Association of Medical School Gap Year Research and Degree Programs With Otolaryngology Interview and Match Outcomes.

OBJECTIVE: To investigate whether a gap year for either research or a master's degree is associated with interview offers or match outcomes among otolaryngology applicants. METHODS: Using the Texas Seeking Transparency in Application to Residency (Texas STAR) database, we conducted a cross-sectional analysis of otolaryngology applicants from 2018 to 2022. Applicants were stratified based on the presence and type of gap year during medical school. Applicant characteristics, signaling, research productivity, and application costs were analyzed, with primary outcomes including number of interview offers and match status. RESULTS: Among 564 otolaryngology applicant respondents to the Texas STAR survey, 160 (28%) reported a gap year, including 64 (40%) applicants participating in a research year, 65 (41%) completing a Master of Public Health or Science (MPH and MSc), and 31 (19%) completing a Master of Business Administration, Education, or other degree (MBA and MEd). Gap-year applicants who completed a research year or MPH/MSc degree received more interview offers (P < .01) than MBA, MEd applicants, or those without a gap year. Applicants with a research year had the most publications, oral presentations, abstracts, posters, and research experiences (all P < .01). When controlling for USMLE scores, clerkship honors, and applications submitted, applicants completing a research year or an MPH/MSc-degree received increased interview offers (P < .01). No significant differences were seen in expenditures or match rates. CONCLUSIONS: Research and MPH/MSc gap years were associated with increased residency interview offers but not increased match success. Further longitudinal studies are needed to assess how yearlong experiences affect long-term career outcomes.

Predisposing, Enabling, and Need Factors Driving Palliative Care Use in Head and Neck Cancer.

OBJECTIVE: Characterizing factors associated with palliative care (PC) use in patients with stage III and VI head and neck cancer using Anderson's behavioral model of health service use. STUDY DESIGN: A retrospective study of the 2004 to 2020 National Cancer Database.gg METHODS: We used multivariate logistic regression to assess the association of predisposing, enabling, and need factors with PC use. We also investigated the association of these factors with interventional PC type (chemotherapy, radiotherapy, surgery) and refusal of curative treatment in the last 6 months of life. RESULTS: Five percent of patients received PC. "Predisposing factors" associated with less PC use include Hispanic ethnicity (adjusted odds ratio [aOR], 086; 95% confidence interval [CI], 0.76-0.97) and white and black race (vs white: aOR, 1.14; 95% CI, 1.07-1.22). "Enabling factors" associated with lower PC include private insurance (vs uninsured: aOR, 064; 95% CI, 0.53-0.77) and high-income (aOR, 078; 95% CI, 0.71-0.85). "Need factors" associated with higher PC use include stage IV (vs stage III cancer: aOR, 2.25; 95% CI, 2.11-2.40) and higher comorbidity index (vs Index 1: aOR, 1.58; 95% CI, 1.42-1.75). High-income (aOR, 0.78; 95% CI, 0.71-0.85) and private insurance (aOR, 0.6; 95% CI, 0.53, 0.77) were associated with higher interventional PC use and lower curative treatment refusal (insurance: aOR, 0.82; 95% CI, 0.55, 0.67; income aOR, 0.48; 95% CI, 0.44, 0.52). CONCLUSION: Low PC uptake is attributed to patients' race/culture, financial capabilities, and disease severity. Culturally informed counseling, clear guidelines on PC indication, and increasing financial accessibility of PC may increase timely and appropriate use of this service.

Novel non-invasive molecular signatures for oral cavity cancer, by whole transcriptome and small non-coding RNA sequencing analyses: Predicted association with PI3K/AKT/mTOR pathway.

INTRODUCTION: Identification of molecular biomarkers in the saliva and serum of oral cavity cancer patients represents a first step in the development of essential and efficient clinical tools for early detection and post-treatment monitoring. We hypothesized that molecular analyses of paired saliva and serum samples from an individual would likely yield better results than analyses of either serum or saliva alone. MATERIALS AND METHODS: We performed whole-transcriptome and small non-coding RNA sequencing analyses on 32 samples of saliva and serum collected from the same patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC). RESULTS: We identified 12 novel saliva and serum miRNAs and a panel of unique miRNA and mRNA signatures, significantly differentially expressed in OSCC patients relative to HC (log2 fold change: 2.6-26.8; DE: 0.02-0.000001). We utilized a combined panel of the 10 top-deregulated miRNAs and mRNAs and evaluated their putative diagnostic potential (>87% sensitivity; 100% specificity), recommending seven of them for further validation. We also identified unique saliva and serum miRNAs associated with OSCC and smoking history (OSCC smokers vs. never-smokers or HC: log2 fold change: 22-23; DE: 0.00003-0.000000001). Functional and pathway analyses indicated interactions between the discovered OSCC-related non-invasive miRNAs and mRNAs and their targets, through PI3K/AKT/mTOR signaling. CONCLUSION: Our data support our hypothesis that using paired saliva and serum from the same individuals and deep sequencing analyses can provide unique combined mRNA and miRNA signatures associated with canonical pathways that may have a diagnostic advantage relative to saliva or serum alone and may be useful for clinical testing. We believe this data will contribute to effective preventive care by post-treatment monitoring of patients, as well as suggesting potential targets for therapeutic approaches.

Identifying Opportunities to Deliver High-Quality Cancer Care Across a Health System: A Clinical Responsibility.

OBJECTIVE: We examined process-related quality metrics for oral squamous cell carcinoma (OSCC) depending on treating facility type across a health system and region. STUDY DESIGN: Retrospective in accordance with Strengthening the Reporting of Observational Studies in Epidemiology guidelines. SETTING: Single health system and region. METHODS: Patients with OSCC diagnosed between 2012 and 2018 were identified from tumor registries of 6 hospitals (1 academic and 5 community) within a single health system. Patients were categorized into 3 care groups: (1) solely at the academic center, (2) solely at community facilities, and (3) combined care at academic and community facilities. Primary outcome measures were process-related quality metrics: positive surgical margin rate, lymph node yield (LNY), adjuvant treatment initiation ≤6 weeks, National Comprehensive Cancer Network (NCCN)-guideline adherence. RESULTS: A total of 499 patients were included: 307 (61.5%) patients in the academic-only group, 101 (20.2%) in the community-only group, and 91 (18.2%) in the combined group. Surgery at community hospitals was associated with increased odds of positive surgical margins (11.9% vs 2.5%, odds ratio [OR]: 47.73, 95% confidence interval [CI]: 11.2-275.86, P < .001) and lower odds of LNY ≥ 18 (52.8% vs 85.9%, OR: 0.15, 95% CI: 0.07-0.33, P < .001) relative to the academic center. Compared with the academic-only group, odds of adjuvant treatment initiation ≤6 weeks were lower for the combined group (OR: 0.30, 95% CI: 0.13-0.64, P = .002) and odds of NCCN guideline-adherent treatment were lower in the community only group (OR: 0.35, 95% CI: 0.18-0.70, P = .003). CONCLUSION: Quality of oral cancer care across the health system and region is comparable to or better-than national standards, indicating good baseline quality of care. Differences by facility type and fragmentation of care present an opportunity for bringing best in-class cancer care across an entire region.

Impact of 18F-FDG PET Intensity Normalization on Radiomic Features of Oropharyngeal Squamous Cell Carcinomas and Machine Learning-Generated Biomarkers.

We aimed to investigate the effects of 18F-FDG PET voxel intensity normalization on radiomic features of oropharyngeal squamous cell carcinoma (OPSCC) and machine learning-generated radiomic biomarkers. Methods: We extracted 1,037 18F-FDG PET radiomic features quantifying the shape, intensity, and texture of 430 OPSCC primary tumors. The reproducibility of individual features across 3 intensity-normalized images (body-weight SUV, reference tissue activity ratio to lentiform nucleus of brain and cerebellum) and the raw PET data was assessed using an intraclass correlation coefficient (ICC). We investigated the effects of intensity normalization on the features' utility in predicting the human papillomavirus (HPV) status of OPSCCs in univariate logistic regression, receiver-operating-characteristic analysis, and extreme-gradient-boosting (XGBoost) machine-learning classifiers. Results: Of 1,037 features, a high (ICC ≥ 0.90), medium (0.90 > ICC ≥ 0.75), and low (ICC < 0.75) degree of reproducibility across normalization methods was attained in 356 (34.3%), 608 (58.6%), and 73 (7%) features, respectively. In univariate analysis, features from the PET normalized to the lentiform nucleus had the strongest association with HPV status, with 865 of 1,037 (83.4%) significant features after multiple testing corrections and a median area under the receiver-operating-characteristic curve (AUC) of 0.65 (interquartile range, 0.62-0.68). Similar tendencies were observed in XGBoost models, with the lentiform nucleus-normalized model achieving the numerically highest average AUC of 0.72 (SD, 0.07) in the cross validation within the training cohort. The model generalized well to the validation cohorts, attaining an AUC of 0.73 (95% CI, 0.60-0.85) in independent validation and 0.76 (95% CI, 0.58-0.95) in external validation. The AUCs of the XGBoost models were not significantly different. Conclusion: Only one third of the features demonstrated a high degree of reproducibility across intensity-normalization techniques, making uniform normalization a prerequisite for interindividual comparability of radiomic markers. The choice of normalization technique may affect the radiomic features' predictive value with respect to HPV. Our results show trends that normalization to the lentiform nucleus may improve model performance, although more evidence is needed to draw a firm conclusion.

A Novel Saliva and Serum miRNA Panel as a Potential Useful Index for Oral Cancer and the Association of miR-21 with Smoking History: a Pilot Study.

Tobacco use is implicated in the carcinogenesis of oral squamous cell carcinoma (OSCC), which is associated with poor survival if not diagnosed early. Identification of novel noninvasive, highly sensitive, and cost-effective diagnostic and risk assessment methods for OSCC would improve early detection. Here, we report a pilot study assessing salivary and serum miRNAs associated with OSCC and stratified by smoking status. Saliva and paired serum samples were collected from 23 patients with OSCC and 21 healthy volunteers, with an equal number of smokers and nonsmokers in each group. Twenty head and neck cancer-related miRNAs were quantified by qPCR (dual-labeled LNA probes) and analyzed by Welch t test (95% confidence interval). Four saliva miRNAs, miR-21, miR-136, miR-3928, and miR-29B, showed statistically significant overexpression in OSCC versus healthy controls (P < 0.05). miR-21 was statistically significantly overexpressed in OSCC smokers versus nonsmokers (P = 0.006). Salivary miR-21, miR-136, and miR-3928, and serum miR-21 and miR-136, showed statistically significant differential expression in early-stage tumors versus controls (P < 0.05), particularly miR-21 in smokers (P < 0.005). This pilot study provides a novel panel of saliva and serum miRNAs associated with oral cancer. Further validation as a potential useful index of oral cancer, particularly miR-21 in smokers and early-stage OSCC is warranted. PREVENTION RELEVANCE: Saliva and serum miR-21, miR-136, miR-3928, and miR-29B, are potentially associated with oral cancer even at an early stage, especially miR-21 in individuals with a smoking history, a further validation in a larger cohort of subjects with premalignant and early malignant lesions need to confirm.

Prognostic value of absolute lymphocyte count in oral cavity squamous cell carcinoma.

Objectives: Absolute lymphocyte count (ALC) has been shown to be a prognostic indicator in other solid tumors. Given this, we aimed to evaluate the prognostic value of ALC in oral cavity squamous cell carcinoma (OSCC). Methods: Using our institutional tumor registry data, we identified patients ≥18 years old who were diagnosed with OSCC between 2012 and 2018. Preoperative ALC values within 30 days of surgery were collected through retrospective chart review. American Joint Committee on Cancer, 7th-edition best stage was used to categorize cancers as early stage (stages 1 and 2) or late-stage (stages 3 and 4). Primary outcomes were likelihood of recurrence and survival rates after 3 years. Results: Of the 412 patients identified, 262 patients had available ALC data and met inclusion criteria. Early stage cancer patients who had lymphopenia did not have any significant difference in their rate of death ([OR], 1.71, CI: 0.54-5.45, p = .36) or likelihood recurrence ([OR], 0.60, CI: 0.06-5.87, p = .66) after controlling for age, tobacco use, alcohol use, positive margins, and adjuvant therapy. Late-stage cancer patients who had lymphopenia also showed no difference in their rate of death ([OR], 2.74, CI: 0.65-11.6, p = .17) or likelihood of recurrence ([OR], 0.38, CI: 0.04-3.36, p = .38). Conclusions and Relevance: This study evaluates the prognostic value of ALC in oral cavity cancers. Our findings demonstrate that pretreatment ALC is not significantly associated with recurrence and survival outcomes patients with OSCC. Level of Evidence: III. Lay Summary: Absolute lymphocyte count (ALC) has been associated with prognosis in several cancers. We found that preoperative ALC was not associated with likelihood of survival or recurrence in patients with early stage or late-stage oral cavity cancer.

Association of Age and Frailty With 30-Day Outcomes Among Patients Undergoing Oral Cavity Cancer Surgery.

OBJECTIVE: To evaluate the impact of age and frailty on 30-day outcomes following surgery for oral squamous cavity carcinoma (OSCC). STUDY DESIGN: Retrospective cross-sectional analysis. SETTING: American College of Surgeons' National Quality Improvement Program (NSQIP) database. METHODS: Patients who underwent OSCC resection were queried via NSQIP (2015-2020). Cases were stratified by age (18-65, 65-75, and older than 75) as well as by modified frailty index scores (mFI 0, mFI 1, and mFI 2+) for comparative analyses. Univariate and multivariable analyses were conducted to examine demographics, perioperative outcomes, and 30-day postoperative adverse events. RESULTS: A total of 3238 patients who underwent OSCC surgery were identified and categorized as nongeriatric ("NGA," age 18-65), younger geriatric ("YGA," age 65-75), and older geriatric ("OGA," age >75) adults. Compared to NGA, geriatric patients had higher the American Society of Anesthesiologists classification, higher modified frailty index scores, and more comorbidities such as hypertension, congestive heart failure, chronic obstructive disease, and diabetes (p < .001). YGAs and OGAs were also less likely to undergo neck dissection (p < .001), composite resection (p = .006), and free flap reconstruction compared to NGAs (p < .001). When controlling for confounders, age was not independently associated with an increased risk of poor outcomes. On the other hand, frailty was found to be independently associated with a higher risk of adverse events (odds ratio: 1.40 [1.15-1.70], p < .001 for mFI 1, odds ratio: 1.45 [1.04-2.02], p = .027 for mFI 2+). CONCLUSION: A higher mFI score, not older age, is associated with an increased risk of 30-day complications following OSCC surgery.

The Representation of Surgery in Oncology Clinical Trials: 2001 to 2022.

BACKGROUND: Surgery is a mainstay of cancer care. Since the advancement of cancer treatment occurs through clinical trials, it is critical to investigate the degree and nature of representation of surgery in oncological clinical trials. METHODS: This observational analysis used publicly available data from clinicaltrials.gov to investigate non-industry-funded oncological clinical trials in the United States between 2012 and 2022. RESULTS: From 2012 to 2022, 1,861 (15.7%) of the 11,843 registered oncologic clinical trials were surgical. There was a 43.2% increase in proportional surgical trials and an 18.9% increase in oncology trials over the last two decades. Surgery+diagnostic-technique trials increased from 5.14 to 12.6% (P < 0.001, 95%CI [- 0.097, - 0.052]), surgery+radiation trials increased from 5.24 to 8.1% (P = 0.004, 95%CI [- 0.047, - 0.0088]), surgery+systemic-therapy trials decreased from 34.5 to 29.2% (P = 0.003, 95%CI [0.018, 0.088]), surgery+supportive-therapy trials increased from 8.0 to 11.3% (P = 0.004, 95%CI [- 0.056, - 0.01]) and 'surgery-as-the-variable' trials decreased from 12.0 to 3.5% (P < 0.001, 95%CI[0.065, 0.1]). Systemic therapy with biologics increased from 38.1 to 53.9% (P < 0.001, 95%CI [- 0.22, - 0.091]). Surgery-vs.-no-surgery trials increased from 16.8 to 37.3% (P = 0.001, 95%CI [- 0.32, - 0.078]). CONCLUSION: Surgical oncology trials increased by 43.2% over the last 10 years. The focus of clinical trials is changing to the encouragement of innovation in more diagnostic and less invasive techniques, and targeted therapies.

Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment.

BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.

Over-The-Counter Hearing Aids: Trends in Information-Seeking Behavior.

Recent Food and Drug Administration approval of over-the-counter (OTC) hearing aids has changed the policy landscape surrounding hearing-assistive technology. Our objective was to characterize trends in information-seeking behavior in the era of OTC hearing aids. Using Google Trends, we extracted the relative search volume (RSV) for hearing health-related topics. The mean RSV in the 2 weeks preceding and following enactment of the FDA's OTC hearing aid ruling were compared using a paired samples t-test. RSV for hearing-related queries increased by 212.5% on the date of FDA approval. There was a 25.6% (p = .02) increase in mean RSV for "hearing aids" before and after the FDA ruling. The most popular searches focused on specific device brands and cost. States with more rural residents represented the highest proportion of queries. Understanding these trends is critical to ensure appropriate patient counseling and improve access to hearing assistive technology.

Improving Post-procedure Outcomes With Clinical Care Pathway for Enteral Access.

Our health system introduced an enteral access clinical pathway (EACP) hoping to increase nutritionist consults and decrease presentation to the Emergency Department, readmission to the hospital, and overall hospital length of stay. We followed patients with short-term access (STA), longterm access (LTA), and short-long-term conversions (SLT) seen in the six months prior to the EACP launch (baseline group) and the six months after (performance group). The baseline cohort consisted of 2,553 patients and the performance cohort of 2,419 patients. Those in the performance group were more likely to receive a nutrition consult (52.4% vs 48.0%, P < .01), less likely to re-present to the ED (31.9% vs 42.6%, P < .001), and less likely to be readmitted to the hospital (31.0% vs 41.6%, P < .001. These findings suggest that the EACP may increase the likelihood of both expert-driven nutritional support and effective discharge planning for hospitalized patients.

The Role of PARP-1 and NF-κB in Bile-Induced DNA Damage and Oncogenic Profile in Hypopharyngeal Cells.

OBJECTIVES/HYPOTHESIS: We recently documented that acidic bile, a gastroesophageal reflux content, can cause invasive hypopharyngeal squamous cell carcinoma, by inducing widespread DNA damage and promoting nuclear factor kappa B (NF-κB)-related oncogenic molecular events. Poly or adenosine diphosphate (ADP)-ribose polymerase-1 (PARP-1), a sensitive sensor of DNA damage, may interact with NF-κB. We hypothesized that PARP-1 is activated in hypopharyngeal cells (HCs) with marked DNA damage caused by acidic bile, hence there is an association between PARP-1 and NF-κB activation or its related oncogenic profile, in this process. STUDY DESIGN: In vitro study. METHODS: We targeted PARP-1 and NF-κB(p65), using pharmacologic inhibitors, 1.0 µM Rucaparib (AG014699) and 10 µM BAY 11-7082 {3-[4=methylphenyl)sulfonyl]-(2E)-propenenitrile}, respectively, or silencing their gene expression (siRNAs) and used immunofluorescence, luciferase, cell viability, direct enzyme-linked immunosorbent assays, and qPCR analysis to detect the effect of targeting PARP-1 or NF-κB in acidic bile-induced DNA damage, PARP-1, p-NF-κB, and B-cell lymphoma 2 (Bcl-2) expression, as well as NF-κB transcriptional activity, cell survival, and mRNA oncogenic phenotype in HCs. RESULTS: We showed that (i) PARP-1 is overexpressed by acidic bile, (ii) targeting NF-κB adequately prevents the acidic bile-induced DNA double-strand breaks (DSBs) by gamma H2A histone family member X (γH2AX), oxidative DNA/RNA damage, PARP-1 overexpression, anti-apoptotic mRNA phenotype, and cell survival, whereas (iii) targeting PARP-1 preserves elevated DNA damage, NF-κB activation, and anti-apoptotic phenotype. CONCLUSION: We document for the first time that the activation of PARP-1 is an early event during bile reflux-related head and neck carcinogenesis and that NF-κB can mediate DNA damage and PARP-1 activation. Our data encourage further investigation into how acidic bile-induced activated NF-κB mediates DNA damage in hypopharyngeal carcinogenesis. LEVEL OF EVIDENCE: NA Laryngoscope, 133:1146-1155, 2023.

Resident Burnout and Well-being in Otolaryngology and Other Surgical Specialties: Strategies for Change.

OBJECTIVE: To perform a literature review on burnout prevalence, factors that affect burnout and well-being, and solutions to address burnout in otolaryngology-head and neck surgery (OTO-HNS) residents and residents in other surgical specialties. DATA SOURCES: Ovid Medline, Embase, and article reference lists. REVIEW METHODS: A literature search was performed to identify articles on resident burnout, distress, wellness, well-being, and quality of life. Articles deemed outside the scope of the current work were excluded. Search was limited to the past 5 years. CONCLUSIONS: Moderate to high burnout has been reported in 35% to 86% of OTO-HNS residents. Among other surgical specialties, resident burnout ranges between 58% and 66% in plastics, 11% and 67% in neurosurgery, 38% and 68% in urology, and 31% and 56% in orthopedics. Highest burnout rates were seen in postgraduate year 2 residents. Factors significantly associated with burnout included hours worked (>80 h/wk), level of autonomy, exercise, and program support. Reported resident work hours have steadily increased: 8% of OTO-HNS residents in 2005 vs 26% in 2019 reported averaging >80 h/wk. Practical implications of resident burnout include decreased empathy, moral distress and injury, poor health, decreased quality of life, increased attrition, decreased desire to pursue fellowship, and increased likelihood of medical errors. Structured mentorship programs, wellness initiatives, and increased ancillary support have been associated with lower burnout rates and improvements in resident well-being across specialties. IMPLICATIONS FOR PRACTICE: Addressing burnout, which is prevalent in OTO-HNS residents, is critical to improving patient care and physician well-being. Surgical specialties can share strategies to effectively address resident burnout through institutional interventions, which can be essential quality improvement initiatives, to promote well-being.

Trends in Residency Applicant Volume in Otolaryngology-Head and Neck Surgery and Peer Specialties.

OBJECTIVE: To evaluate the 2020 to 2021 Otolaryngology residency application cycle in the context of recent trends. STUDY DESIGN: Retrospective data analysis. SETTING: Disruptions caused by the COVID-19 pandemic may significantly alter trends among residency applicants, especially in highly competitive and/or smaller specialties. METHODS: Applicant and residency statistics from Electronic Residency Application Service (ERAS) and National Residency Matching Program (NRMP) were extracted from the 2016 to 2021 and 2011 to 2021, respectively. Trends in Otolaryngology-Head and Neck Surgery (OHNS) were compared to peer specialties (PS) including Dermatology, Neurological Surgery, Orthopedic Surgery, and Integrated Pathway for Plastic and Reconstructive Surgery (PRS). The ratio of the number of applicants per positions (APP) was used to reflect the degree of competition. RESULTS: Between 2011 and 2021, the number of OHNS programs and positions expanded less than those of PS and General Surgery. The increase in the APP ratio was significantly greater for OHNS compared to those Dermatology, Orthopedic Surgery, General Surgery and all PGY1 residency positions for both US MD and all applicants (P < .01 for each). OHNS expansion of US MD (P = .046), but not all applicants (P = .169), outgrew that of Neurosurgery. CONCLUSION: The 2020 to 2021 cycle affected by the COVID-19 pandemic saw a continuation of the recent trend in the expanding OHNS applicant pool. OHNS remains one of the specialties with the highest APP ratio and has observed a significant growth compared to PS since 2018. Understanding and anticipating trends in residency application cycles is critical for designing processes to optimize the best fit between applicants and programs.

The Effect of Tobacco Smoke N-Nitrosamines, NNK and NDEA, and Nicotine, on DNA Mismatch Repair Mechanism and miRNA Markers, in Hypopharyngeal Squamous Cell Carcinoma: An In Vivo Model and Clinical Evidence.

Deregulation of the DNA mismatch repair (MMR) mechanism has been linked to poor prognosis of upper aerodigestive tract cancers. Our recent in vitro data have provided evidence of crosstalk between deregulated miRNAs and MMR genes, caused by tobacco smoke (TS) N-Nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in hypopharyngeal cells. Here, we explored whether chronic exposure to TS components can affect MMR mechanism and miRNA profiles in hypopharyngeal mucosa. Using a mouse model (C57Bl/6J wild type) of in vivo 14-week exposure to NNK (0.2 mmol/L) and N-Nitrosodiethylamine (NDEA; 0.004 mmol/L), with or without nicotine (0.02 µmol/L), we provide direct evidence that TS components can promote dysplasia, significant downregulation of Msh2 and Mlh1 genes and deregulation of miR-21, miR-155, miR-34a, and miR-451a. By analyzing eight human specimens from tobacco smokers and eight controls, we provide clinical evidence of a significant reduction in hMSH2 and hMLH1 mRNAs in hypopharyngeal squamous cell carcinoma (HSCC). In summary, deregulation of the MMR mechanism and miRNAs is caused by chronic exposure to TS-related N-Nitrosamines, with or without nicotine, in the early stages of upper aerodigestive tract carcinogenesis, and can also be detected in human HSCC. Thus, we encourage future studies to further elucidate a possible in vivo dose-dependent effect of individual or combined N-Nitrosamines, NNK and/or NDEA, and nicotine, on the MMR mechanism and their clinical testing to elaborate prognosis and risk assessment.

Noxious Combination of Tobacco Smoke Nitrosamines with Bile, Deoxycholic Acid, Promotes Hypopharyngeal Squamous Cell Carcinoma, via NFκB, In Vivo.

Tobacco smoking is the most known risk factor for hypopharyngeal cancer. Bile reflux has recently been documented as an independent risk factor for NFκB-mediated hypopharyngeal squamous cell carcinoma. However, the carcinogenic effect of tobacco smoke on the hypopharynx and its combination with bile has not yet been proven by direct evidence. We investigated whether in vivo chronic exposure (12-14 weeks) of murine (C57Bl/6J) hypopharyngeal epithelium to tobacco smoke components (TSC) [N-nitrosamines; 4-(N-Methyl-N-Nitrosamino)-1-(3-pyridyl)-1-butanone (0.2 mmol/L), N-nitrosodiethylamine (0.004 mmol/L)], as the sole drinking fluid 5 days per week, along with topically applied (two times/day) bile [deoxycholic acid (0.28 mmol/L)], can accelerate a possible TSC-induced neoplastic process, by enhancing NFκB activation and the associated oncogenic profile, using histologic, IHC, and qPCR analyses. We provide direct evidence of TSC-induced premalignant lesions, which can be exacerbated by the presence of bile, causing invasive carcinoma. The combined chronic exposure of the hypopharynx to TSC with bile causes advanced NFκB activation and profound overexpression of Il6, Tnf, Stat3, Egfr, Wnt5a, composing an aggressive phenotype. We document for the first time the noxious combination of bile with a known risk factor, such as tobacco smoke nitrosamines, in the development and progression of hypopharyngeal cancer, via NFκB, in vivo. The data presented here encourage further investigation into the incidence of upper aerodigestive tract cancers in smokers with bile reflux and the early identification of high-risk individuals in clinical practice. This in vivo model is also suitable for large-scale studies to reveal the nature of inflammatory-associated aerodigestive tract carcinogenesis and its targeted therapy. PREVENTION RELEVANCE: Early assessment of bile components in refluxate of tobacco users can prevent the chronic silent progression of upper aerodigestive tract carcinogenesis. This in vivo model indicates that bile reflux might have an additive effect on the tobacco-smoke N-nitrosamines effect and could be suitable for large-scale studies of diagnostic and therapeutic interventions.

Guideline - Adherence in advanced stage head and neck cancer is associated with improved survival - A National study.

OBJECTIVES: Understanding the prevalence of guideline non-adherence among patients with advanced head and neck cancer (HNC) and its impact on survival may facilitate increased adherence. Our objective was to perform a detailed analysis of overall National Comprehensive Care Network (NCCN) guideline adherence in a national cohort. METHODS: Using the National Cancer Database, we analyzed site-specific NCCN guideline adherence for treatment of 100,074 overall stage III and IVA HNC patients from 2004 to 2013. Main outcomes were guideline adherence rates and overall survival (OS). Adherence was categorized by treatment: surgery/ radiation. Reasons were categorized as: (1) high risk; (2) refusal; (3) not planned. RESULTS: After exclusion, the care of 25,620 patients was defined as non-adherent (25.6%), yet adherence rates significantly improved across the study's years. After multivariate analysis, non-adherence was associated with age ≥ 65, female gender, black race, comorbidity score ≥ 1, insurance status, clinical staging, primary site, and facility type. Patients not managed according to NCCN guidelines had a significantly reduced OS compared with patients treated on-guideline (hazard ratio (HR) = 1.51 (95 %CI 1.48-1.54), p < 0.001). 'Not planned' patients had reduced OS when compared to adherent patients (HR = 1.27 (95 %CI 1.23-1.30), p < 0.001). Off-guideline treated patients due to 'risk factors' had a decrease in overall survival (OS) compared with other reasons (p < 0.001 for all). CONCLUSIONS: Despite improvement over time, non-adherence to NCCN guidelines for advanced stage HNC remains high. Non-adherence is associated with decreased OS, regardless of the reason. Despite concerns from both patient and physician, efforts should be made to increase guideline awareness and adherence.