Faculty Bibliography

An evolving paradigm in global outreach in radiation oncology has been the implementation of a more region-specific, needs-based approach to help close the gap in radiation services to low- and middle-income countries through the use of innovative tools in information and communication technology. This report highlights 4 information and communication technology tools in action today: (1) the NCCN Framework for Resource Stratification of NCCN guidelines, (2) ASTRO e-Contouring, (3) i.treatsafely.org, and (4) ChartRounds.com. We also render special consideration to matters related to global outreach that we believe require distinct attention to help us meet the goals established by the 2011 United Nations Declaration on noncommunicable diseases: (1) trainee advancement toward careers in global health, (2) ethical challenges of international outreach, (3) critical importance of political advocacy, and (4) collaboration with Industry.

Fibroblast growth factor (FGF) signaling is vital for many biological processes, beginning with development. The importance of FGF signaling for skeleton formation was first discovered by the analysis of genetic FGFR mutations which cause several bone morphogenetic disorders, including achondroplasia, the most common form of human dwarfism. The formation of the long bones is mediated through proliferation and differentiation of highly specialized cells - chondrocytes. Chondrocytes respond to FGF with growth inhibition, a unique response which differs from the proliferative response of the majority of cell types; however its molecular determinants are still unclear. Quantitative phosphoproteomic analysis was utilized to catalogue the proteins whose phosphorylation status is changed upon FGF1 treatment. The generated dataset consists of 756 proteins. We were able to localize the divergence between proliferative (canonical) and inhibitory (chondrocyte specific) FGF transduction pathways immediately upstream of AKT kinase. Gene Ontology (GO) analysis of the FGF1 regulated peptides revealed that many of the identified phosphorylated proteins are assigned to negative regulation clusters, in accordance with the observed inhibitory growth response. This is the first time a comprehensive subset of proteins involved in FGF inhibitory response is defined. We were able to identify a number of targets and specifically discover glycogen synthase kinase3beta (GSK3beta) as a novel key mediator of FGF inhibitory response in chondrocytes.

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.

Pleomorphic xanthoastrocytoma (PXA) is a World Health Organization (WHO) Grade II glioma occurring primarily in children and young adults. Most PXAs harbor the known activating mutation BRAF V600E. We report a case of locally recurrent PXA with anaplastic features in a 10-yr-old female. The PXA was negative by immunohistochemical (IHC) staining for BRAF V600E mutation. Whole-exome and transcriptome sequencing of the tumor confirmed the absence of BRAF V600E, but identified copy-number alterations (including loss of the tumor suppressor CDKN2A) and a novel TMEM106B-BRAF fusion. Based on similar BRAF fusion proteins, this novel fusion is predicted to result in activation of BRAF signaling. Demonstration of positive IHC for phospho-ERK1/2 and phospho-MEK1/2 supported this prediction, and implicated MEK inhibitors as a potential therapeutic strategy.

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.

The production and perception of music is preferentially mediated by cortical areas within the right hemisphere, but little is known about how these brain regions individually contribute to this process. In an experienced singer undergoing awake craniotomy, we demonstrated that direct electrical stimulation to a portion of the right posterior superior temporal gyrus (pSTG) selectively interrupted singing but not speaking. We then focally cooled this region to modulate its activity during vocalization. In contrast to similar manipulations in left hemisphere speech production regions, pSTG cooling did not elicit any changes in vocal timing or quality. However, this manipulation led to an increase in the pitch of speaking with no such change in singing. Further analysis revealed that all vocalizations exhibited a cooling-induced increase in the frequency of the first formant, raising the possibility that potential pitch offsets may have been actively avoided during singing. Our results suggest that the right pSTG plays a key role in vocal sensorimotor processing whose impact is dependent on the type of vocalization produced.

BACKGROUND: Cochlear implants (CIs) successfully restore hearing in postlingually deaf adults, but in doing so impose a frequency-position function in the cochlea that may differ from the physiological one. PURPOSE: The CI-imposed frequency-position function is determined by the frequency allocation table programmed into the listener's speech processor and by the location of the electrode array along the cochlea. To what extent can postlingually deaf CI users successfully adapt to the difference between physiological and CI-imposed frequency-position functions? RESEARCH DESIGN: We attempt to answer the question by combining behavioral measures of electroacoustic pitch matching (PM) and measures of electrode location within the cochlea. STUDY SAMPLE: The participants in this study were 16 adult CI users with residual hearing who could match the pitch of acoustic pure tones presented to their unimplanted ears to the pitch resulting from stimulation of different CI electrodes. DATA COLLECTION AND ANALYSIS: We obtained data for four to eight apical electrodes from 16 participants with CIs (most of whom were long-term users), and estimated electrode insertion angle for 12 of these participants. PM functions in this group were compared with the two frequency-position functions discussed above. RESULTS: Taken together, the findings were consistent with the possibility that adaptation to the frequency-position function imposed by CIs does happen, but it is not always complete. CONCLUSIONS: Some electrodes continue to be perceived as higher pitched than the acoustic frequencies with which they are associated despite years of listening experience after cochlear implantation.

BACKGROUND: Most head and neck (H&N) cancer patients receive high-dose external beam radiation therapy (RT), often in combination with surgery and/or chemotherapy. Unfortunately, high-dose RT has significant adverse effects on the oral and maxillofacial tissues, some of which persist for the life of the patient. However, dental management of these patients is based largely on individual and expert opinion, as few studies have followed patients prospectively to determine factors that predict adverse oral sequelae. In addition, many previous studies were conducted before wide-spread adoption of intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy. The objective of this multi-center study is to systematically evaluate the oral health of subjects for 2 years after commencement of RT, with the goal of identifying risk factors that predict adverse oral outcomes post-RT. METHODS: This is a prospective multi-center longitudinal cohort study of H&N cancer patients who receive high-dose RT with curative intent. Planned enrollment is 756 subjects at 6 primary clinical sites (and their affiliated sites) in the USA. A baseline visit is conducted prior to the beginning of RT. Follow-up visits are conducted at 6, 12, 18 and 24 months from the start of RT. The primary outcome measure is the 2-year rate of tooth loss in patients who have received at least one session of external beam RT for H&N cancer. Secondary outcome measures include the incidence of exposed intraoral bone; incidence of post-extraction complications; change in Decayed Missing and Filled Surfaces (DMFS); change in periodontal measures; change in stimulated whole salivary flow rates; change in mouth opening; topical fluoride utilization; chronic oral mucositis incidence; changes in RT-specific quality of life measures; and change in oral pain scores. DISCUSSION: This study will contribute to a better understanding of the dental complications experienced by these patients. It will also enable identification of risk factors associated with adverse outcomes such as tooth loss and osteoradionecrosis. These findings will support the development of evidence-based guidelines and inform the planning of future interventional studies, with the goal of advancing improvements in patient care and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02057510 , registered 5 February 2014.

Objective Perioperative lumbar drain (LD) use in the setting of endoscopic cerebrospinal fluid (CSF) leak repair is a well-established practice. However, recent data suggest that LDs may not provide significant benefit and may thus confer unnecessary risk. To examine this, we conducted a meta-analysis to investigate the effect of LDs on postoperative CSF leak recurrence following endoscopic repair of CSF rhinorrhea. Data Sources A comprehensive search was performed with the following databases: Ovid MEDLINE (1947 to November 2015), EMBASE (1974 to November 2015), Cochrane Review, and PubMed (1990 to November 2015). Review Method A meta-analysis was performed according to PRISMA guidelines. Results A total of 1314 nonduplicate studies were identified in our search. Twelve articles comprising 508 cases met inclusion criteria. Overall, use of LDs was not associated with significantly lower postoperative CSF leak recurrence rates following endoscopic repair of CSF rhinorrhea (odds ratio: 0.89, 95% confidence interval: 0.40-1.95) as compared with cases performed without LDs. Subgroup analysis of only CSF leaks associated with anterior skull base resections (6 studies, 153 cases) also demonstrated that lumbar drainage did not significantly affect rates of successful repair (odds ratio: 2.67, 95% confidence interval: 0.64-11.10). Conclusions There is insufficient evidence to support that adjunctive lumbar drainage significantly reduces postoperative CSF leak recurrence in patients undergoing endoscopic CSF leak repair. Subgroup analysis examining only those patients whose CSF leaks were associated with anterior skull base resections demonstrated similar results. More level 1 and 2 studies are needed to further investigate the efficacy of LDs, particularly in the setting of patients at high risk for CSF leak recurrence.

Rapidly progressive Alzheimer's disease (rpAD) is a particularly aggressive form of Alzheimer's disease, with a median survival time of 7-10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer's disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer's disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC-MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n = 22 for each patient group) and protein expression differences were quantified. On average, 913 +/- 30 (mean +/- SEM) proteins were quantified in plaques from each patient and 279 of these proteins were consistently found in plaques from every patient. We found significant differences in protein composition between rpAD and sAD plaques. We found that rpAD plaques contained significantly higher levels of neuronal proteins (p = 0.0017) and significantly lower levels of astrocytic proteins (p = 1.08 x 10-6). Unexpectedly, cumulative protein differences in rpAD plaques did not suggest accelerated typical sAD. Plaques from patients with rpAD were particularly abundant in synaptic proteins, especially those involved in synaptic vesicle release, highlighting the potential importance of synaptic dysfunction in the accelerated development of plaque pathology in rpAD. Combined, our data provide new direct evidence that amyloid plaques do not all have the same protein composition and that the proteomic differences in plaques could provide important insight into the factors that contribute to plaque development. The cumulative protein differences in rpAD plaques suggest rpAD may be a novel subtype of Alzheimer's disease.