Faculty Bibliography

Therapeutic monocolonal antibodies (MAbs) are a new, rapidly growing class of medications that frequently have poorly characterized side-effect profiles. We present a patient who developed inflammatory lesions of the vocal folds in temporal relation to the initiation of alirocumab. Lesions of the vocal folds represent a previously unreported adverse effect of alirocumab therapy, making it the second MAb documented with such a side effect. The potential laryngeal effects of alirocumab specifically, and of MAbs more broadly, warrant investigation. Laryngoscope, 2016.

OBJECTIVES/HYPOTHESIS: Quantification of clinical outcomes after vocal fold (VF) interventions is challenging with current technology. High-speed digital imaging and optical coherence tomography (OCT) of excised larynges assess intact laryngeal function, but do not provide critical biomechanical information. We developed a protocol to quantify tissue properties in intact, excised VFs using dynamic nanomechanical analysis (nano-DMA) to obtain precise biomechanical properties in the micrometer scale. STUDY DESIGN: Experimental animal study. METHODS: Three pig larynges were bisected in the sagittal plane, maintaining an intact anterior commissure, and subjected to nano-DMA at nine locations with a 250-mum flat-tip punch and frequency sweep load profile (10-105 Hz, 1,000 muN peak force) across the free edge of the VF and inferiorly along the conus elasticus. RESULTS: Storage, loss, and complex moduli increased inferiorly from the free edge. Storage moduli increased from a mean of 32.3 kPa (range, 6.5-55.38 kPa) at the free edge to 46.3kPa (range, 7.4-71.6) 5 mm below the free edge, and 71.4 kPa (range, 33.7-112 kPa) 1 cm below the free edge. Comparable values were 11.6 kPa (range, 5.0-20.0 kPa), 16.7 kPa (range, 5.7-26.8 kPa), and 22.6 kPa (range, 9.7-38.0 kPa) for loss modulus, and 35.7 kPa (range, 14.4-56.4 kPa), 50.1 kPa (range, 18.7-72.8 kPa), and 75.4 kPa (range, 42.0-116.0 kPa) for complex modulus. Another larynx repeatedly frozen and thawed during technique development had similarly increased storage, loss, and complex modulus trends across locations. CONCLUSIONS: Nano-DMA of the intact hemilarynx provides a platform for quantification of biomechanical responses to a myriad of therapeutic interventions to complement data from high-speed imaging and OCT. LEVEL OF EVIDENCE: NA Laryngoscope, 2016.

OBJECTIVES: This study aims (1) to present a case of asystole during direct laryngoscopy in an otherwise healthy patient at an outpatient surgery center and (2) to review literature on cardiac complications, specifically asystole and bradycardia, during direct laryngoscopy. METHODS: A 67-year-old woman with no prior cardiac history underwent induction with succinylcholine and remifentanil for direct laryngoscopy and vocal fold augmentation. During suspension laryngoscopy, the patient became asystolic, and advanced care life support measures were started. The patient regained a cardiac rhythm after chest compressions and epinephrine and was transferred to a tertiary care hospital for further treatment. She remained intubated overnight, requiring pressors, and regained normal cardiac function over the next few days. RESULTS: A structured literature review uncovered few reports of asystole during suspension laryngoscopy. Although bradycardia is common during suspension laryngoscopy, likely secondary to stimulation of afferent visceral sensory parasympathetic fibers of the vagus nerve, asystole is rare. CONCLUSIONS: Cardiac complications are possible in otolaryngologic surgery, especially with activation of the oculocardiac or trigeminocardiac reflexes. Asystole during direct laryngoscopy, although rare, is not always predictable from medicine or cardiac risk indices. Awareness, rapid recognition, and early implementation of advanced care life support are crucial to avoid further complications.

This study employs validated cough assessment tools to prospectively determine the impact of tramadol on cough severity and quality of life in subjects with neurogenic cough. The study was a prospective case series with planned data collection at a tertiary care academic medical center laryngology practice. Sixteen consecutive collected subjects with neurogenic cough prospectively completed pre- and posttreatment validated cough assessment tools, the cough severity index (CSI) and Leicester Cough Questionnaire (LCQ). All subjects in the study reported at least some improvement in their cough symptoms. In a Wilcoxon signed rank test that compared paired results, CSI scores improved from 23 to 14 and LCQ scores improved from 74 to 103 ( P = .003 and P = .005, respectively). This small preliminary assessment suggests that tramadol warrants additional evaluation as a treatment for neurogenic cough.

OBJECTIVES/OBJECTIVE:Paradoxical vocal fold motion (PVFM) consists of intermittent adduction of the vocal folds during inspiration, resulting in stridor and worsened by anxiety and stress. The purpose of this study was to assess the impact of PVFM on quality of life in our pediatric patient population. STUDY DESIGN/METHODS:This is a prospective, descriptive survey study. METHODS:Thirty-nine consecutive patients (ages 12-17 years) presenting with a PVFM diagnosis for respiratory retraining sessions with speech-language pathology were recruited. Patients completed a brief demographic questionnaire and the Short Form 36, version 2, a validated tool for measuring health-related quality of life. RESULTS:There were 31 (79%) girls and 8 (21%) boys with a mean age of 15.5 years. Subjects reported regular participation in competitive extracurricular activities, including track or cross country (30.8%), swimming (17.9%), and cheerleading or dancing (15.4%). Of the patients in the study, 46.2% were straight-A students. On the SF-36 (population averages normalized to a score of 50), the general health of patients with PVFM was better than that of the general population (53.27); however, their physical health limited their role activities more severely (42.82). In addition, a greater proportion of the group with PVFM was at risk for first-stage depression screening when compared with the general population (28% versus 18%). CONCLUSIONS:We demonstrate a measurable detrimental impact of PVFM on health-related quality of life. This is consistent with previously published literature showing a preponderance of females with PVFM, most of whom are high achievers academically and athletically.

HYPOTHESIS:Custom prostheses could be used to recreate the ossicular chain and improve hearing. BACKGROUND:Ossicular discontinuity or fixation occurs in 55% of cases of conductive hearing loss, with most cases involving the incus. Reconstruction has been achieved by a variety of methods; however, there has been little improvement in hearing outcomes in decades. METHODS:Precise measurements of anatomic dimensions, weight, and center of gravity were taken from 19 cadaveric incudes. These measurements were combined with measurements from the medical literature and micro-computed tomography (micro-CT) of cadaveric temporal bones to generate a rasterizable incus model. As a proof of concept, incudal replacements including possible anatomic variations were then three-dimensionally (3-D) printed and inserted into a cadaveric temporal bone. RESULTS:Our measurements of cadaveric incudes corresponded well with those from the medical literature. These measurements were combined with anatomical information from micro-CT allowing identification of critical features of the incus, which remained constant. Other model features were modified to increase stability and facilitate synthesis, including broadening and thickening of the lenticular process and the incudomalleolar articulation. 3-D printed incudal replacements based on this model readily fit into a cadaveric temporal bone and successfully bridged the gap between malleus and incus. CONCLUSION:We have generated a model for custom 3-D synthesis of incudal prostheses. While current 3-D printing in biocompatible materials at the size required is limited, the technology is rapidly advancing, and 3-D printing of incudal replacements with polylactic acid (PLA) is of the correct size and shape.

Objective Compare survival outcomes between unimodality and multimodality treatments for early-stage tonsil squamous cell carcinoma (SCC). Study Design and Setting Review of the National Cancer Database. Subjects and Methods Patients were selected if they were <70 years old with clinical stage I-II SCC of the tonsil, as documented in the National Cancer Database from 1998 to 2011. Palliative and nonstandard treatments were excluded. Propensity score matching was performed, controlling for tumor stage, age, race, comorbidity, insurance status, and year of diagnosis. Overall survival (OS) was compared with the Kaplan-Meier method and log-rank test. Results We identified 3247 patients. Radiotherapy (RT) was delivered in 1295 patients (39.9%), surgery in 824 (25.4%), and surgery + RT in 1128 (34.7%). Patients treated with surgery + RT had the highest 5-year OS (81.1%), followed by surgery (67.4%) and RT (63.4%; P < .001). In a propensity score-matched subpopulation of 2378 patients, the 5-year OS was 78.8% for surgery + RT, 66.7% for surgery, and 64.5% for RT ( P < .001). Among patients who underwent surgical tonsillectomy plus elective neck dissection and/or adjuvant RT, the 5-year OS was equal ( P = .29), and all were superior to RT alone ( P < .001). Conclusion Multimodality treatment is associated with the greatest survival in early-stage tonsil cancer. The addition of tonsillectomy to RT confers a 20% increase in survival. The current guidelines might not offer the most effective treatment. An up-front surgical approach, followed by appropriately selected adjuvant therapy, may result in improved survival for early-stage tonsil SCC. These findings merit investigation in a prospective clinical trial.

OBJECTIVE: An obstacle to clinical use of RNA-based gene suppression is instability and inefficiency of current delivery modalities. Nanoparticle delivery likely holds great promise, but the kinetics and transfection conditions must be optimized prior to in vivo utility. We investigated a RNA nanoparticle complex incorporating a lipitoid transfection reagent in comparison to a commercially available reagent. STUDY DESIGN: In vitro. METHODS: We investigated which variables influence transfection efficiency of lipitoid oligomers and a commercially available reagent across species, in vitro. These variables included duration, dose, and number of administrations, as well as serum and media conditions. The target gene was Smad3, a signaling protein in the transforming growth factor-beta cascade implicated in fibroplasia in the vocal folds and other tissues. RESULTS: The two reagents suppressed Smad3 mRNA for up to 96 hours; lipitoid performed favorably and comparably. Both compounds yielded 60% to 80% mRNA knockdown in rat, rabbit, and human vocal fold fibroblasts (P < 0.05 relative to control). Dose and number of administrations played a significant role in gene suppression (P < 0.05). Suppression was more dose-sensitive with lipitoid. At a constant siRNA concentration, a 50% decrease in gene expression was observed in response to a five-fold increase in lipitoid concentration. Increased number of administrations enhanced gene suppression, approximately 45% decrease between one and four administrations. Neither serum nor media type altered efficiency. CONCLUSION: Lipitoid effectively knocked down Smad3 expression across multiple transfection conditions. These preliminary data are encouraging, and lipitoid warrants further investigation with the goal of clinical utility. LEVEL OF EVIDENCE: NA. Laryngoscope, 2016.

PURPOSE: Squamous cell carcinoma of unknown primary (SCCHNUP) is commonly treated with comprehensive radiation to the laryngopharynx and bilateral necks. In 1998, we established a departmental policy to treat SCCHNUP with radiation directed to the oropharynx and bilateral neck. METHODS: From 1998-2011, 60 patients were treated - N1: 18%, N2: 75% and N3: 7%. 82% underwent neck dissection. 55% received IMRT and 62% underwent concurrent chemoradiotherapy. RESULTS: At median follow-up of 54months, 5 patients failed regionally and 4 emerged with a primary (tongue base, hypopharynx and thoracic esophagus). Five-year rates of regional control, primary emergence, distant metastasis, disease-free survival and overall survival were 90%, 10%, 20%, 72% and 79%, respectively. The 5year rate of primary emergence in a non-oropharynx site was 3%. CONCLUSION: This is the first demonstration that an oropharynx-directed approach yields low rates of primary emergence in SCCHNUP with excellent oncologic outcomes.