Faculty Bibliography

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.

DICER1 encodes an endoribonuclease involved in microRNA maturation and therefore has an important role in gene transcript regulation. Germline mutations scattered along DICER1 are associated with DICER1 syndrome which prominently features thyroid nodules. The tumors typically carry a second, somatic mutation in the RNase IIIb catalytic domain, referred to as "hotspot." These hotspot mutations occur in*1-2% of thyroid papillary carcinomas (PTC). The incidence of the hotspot mutations in thyroid nodules in adults, their association with malignancy and with other, germline DICER1 mutations remain largely unknown. We analyzed 6,734 consecutive clinical FNA samples from typically indeterminate cytology thyroid nodules for hotspot DICER1mutations using ThyroSeq v3 targeted next generation sequencing (NGS) assay from 11/2017-05/2018. Available follow-up was collected. A subgroup of cases underwent full DICER1 coding region and exon-intron boundaries analysis using a custom Fluidigm Access Array followed by NGS on Illumina MiSeq. Somatic DICER1 hotspot mutations were identified in 135 (2.0%) of nodules, with D1810H/V/Y and D1709G/E/N being most common. Median patient age was 37 years (range 19-79 y), 93% were females. Follow-up was available for 27 patients: 15 underwent surgery with benign diagnoses in 9 cases, NIFTP in 5 and follicular variant PTC in 1. Twelve patients were managed non-surgically, including one with a stable nodule harboring DICER1mutation at an allele frequency unchanged over 10 years between FNAs. A subset of 11 positive cases was tested for alteration in the entire DICER1 gene, which confirmed the hotspot mutations in 10 and detected additional alterations in 9 (90%), including non-hotspot mutations in 8 and LOH in 1 case. We report for the first time that likely somatic hotspot DICER1 mutations are relatively common and found in*2% of thyroid nodules in adults, who are typically mid-age women. At surgery, most of these nodules are benign, with*33% risk of NIFTP and*7% risk of follicular variant PTC. Our analysis also shows that somatic hotspot mutations are usually accompanied by a second, loss of function DICER1 mutation, which may in some cases be germline in nature

BACKGROUND:Delays in postoperative head and neck (HN) radiotherapy have been associated with decreased overall survival; however, the impact of delays in postoperative HN chemoradiotherapy remains undefined. METHODS:All patients with nonmetastatic HN cancer (oral cavity, oropharynx, larynx, hypopharynx) who underwent curative intent surgery and received adjuvant chemoradiotherapy were identified from the National Cancer Database (2005-2012). Overall treatment time (OTT) was defined as the time from surgery to the end of radiation therapy. Statistical methods included Cox proportional hazards modeling, which adjusted for clinicopathologic, demographic, and socioeconomic factors. Recursive partitioning analysis (RPA) identified the optimal threshold of OTT via conditional inference trees to estimate the greatest differences in overall survival (OS) on the basis of randomly selected training and validation sets. RESULTS:A total of 16,733 patients were included, with a median follow-up of 37 months. Median OS for OTT in a predefined threshold of ≤ 13 weeks was 10.1 years (95% confidence interval [CI], 9.8 years; not reached) compared with 8.7 years (95% CI, 8.2-9.2 years) in > 13 weeks. On multivariate analysis, OTT of > 13 weeks versus ≤ 13 weeks independently increased mortality risk (hazard ratio, 1.10; 95% CI, 1.04-1.17; P = < 0.001). RPA identified an optimal OTT threshold of 97 days (interquartile range: 96-98 days). The OTT threshold of 97 days was confirmed in a full Cox regression model estimating the risk of death according to overall treatment time as a continuous variable. CONCLUSION/CONCLUSIONS:In this large hospital-based national data, an OTT of greater than approximately 14 weeks most consistently increased the risk of death. LEVEL OF EVIDENCE/METHODS:4. Laryngoscope, 2018.

Objectives/UNASSIGNED:Edema is a frequent clinical observation following chemoradiation treatment (CRT) of oral/oropharyngeal cancer and is thought to contribute to post-CRT swallowing impairment. Our aims were to reliably quantify pharyngeal edema pre- and post-CRT from videofluoroscopic (VF) swallowing studies and to explore the relationship between edema and swallowing impairment. Swallowing impairment was captured using patient-reported swallowing outcomes (EAT-10) and with VF confirmation of impairment (DIGEST). Methods/UNASSIGNED:40 patients (24 M, age 38-76) with oral/oropharyngeal cancer received radiotherapy (70 Gy, 7 weeks) and 3 weekly doses of cisplatin. VF and EAT-10 were completed pre- and 1-month post-CRT. Edema was captured by measuring posterior pharyngeal wall (PPW) thickness, vallecular space, and pharyngeal area (PA) on a single post-swallow rest frame. Wilcoxon sign rank tests and paired t-tests evaluated within-subject changes in impairment and edema respectively. A linear mixed effect regression model explored the influence of time, patient-reported outcomes, and functional impairment on measures of edema. Results/UNASSIGNED:Swallowing function (EAT-10 and DIGEST) was significantly worse post-CRT. PPW thickness (but not vallecular space and pharyngeal area) was significantly worse post-CRT. PPW thickness was only significantly influenced by time (pre- vs. post-CRT) but not by measures of swallow function. Conclusion/UNASSIGNED:Our findings establish the use of PPW thickness as a reliable measure of acute edema in post-CRT treatment. In this small, retrospective sample, edema was not significantly correlated with either patient-reported or measured swallow function. Prospective longitudinal work, examining the relationship between objective measures of edema, patient perception of impairment, and swallow function and biomechanics is warranted. Level of Evidence/UNASSIGNED:4.

PURPOSE:To assess the safety of medical-ward bedside percutaneous dilatational tracheostomy (GWB-PDT). MATERIALS AND METHODS:A retrospective study of all patients who underwent elective GWB-PDT between 2009 and 2015. A joint otolaryngology-ICU team performed all GWB-PDTs. The patients were followed until decannulation, discharge or death. Complications were divided into early (within 24 h) and late, and into minor and major. RESULTS:Two hundred and fifty six patients were included in the study. The mean age was 77.7 ± 11.8 Medical history included cardiac comorbidities (42.6%) and cerebrovascular accidents (34.4%). Overall, 48 patients (18.9%) had 60 complications, of which 70% (42/60) were minor (13 early; 29 late complications). Fifteen patients (5.9%) had major complications. Eight patients had early major complications (loss of airway - two patients [0.8%], pneumothorax - two patients [0.8%], resuscitation - one patient [0.4%], and a single patient (0.4%) died within 24 h following PDT). Two additional patients (0.8%) underwent conversion to an open tracheostomy. Seven patients had late complications (airway complications in six patients [2.3%] and major bleeding in a single patient [0.4%]). Of the seven patients with late major complications, three had two major complications. Half of the complications occurred by POD 3. CONCLUSION:GWB-PDT is a feasible and safe solution for tracheostomies in general-ward ventilated patients.

BACKGROUND AND PURPOSE/OBJECTIVE:Few studies have shown MR imaging features and ADC correlating with molecular markers and survival in patients with glioma. Our purpose was to correlate MR imaging features and ADC with molecular subtyping and survival in adult diffuse gliomas. MATERIALS AND METHODS/METHODS:promoter methylation, and overall survival. RESULTS:wild-type glioma. Other MR imaging features were not statistically significant predictors of survival. CONCLUSIONS:wild-type gliomas.

OBJECTIVE:For the first time in 30 years, the eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual offers major changes in the staging of oral cavity cancer. We evaluated the predictive ability of the new staging system for oral cavity cancer to validate these changes and hypothesized that the new system would improve prognostic accuracy. METHODS:We conducted a retrospective cohort study of patients with oral cavity squamous cell carcinoma in the National Cancer Data Base from 2009 to 2013 and applied the seventh and eighth edition staging AJCC staging systems to all patients. Stage-specific overall survival was calculated using the Kaplan-Meier method and concordance indices to measure the system's prognostic accuracy. RESULTS:We identified 39,361 patients with a median follow-up of 27.1 months (range 0.1-80.4 months). In the seventh edition, there were 43.0%, 15.0%, 10.6%, and 25.7% of patients with pathologic stage I, II, III, and IV disease, respectively. After restaging based on eighth edition pathological guidelines, 10.0% of patients were upstaged (38.1%, 18.1%, 14.2%, and 25.2%, respectively, with stage I, II, III, and IV disease, respectively). The survival concordance index improved from the seventh to eighth edition for pathological staging (concordance index 0.699 and 0.704, respectively) and for clinical staging (concordance index 0.714 and 0.715, respectively). CONCLUSION:We provide validation of the new AJCC staging system for oral cavity cancer. Eighth edition AJCC staging guidelines upstage a substantial number of patients with greater depth of invasion or extranodal extension. This resulted in slightly improved prognostication. LEVEL OF EVIDENCE:2c. Laryngoscope, 128:2351-2360, 2018.

Creation of a pleasing dorsal nasal profile in the anterior and lateral views requires proper analysis and planning to determine the required series of steps to accomplish the desired outcome. The widened nasal dorsum is a common esthetic complaint of the patient seeking rhinoplasty. Often patients seek an unrealistic result that, if accomplished, would leave them with a restricted nasal vault and nasal airway compromise. Nasal function must be balanced with the patient and surgeon's desire to narrow the nasal dorsum. Various techniques are used to control the width of the upper third, or bony vault, and middle third, or cartilaginous vault.