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ObjectivesTo explore lymphocyte infiltration as a potential mechanism behind CXCL14-mediated tumor growth suppression in oral cavity squamous cell carcinoma (OSCC).MethodsWe analyzed single cell RNA-sequencing (scRNA-seq) data from OSCC to identify expression changes among malignant cells in lymph nodes (LN) versus primary tumors. CXCL14 expression in murine OSCC cell lines was quantified using qRT-PCR. Short hairpin RNA knockdown of CXCL14 was performed in mouse oral cavity (MOC)1 cells, and CXCL14 overexpression was performed in MOC2 cells. Cells in each condition were injected into C57BL/6 mice with and without T cell depletion, and tumor volume was measured. At 30 days, tumors were dissociated and analyzed by flow cytometry for CD45+CD3+ T cells. CXCL14 expression was correlated with gene expression signatures of tumor infiltrating lymphocytes (TIL) in scRNA-seq data, as well as TCGA tumors.ResultsscRNA-seq revealed CXCL14 as the most significantly downregulated gene among malignant cells in LNs relative to primary tumor, supporting a role in preventing invasion and/or metastasis. In a murine immunocompetent model, CXCL14 expression was higher in indolent MOC1 cells than in more aggressive MOC2 cells. Tumor growth in vivo was significantly increased by CXCL14 knockdown in MOC1 cells relative to control, with a corresponding decrease in TIL. In MOC2 cells, tumor growth was significantly reduced by CXCL14 overexpression relative to control and TIL were increased. Both effects were lost with T cell depletion. In a human tumor scRNA-seq cohort, we found that only malignant cell CXCL14, but not non-malignant cell or fibroblast CXCL14, was associated with TIL. Bulk CXCL14 from the TCGA cohort had no association with TIL.ConclusionsHigher CXCL14 expression by tumor cells is associated with reduced tumor growth and increased TIL, supporting immune-mediated suppression of tumor growth in OSCC. Given that CXCL14 is downregulated in LN metastases compared with primary tumors, our data raise the possibility that CXCL14-mediated immune infiltration may discourage invasion and metastasis. In human scRNA-seq data, only malignant cell-specific CXCL14 was associated with TIL, suggesting a critical context-dependent effect of CXCL14 expression.

Objectives The submental island flap can be used to reconstruct defects of the oral cavity and oropharynx. The objective of this study is to describe functional outcomes after this reconstruction. Methods Retrospective chart review was performed for 82 patients who underwent submental flap reconstruction of oral cavity cancer defects and 11 with oropharyngeal cancer defects. Primary outcomes were feeding tube use at last follow‐up and time from surgery to first oral intake. The secondary outcome was the need for tracheostomy. Results Feeding tube use at last follow‐up was 9% in the oral cavity group and 36% in the oropharynx group. Median time to oral intake was 7 days in both groups. Tracheostomy was avoided in 87% of oral cavity patients and in 46% of oropharynx patients. In regression analysis of the entire cohort, the outcomes of persistent feeding tube use at last follow‐up and tracheostomy were associated with the following variables: prior irradiation, oropharyngeal primary site, and adjuvant treatment status. Among the oral cavity group, prior irradiation was associated with persistent feeding tube use. Conclusion The submental flap can be used in a wide range of oral cavity and oropharyngeal defects, even in elderly patients. This flap can be performed for oral cancers with avoidance of tracheostomy in most cases and reliable resumption of oral diet. Level of Evidence 4

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a rare tumor that morphologically resembles high-grade adenoid cystic carcinoma (ACC) but exhibits indolent clinical behavior. Both demonstrate MYB proto-oncogene upregulation, though HMSC lacks the MYB translocation characteristic of ACC. We performed single-cell RNA sequencing on an HMSC tumor and compared expression patterns with published ACC and oropharyngeal squamous cell carcinoma (OPSCC) datasets. Malignant HMSC cells clustered separately from ACC and lacked bicellular luminal and myoepithelial differentiation. A greater proportion of HMSC cells expressing HPV-related genes (HPVon) expressed MYB (83% vs. 62%, p = 0.022) and MYB targets (p = 6.4 × 10 −6 ), supporting an HPV-MYB association. Validation in HPV + OPSCC revealed MYB upregulation in HPVon cells from 7/10 tumors (p < 0.05). A 264-gene signature from HPVon HMSC cells correlated with worse prognosis in HPV + OPSCC (p < 0.003), suggesting an alternate role for HPV. Further validation of the HPV-MYB association and gene signature may improve therapeutic strategies in HPV-related malignancies.

Background There is a rare need for postoperative non‐invasive positive pressure ventilation (NIPPV) following microvascular reconstruction of the head and neck. In midface reconstruction, the free flap vascular pedicle is especially vulnerable to the compressive forces of positive pressure delivery. Case A 60 year old female with Amyotrophic Lateral Sclerosis (ALS) presented with squamous cell carcinoma of the anterior maxilla, for which she underwent infrastructure maxillectomy and fibula free flap reconstruction. To avoid tracheotomy, the patient was extubated postoperatively and transitioned to NIPPV immediately utilizing a full‐face positive pressure mask with a soft and flexible sealing layer. The patient was successfully transitioned to NIPPV immediately after extubation. The free flap exhibited no signs of vascular compromise postoperatively, and healed very well. Conclusion Postoperative non‐invasive positive pressure ventilation can be successfully applied following complex microvascular midface reconstruction to avoid tracheotomy in select patients without vascular compromise of the free flap.

Objectives To describe a 10‐year single center experience with parotid gland malignancies and to determine factors affecting outcomes. Study Design Retrospective review. Methods The institutional cancer registry was used to identify patients treated surgically for malignancies of the parotid gland between January 2005 and December 2014. Clinical and pathologic data were collected retrospectively from patient charts and analyzed for their association with overall survival (OS) and disease‐free survival (DFS). Results Two hundred patients were identified. Mean age at surgery was 57.8 years, and mean follow‐up time was 52 months. One hundred two patients underwent total parotidectomy, while 77 underwent superficial parotidectomy, and 21 underwent deep lobe resection. Seventy patients (35%) required facial nerve (FN) sacrifice. Acinic cell carcinoma was the most common histologic type (22%), followed by mucoepidermoid carcinoma (21.5%) and adenoid cystic carcinoma (12.5%). Twenty‐nine patients (14.5%) experienced recurrences, with mean time to recurrence of 23.6 months (range: 1‐82 months). Five‐ and 10‐year OS were 81% and 73%, respectively. Five‐ and 10‐year DFS were 80% and 73%, respectively. In univariate analyses, age > 60, histologic type, positive margins, high grade, T‐stage, node positivity, perineural invasion, and FN involvement were predictors of OS and DFS. In the multivariate analysis, histology, positive margins, node positivity, and FN involvement were independent predictors of OS and DFS. Conclusions Our single‐center experience of 200 patients suggests that histology, positive margins, node positivity, and FN involvement are independently associated with outcomes in parotid malignancies. Level of Evidence 4

Analysis of premalignant tissue has identified the typical order of somatic events leading to invasive tumors in several cancer types. For other cancers, premalignant tissue is unobtainable, leaving genetic progression unknown. Here, we demonstrate how to infer progression from exome sequencing of primary tumors. Our computational method, PhylogicNDT, recapitulated the previous experimentally determined genetic progression of human papillomavirus-negative (HPV – ) head and neck squamous cell carcinoma (HNSCC). We then evaluated HPV + HNSCC, which lacks premalignant tissue, and uncovered its previously unknown progression, identifying early drivers. We converted relative timing estimates of driver mutations and HPV integration to years before diagnosis based on a clock-like mutational signature. We associated the timing of transitions to aneuploidy with increased intratumor genetic heterogeneity and shorter overall survival. Our approach can establish previously unknown early genetic progression of cancers with unobtainable premalignant tissue, supporting development of experimental models and methods for early detection, interception and prognostication.

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic–polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1hi TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8+ T cells. Overall, the CD8+/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).

A 78-year-old woman with rheumatoid arthritis was admitted to the Massachusetts Eye and Ear Infirmary because of pain in the right side of the throat, odynophagia, and a tonsillar mass. A diagnostic procedure was performed. Presentation of Case Dr. Pritha Sen (Medicine): A 78-year-old woman with diabetes mellitus and rheumatoid arthritis was admitted to Massachusetts Eye and Ear Infirmary because of pain in the right side of the throat, odynophagia, and a right tonsillar mass. The patient had been in her usual health until approximately 7 weeks before this presentation, when pain developed in the right posterior region of her throat, which she attributed to recent dental work. Two weeks later, she went to another hospital because of persistent pain; a throat specimen was obtained for culture and amoxicillin–clavulanate was prescribed. The throat culture was . . .

Objective The need for intensive care unit (ICU) admission and mechanical ventilation after head and neck microvascular free flap reconstructive surgery remains controversial. Our institution has maintained a longstanding practice of immediately taking patients off mechanical ventilation with subsequent transfer to intermediate, non‐ICU level of care with specialized otolaryngologic nursing. Our objective was to describe postoperative outcomes for a large cohort of patients undergoing this protocol and to examine the need for routine ICU transfer. Materials and Methods We performed a retrospective review of 512 consecutive free flaps treated with a standard protocol of immediate postoperative transfer to an intermediate‐level care unit with specialized otolaryngology nursing. Outcome measures included ICU transfer, ventilator requirement, flap failure, postoperative complications, and length of stay. Predictors of ICU transfer were identified by multivariable logistic regression. Results The vast majority of patients did not require intensive care. Only a small fraction (n = 18 patients, 3.5%) subsequently transferred to the ICU, most commonly for respiratory distress, cardiac events, and infection. The most common complications were delirium/agitation (n = 55; 10.7%) and pneumonia (n = 51; 10.0%). Sixty‐five cases (12.7%) returned to the OR, most commonly for hematoma/bleeding (n = 41; 8.0%) and anastomosis revision (n = 20; 3.9%). Heavy alcohol consumption and greater number of medical comorbidities were significant predictors of subsequent ICU transfer. Conclusions Among head and neck free flap patients, routine cessation of mechanical ventilation and transfer to intermediate‐level care with specialized ENT nursing was found to be safe with infrequent subsequent ICU transfer and low complication rates. Routine transfer to intermediate‐level care in this population may prevent unnecessary ICU utilization and facilitate the delivery of high‐value, disease‐centered care. Level of Evidence 3b

Adenoid cystic carcinoma of the minor salivary glands can be challenging and marked by high rates of local recurrence despite appropriate surgical resection. Management of this pathology in the base of the tongue is particularly difficult given the poor functional outcomes traditionally associated with an aggressive surgical approach. This article presents a case series of patients who underwent up-front surgical resection followed by free tissue transfer reconstruction. A retrospective analysis was performed of patients with adenoid cystic carcinoma of the base of the tongue who underwent composite resection and reconstruction with a radial forearm free flap. Three patients met inclusion criteria and underwent analysis. All patients achieved locoregional control after at least 4 years of surveillance. In addition, all patients were decannulated and were swallowing without the need for gastrostomy tube feeding. This series demonstrates that for select patients with adenoid cystic carcinoma of the base of the tongue, excellent locoregional control can be achieved with acceptable functional outcomes and prolonged survival when appropriate reconstructive measures are employed.