Faculty Bibliography

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To develop a clinically relevant model of oropharyngeal concurrent chemoradiation therapy (CCRT) in order to quantify the effects of CCRT on tongue function and structure. CCRT for advanced oropharyngeal cancer commonly leads to tongue base dysfunction and dysphagia. However, no preclinical models currently exist to study the pathophysiology of CCRT-related morbidity, thereby inhibiting the development of targeted therapeutics. STUDY DESIGN/METHODS:Animal model. METHODS:Twenty-one male Sprague-Dawley rats were randomized into three groups: 2 week (2W), 5 month (5M), and control (C). The 2W and 5M animals received cisplatin, 5-fluorouracil, and five fractions of 7 Gy to the tongue base; the C animals received no intervention. In vivo tongue strength and displacement, as well as hyoglossus muscle collagen content, were assessed. Analyses were conducted 2 weeks or 5 months following completion of CCRT in the 2W and 5M groups, respectively. RESULTS:Peak tetanic and twitch tongue forces were significantly reduced in both 2W and 5M animals compared to controls (tetanic: P = .0041, P = .0089, respectively; twitch: P = .0201, P = .0020, respectively). Twitch half-decay time was prolonged in 2W animals compared to controls (P = .0247). Tongue displacement was significantly reduced across all testing parameters in 5M animals compared to both the C and 2W groups. No differences in collagen content were observed between experimental groups. CONCLUSIONS:The current study is the first to describe a preclinical model of CCRT to the head and neck with an emphasis on clinical relevance. Tongue strength decreased at 2 weeks and 5 months post-CCRT. Tongue displacement increased only at 5 months post-CCRT. Fibrosis was not detected, implicating alternative causative factors for these findings. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2017.

The subciliary and skin pinch approaches are the most widely accepted techniques for treating dermatochalasis of the lower eyelid. Direct excision (DE) is an accepted method for treating festoons; however, it is not a popular technique for the treatment of dermatochalasis and pigment of the lower lid. DE of the lower lid offers a safe and excellent aesthetic result for dermatochalasis and pigment of the lower lid, without causing lower lid malposition, which can occur with more traditional methods. In addition to being able to remove significantly more skin without risking lower lid malposition, this procedure allows for removal of the most pigmented and poorly textured skin overlying the nasojugal groove. It is an effective alternative to the conventional subciliary and skin pinch approaches.

PURPOSE/OBJECTIVE:Recent advances in sodium brain MRI have allowed for increased signal-to-noise ratio, faster imaging, and the ability of differentiating intracellular from extracellular sodium concentration, opening a new window of opportunity for clinical application. In gliomas, there are significant alterations in sodium metabolism, including increase in the total sodium concentration and extracellular volume fraction. The purpose of this study is to assess the feasibility of using sodium MRI quantitative measurements to evaluate gliomas. METHODS:), apparent intracellular sodium concentration (aISC), and apparent total sodium concentration (aTSC). Measurements were made within the contralateral normal-appearing putamen, contralateral normal-appearing white matter (NAWM), and solid tumor regions (area of T2-FLAIR abnormality, excluding highly likely areas of edema, cysts, or necrosis). Paired samples t test were performed comparing NAWM and putamen and between NAWM and solid tumor. RESULTS:(p = 0.19). CONCLUSION/CONCLUSIONS:Quantitative sodium measurements can be done in glioma patients and also has provided further evidence that total sodium and extracellular volume fraction are increased in gliomas.

Introduction Photobiomodulation (PBM Therapy) formerly known as Low Level Laser Therapy (LLLT) is an effective treatment for reducing the incidence and severity of oral mucositis (OM) after high dose chemotherapy and/or radiotherapy. However, reported PBM irradiation parameters, dose per point, number of treatment points or treatment intervals vary widely Objectives To systematically review randomized clinical trials (RCTs), summarise the PBM parameters and detain the most effective treatment regimen. Methods Online databases were searched for RCTs comparing efficacy of PBM verses controls for prevention or treatment cancer therapy induced OM. Papers were scored for quality and effect size for the primary outcome, irradiation parameters and dose were compared with outcomes. Results There was lots of mistakes and missing treatment data (i.e. laser wavelength ranges, power, beam sizes, energy applied and treatment duration) on the reported data, however the majority of the randomized clinical trials reported positive effects: PBM reduced pain, onset of OM, and improved overall quality of life of the patients that received PBM. Conclusions Although no precise conclusion can be drawn due to a large variation on the reported data, PBM used for OM confidently recommend an optimal treatment guideline for this condition

BACKGROUND:Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS:We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS:Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS:Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

We conducted a retrospective chart review of 27 patients-7 men and 20 women, aged 47 to 94 years (mean: 71.3)-with symptomatic epiphora secondary to dacryostenosis who had undergone thulium: YAG (Tm:YAG) laser dacryocystorhinostomy (DCR). Among them, dacryostenosis had been documented in 35 eyes by dacryocystography. The Tm:YAG procedure involved the administration of local anesthesia, after which a 600-μm laser fiber was inserted into the lacrimal canaliculi and then into the nasolacrimal duct. Under endoscopic visualization, the DCR was performed anterior and inferior to the middle turbinate, which created an opening. Silicone stents were then inserted and tied intranasally. In the immediate postoperative period, all 27 patients noted initial improvement. During a follow-up of 22 days to 25 months (mean: 11.3 mo), 24 of the 27 patients (89%) remained symptom-free, while the remaining 3 patients (11%) experienced a treatment failure and required revision surgery. To the best of our knowledge, only two articles on thulium laser therapy for DCR have been previously published, both approximately 25 years ago; both involved the use of a thulium along with holmium and chromium in cadavers. As far as we know, our case series is the largest in the English-language literature that has documented the use of the thulium in laser therapy for DCR, and it is the only in vivo study. We found that DCR with the Tm:YAG laser was an effective and affordable option for patients with symptomatic epiphora secondary to lacrimal obstruction.

OBJECTIVE:To investigate the individualized learning plan (ILP) as a tool in assessment of residents' milestone achievements as they pertain to Otology subcompetencies: Chronic Ear Disease, Pediatric Otitis Media, and Hearing Loss. STUDY DESIGN/METHODS:Prospective study. METHODS:Twenty otolaryngology residents were instructed to use an ILP and identify six milestones from three otology-related subcompetencies to focus on during the course of a 3-month rotation. They were also asked to plan out specific activities which would help them achieve these milestones, to specify whether or not they successfully achieved them, by what instructional or learning methods and to identify any barriers. The completed ILPs were reviewed by a faculty member. MAIN OUTCOME MEASURES/METHODS:The effectiveness of the ILP was assessed by response compliance rate, corroboration of self-reported milestone achievement with faculty evaluations and the ability to set attainable milestones. RESULTS:There was 95% compliance in using an ILP to achieve milestones. Self-reported milestone scores corresponded to the faculty evaluations in a large majority (89.6%) of patients, and tended to be underestimated by the residents. Out of 114 total milestones identified, 44 (38.6%) were not achieved, with particular overestimation in the use of independent study as a learning method. CONCLUSION/CONCLUSIONS:The ILP is an effective tool in measuring residents' achievement of otology-related milestones, and could possibly be used to supplement or replace faculty assessment. The ILP provides valuable information on barriers to achieving milestones and informs trainees on how to set attainable goals as they pertain to patient care and medical knowledge in otology.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Upper airway stimulation (UAS) is an effective treatment for obstructive sleep apnea (OSA). Previous data have demonstrated a correlation between the phenotype of tongue motion and therapy response. Closed loop hypoglossal nerve stimulation implant offers five different electrode configuration settings which may result in different tongue motion. STUDY DESIGN/METHODS:Two-center, prospective consecutive trial in a university hospital setting. METHODS:Clinical outcomes of 35 patients were analyzed after at least 12 months of device use. Tongue motion was assessed at various electrode configuration settings. Correlation between the tongue motion and treatment response was evaluated. RESULTS:OSA severity was significantly reduced with the use of UAS therapy (P < .001). Changes in tongue motion patterns were frequently observed (58.8%) with different electrode configuration settings. Most of the patients alternated between right and bilateral protrusion (73.5%), which are considered to be the optimal phenotypes for selective UAS responses. Different voltage settings were required to achieve functional stimulation levels when changing between the electrode settings. CONCLUSIONS:UAS is highly effective for OSA treatment in selected patients with an apnea-hypopnea index between 15 and 65 events per hour and higher body mass index. Attention should be given to patients with shifting tongue movement in response to change of electrode configuration. The intraoperative cuff placement should be reassessed when tongue movement shifting is observed. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2017.

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Once activated at the surface of cells, G protein-coupled receptors (GPCRs) redistribute to endosomes, where they can continue to signal. Whether GPCRs in endosomes generate signals that contribute to human disease is unknown. We evaluated endosomal signaling of protease-activated receptor-2 (PAR₂), which has been proposed to mediate pain in patients with irritable bowel syndrome (IBS). Trypsin, elastase, and cathepsin S, which are activated in the colonic mucosa of patients with IBS and in experimental animals with colitis, caused persistent PAR₂-dependent hyperexcitability of nociceptors, sensitization of colonic afferent neurons to mechanical stimuli, and somatic mechanical allodynia. Inhibitors of clathrin- and dynamin-dependent endocytosis and of mitogen-activated protein kinase kinase-1 prevented trypsin-induced hyperexcitability, sensitization, and allodynia. However, they did not affect elastase- or cathepsin S-induced hyperexcitability, sensitization, or allodynia. Trypsin stimulated endocytosis of PAR₂, which signaled from endosomes to activate extracellular signal-regulated kinase. Elastase and cathepsin S did not stimulate endocytosis of PAR₂, which signaled from the plasma membrane to activate adenylyl cyclase. Biopsies of colonic mucosa from IBS patients released proteases that induced persistent PAR₂-dependent hyperexcitability of nociceptors, and PAR₂ association with β-arrestins, which mediate endocytosis. Conjugation to cholestanol promoted delivery and retention of antagonists in endosomes containing PAR₂ A cholestanol-conjugated PAR₂ antagonist prevented persistent trypsin- and IBS protease-induced hyperexcitability of nociceptors. The results reveal that PAR₂ signaling from endosomes underlies the persistent hyperexcitability of nociceptors that mediates chronic pain of IBS. Endosomally targeted PAR₂ antagonists are potential therapies for IBS pain. GPCRs in endosomes transmit signals that contribute to human diseases.