Faculty Bibliography

OBJECTIVES/HYPOTHESIS: Mesenchymal stem cells (MSCs) hold therapeutic promise for vocal fold scar, yet the precise mechanism(s) underlying tissue level changes remain unclear. We hypothesize that MSCs interact with native fibroblasts to favorably affect healing. Furthermore, we hypothesize that these interactions vary based on MSC source. METHODS: Vocal fold fibroblasts (VFFs), adipose-derived stem cells, and bone marrow-derived stem cells (BMSCs) were extracted from Sprague-Dawley rats; and a coculture model was employed culturing VFFs +/- transforming growth factor (TGF-beta1) (10 ng/mL) +/- MSCs. Monoculture MSCs were also prepared as a control. Both extracellular matrix (ECM) and components of the TGF-beta signaling pathway were analyzed via polymerase chain reaction and western blotting. RESULTS: Significantly decreased TGF-beta1 mRNA and alpha-smooth muscle actin protein was observed in VFFs in response to TGF-beta1 in the coculture with both MSCs (P < 0.05, P < 0.01). BMSCs significantly downregulated collagen I (P < 0.05), collagen III (P < 0.05), Smad3 (P < 0.01), and TGF-beta1 receptor I (P < 0.01) mRNA in VFFs. Hyaluronic synthase-1 and 2 increased in cocultured BMSCs when compared with monocultured BMSCs at baseline and in response to TGF-beta1 (P < 0.01). CONCLUSION: MSCs had a favorable effect on ECM regulation as well as suppression of TGF-beta1 signaling in VFF. Bidirectional paracrine signaling was also observed as VFFs altered ECM regulation in MSCs. These data provide insight into the regenerative effects of MSCs and provide a foundation for clinical application. LEVEL OF EVIDENCE: N/A. Laryngoscope, 2016.

OBJECTIVES/HYPOTHESIS: In response to concerns regarding physician-industry relationships, the Physician Sunshine Act of 2010 was passed in an effort to increase transparency and accountability. Our objective was to determine whether there is an association between industry support and scholarly impact among academic otolaryngologists. METHODS: Faculty listings, academic rank, and fellowship training of academic otolaryngologists were accessed from departmental websites. H-indices, number of publications, and publication range (years) of each individual were calculated using the Scopus database. The Center for Medicare and Medicaid Services Open Payments database was used to determine industry payments during 2014 to each otolaryngologist. RESULTS: Of 1,515 otolaryngologists, 65.4% received industry support and 15.8% received support > $1,000. No difference in impact, as measured by the h-index, was noted upon comparison of those receiving support and those who did not (P > 0.05). Individuals receiving > $1,000 had higher h-indices and total publications than those receiving < $1,000 or receiving no support (H = 17.8 vs. 10.9, P < 0.0001), even upon controlling for academic seniority. Upon organization by subspecialty, individuals receiving > $1,000 had greater scholarly impact among most subspecialties. Industry contributions increased with advancing experience. CONCLUSION: Receiving industry contributions greater than $1,000 is associated with greater scholarly impact among academic otolaryngologists. In a smaller surgical specialty, such as otolaryngology-head and neck surgery, direct industry research support-as well as indirect contributions through the support of educational programs, consulting, and other expenses-potentially impacts scholarly discourse; these findings do not reflect a causal relationship and may require further characterization. LEVEL OF EVIDENCE: N/A. Laryngoscope, 2016.

Physical features of sensory stimuli are fixed, but sensory perception is context dependent. The precise mechanisms that govern contextual modulation remain unknown. Here, we trained mice to switch between two contexts: passively listening to pure tones and performing a recognition task for the same stimuli. Two-photon imaging showed that many excitatory neurons in auditory cortex were suppressed during behavior, while some cells became more active. Whole-cell recordings showed that excitatory inputs were affected only modestly by context, but inhibition was more sensitive, with PV+, SOM+, and VIP+ interneurons balancing inhibition and disinhibition within the network. Cholinergic modulation was involved in context switching, with cholinergic axons increasing activity during behavior and directly depolarizing inhibitory cells. Network modeling captured these findings, but only when modulation coincidently drove all three interneuron subtypes, ruling out either inhibition or disinhibition alone as sole mechanism for active engagement. Parallel processing of cholinergic modulation by cortical interneurons therefore enables context-dependent behavior.

Purpose/UNASSIGNED:Pediatric sarcomas provide a unique diagnostic challenge. There is considerable morphologic overlap between entities, increasing the importance of molecular studies in the diagnosis, treatment, and identification of therapeutic targets. We developed and validated a genome-wide DNA methylation based classifier to differentiate between osteosarcoma, Ewing's sarcoma, and synovial sarcoma. Materials and Methods/UNASSIGNED:DNA methylation status of 482,421 CpG sites in 10 Ewing's sarcoma, 11 synovial sarcoma, and 15 osteosarcoma samples were determined using the Illumina Infinium HumanMethylation450 array. We developed a random forest classifier trained from the 400 most differentially methylated CpG sites within the training set of 36 sarcoma samples. This classifier was validated on data drawn from The Cancer Genome Atlas (TCGA) synovial sarcoma, TARGET Osteosarcoma, and a recently published series of Ewing's sarcoma. Results/UNASSIGNED:Methylation profiling revealed three distinct patterns, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from TCGA were accurately classified as synovial sarcoma (10/10, sensitivity and specificity 100%), all but one sample from TARGET-OS were classified as osteosarcoma (85/86, sensitivity 98%, specificity 100%) and 14/15 Ewing's sarcoma samples classified correctly (sensitivity 93%, specificity 100%). The single misclassified osteosarcoma sample demonstrated high EWSR1 and ETV1 expression on RNA-seq although no fusion was found on manual curation of the transcript sequence. Two additional clinical samples, that were difficult to classify by morphology and molecular methods, were classified as osteosarcoma when previously suspected to be a synovial sarcoma and Ewing's sarcoma on initial diagnosis, respectively. Conclusion/UNASSIGNED:Osteosarcoma, synovial sarcoma, and Ewing's sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide diagnostic assistance when histological and standard techniques are inconclusive.

Purpose: Facial composite defects resulting from trauma can cause devastating and life limiting deformities. Full face transplants have been restoring the oral cavity and the upper airway in a single stage procedure. Literature on face transplants mostly consists of detailed surgical techniques and allograft selection, but do not constitute a compilation of data on postoperative outcomes such as swallow function. This is the first reported case of systematic review of the swallowing rehabilitation course post-facial transplantation. Method(s): Fourty one-year old male with oropharyngeal dysphagia after full face vascularized allotransplant is presented. Videofluoroscopic swallow study (VFSS) was conducted prior to surgery and at 8 time points post-operatively (day 13, 26, 48, 63, 77, 105, 6 months and 9 months) to assess swallow function. Outcome measures included Penetration Aspiration Scale (PAS) and ordinal ratings of residue in the valleculae and pyriform sinuses for 3 and 5 ml thin liquid boluses. Worst PAS scores categorized subject as unsafe (>=3) or safe (<=2). Result(s): Despite rigorous daily swallow treatment, the patient's liquid dysphagia did not imrpove. Unsafe PAS (>=3) were present in the first 7 VFSS post-operatively for 3 ml and 5 ml thin liquid boluses. Worse residue was noted in pyriform sinuses vs. valleculae in all VFSS. Conclusions (Including Clinical Relevance): Early swallow treatment is crucial for safety and successful oral intake of thin liquid postfull facial transplantation. Future analyses will examine the relationship between post-operatively edema and residue with the longterm goal of maximizing therapeutic protocols

Purpose: Edema is a frequent clinical observation after chemoradiation treatment (XRT) for oral/oropharyngeal cancer (O/OP Ca). Our aim is to quantify within-subject measures of edema from pre- and post-XRT videofluoroscopy (VF) and to explore the relationship between edema and aspiration. Method(s): Fourty patients (24 male; ages 38-76) diagnosed with O/OP Ca received radiotherapy (70 Gy, 7 weeks) and 3 weekly doses of cisplatin. VF was completed pre- and again 4 weeks post-XRT. 3 pixel-based measures captured edema from a post-swallow rest frame of a 5 ml thin liquid bolus: posterior pharyngeal wall (PPW) thickness, pharyngeal area (PA) and vallecular space (VS). Worst PAS scores categorized subjects as unsafe (>=3) or safe (<=2). Repeated measures ANOVAs were used to explore the relationship between the edema measure (pre- vs post-XRT) and swallow safety (safe vs unsafe). Result(s): The proportion of patients with unsafe swallows increased from 8/40 pre-XRT to 14/40 post-XRT, though this was not significant (p = 0.2). A significant main effect was confirmed in reduced PA post-XRT [F = 29.9, p = 0.00] and a trending increase was observed for PPW [F = 3.2, p = 0.08]. However, no significant differences between unsafe vs safe groups were found for any edema variables. Conclusions (Including Clinical Relevance): The data confirm that post-XRT edema can be quantified on VF by measuring PPW thickness and PA. A significant worsening in edema measures in individuals with unsafe compared with safe swallows was not detected. The data was limited by a low proportion of post-XRT aspirators. Future analyses will examine the relationship between edema and residue

Introduction No evidence-based guidelines exist for preventive dental care before ra-diation therapy (RT) in head and neck cancer (HNC) patients. An ongoing multi-center, prospective cohort study, Clinical Registry of Dental Outcomes in HNC patients (OraRad) (1U01DE022939-01), is addressing this knowledge gap. Objectives Evaluate dental disease and associated factors pre-RT. Methods OraRad enrolls patients at six U.S. clinical centers pre-RT; follows them every 6 months for 2 years post-RT with primary outcome of tooth loss. Calibrated examiners assess caries and periodontal disease using validated scales and standardized procedures. Results Baseline measures were reported for 356 participants with mean (SD) age 59.9 (11.0) years; 77% male. Pre-RT dental disease parameters (means) include: number of teeth 22.9; decayed, missing, filled surfaces (DMFS) 33.3 with 1.6 decayed surfaces; clinical attachment level 1.8mm; and probing depth 2.4 mm with 13.5% of tooth sites >=4mm. Participants with at least a high school diploma had more teeth and fewer tooth sites with PD >=4mm compared to those with less education. Patients who received routine dental care had more total teeth pre-RT vs. those without (24.0 vs. 19.8, respectively). We found 37.2% of patients had at least 1 decayed surface and 47.4% had a least one tooth with a probing depth >4mm. Conclusions A high proportion of patients have dental disease at the start of RT for HNC. Observing dental outcomes post-RT, OraRad has the potential to determine the risk of dental disease at the start of RT and determine the best treatment recommendations for HNC patients pre-and post-RT

The mal de debarquement syndrome (MdDS) is a movement disorder, occurring predominantly in women, is most often induced by passive transport on water or in the air (classic MdDS), or can occur spontaneously. MdDS likely originates in the vestibular system and is unfamiliar to many physicians. The first successful treatment was devised by Dai et al. (1), and over 330 MdDS patients have now been treated. Here, we report the outcomes of 141 patients (122 females and 19 males) treated 1 year or more ago. We examine the patient's rocking frequency, body drifting, and nystagmus. The patients are then treated according to these findings for 4-5 days. During treatment, patients' heads were rolled while watching a rotating full-field visual surround (1). Their symptom severity after the initial treatment and at the follow-up was assessed using a subjective 10-point scale. Objective measures, taken before and at the end of the week of treatment, included static posturography. Significant improvement was a reduction in symptom severity by more than 50%. Objective measures were not possible during the follow-up because of the wide geographic distribution of the patients. The treatment group consisted of 120 classic and 21 spontaneous MdDS patients. The initial rate of significant improvement after a week of treatment was 78% in classic and 48% in spontaneous patients. One year later, significant improvement was maintained in 52% of classic and 48% of spontaneous subjects. There was complete remission of symptoms in 27% (32) of classic and 19% (4) of spontaneous patients. Although about half of them did not achieve a 50% improvement, most reported fewer and milder symptoms than before. The success of the treatment was generally inversely correlated with the duration of the MdDS symptoms and with the patients' ages. Prolonged travel by air or car on the way home most likely contributed to the symptomatic reversion from the initial successful treatment. Our results indicate that early diagnosis and treatment can significantly improve results, and the prevention of symptomatic reversion will increase the long-term benefit in this disabling disorder.