IMPORTANCE Biomarkers that reflect prognosis and cellular immunity in patients with head and neck squamous cell carcinoma (HNSCC) are a prerequisite for improving individualized treatment that limits the intensity and morbidity of conventional treatment and may be useful in the introduction of new immunotherapy regimens.OBJECTIVE To determine if specific classes of tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens have prognostic value for outcomes in a large training and validation cohort of patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTSIn this prospective, epidemiologic study with a median follow-up of 47.5 months, in 464 previously untreated patients with available tissue for construction of tissue microarray, HNSCC disease sites included oral cavity ( 228), oropharynx (147), larynx (74), and hypopharynx (15). The training cohort consisted of 241 patients and the validation cohort consisted of 223 patients. Overall tumor stage was I (55), II (69), III (71), or IV (269). Patients were enrolled between November 2008 and October 2014. Data were analyzed between October 2018 and April 2019.MAIN OUTCOMES AND MEASURES Semiquantitative levels of CD4, CD8, and FoxP3 lymphocytes were assessed by immunohistologic analysis and correlations with clinical prognostic factors, initial treatment modality, and overall survival (OS) and disease-specific (DSS) survival were determined. A principal component analysis was performed to generate a combined TIL-weighted sum score (TIL ws ). RESULTSOf the 464 participants, 135 (29%) were women; mean (SD) age was 61.1 (11.8) years. Higher CD8 counts were associated with improved OS in both training and validation sets (HR, 0.94; 95% CI, 0.90-0.98; and HR, 0.97; 95% CI, 0.95-0.99, respectively). Higher TIL ws levels were associated with improved OS and DSS in both the training set (HR, 0.91; 95% CI, 0.86-0.96; and HR, 0.93; 95% CI, 0.87-0.99, respectively) and validation set (HR, 0.96; 95% CI, 0.93-0.99; and HR, 0.94; 95% CI, 0.89-0.99, respectively). A multivariable Cox model controlling for batch, age, clinical stage, disease site, comorbidities, HPV status, and smoking, showed that higher TIL ws levels were associated with improved OS and DSS (HR, 0.94; 95% CI, 0.92-0.97; and HR, 0.94; 95% CI, 0.90-0.98, respectively). When grouped by treatment (surgery vs chemoradiation) and tested for interaction, treatment was found to be an effect modifier for CD4 levels and OS. Low CD4 levels were showed greater association with decreased survival in the chemoradiation cohort than the surgery cohort. CONCLUSIONS AND RELEVANCEThe findings from this large cohort study suggest that levels of TILs are an independent prognostic factor in patients with HNSCC. Subsets of TILs and combined TIL scores may be clinically useful predictive and prognostic factors.

Background: Accurate, individualized prognostication in oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision-making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation. Methods: Four OPSCC calculators were identified that integrate HPV in their estimation of five-year overall survival. Treatment outcomes for 856 patients with OPSCC evaluated at a single institution from 2003–2016 were analyzed. Predicted survival probabilities were generated for each patient using each calculator. Calculator performance was assessed and compared using Kaplan-Meier plots, receiver operating characteristic (ROC) curves, concordance statistics (C-indices), and calibration plots. Results: Correlation between pairs of calculators varied, with coefficients ranging from 0.63 to 0.90. Only three of six pairs of calculators yielded predictions within 10% of each other for at least 50% of patients. Kaplan-Meier curves of calculator-defined risk groups showed reasonable stratification. Areas under the ROC curve ranged from 0.74 to 0.80, and C-indices from 0.71 to 0.78. Each calculator demonstrated superior discriminatory ability compared to American Joint Committee on Cancer 7th and 8th Editions clinical staging. Among models, the Denmark calculator was best-calibrated to observed outcomes. Conclusions: Existing calculators exhibited reasonable estimation of survival in OPSCC, but there was considerable variability in predictions for individual patients, which limits clinical utility. Given the increasing role of personalized treatment for OPSCC, further work is needed to improve accuracy and precision, possibly through the identification and incorporation of additional biomarkers.

Background The principles of global surgery should be taught as a part of the core curriculum in medical schools. The need for medical students to be familiar with the topic is increasing in acceptance. There is, however, a paucity of data on how medical students are exposed to global surgery. This study aims to evaluate exposure of medical students to global surgery, awareness of the key messages of the Lancet Commission on Global Surgery, global surgery career aspirations and barriers to said aspirations. Methods ISOMERS was a multi-centre, online, cross-sectional survey of final year medical students globally. The questionnaire utilised a combination of Likert-scale, multiple-choice, and free text questions. Results In this study, 1593 final year medical students from 144 medical schools in 20 countries participated. The majority (n = 869/1496, 58.1%) believed global surgery to be relevant, despite 17.7% (n = 271/1535) having any exposure to global surgery. Most participants (n = 1187/1476, 80.4%) wanted additional resources on global surgery. Difficulty in providing appropriate care for patients living abroad (n = 854/1242, 68.8%) was the most common perceived barrier to a career in global surgery. Conclusions Participants believed global surgery was a relevant topic for medical students and wanted additional resources that they could access on global surgery. It is critical for medical students to become aware that global surgery is a field that aims to address inequity in surgical care not just internationally, but nationally and locally as well.

Introduction: Disruption of E-cadherin function and increased expression of vimentin and the transcriptional oncogene, SOX2, are thought to characterize epithelial to mesenchymal transition (EMT) in HNSCC that contributes to invasive and metastatic behavior. To determine if such changes relate to prognosis or host immune response, expression of these markers and correlations with clinical characteristics, histologic worst pattern of invasion (WPOI) and tumor infiltrating lymphocytes (TIL) and survival were assessed. Methods: Immunohistologic expression of markers was determined in tissue microarrays from 274 previously untreated HNSCC patients. Expression was correlated with levels of TILs in microcores and WPOI in biopsy specimens. Correlations were assessed by Kruskal-Wallis testing and Spearman correlation coefficients where appropriate. Overall and relapse-free survival were analyzed with Cox proportional hazards models. Median follow up was 60.0 months. Results: Loss of E-cadherin expression was significantly associated with low or absent SOX2 expression (R=0.433, p<0.0001). SOX2 expression and low grade WPOI were significantly associated with favorable overall (OS) and relapse free (RFS) survival in multivariable analysis. E-cadherin expression did not correlate with TILs, however WPOI score correlated indirectly with CD4, CD8, and FoxP3 levels. When grouped by primary treatment, lower grades (1,2) of WPOI predicted improved RFS and OS in patients treated with primary surgery but not for patients treated with chemoradiation. Conclusion: The findings suggest that SOX2 expression and WPOI are significant prognostic factors and that WPOI correlates with decreased T cell infiltration. The combination of markers and TILs might be useful in selecting patients for primary surgery.

Introduction: Mutation of TP53 is the most common genetic abnormality in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation and expression of p53 protein in tumor cells. Disruptive TP53 mutations are consistently associated with poor prognosis but correlations of p53 expression with mutation or prognosis have been variable and the usefulness of p53 as a target for immunotherapy is unknown. Favorable prognosis is associated with the accumulation of T lymphocytes (TILs) in the tumor microenvironment and an immune response to p53 has been suggested by demonstration of antibodies to p53 and p53-restricted cytotoxic cells in patients with HNSCC. To investigate if p53 expression is related to accumulation of TILs, p53 expression was measured in a prospective cohort of patients with HNSCC and correlations with TILs and prognosis were determined.Methods: Studied were 534 previously untreated patients (n) with oral cavity (273), oropharynx (158), larynx (81) or hypopharynx ( 22) cancers. Expression of p53, p21, and p16 and levels of T cell infiltrates (CD4, CD8, FoxP3) were assessed by immunohistology in tissue microarrays from biopsy specimens. HPV testing by routine pathology was available for 401 patients. Associations with clinical variables were tested using Kruskal-Wallis tests (p53, p21) or Chi-square test (p16). Kaplan-Meier and Cox regression methods were used to evaluate univariable and multivariable associations of protein expression with TIL levels and overall survival (OS) and disease specific survival (DSS) after adjusting for known prognostic factors. Median follow up was 44 months.

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Background: Tumor infiltrating lymphocytes (TILs) have recently emerged as an important factor in informing treatment decisions for head and neck squamous cell carcinoma (HNSCC). Nevertheless, little is known about the role of modifiable risk factors, such as diet, on TILs. Methods: Immunohistologic expression of CD4, CD8, CD68, CD103, CD104 and FOXP3 were assessed in tissue microarrays from 233 previously untreated HNSCC patients. Associations between these markers and pre-treatment dietary patterns were then evaluated using linear regression models. Logistic regression models assessing the associations between baseline serum carotenoids, tocopherols and TILs were conducted on a smaller subset of 70 patients. Cox proportional hazard models were used to evaluate the joint association between diet and TILs on overall and recurrence free survival. Results: High intake of a Western dietary pattern decreased CD8+ and FOXP3+ infiltrates after adjustment for age, sex and batch (p-value: 0.03 and 0.02, respectively). Multivariate logistic regression models demonstrated significant increases in CD8+ (OR: 2.21; p-value: 0.001) and FOXP3+ (OR: 4.26; p-value: &lt;0.0001) among patients with high gamma tocopherol. Conversely, high levels of xanthophylls (OR: 0.12; p-value:&lt;0.0001), lycopene (OR: 0.36; p-value: 0.0001) and total carotenoids (OR: 0.31; p-value: &lt;0.0001) significantly decreased CD68+. Among those with high CD4+ (HR: 1.77; p-value: 0.03), CD68+ (HR: 2.42; p-value: 0.004), CD103+ (HR: 3.64; p-value: 0.03) and FOXP3+ (HR: 3.09; p-value: 0.05) infiltrates, having a high Western dietary pattern significantly increased the risk of overall mortality when compared to those with a low Western dietary pattern, even after adjusting for age, sex, stage, disease site, HPV status, and TMA; a similar effect was found between the high Western dietary pattern and FOXP3+ (HR: 2.93; p-value: 0.0002) on recurrence free survival in fully adjusted models. Conclusion: Dietary patterns and serum carotenoids may play an important role in modifying TILs, and ultimately, outcome after diagnosis with HNSCC. The results of this study could inform dietary interventions among high risk individuals in an attempt to moderate risk and improve HNSCC prognosis. Citation Format: Ilona Argirion, Anna E. Arthur, Katie R. Zarins, Emily Bellile, Lahin Amlani, Jeremy M. Taylor, Greg T. Wolf, Jonathan McHugh, Ariane Nguyen, Alison M. Mondul, Laura S. Rozek, The University of Michigan Head and Neck SPORE Program. Pretreatment diet, serum carotenoids and tocopherols influence tumor immune response in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4644.