Upper aerodigestive squamous cell carcinoma (UASCC) presents significant challenges in clinical management due to its aggressive nature. Here, we elucidate the role of MLL3 mutations as early, clonal genomic events in UASCC tumorigenesis, highlighting their role as foundational drivers of cancer development. Utilizing CRISPR-edited, cross-species organoid modeling, we demonstrate that loss of MLL3 contributes to early squamous neoplastic evolution. Furthermore, we identify an MLL3/GRHL2 protein complex that regulates the UASCC epigenome, particularly impacting immune response pathways. Notably, a novel MLL3/GRHL2-IRF1 axis promotes the expression of Th1 chemokines, enhancing anti-tumor immunity by facilitating T cell infiltration into the tumor microenvironment. Consequently, MLL3 regulates the in vivo efficacy of immune checkpoint blockade (ICB) therapy, corroborated by the strong association between MLL3 expression and human patients’ clinical response to ICB therapy. Our work underscores the significance of MLL3 in UASCC pathogenesis and highlights the interplay between MLL3/GRHL2 and immune response pathways as potential therapeutic targets for UASCC treatment.

Background: The global coronavirus disease-19 (COVID-19) pandemic has resulted in procedural delays around the world; however, timely and aggressive surgical resection for malignant brain tumor patients is essential for outcome optimization. To investigate the association between COVID-19 and outcomes of these patients, we queried the 2020 National Inpatient Sample (NIS) for differences in rates of surgical resection, time to surgery, mortality, and discharge disposition between patients with and without confirmed COVID-19 infection. Methods: Patient data were taken from the NIS from April 2020 to December 2020. COVID-19 diagnosis was determined with the International Classification of Diseases, Tenth Revision, Clinical Modification code U07.1. Results: A total of 30,671 malignant brain tumor patients met inclusion criteria and 738 (2.4%) patients had a confirmed COVID-19 diagnosis. COVID-19-positive patients had lower likelihood of receiving surgery (Odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29–0.63, P < 0.0001), increased likelihood of mortality (OR 2.18, 95% CI 1.78–2.66, P < 0.0001), and increased likelihood of non-routine discharge (OR 1.25, 95% CI 1.13–1.39, P < 0.0001). Notably, COVID patients receiving surgery were not associated with surgical delay (P = 0.17). Conclusion: COVID-19 infection was associated with worse patient outcome in malignant brain tumor patients, including decreased likelihood of receiving surgery, increased likelihood of mortality, and increased likelihood of non-routine discharge. Our study highlights the need to balance the risks and benefits of delaying surgery for malignant brain tumor patients with COVID-19. Although the COVID-19 pandemic is no longer a public health emergency, understanding the pandemic’s impact on outcome provides important insight in effective triage for these patients in the situations where resources are limited.

Objective: We sought to determine the incidence and outcomes of head and neck cancer (HNC) among patients with schizophrenia.Study Design: Cohort study utilizing TriNetX, a database containing millions of deidentified clinical records.Setting: Multicenter study utilizing records from 68 healthcare organizations.Methods: A cohort of patients with schizophrenia was analyzed for the annual incidence of HNC diagnosis between 2011 and 2021. TriNetX was queried for adult patients with HNC with and without schizophrenia (or long‐term antipsychotic use, as a surrogate). Cohorts were 1:1 propensity‐matched based on sociodemographic variables to produce matched cohorts of 25,077 patients each. Outcomes included mortality, recurrence in lymph nodes and lung, systemic treatment, failure to thrive, and hospice enrollment. Outcomes are reported as hazard ratio (HR; Cox proportional hazards model) and odds ratio (OR) with 95% CI.Results: Incidence of HNC in patients with schizophrenia peaked at 0.061% in 2012. HNC patients with schizophrenia have a significantly increased risk of mortality (HR 1.37, 95% CI 1.10‐1.72), locoregional recurrence (OR 1.36, 95% CI 1.30‐1.43), distant metastases to the lung (OR 1.72, 95% CI 1.59‐1.87), chemotherapy (OR 4.26, 95% CI 3.88‐4.69), radiation (OR 2.47, 95% CI 2.19‐2.78), failure to thrive (OR 2.41, 95% CI 2.32‐2.73), and hospice enrollment (OR 3.17, 95% CI 2.66‐3.76) compared to HNC patients without schizophrenia.Conclusion: HNC patients with schizophrenia have a significant increase in risk of mortality, recurrence, and poor outcomes compared to those without schizophrenia. These findings support a renewed focus on ensuring safety nets for this vulnerable population to ensure appropriate cancer screening and care.

Objective: Understand the characteristics of cannabis use, including frequency, mode, and purpose, among head and neck cancer (HNC) survivors.Methods: A cross‐sectional survey was distributed using ResearchMatch and online support groups for survivors of HNC. Respondents answered questions regarding demographics, cancer history, cannabis use, and knowledge of cannabis and completed a Short Form‐12 Questionnaire. Multivariate logistic regression and descriptive statistics were utilized for analysis.Results: Of 92 respondents, 75% were current or former cannabis users and 25% were never users. Cannabis users were less likely to have above‐median household income (OR 0.115, 95% CI 0.0139–0.662) and live outside of the United States (OR 0.0697, 95% CI 0.0026–0.7404) than current or former users. 36.2% and 27.5% of cannabis users reported occasional (1–5 days/month) and daily use, respectively. The most common mode of use was in edible products (46.4%). The most common reasons for use were to treat pain (79.4%), improve sleep (76.5%), cope with stress (64.7%), and recreation (63.6%). 19.2% of respondents reported receiving information regarding cannabis use in relation to cancer. Of those who had received information, the most common sources were a physician treating cancer (38.1%), friends (33.3%), and cancer support groups (33.3%). 45.6% of respondents reported significant or very high interest in receiving information about cannabis use in relation to cancer.Conclusions: Cannabis use for treatment of cancer‐associated symptoms and recreation is common among HNC survivors. Many survivors are interested in information regarding cannabis use, but few have received information from a reputable source.Level of Evidence: Level 4.