Faculty Bibliography

The incidence of thyroid cancer in Graves'Disease (GD) patients is estimated to be low. However, it is unclear what impact the recent rise in the incidence of thyroid cancers has had in this population. Furthermore, it is not clear if these cancers behave more aggressively than cancers in the general population. We investigated the incidence of malignancy and its features in a contemporary cohort of GD patients treated by surgery. All patients who underwent thyroidectomy for GD in our center were reviewed from 2013-2018. Demographics, clinicopathologic features, rate of incidental cancer and outcomes were reviewed. We identified 130 patients with GD who underwent thyroidectomy. Median age was 40.5 (16-80). Majority were female (112, 86%). All but five (4%) were radioactive iodine naive. Thirtyfour (26%) were found to harbor malignancy. While the majority (18, 53%) were papillary microcarcinoma; 12 (34%) had multifocal disease; 10 (29%) had tall cell features, 3 (9%) had positive lymph nodes, and 2 (6%) had extrathyroidal extension. One patient (3%) was diagnosed with follicular carcinoma. No permanent hyperparathyroidism or recurrent laryngeal nerve injury was encountered. With a median follow up of 23 months no recurrences were identified. The risk of incidental malignancy in GD patients was high in our cohort. While the majority were low risk microcarcinomas, a number of patients harbored higher risk tall cell features. Our data suggest that for GD patients who are medically managed, careful surveillance and biopsy of suspicious nodules might be warranted. The outcome of surgical treatment was excellent for controlling both hyperthyroidism and cancer

Oral cancer is a growing health issue in low- and middle-income countries due to betel quid, tobacco, and alcohol use and in younger populations of middle- and high-income communities due to the prevalence of human papillomavirus. The described point-of-care, smartphone-based intraoral probe enables autofluorescence imaging and polarized white light imaging in a compact geometry through the use of a USB-connected camera module. The small size and flexible imaging head improves on previous intraoral probe designs and allows imaging the cheek pockets, tonsils, and base of tongue, the areas of greatest risk for both causes of oral cancer. Cloud-based remote specialist and convolutional neural network clinical diagnosis allow for both remote community and home use. The device is characterized and preliminary field-testing data are shared.

OBJECTIVES/OBJECTIVE:Research has shown improvement in apnea-hypopnea index in children with mild obstructive sleep apnea treated with anti-inflammatory medications. Data on quality of life outcomes in children receiving these medications is lacking. We aim to assess quality of life in children with mild obstructive sleep apnea treated with montelukast and fluticasone. METHODS:Children between 3 and 16 years old with mild sleep apnea (apnea-hypopnea index > 1 and ≤ 5) presenting to a pediatric otolaryngology clinic were recruited prospectively and treated with 4 months of montelukast and fluticasone. Subjects' caregivers completed the OSA-18, a validated quality of life survey, at baseline and 4 months. Children with ongoing obstruction at follow-up underwent adenotonsillectomy. RESULTS:Thirty-one patients were included. Mean (SD) age was 6.8 (3.9) years. Most subjects (54.8%) were black and 48% were obese. Mean (SD) apnea-hypopnea index of the subjects was 2.8 (1.0). The mean (SD) baseline OSA-18 score was 60.2 (18.5), indicating a moderate impact of sleep disturbance on quality of life. Following treatment, there was significant improvement (p < 0.005) in mean OSA-18 score. Four children discontinued montelukast due to behavioral side effects. Seven children (22%) underwent adenotonsillectomy after failing medical therapy. Demographic factors such as obesity [OR 0.63 (0.11, 3.49)] and apnea hypopnea index [OR 1.38 (0.59, 3.66)] failed to predict which children would respond to anti-inflammatory medications. CONCLUSIONS:Children with mild obstructive sleep apnea treated with montelukast and fluticasone experience significant improvements in quality of life. Further research is needed to determine optimal duration of therapy.

BACKGROUND:H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS:Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS/RESULTS:Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION/CONCLUSIONS:The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

OBJECTIVES/OBJECTIVE:To determine the accuracy of a modern navigation system in temporal bone surgery. While routine in other specialties, navigation has had limited use in the temporal bone due to issues of accuracy, perceived impracticality, and value. STUDY DESIGN/METHODS:Prospective observational study. SETTING/METHODS:Temporal bone laboratory. SUBJECTS AND METHODS/METHODS:Eighteen cadaveric specimens were dissected after rigid fiducials were implanted and computed tomography scans were obtained. Target registration and target localization errors were then measured at various points. RESULTS:The mean overall target registration error was 0.48 ± 0.29 mm. The mean target localization error was 0.54 mm at the sinodural angle, 0.48 mm at the lateral semicircular canal, 0.55 mm at the round window, 0.39 mm at the oval window, and 0.52 mm at the second genu of the facial nerve. CONCLUSION/CONCLUSIONS:A modern navigation system demonstrated submillimeter accuracy for all points of interest. Its use in clinical as well as training settings has yet to be fully elucidated.

Acoustic coordinated reset (CR) therapy based on neuromodulation and neuroplasticity principles has been proposed for the treatment of tonal tinnitus. The original therapy involved periodic delivery of randomly ordered sequences of four low-level tones centered around the frequency of a tone that matched the tinnitus pitch, f_T, with fixed ratios relative to f_T and delivered several hours/day over several weeks. Here we transform the original CR tone selection method to a more perceptually-relevant equivalent rectangular bandwidth (ERB) frequency scale, the ERB_N-number scale. Specifically, we provide a mathematical model that enables calculation of CR tones that accounts for f_T- and hearing loss-related ERB widening and ERB overlaps and gaps of CR tone alignments. Further, the model ensures symmetric CR tone alignments based on modelling studies that indicate the effect is optimal if the CR stimuli are symmetrically spaced relative to the tinnitus-related population of abnormally synchronized cortical neurons to activate the adjacent sub-populations. We also present experimentally testable ERB-based CR tone alignment strategies and explain how to use the ERB-based model in experiments, clinical studies, other types of tinnitus sound treatment such as tailor-made notch music training and limitations of our approach.

BACKGROUND:Low socioeconomic status has been linked with numerous poor health outcomes, but data are limited regarding the impact of insurance status on inflammatory bowel disease (IBD) outcomes. We aimed to characterize utilization of healthcare resources by IBD patients based on health insurance status, using Medicaid enrollment as a proxy for low socioeconomic status. METHODS:We retrospectively identified adult patients with IBD engaged in a colorectal cancer surveillance colonoscopy program from July 2007 to June 2017. Our primary outcomes included emergency department (ED) visits, inpatient hospitalizations, biologic infusions, and steroid exposure, stratified by insurance status. We compared patients who had ever been enrolled in Medicaid with all other patients. RESULTS:Of 947 patients with IBD, 221 (23%) had been enrolled in Medicaid. Compared with patients with other insurance types, patients with Medicaid had higher rates of ever being admitted to the hospital (77.6% vs 42.6%, P < 0.0001) or visiting the ED (90.5% vs 38.4%, P < 0.0001). When adjusted for sex, age at first colonoscopy, and ethnicity, patients with Medicaid had a higher rate of inpatient hospitalizations (Rate ratio [RR] 2.95; 95% CI 2.59-3.36) and ED visits (RR 4.24; 95% CI 3.82-4.70) compared to patients with other insurance. Patients with Medicaid had significantly higher prevalence of requiring steroids (62.4% vs 37.7%, P < 0.0001), and after adjusting for the same factors, the odds of requiring steroids in the patients with Medicaid was increased (OR 3.77; 95% CI 2.53-5.62). CONCLUSIONS:Medicaid insurance was a significant predictor of IBD care and outcomes. Patients with Medicaid may have less engagement in IBD care and seek emergency care more often.

Neutrophil elastase is a serine protease that has been implicated in the pathogenesis of inflammatory bowel disease. Due to post-translational control of its activation and high expression of its inhibitors in the gut, measurements of total expression poorly reflect the pool of active, functional neutrophil elastase. Fluorogenic substrate probes have been used to measure neutrophil elastase activity, though these tools lack specificity and traceability. PK105 is a recently described fluorescent activity-based probe, which binds to neutrophil elastase in an activity-dependent manner. The irreversible nature of this probe allows for accurate identification of its targets in complex protein mixtures. We describe the reactivity profile of PK105b, a new analogue of PK105, against recombinant serine proteases and in tissue extracts from healthy mice and from models of inflammation induced by oral cancer and Legionella pneumophila infection. We apply PK105b to measure neutrophil elastase activation in an acute model of experimental colitis. Neutrophil elastase activity is detected in inflamed, but not healthy, colons. We corroborate this finding in mucosal biopsies from patients with ulcerative colitis. Thus, PK105b facilitates detection of neutrophil elastase activity in tissue lysates, and we have applied it to demonstrate that this protease is unequivocally activated during colitis.