Faculty Bibliography

OBJECTIVES: Interactions between mesenchymal stem cells (MSCs) and native vocal fold fibroblasts (VFFs) have not been described in spite of promising preliminary data regarding the effects of MSCs on vocal fold repair in vivo. The current study employed a conditioned media (CM) model to investigate the paracrine effects of bone marrow-derived mesenchymal stem cells (BMSCs) on VFFs. METHODS: Human VFFs were treated with transforming growth factor-beta1 (TGF-beta1; 10 ng/mL), CM from human BMSCs following 48 hours of TGF-beta1 stimulation, or CM+TGF-beta1. Proliferation, immunocytochemistry for alpha smooth muscle actin (alphaSMA), migration, and collagen gel contraction were quantified as well as transcription of components of the TGF-beta signaling pathway. RESULTS: Transforming growth factor-beta1 accelerated proliferation and induced alphaSMA in VFFs; these effects were suppressed with CM ( P = .009, P < .001, respectively). The CM+TGF-beta1 condition increased cell migration ( P = .02) and decreased gel contraction; CM+TGF-beta1 also inhibited TGF-beta signaling via significant upregulation of NR4A1 as well as downregulation of S MAD3 and TGF-beta1 relative to TGF-beta1 stimulation in the absence of CM ( P = .002, P < .001, and P = .005, respectively). CONCLUSIONS: Conditioned media affected many profibrotic cell activities in TGF-beta1-stimulated VFFs, likely related to altered TGF-beta signaling. These data provide preliminary insight regarding the antifibrotic effects of MSCs and further support their progression to clinical utility.

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.

Optic gliomas are brain tumors characterized by slow growth, progressive loss of vision, and limited therapeutic options. Optic gliomas contain various amounts of myxoid matrix, which can represent most of the tumor mass. We sought to investigate biological function and protein structure of the myxoid matrix in optic gliomas to identify novel therapeutic targets. We reviewed histological features and clinical imaging properties, analyzed vasculature by immunohistochemistry and electron microscopy, and performed liquid chromatography-mass spectrometry on optic gliomas, which varied in the amount of myxoid matrix. We found that although subtypes of optic gliomas are indistinguishable on imaging, the microvascular network of pilomyxoid astrocytoma, a subtype of optic glioma with abundant myxoid matrix, is characterized by the presence of endothelium-free channels in the myxoid matrix. These tumors show normal perfusion by clinical imaging and lack histological evidence of hemorrhage organization or thrombosis. The myxoid matrix is composed predominantly of the proteoglycan versican and its linking protein, a vertebrate hyaluronan and proteoglycan link protein 1. We propose that pediatric optic gliomas can maintain blood supply without endothelial cells by using invertebrate-like channels, which we termed primitive myxoid vascularization. Enzymatic targeting of the proteoglycan versican/hyaluronan and proteoglycan link protein 1 rich myxoid matrix, which is in direct contact with circulating blood, can provide novel therapeutic avenues for optic gliomas of childhood.

Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4^DCAF1, thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4^DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. In addition, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRL) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4^DCAF1 Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors. Mol Cancer Ther; 16(8); 1693-704. ©2017 AACR.

PURPOSE OF REVIEW: To provide an overview of the treatment options for nonflaccid facial paralysis including physical rehabilitation, botulinum toxin injection and surgical intervention. To also describe recent technique advances regarding facial synkinesis in each zone of facial movement. RECENT FINDINGS: Physical therapy and neuromodulation with botulinum toxin continues to be the main treatment strategy for facial synkinesis. Treating the orbicularis oculi, mentalis and platysma muscles with neurotoxin has been well described. A symmetric smile can also be improved with ipsilateral depressor anguli oris and the contralateral depressor labi inferioris weakening. Novel surgical techniques to selectively ablate specific facial muscles have also been recently described. SUMMARY: Nonflaccid facial paralysis is a spectrum of hypokinetic and hyperkinetic movement following facial nerve injury that is best treated in a patient-tailored graduated fashion. Novel techniques are evolving to maximize patient function while minimizing morbidity.

BACKGROUND: Unilateral radiotherapy (RT) of oropharyngeal carcinomas is accepted for patients with lateralized primary and low-volume nodal disease. Utilizing prospectively defined criteria of laterality and staging positron emission tomography (PET)/CT, we studied outcomes in patients with advanced-stage oropharyngeal cancer undergoing unilateral RT. METHODS: Thirty-seven patients with oropharyngeal tumors >1 cm from midline regardless of node status underwent unilateral RT and were followed prospectively. Patient characteristics: T1 = 11; T2 = 22; T3 = 4; N0 = 3; N1 = 9; N2a = 3; N2b = 21; and Nx = 1. Dosimetry were determined and weekly National Comprehensive Cancer Network (NCCN) distress thermometer data were collected. RESULTS: At median follow-up of 32 months, 3-year locoregional control, contralateral regional failure, distant metastasis-free survival, and disease-free survival were 96%, 0%, 7%, and 93%, respectively. CONCLUSION: Low rates of contralateral neck failure are demonstrated utilizing prospectively defined criteria for unilateral RT. The tolerances of contralateral organs are respected and patients report low to moderate levels of distress throughout treatment.

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.

The American Academy of Facial Plastic and Reconstructive Surgery FACE TO FACE database was created to gather and organize patient data primarily from international humanitarian surgical mission trips, as well as local humanitarian initiatives. Similar to cloud-based Electronic Medical Records, this web-based user-generated database allows for more accurate tracking of provider and patient information and outcomes, regardless of site, and is useful when coordinating follow-up care for patients. The database is particularly useful on international mission trips as there are often different surgeons who may provide care to patients on subsequent missions, and patients who may visit more than 1 mission site. Ultimately, by pooling data across multiples sites and over time, the database has the potential to be a useful resource for population-based studies and outcome data analysis. The objective of this paper is to delineate the process involved in creating the AAFPRS FACE TO FACE database, to assess its functional utility, to draw comparisons to electronic medical records systems that are now widely implemented, and to explain the specific benefits and disadvantages of the use of the database as it was implemented on recent international surgical mission trips.

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.

BACKGROUND: The incidence of well-differentiated thyroid cancer (WDTC) is increasing. Patients with higher socioeconomic status have higher rates of WDTC, possibly due to increased imaging and overdiagnosis. We compared methods of WDTC diagnosis in patients treated at a public and an adjacent private university hospital. MATERIALS AND METHODS: Patients with WDTC at the two hospitals between 2004 and 2010 were included. Patients were categorized into having their WDTC discovered on physical examination or on unrelated imaging. Demographic and pathologic data were collected. T-test was used for quantitative variables, and chi-squared test was used for categorical values. Binomial logistic regression was used to asses for confounding. RESULTS: Among 473 patients, 402 (85%) were from the university hospital, and 71 (15%) were from the public hospital. Patients from the university hospital were older (mean age: 49 versus 44, P = 0.02) and had a different racial composition compared to those from the public hospital. The patients at the public hospital had larger tumors (23 versus 18 mm, P = 0.04). Patients from the university hospital were more likely to have WDTC detected by imaging than patients in the public hospital (46% versus 28%, P < 0.01) on univariate analysis. CONCLUSIONS: This study demonstrates that patients with WDTC treated at a university hospital are more likely to have their tumor detected on unrelated imaging than those treated at a public hospital. These data may support the hypothesis that patients with improved insurance are more likely to have WDTC detected by imaging.