage I to II EC at 13 institutions in China treated between 2003 and 2015. All patients underwent adjuvant radiotherapy and were divided into low-risk (LR), intermediate-risk (IR), high-intermediate risk (HIR) and high-risk (HR) groups according to ESMO-ESGO-ESTRO risk group consensus. XXResult(s): A total of 1048 cases were included. Stage I disease accounted for 85.9% of the cohort. Proportion of HR disease was 27.6%, HIR 17.7%, IR 27.7% and LR 27.1%. Patients received adjuvant VBT alone (n = 474), pelvic external beam radiotherapy (EBRT) alone (n = 116) or combined EBRT with VBT (n = 458). An increasing trend was found toward referrals for VBT alone. Historical data demonstrate that the clinical practice of adjuvant VBT alone increased significantly in the LR to HIR groups over the past 13 years. However, in the HR group, the proportion of VBT alone or as a boost after EBRT stayed stable in the corresponding period.All institutions commonly use High-dose-rate VBT prescribed to 0.5-cm depth from the vaginal surface with 14 and 17 different dose-fractionation schedules for VBT alone and VBT boost, respectively. The most common fractionation for VBT alone is 5 Gy in six fraction (407/474) and the most common fractionation for VBT as a boost after EBRT is 5 Gy in two fractions (178/458). Proximal 2-3 cm vagina was the most often irradiated vaginal target (61.3%). The most commonly used applicators were the multichannel vaginal cylinder (79.6%). The median follow-up time was 56 months. For LR to HIR patients, VBT alone achieved comparable survival to EBRT. Compared to EBRT, patients receiving VBT had significantly decreased incidence of grade 1-2 early and late gastrointestinal and urinary reactions, and the rate of grade 3-4 acute hematological toxicity. XXConclusion(s): There is remarkable heterogeneity among VBT dose-fractionation schedules. An increasing trend was found toward referrals for VBT alone. The clinical practice of adjuvant VBT alone increased significantly in LR to HIR groups over the past 13 years. In LR to HIR group, VBT alone achieved comparable survival to EBRT.XXCopyright

OBJECTIVE/UNASSIGNED:Oversimplified clinical dogma suggests that laryngeal diseases fall into two broad, mutually exclusive diagnostic categories-mucosal injury or neuromuscular/functional disorders. Extensive investigation in the lower airway as well as other organ systems suggest complex interactions between tissue types underlying both tissue health and pathological states. To date, no such relationship has been described in the vocal folds, likely the most bioactive organ in the body. We hypothesize interactions between the vocal fold muscle and mucosa likely contribute to aberrant phonatory physiology and warrant further investigation to ultimately develop novel therapeutic strategies. METHODS/UNASSIGNED:Primary culture of myoblasts from rat thyroarytenoid muscle and fibroblasts from the vocal fold mucosa were established. Co-culture and conditioned media experiments were performed to established bidirectional interactions between cell types. Transforming Growth Factor (TGF)-β was employed to stimulate a fibrotic phenotype in culture. In addition to quantitative PCR, standard migration and proliferation assays were performed as well as immunocytochemistry. RESULTS/UNASSIGNED:Bidirectional cell-cell interactions were observed. Without TGF-β stimulation, myoblast conditioned media inhibited fibroblast migration, but enhanced proliferation. Conversely, fibroblast conditioned media increased both myoblast proliferation and migration. Myoblast conditioned media decreased TGF-β-mediated gene expression and of particular interest, ACTA2 mRNA expression. In both co-culture and in response to fibroblast conditioned media, myosin heavy chain (Myh2) mRNA expression decreased in myoblasts. CONCLUSIONS/UNASSIGNED:These data are the first to describe interactions between cell types within the vocal fold. The implications for these interactions in vivo warrant further investigation to develop and refine optimal treatment strategies.

PURPOSE/OBJECTIVE:Since the COVID-19 pandemic began, emergency departments (ED) across the country have seen a significant decrease in patient visits. We aim to evaluate the impact of COVID-19 on ED visits for acute otolaryngologic complaints in New York City, one of the first epicenters of the pandemic in the US. MATERIALS AND METHODS/METHODS:We conducted a retrospective study of patients who presented to the ED with a primary diagnosis of an acute otolaryngologic complaint between March 1 and May 31 in 2019 and 2020. This was a multicenter study, including two tertiary care hospital systems encompassing Manhattan, Bronx, Queens, and Long Island. RESULTS:A total of 10,162 patients were identified. Significantly fewer patients presented to the ED for acute otolaryngologic complaints in 2020 (7332 vs 2830, p < 0.001). The rate of total otolaryngology-related ED visits was decreased by a factor of 0.635 (95% CI 0.6079 to 0.6634). In a subgroup analysis of each individual diagnosis, there was a significant decrease in rate of ED visits for 13 out of 18 diagnoses, including for life-threatening conditions, such as anaphylaxis. There was no significant difference based on which borough in New York City. Pediatric patients (age 0-17) were more significantly impacted by the pandemic compared to other age groups. CONCLUSION/CONCLUSIONS:The COVID-19 pandemic has led to a reduction in the utilization of ED for acute otolaryngologic complaints, including those requiring emergent management, and an even more significant reduction in the pediatric population. Healthcare providers should encourage patients to seek appropriate care, particularly for those illnesses with significant associated morbidity and mortality.

Vocal fold (VF) fibrosis is a major cause of intractable voice-related disability and reduced quality of life. Excision of fibrotic regions is suboptimal and associated with scar recurrence and/or further iatrogenic damage. Non-surgical interventions are limited, putatively related to limited insight regarding biochemical events underlying fibrosis, and downstream, the lack of therapeutic targets. YAP/TAZ integrates diverse cell signaling events and interacts with signaling pathways related to fibrosis, including the TGF-β/SMAD pathway. We investigated the expression of YAP/TAZ following vocal fold injury in vivo as well as the effects of TGF-β1 on YAP/TAZ activity in human vocal fold fibroblasts, fibroblast-myofibroblast transition, and TGF-β/SMAD signaling. Iatrogenic injury increased nuclear localization of YAP and TAZ in fibrotic rat vocal folds. In vitro, TGF-β1 activated YAP and TAZ in human VF fibroblasts, and inhibition of YAP/TAZ reversed TGF-β1-stimulated fibroplastic gene upregulation. Additionally, TGF-β1 induced localization of YAP and TAZ in close proximity to SMAD2/3, and nuclear accumulation of SMAD2/3 was inhibited by a YAP/TAZ inhibitor. Collectively, YAP and TAZ were synergistically activated with the TGF-β/SMAD pathway, and likely essential for the fibroplastic phenotypic shift in VF fibroblasts. Based on these data, YAP/TAZ may evolve as an attractive therapeutic target for VF fibrosis.