Faculty Bibliography

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.

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.

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.

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.

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.

BACKGROUND: Lip cancer is one of the most curable primary head and neck malignancies, as the prominent location typically lends to an early diagnosis. The incidence of lip cancer varies by sex, ethnicity, and region, but is estimated to be up to 2.5/100 000 in the United States (squamous cell carcinoma [SCC]). METHODS: This article will review the current literature and National Comprehensive Cancer Network practice guidelines in the treatment of lip cancer. RESULTS: Resection of lip cancer with negative margins remains the mainstay of therapy. Positive nodal disease should be treated with neck dissection and adjuvant radiotherapy. CONCLUSION: Lip cancer remains highly curable when diagnosed at an early stage. A multidisciplinary approach is crucial to treating patients with advanced-stage lip cancer.

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.

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.