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BackgroundSinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown.MethodsWe evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788-6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion.ResultsOverall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/- CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling.ConclusionCollectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.

Organ preservation protocols are commonly used as first line therapy for advanced laryngeal cancer. Recurrence thereafter is associated with poor survival. The aim of this study is to identify genetic alterations associated with survival among patients with recurrent laryngeal cancer undergoing salvage laryngectomy. Sixty-two patients were sequenced using a targeted panel, of which twenty-two also underwent transcriptome sequencing. Alterations were grouped based on biologic pathways and survival outcomes were assessed using Kaplan-Meier analysis and multivariate cox regression. Select pathways were evaluated against The Cancer Genome Atlas (TCGA) data. Patients with mutations in the Oxidation pathway had significantly worse five-year disease specific survival (1% vs. 76%, p = 0.02), while mutations in the HN-Immunity pathway were associated with improved five-year disease specific survival (100% vs. 62%, p = 0.02). Multivariate analysis showed mutations in the Oxidation pathway remained an independent predictor of disease specific survival (HR 3.2, 95% CI 1.1-9.2, p = 0.03). Transcriptome analysis of recurrent tumors demonstrated that alterations in the Oxidation pathway were associated a positive Ragnum hypoxia signature score, consistent with enhanced pathway activity. Further, TCGA analyses demonstrated the prognostic value of oxidation pathway alterations in previously untreated disease. Alterations in the Oxidation pathway are associated with survival among patients with recurrent laryngeal cancer. These prognostic genetic biomarkers may inform precision medicine protocols and identify putatively targetable pathways to improve survival in this cohort.

Objective: We evaluated vessel counts in the pharyngeal mucosal margins of patients who underwent salvage laryngectomy to establish whether mucosal vascularity might predict fistula risk. Study Design: Retrospective cohort. Setting: Tertiary Medical Center. Methods: Patients who underwent salvage total laryngectomy at our institution between 1999 and 2015 were identified. Pharyngeal mucosal margins from laryngectomy specimens were evaluated histologically for each patient, and vessel counts were performed on 5 ×10 images. The primary outcome measure was fistula within 30 days of surgery and mean vessel counts were assessed as the principle explanatory variable. Results: Seventy patients were included and 40% developed a postoperative fistula. There was a large difference in the mean vessel count in patients who did develop fistula (48.6 vessels/×10 field) compared to those who did not (34.7 vessels/×10 field). A receiver operative characteristic curve found that a cutoff value of 33.9 vessels/×10 field provided a sensitivity of 75% and specificity of 62% to predict the likelihood of fistula occurrence (area under the curve = 0.71, 95% confidence interval [CI]: 0.59‐0.83). In a binary logistic regression, patients with vessel counts greater than 33.9 had a 5‐fold increased risk of developing fistula (95% CI: 1.8‐16.45). Histologically, vessels in the pharyngeal mucosa of patients who developed fistulas were more disorganized. Conclusion: After salvage laryngectomy, patients with higher mean mucosal margin vessel counts are at increased risk of fistula. The mechanism is unknown, but the disorganization of the vasculature may contribute to poor wound healing. Vessel counting may allow for fistula risk stratification and guide postoperative care. [ABSTRACT FROM AUTHOR]

Objective: Bioselection to assess tumor response after induction chemotherapy has been introduced as an alternative treatment strategy to total laryngectomy for patients with advanced larynx squamous cell carcinoma (LSCC). Tumor-infiltrating lymphocytes (TILs) have proven to serve as prognostic biomarkers in head and neck cancer but have not been evaluated as a way to select patients for treatment paradigms. The aim of this study is to evaluate the role of pretreatment TILs in patients with advanced LSCC undergoing the bioselection paradigm. Study Design: Retrospective study. Setting: Tertiary care hospital. Methods: Patients with advanced LSCC treated with bioselection and available tissue were included (N = 76). Patients were stratified into CD8-low and CD8-high cohorts by using the median TIL count. Kaplan-Meier survival analysis and multivariate cox regression were performed with SPSS version 26 (IBM). Results: After controlling for tobacco use, tumor site, and stage, a high CD8 TIL count was an independent predictor of improved 5-year disease-specific survival (hazard ratio, 0.17 [95% CI, 0.03-0.84]; P =.03). CD8 TIL counts did not predict response to induction chemotherapy; however, subgroup analysis of patients treated with chemoradiation therapy revealed that CD8 TIL count was significantly associated with degree of response (P =.012). Conclusion: These findings support prior data published by our group showing that TILs are predictive of disease-specific survival in patients with head and neck cancer. CD8 TIL counts were significantly associated with degree of clinical response after induction chemotherapy. These results suggest that pretreatment assessment of tumor-infiltrating CD8 cells could be useful in selecting patients. [ABSTRACT FROM AUTHOR]

Objectives  Targeted inhibitors of the PI3 kinase (PI3K) pathway have shown promising but incomplete antitumor activity in preclinical chordoma models. The aim of this study is to advance methodology for a high-throughput drug screen using chordoma models to identify new combination therapies for chordoma. Study Design  Present work is an in vitro study. Setting  The study conducted at an academic research laboratory. Materials and Methods  An in vitro study on automated high-throughput screening of chordoma cells was performed using a library of 1,406 drugs as both mono- and combination therapies with PI3K inhibitors. Combination indices were determined for dual therapies and synergistic outliers were identified as potential therapeutic agents. T (brachyury) siRNA knockdown in combination with PI3K pathway inhibition was also assessed. Results  Fifty-nine combination therapies were identified as having potential therapeutic efficacy. Effective combinations included PI3K inhibitors with GSK1838705A (ALK/IGF-1R inhibitor), LY2874455 (VEGFR/FGFR inhibitor), El1 (selective Ezh2 inhibitor), and (-)-p-bromotetramisole oxalate (alkaline phosphatase inhibitor). The top ranking targets identified included ALK, PDGFR, VEGFR, aurora kinase, and BCL-2. T (brachyury) inhibition produced significant reduction in cell viability and growth; however PI3K inhibition in combination with T (brachyury) knockdown did not result in further reduction in growth and viability in vitro. Conclusion  High throughput with in vitro combination screening is feasible with chordoma cells and allows for rapid identification of synergistic dual-therapies. Potential combination therapies and targetable pathways were identified. T (brachyury) knockdown produced significant reduction in cell viability, but did not show additional benefit with PI3K pathway inhibition in this model. Further in vitro and in vivo validation of these therapeutic combinations is warranted. [ABSTRACT FROM AUTHOR]

Objective: To create a longitudinal near-peer mentorship program for medical students applying to otolaryngology. Methods: A program for longitudinal near-peer mentorship was designed based on a needs analysis of senior medical students. Program objectives were to (1) provide didactic education on common otolaryngology consults, (2) facilitate resident-student networking, and (3) enable applicants to meet other students. Senior otolaryngology residents were matched with medical students from across the United States applying to otolaryngology for a series of online small group meetings. Sessions included resident-designed didactics covering high-yield clinical scenarios and a mentorship component focused on transition to residency topics. Program evaluation included anonymized pre- and post-tests for each didactic session and an anonymous post-program participant survey. Results: There were 40 student participants from across the United States, with an average attendance of 73% of sessions per participant. Performance on didactic testing improved for 2 of the 3 sessions. Participants stated they would be very likely to recommend each session to another student in the future (4.96/5.00, obs = 155). Participants stated the most valuable part of the program was interacting with residents (82% of responses), transition to residency advice (28%), and learning about otolaryngology consults (28%). Suggestions for improvement included expanding content, increasing the number of sessions, and involving additional faculty and residents. Conclusion: A longitudinal virtual experience can be valuable for near-peer mentorship for medical students applying to otolaryngology. [ABSTRACT FROM AUTHOR]

Objectives Examine the postoperative growth rate of residual juvenile angiofibroma (JA) in a large series of patients relative to pediatric growth parameters and other prognostic factors. Establish an algorithm for postoperative surveillance of patients with JA. Design Retrospective case series. Setting Tertiary referral academic center. Participants Pediatric patients undergoing surgical resection of JA between September 2005 and June 2015. Main Outcome Measures Postoperative recurrence and tumor growth rates. Results Thirty-eight patients were identified with a mean follow-up of 24.1 months. Sixty-eight percent (26/34) of patients achieved gross total resection, and 32% (12/38) had persistent postoperative disease. Of those with postoperative residual tumor, all had preoperative skull base involvement and residual blood supply from the internal carotid artery following embolization. Sixty-seven percent (8/12) of patients with postoperative residual tumor demonstrated radiographic stability of disease with scans being completed approximately every 6 months. Radiographic rates of disease progression ranged from 4.1 to 9.22 mm/year. Conclusions Patients with preoperative skull base involvement and residual vascularity following preoperative embolization are more likely to have residual postoperative disease, and a longer postoperative follow-up is warranted in these patients. Progression of residual disease occurred approximately 7.5 months postoperatively. Younger patients may be more likely to need further intervention for postoperative residual disease, and postoperative imaging at 6-month intervals appears appropriate. [ABSTRACT FROM AUTHOR]

Objectives To compare the clinical utility of four juvenile nasal angiofibroma (JNA) staging systems in a large cohort of patients. Design Retrospective case series. Setting Tertiary referral academic center. Participants Pediatric patients undergoing surgical resection of JNAs between January 2008 and June 2015. Main Outcome Measures Intraoperative blood loss and transfusions, number of staged operations, postoperative residual disease, and recurrent disease. Results In total, 34 patients were identified; all underwent preoperative embolization followed by surgery. Of the 34 patients, 33 (97%) underwent an exclusively endoscopic surgical approach, with 6 (18%) requiring planned staged operations. Ten (29%) patients had residual disease and three (9%) required further surgical resection. Using the area under the curve (AUC) of receiver operating characteristic curves, the University of Pittsburgh Medical Center (UPMC) staging system was most predictive of patients who required staged procedures, received intraoperative transfusions, and had residual postoperative disease (AUC: 0.89, 0.88, 0.86, respectively). Conclusions The UPMC JNA staging system accounts for both route of skull base extension and tumor vascularity, which are two important tumor attributes in the age of preoperative embolization and endoscopic endonasal surgery. The UPMC staging system is a reliable modern staging system that closely reflects prognostic information and aids in surgical planning. [ABSTRACT FROM AUTHOR]

Objectives: In an evolving era of immunotherapeutic options for persistent or recurrent laryngeal squamous cell carcinoma (LSCC), there is a need for improved biomarkers of treatment response and survival to inform optimal treatment selection and prognostication. Herein, our primary objective was to explore correlations between tumor infiltrating lymphocytes (TILs) and PD-L1 Combined Positive Score (CPS). Secondarily, we sought to explore their combined association with survival outcomes in patients with persistent or recurrent LSCC treated with salvage surgery.Materials and Methods: This was a retrospective cohort study at a single academic medical center. Immunohistochemistry staining for TILs and PD-L1 was performed on a tissue microarray of persistent or recurrent LSCC pathologic specimens. Correlations between TIL subsets and PD-L1 CPS were examined using Pearson's correlation coefficient and survival outcomes were analyzed with the Kaplan-Meier method and log-rank tests.Results: Only CD103+ TILs showed a statistically significant, weakly-positive correlation with PD-L1 CPS (r2 = 0.264, p < 0.015). No other TIL subsets correlated with PD-L1 CPS in our cohort. The most favorable survival outcomes were seen in patients with pathologic N0 tumors showing high CD103+ TILs and/or high PD-L1 CPS staining.Conclusion: Among patients with persistent or recurrent LSCC, CD103+ TILs only modestly correlated with PD-L1 CPS. A combined biomarker score incorporating CD103+ TILs and PD-L1 CPS greatly enhanced survival discrimination. This model may have additional utility in predicting the clinical benefit of immunotherapies in persistent or recurrent LSCC in the future. [ABSTRACT FROM AUTHOR]