Faculty Bibliography

Pain is rated by oral cancer patients as the worst symptom and significantly impairs a patient's ability to eat, talk, and drink. Mediators, secreted from oral cancer microenvironment, excite primary afferent neurons, which in turn generate pain. Oral cancer cells release TNFalpha which induces acute inflammation and nociception in mice. We hypothesize that TNFalpha activates Schwann cells to amplify pain signals. First, we confirmed the involvement of TNFalpha in oral cancer pain in patients and animal models. We found that oral cancer tissues collected from patients have higher TNFalpha concentration compared to anatomically matched normal tissues. Differences in TNFalpha concentration between the tumor and anatomically matched normal tissues correlate positively with total pain scores. In a Nitroquinoline 1-oxide (4NQO) mouse oral cancer model we demonstrated reduced mechanical hypersensitivity (P<0.05, N=8) with the dolognawmeter gnawing assay when TNFalpha was neutralized with C-87. Using a non-contact co-culture model, we found that HSC-3 cells induced a more activated human primary Schwann cells phenotype with increased proliferation (P<0.05) and migration (P<0.05); introduction of C-87 in the co-culture reduced Schwann cell proliferation (P<0.05) and migration (P<0.05) induced by HSC-3 cells. After removal of the co-cultured cancer cells, cancer-activated Schwann cells secrete greater amounts of TNFalpha and nerve growth factor (NGF), another known nociceptive mediator in the oral cancer microenvironment, compared to Schwann cells initially co-cultured with DOK (P<0.05) or naive Schwann cells (P<0.05). To determine whether activated Schwann cells mediate oral cancer pain, we cultured Schwann cells in hypoxic conditions - a known cancer stimulus that induces robust Schwann cell activation. Schwann cell supernatant was then collected and injected into the mouse cheek. Supernatant from hypoxia-activated Schwann cells induced greater facial allodynia (measured with von Frey filaments) in mice (P<0.05, N=7), compared to supernatant from Schwann cells cultured in normoxic conditions (N=5). C-87 significantly reduced facial allodynia caused by hypoxiaactivated Schwann cells (P<0.05, N=5). We infer from our results that TNFalpha plays a role in the activation of Schwann cells and that cancer-activated Schwann cells are a source of nociceptive mediators in the cancer microenvironment. Inhibition of Schwann cell activation might be clinically useful for alleviating oral cancer pain

BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. BYL719 exerts its therapeutic effect by suppressing AKT and other proliferative signaling mechanisms. Despite PI3K inhibition and AKT suppression, residual activity of protein S6, a core marker of proliferative activation, has been observed. HER3, either via dimerization or activation by its ligand neurgeulin (NRG), is known to activate PI3K. Thus, we hypothesized that co-targeting HER3 and PI3K would lead to greater suppression of the PI3K-AKT signaling pathway and greater tumor suppression than with BYL719 alone. We investigated biochemical expression and activation of the HER3-PI3K-AKT-S6 pathway in HNSCC cell lines and patient-derived xenografts (PDXs). Antitumor effects of HER3 and PI3K inhibitors alone and in combination were evaluated in cell culture and murine models. Treatment of HNSCC cell lines with BYL719 significantly reduced AKT activation and suppressed tumor growth. However, S6 was persistently activated despite suppression of AKT. Combination treatment with KTN3379, a monoclonal antibody targeted against HER3, and BYL719 led to enhanced suppression of in vitro and in vivo cancer growth and durable suppression of AKT and S6. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC.

OBJECTIVE:To develop a clinical consensus statement on the use of balloon dilation of the eustachian tube (BDET). METHODS:An expert panel of otolaryngologists was assembled with nominated representatives of general otolaryngology and relevant subspecialty societies. The target population was adults 18 years or older who are candidates for BDET because of obstructive eustachian tube dysfunction (OETD) in 1 or both ears for 3 months or longer that significantly affects quality of life or functional health status. A modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. RESULTS:After 3 iterative Delphi method surveys, 28 statements met the predefined criteria for consensus, while 28 statements did not. The clinical statements were grouped into 3 categories for the purposes of presentation and discussion: (1) patient criteria, (2) perioperative considerations, and (3) outcomes. CONCLUSION/CONCLUSIONS:This panel reached consensus on several statements that clarify diagnosis and perioperative management of OETD. Lack of consensus on other statements likely reflects knowledge gaps regarding the role of BDET in managing OETD. Expert panel consensus may provide helpful information for the otolaryngologist considering the use of BDET for the management of patients with OETD.

BACKGROUND:The prevalence of sinuses' anatomic variations in the healthy pediatric population has not been studied. The study describes the prevalence of known anatomic variations with regard to gender and age in this population. METHODS:A single academic institute observational cohort study. A total of 200 head CT scans were reviewed, subdivided into five equal age subgroups (0-4.99; 5-7.99; 8-10.99; 11-13.99; 14-17 years), with an equal male to female ratio. Different subgroups were randomly assigned to two senior residents (100 CTs each). A senior rhinologist and radiologist were randomly selected to review 100 CTs each. Consensus was reached after a joint review. Each CT was evaluated for the presence of sinuses and the following variations: deviated septum, frontoethmoidal, infraorbital, posterior-ethmoid cells (Kuhn, Haller, and Onodi cells, respectively) and concha bullosa. Definitions were made according to the European Position on Rhinosinusitis 2012. RESULTS:Gender did not affect sinus development or anatomical variations. The frontal and sphenoid sinuses were significantly less developed in the 0-4.99 years group. The point prevalence of concha bullosa and deviated septum significantly increased with age. The point prevalence of Haller cells demonstrated borderline significance among age groups, with children 0-4.99 demonstrating the lowest point prevalence. A significant association was found between the existence of Haller cells to Kuhn and Onodi cells. CONCLUSIONS:Anatomical variations should be expected in the pediatric population. Familiarity with their point prevalence and associations may assist pediatric endoscopic sinus surgery planning.

OBJECTIVES:The purpose of this study was to obtain an electrophysiological analog of masking release using speech-evoked cortical potentials in steady and modulated maskers and to relate this masking release to behavioral measures for the same stimuli. The hypothesis was that the evoked potentials can be tracked to a lower stimulus level in a modulated masker than in a steady masker and that the magnitude of this electrophysiological masking release is of the same order as that of the behavioral masking release for the same stimuli. DESIGN:Cortical potentials evoked by an 80-ms /ba/ stimulus were measured in two steady maskers (30 and 65 dB SPL), and in a masker that modulated between these two levels at a rate of 25 Hz. In each masker, a level series was undertaken to determine electrophysiological threshold. Behavioral detection thresholds were determined in the same maskers using an adaptive tracking procedure. Masking release was defined as the difference between signal thresholds measured in the steady 65-dB SPL masker and the modulated masker. A total of 23 normal-hearing adults participated. RESULTS:Electrophysiological thresholds were uniformly elevated relative to behavioral thresholds by about 6.5 dB. However, the magnitude of masking release was about 13.5 dB for both measurement domains. CONCLUSIONS:Electrophysiological measures of masking release using speech-evoked cortical auditory evoked potentials correspond closely to behavioral estimates for the same stimuli. This suggests that objective measures based on electrophysiological techniques can be used to reliably gauge aspects of temporal processing ability.

The Eating Assessment Tool-10 (EAT-10) is a 10-item patient-reported outcome measure (PROM) for dysphagia patients. The objective of this study was to translate and validate the EAT-10_Heb and to test for a correlation between its score and residue, penetration and aspiration on Fiberoptic Endoscopic Examination of Swallowing (FEES). 136 patients visiting two specialized dysphagia clinics and undergoing FEES between April 2015 and August 2017, filled the EAT-10_Heb. 23 patients refilled the EAT-10_Heb during a 2-week period following their first visit. FEES were scored for residue (1 point per consistency, maximum 3 points) and penetration and aspiration (1 point for penetration, 2 points for aspiration per consistency, maximum 6 points). 51 healthy volunteers also filled the EAT-10_Heb. Internal consistency and test-retest reproducibility were examined for reliability testing. Validity was established by comparing EAT-10_Heb scores of dysphagia patients to healthy controls. The EAT-10_Heb score was then correlated with the FEES score. Internal consistency of the EAT-10_Heb was high (Cronbach's alpha = 0.925) as was the test-retest reproducibility (Spearman's correlation coefficient = 0.82, p < 0.0001). The median EAT-10_Heb score was significantly higher in the dysphagia group compared to healthy controls (13, IQR 7-22 points for dysphagia patients compared to 0, IQR 0-0 points for healthy controls, p < 0.0001). A weak correlation was found between the EAT-10_Heb scores and the FEES score (Pearson's correlation coefficient = 0.376, p < 0.0001). While the EAT-10_Heb was found to be a reliable and valid PROM, it only weakly correlates with the pathological findings on FEES examination.

Purpose: The purpose of this study is to quantify interfractional dosimetric variations in radiotherapy of oropharyngeal cancer and investigate the application of statistical process control (SPC) to determine significantly deviated fractions for management.
Method(s): Thirteen oropharyngeal cancer patients treated by IMRT or VMAT with daily CBCT were retrospectively reviewed. CBCT images of every other fraction were imported to the software Velocity and registered to planning CT using the 6DOF couch shifts generated during patient setup. Using Velocity Adaptive Monitoring module, the setup-corrected CBCT was matched to planning CT using a deformable registration. The module also generated dose volume histograms (DVHs) at each CBCT from planning doses for the deformed plan structure sets. Volumes and dose metrics at each fraction were calculated and rated with plan values to evaluate interfractional dosimetric variations using a SPC framework. T-tests between plan and fraction volumes were performed to find statistically insignificant fractions. Average, upper and lower process capacity limits (UCL, LCL) of each dose metric were derived from these fractions using conventional SPC guidelines.
Result(s): GTV and OAR volumes in first 13 fractions had no significantly changes from the plan, subsequently reduced by 10% to treatment completion, except oral cavity. There were 3%-4% increases in parotid mean doses, but no significant differences in dose metrics of GTVand other OARs. The changes were organ and patient dependent. Control charts for various dose metrics were generated to assess the metrics for individual patient. The occurrences of one or several dose metrics out of the control limits warrant immediate investigation of the fraction.
Conclusion(s): Daily CBCT could be used to monitor dosimetric variations of targets and OARs resulting from volume changes and tissue deformation in oropharyngeal cancer radiotherapy. Treatment review with guidance of a SPC tool may enable objectively and consistently identify significantly deviated fractions

OBJECTIVES/OBJECTIVE:The medial sural artery perforator (MSAP) free flap is an uncommonly utilized soft tissue flap in head and neck reconstruction. It is a thin, pliable, fasciocutaneous flap that provides significant pedicle length. The donor site can be closed primarily, and its location is more aesthetically pleasing to patients. We aim to describe the MSAP flap and compare it to other commonly used free flaps in the head and neck. STUDY DESIGN/METHODS:Retrospective case series. METHODS:A retrospective review of all MSAP cases performed at New York University Langone Health was performed from July 2016 to November 2017. We examined the patients' age, diagnosis, history of prior radiation therapy, and comorbidities, as well as flap-specific information and recipient site. RESULTS:(15 cm × 8 cm). The flaps ranged from 5 to 12 mm in thickness. Venous coupler size ranged from 2.0 to 3.5 mm. Primary closure of the donor site was achieved in 18 of 21 flaps. Twenty of 21 flaps were transferred successfully. CONCLUSION/CONCLUSIONS:The MSAP flap is a highly versatile and reliable option for a thin, pliable soft tissue flap with a donor site that may be preferable over the radial forearm free flap and anterolateral thigh flap in complex head and neck reconstruction. LEVEL OF EVIDENCE/METHODS:4. Laryngoscope, 2018.