Faculty Bibliography

We propose a new mechanism of sensory modulation through cutaneous dopaminergic signalling. We hypothesize that dopaminergic signalling contributes to differential cutaneous sensitivity in darker versus lighter pigmented humans and mouse strains. We show that thermal and mechanical cutaneous sensitivity is pigmentation dependent. Meta-analyses in humans and mice, along with our own mouse behavioural studies, reveal higher thermal sensitivity in pigmented skin relative to less-pigmented or albino skin. We show that dopamine from melanocytes activates the D1-like dopamine receptor on primary sensory neurons. Dopaminergic activation increases expression of the heat-sensitive TRPV1 ion channel and reduces expression of the mechanically-sensitive Piezo2 channel; thermal threshold is lower and mechanical threshold is higher in pigmented skin.

BACKGROUND: Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS: Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS: Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION: Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01801449. FUNDING: NIH, NIAMS, and NIAID.

BACKGROUND:Transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) has been associated with improved long-term dysphagia symptomatology compared with chemoradiation. Dysphagia in the perioperative period has been inadequately characterized. The objective of this study was to characterize short-term swallowing outcomes after TORS for OPSCC. METHODS:Patients undergoing TORS for OPSCC were enrolled prospectively. The Eating Assessment Tool 10 (EAT-10) was used as a measure of swallowing dysfunction (score >2) and was administered on postoperative day (POD) 1, 7, and 30. Patient demographics, weight, pain level, and clinical outcomes were recorded prospectively and focused on time to oral diet, feeding tube placement, and dysphagia-related readmissions. RESULTS:A total of 51 patients were included with pathologic T stages of T1 (n = 24), T2 (n = 20), T3 (n = 3), and Tx (n = 4). Self-reported preoperative dysphagia was unusual (13.7%). The mean EAT-10 score on POD 1 was lower than on POD 7 (21.5 vs 26.6; P = .005) but decreased by POD 30 (26.1 to 12.2; P < .001). Forty-seven (92.1%) patients were discharged on an oral diet, but 57.4% required compensatory strategies or modification of liquid consistency. Ninety-eight percent of patients were taking an oral diet by POD 30. There were no dysphagia-related readmissions. CONCLUSION/CONCLUSIONS:This prospective study shows that most patients who undergo TORS experience dysphagia for at least the first month postoperatively, but nearly all can be started on an oral diet. The dysphagia-associated complication profile is acceptable after TORS with a minority of patients requiring temporary feeding tube placement. Aggressive evaluation and management of postoperative dysphagia in TORS patients may help prevent dysphagia-associated readmissions. Cancer 2017;123:3132-40. © 2017 American Cancer Society.

Importance/UNASSIGNED:Free flap reconstruction of the head and neck is routinely performed with success rates around 94% to 99% at most institutions. Despite experience and meticulous technique, there is a small but recognized risk of partial or total flap loss in the postoperative setting. Historically, most microvascular surgeons involve resident house staff in flap monitoring protocols, and programs relied heavily on in-house resident physicians to assure timely intervention for compromised flaps. In 2003, the Accreditation Council for Graduate Medical Education mandated the reduction in the hours a resident could work within a given week. At many institutions this new era of restricted resident duty hours reshaped the protocols used for flap monitoring to adapt to a system with reduced resident labor. Objectives/UNASSIGNED:To characterize various techniques and frequencies of free flap monitoring by nurses and resident physicians; and to determine if adapted resident monitoring frequency is associated with flap compromise and outcome. Design, Setting, and Participants/UNASSIGNED:This multi-institutional retrospective review included patients undergoing free flap reconstruction to the head and/or neck between January 2005 and January 2015. Consecutive patients were included from different academic institutions or tertiary referral centers to reflect evolving practices. Main Outcomes and Measures/UNASSIGNED:Technique, frequency, and personnel for flap monitoring; flap complications; and flap success. Results/UNASSIGNED:Overall, 1085 patients (343 women [32%] and 742 men [78%]) from 9 institutions were included. Most patients were placed in the intensive care unit postoperatively (n = 790 [73%]), while the remaining were placed in intermediate care (n = 201 [19%]) or in the surgical ward (n = 94 [7%]). Nurses monitored flaps every hour (q1h) for all patients. Frequency of resident monitoring varied, with 635 patients monitored every 4 hours (q4h), 146 monitored every 8 hours (q8h), and 304 monitored every 12 hours (q12h). Monitoring techniques included physical examination (n = 949 [87%]), handheld external Doppler sonography (n = 739 [68%]), implanted Doppler sonography (n = 333 [31%]), and needle stick (n = 349 [32%]); 105 patients (10%) demonstrated flap compromise, prompting return to the operating room in 96 patients. Of these 96 patients, 46 had complete flap salvage, 22 had partial loss, and 37 had complete loss. The frequency of resident flap checks did not affect the total flap loss rate (q4h, 25 patients [4%]; q8h, 8 patients [6%]; and q12h, 8 patients [3%]). Flap salvage rates for compromised flaps were not statistically different. Conclusions and Relevance/UNASSIGNED:Academic centers rely primarily on q1h flap checks by intensive care unit nurses using physical examination and Doppler sonography. Reduced resident monitoring frequency did not alter flap salvage nor flap outcome. These findings suggest that institutions may successfully monitor free flaps with decreased resident burden.

Acoustic trauma or inner ear disease may predominantly injure one ear, causing asymmetric sensorineural hearing loss (SNHL). While characteristic frequency (CF) map plasticity of primary auditory cortex (AI) contralateral to the injured ear has been detailed, there is no study that also evaluates ipsilateral AI to compare cortical reorganization across both hemispheres. We assess whether normal isomorphic mirror image relationship between the two hemispheres is maintained or disrupted in mild-to-moderate asymmetric SNHL of adult squirrel monkeys. At week 24 following induction of acoustic injury to the right ear, functional organization of the two hemispheres differs in direction and magnitude of interaural CF difference, percentage of recording sites with spectrally non-overlapping binaural activation, and the concurrence of peripheral and central activation thresholds. The emergence of this anisomorphic cortical reorganization of the two hemispheres is replicated by simulation based on spike-timing-dependent plasticity, where: 1) AI input from the contralateral ear is dominant, 2) reestablishment of relatively shorter contralateral ear input timing drives reorganization, and 3) only AI contralateral to the injured ear undergoes major realignment of interaural frequency maps that evolve over months. Asymmetric SNHL disrupts isomorphic organization between the two hemispheres and results in relative local hemispheric autonomy, potentially impairing performance of tasks that require binaural input alignment or interhemispheric processing.

Objective To systematically review the anatomy of the ossicular chain. Data Sources Google Scholar, PubMed, and otologic textbooks. Review Methods A systematic literature search was performed on January 26, 2015. Search terms used to discover articles consisted of combinations of 2 keywords. One keyword from both groups was used: [ ossicular, ossicle, malleus, incus, stapes] and [ morphology, morphometric, anatomy, variation, physiology], yielding more than 50,000 hits. Articles were then screened by title and abstract if they did not contain information relevant to human ossicular chain anatomy. In addition to this search, references of selected articles were studied as well as suggested relevant articles from publication databases. Standard otologic textbooks were screened using the search criteria. Results Thirty-three sources were selected for use in this review. From these studies, data on the composition, physiology, morphology, and morphometrics were acquired. In addition, any correlations or lack of correlations between features of the ossicular chain and other features of the ossicular chain or patient were noted, with bilateral symmetry between ossicles being the only important correlation reported. Conclusion There was significant variation in all dimensions of each ossicle between individuals, given that degree of variation, custom fitting, or custom manufacturing of prostheses for each patient could optimize prosthesis fit. From published data, an accurate 3-dimensional model of the malleus, incus, and stapes can be created, which can then be further modified for each patient's individual anatomy.

OBJECTIVE: The human voice is sexually dimorphic in obvious ways, such as differences in fundamental frequency and gross laryngeal anatomy, but also in less apparent ways, such as in the prevalence and types of voice disorders and the manifestation of voice changes in advanced age. Differences between males and females are rarely explored, however, in mechanistic animal studies. The goal of this study was to explore sexual dimorphism in laryngeal function and structure in adult rats by examining ultrasonic vocalization acoustics and muscle fiber size and type in the thyroarytenoid muscle. STUDY DESIGN: Animal group comparison. METHODS: Spontaneous ultrasonic vocalizations from 10 male adult rats and 10 female adult rats were recorded, classified, and acoustically analyzed. Cross-sections of the thyroarytenoid muscle were stained and imaged for analysis of muscle fiber size and type. Acoustic and muscle parameters were statistically compared between sexes. RESULTS: Male rats had a lower mean frequency of short ultrasonic vocalizations. Male rats also had a larger mean fiber size in the external division of the thyroarytenoid and larger overall muscle area in both the vocalis and external divisions of the thyroarytenoid. However, muscle fiber type compositions were similar between sexes in both the vocalis and external division of the thyroarytenoid muscles. CONCLUSION: Functional and structural laryngeal differences exist between adult male and female rats; therefore, the rat model can be used to further study sexual dimorphism of the voice. LEVEL OF EVIDENCE: NA. Laryngoscope, 2017.

OBJECTIVES: To analyze clinical, treatment and outcome data for patients with salivary ductal carcinoma in a large population-based sample. MATERIALS AND METHODS: The National Cancer Database was queried to identify patients diagnosed with salivary ductal carcinoma between 2004 and 2013. Kaplan Meier and Cox regression analysis were used to assess overall survival (OS) and identify impact of specific variables on OS. RESULTS: A total of 495 patients were identified. The most common site of tumor origin was the parotid (80%). 130 patients (26.3%) presented with early stage (I-II) disease, 257 patients (51.9%) with locoregionally advanced pathologic stage (III-IVB) disease and 41 patients (8.3%) with metastatic disease. The 5year OS for these patients was 79.5%, 40.4% and 0% respectively. At presentation, 46.6% had node positive disease. Surgery was performed in 100% of patients with early stage disease, 98.4% with advanced disease and 90.2% with metastatic disease. Radiation therapy, generally postoperative radiation, was given to 58.5% of patients with stage I-II disease, 71.6% with stage III-IVB disease and 53.7% with metastatic disease. Chemotherapy was utilized in 5.4% of patients with stage I-II disease, 35% with stage III-IVB and 70.7% with metastatic disease. On multivariable analysis, there were no significant differences in OS based on receipt of adjuvant radiotherapy, chemotherapy, or chemoradiotherapy. CONCLUSION: Salivary ductal carcinoma represents an uncommon and aggressive subset of salivary tumors for which current adjuvant treatments do not have a detectable impact on overall survival.