Neighborhood-Level Disadvantage and Delayed Adjuvant Therapy in Head and Neck Cancer.

Importance: For patients with head and neck squamous cell carcinoma (HNSCC), initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery is recommended by the National Comprehensive Cancer Network Guidelines and the Commission on Cancer. Although individual-level measures of socioeconomic status are associated with receipt of timely, guideline-adherent PORT, the role of neighborhood-level disadvantage has not been examined. Objective: To characterize the association of neighborhood-level disadvantage with delays in receiving PORT. Design, Setting, and Participants: This retrospective cohort study included 681 adult patients with HNSCC undergoing curative-intent surgery and PORT from 2018 to 2020 at 4 US academic medical centers. The data were analyzed between June 21, 2023, and March 5, 2024. Main Outcome Measures and Measures: The primary outcome was delay in initiating guideline-adherent PORT (ie, >6 weeks after surgery). Time-to-PORT (TTP) was a secondary outcome. Census block-level Area Deprivation Index (ADI) scores were calculated and reported as national percentiles (0-100); higher scores indicate greater deprivation. The association of ADI scores with PORT delay was assessed using multivariable logistic regression adjusted for demographic, clinical, and institutional characteristics. PORT initiation across ADI score population quartiles was evaluated with cumulative incidence plots and Cox models. Results: Among 681 patients with HNSCC undergoing surgery and PORT (mean [SD] age, 61.5 [11.2] years; 487 [71.5%] men, 194 [29.5%] women) the PORT delay rate was 60.8% (414/681) and median (IQR) TTP was 46 (40-56) days. The median (IQR) ADI score was 62.0 (44.0-83.0). Each 25-point increase in ADI score was associated with a corresponding 32% increase in the adjusted odds ratio (aOR) of PORT delay (aOR, 1.32; 95% CI, 1.07-1.63) on multivariable regression adjusted for institution, age, race and ethnicity, insurance, comorbidity, cancer subsite, stage, postoperative complications, care fragmentation, travel distance, and rurality. Increasing ADI score population quartiles were associated with increasing TTP (hazard ratio of PORT initiation, 0.71; 95% CI, 0.53-0.96; 0.59; 95% CI, 0.44-0.77; and 0.54; 95% CI, 0.41-0.72; for ADI quartiles 2, 3, and 4 vs ADI quartile 1, respectively). Conclusions and Relevance: Increasing neighborhood-level disadvantage was independently associated with a greater likelihood of PORT delay and longer TTP in a dose-dependent manner. These findings indicate a critical need for the development of multilevel strategies to improve the equitable delivery of timely, guideline-adherent PORT.

Trends in ototoxicity monitoring among cisplatin-treated patients with cancer.

PURPOSE: This study aims to characterize patterns in ototoxicity monitoring and identify potential barriers to audiologic follow-up. METHODS: We performed a single-institution retrospective cohort study on adult (≥ 18 years old) cancer patients treated with cisplatin from January 2014 to September 2021. Our primary outcomes were rates of baseline and post-treatment audiograms at the following time points: 3, 6, 12, and greater than 12 months. Time-to-event analyses were performed to describe additional insights to ototoxicity monitoring patterns. RESULTS: Nine hundred fifty-five patients with cancer were included for analysis. The most common primary cancer sites were head and neck (64%), followed by cervical (24%). Three hundred seventy-three patients (39%) underwent baseline audiometric assessment, 38 patients (4%) received audiologic evaluation during chemotherapy, and 346 patients (36%) obtained at least one post-treatment audiogram. Audiologic follow-up was greatest within 3 months of completing chemotherapy (26%), but this tapered dramatically to less than 10% at every other post-treatment time point. Patients with head and neck cancer achieved higher rates of audiologic follow-up at every time point than patients with non-head and neck cancer except for during treatment. CONCLUSIONS: Ototoxicity monitoring is an inconsistent practice, particularly during chemotherapy and for long-term surveillance of hearing loss. Patients with non-head and neck cancer may be at increased risk for loss of audiologic follow-up. IMPLICATIONS FOR CANCER SURVIVORS: Cisplatin ototoxicity is a common occurrence that can be effectively managed with auditory rehabilitation. Therefore, referrals to audiology and counseling on treatment-related ototoxicity are recommended throughout chemotherapy and cancer survivorship.

Blocking senescence and tolerogenic function of dendritic cells induced by γδ Treg cells enhances tumor-specific immunity for cancer immunotherapy.

BACKGROUND: Regulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy. METHODS: Senescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence and dysfunction induced by Treg cells. Impaired tumor antigen HER2-specific recognition and immune response of senescent DCs induced by γδ Treg cells were explored in vitro and in vivo in humanized mouse models. In addition, the DC-based HER2 tumor vaccine immunotherapy in breast cancer models was performed to explore the enhanced antitumor immunity via prevention of DC senescence through blockages of STAT3 and programmed death-ligand 1 (PD-L1) signaling. RESULTS: We showed that tumor-derived γδ Treg cells promote the development of senescence in DCs with tolerogenic functions in breast cancer. Senescent DCs induced by γδ Treg cells suppress Th1 and Th17 cell differentiation but promote the development of Treg cells. In addition, we demonstrated that PD-L1 and STAT3 signaling pathways are critical and involved in senescence induction in DCs mediated by tumor-derived γδ Treg cells. Importantly, our complementary in vivo studies further demonstrated that blockages of PD-L1 and/or STAT3 signaling can prevent γδ Treg-induced senescence and reverse tolerogenic functions in DCs, resulting in enhanced HER2 tumor-specific immune responses and immunotherapy efficacy in human breast cancer models. CONCLUSIONS: These studies not only dissect the suppressive mechanism mediated by tumor-derived γδ Treg cells on DCs in the tumor microenvironment but also provide novel strategies to prevent senescence and dysfunction in DCs and enhance antitumor efficacy mediated by tumor-specific T cells for cancer immunotherapy.

Airway protection and outcomes after staged versus concurrent bilateral neck dissections with transoral base of tongue cancer resection.

OBJECTIVES: To assess airway, safety, and resource utilization outcomes between transoral base of tongue (BOT) surgery with staged versus concurrent bilateral neck dissections (BND). METHODS: A retrospective cohort study of patients with human papilloma virus (HPV)-related BOT cancer who underwent transoral surgery and BND from January 2015 through June 2022 was conducted. Free flap patients were excluded. RESULTS: Of 126 patients (46 [37%] staged and 80 [63%] concurrent BND), there were no significant differences in rates of postoperative intubation, tracheostomy, intensive care admission, operative takebacks, gastrostomy, and 30-day readmission. Total operative time (median difference 1.4 [95% CI 0.9-1.8] hours), length of stay (1.0 [1.0-1.0] day), and time between primary surgery and adjuvant therapy initiation (4.0 [0.0-8.0] days) were lower in the concurrent BND cohort. CONCLUSION: Concurrent BND alongside transoral BOT resection is safe with similar airway outcomes and lower total operative time, length of stay, and time to adjuvant therapy initiation compared to staged BND.

Poor Dental Health as a Risk Factor for Alveolar Ridge Malignancies.

OBJECTIVE: To determine the association between poor dental health and risk of oral cavity squamous cell cancer (OCSCC) at individual tumor subsites. STUDY DESIGN: Case-control and cross-sectional METHODS: A case-control study was performed using a population-based cohort in North Carolina (Carolina Head and Neck Cancer Epidemiology Study [CHANCE]). A secondary cross-sectional analysis was performed with an institutional cohort (WashU/Siteman). Cases were adults with primary OCSCC and an identifiable tumor subsite. In the CHANCE cohort, controls were adults without head and neck cancer. In the Washington University/Siteman cohort, patients with tongue cancer served as the comparator group. We used number of missing teeth (categorized 0-6, 7-24, 25-28) as a surrogate for poor dental health, which was self-reported in CHANCE and measured on a pretreatment computed tomography scan in the WashU/Siteman study. Adjusted odds ratios (aORs) for missing teeth were estimated for each tumor subsite using binomial logistic regression models. RESULTS: Near complete tooth loss (25-28 teeth) was associated with a 3.5-fold increased risk of alveolar ridge malignancy (aOR: 3.51; 95% confidence interval [CI]: 1.14-11.01, P = .03) in the CHANCE study. This association was confirmed in our cross-sectional analysis (WashU/Siteman study) where missing 25-28 teeth was associated with an increased risk of alveolar ridge compared to tongue cancer (aOR: 4.60; 95% CI: 1.97-11.10, P = .001). CONCLUSIONS: This study suggests an association between poor dental health and risk of alveolar ridge cancer independent of smoking, alcohol use, age, race, and sex. Future prospective and translational studies are needed to confirm this association and elucidate the mechanism of dental disease in alveolar ridge malignancies.

Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state.

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted.

Delays Starting Postoperative Radiotherapy Among Head and Neck Cancer Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: Initiating postoperative radiotherapy (PORT) within 6 weeks (42 days) of surgery is the first and only Commission on Cancer (CoC) approved quality metric for head and neck squamous cell carcinoma (HNSCC). No study has systematically reviewed nor synthesized the literature to establish national benchmarks for delays in starting PORT. DATA SOURCES: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed a systematic review of PubMed, Scopus, and CINAHL. REVIEW METHODS: Studies that described time-to-PORT or PORT delays in patients with HNSCC treated in the United States after 2003 were included. Meta-analysis of proportions and continuous measures was performed on nonoverlapping datasets to examine the pooled frequency of PORT delays and time-to-PORT. RESULTS: Thirty-six studies were included in the systematic review and 14 in the meta-analysis. Most studies utilized single-institution (n = 17; 47.2%) or cancer registry (n = 16; 44.4%) data. Twenty-five studies (69.4%) defined PORT delay as >6 weeks after surgery (the definition utilized by the CoC and National Comprehensive Cancer Network Guidelines), whereas 4 (11.1%) defined PORT delay as a time interval other than >6 weeks, and 7 (19.4%) characterized time-to-PORT without defining delay. Meta-analysis revealed that 48.6% (95% confidence interval [CI], 41.4-55.9) of patients started PORT > 6 weeks after surgery. Median and mean time-to-PORT were 45.8 (95% CI, 42.4-51.4 days) and 47.4 days (95% CI, 43.4-51.4 days), respectively. CONCLUSION: Delays in initiating guideline-adherent PORT occur in approximately half of patients with HNSCC. These meta-analytic data can be used to set national benchmarks and assess progress in reducing delays.

Patient Navigation for Timely, Guideline-Adherent Adjuvant Therapy for Head and Neck Cancer: A National Landscape Analysis.

BACKGROUND: Aligned with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers, in November 2021 the Commission on Cancer approved initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery for head and neck cancer (HNC) as its first and only HNC quality metric. Unfortunately, >50% of patients do not commence PORT within 6 weeks, and delays disproportionately burden racial and ethnic minority groups. Although patient navigation (PN) is a potential strategy to improve the delivery of timely, equitable, guideline-adherent PORT, the national landscape of PN for this aspect of care is unknown. MATERIALS AND METHODS: From September through November 2022, we conducted a survey of health care organizations that participate in the American Cancer Society National Navigation Roundtable to understand the scope of PN for delivering timely, guideline-adherent PORT for patients with HNC. RESULTS: Of the 94 institutions that completed the survey, 89.4% (n=84) reported that at least part of their practice was dedicated to navigating patients with HNC. Sixty-eight percent of the institutions who reported navigating patients with HNC along the continuum (56/83) reported helping them begin PORT. One-third of HNC navigators (32.5%; 27/83) reported tracking the metric for time-to-PORT at their facility. When estimating the timeframe in which the NCCN and Commission on Cancer guidelines recommend commencing PORT, 44.0% (37/84) of HNC navigators correctly stated ≤6 weeks; 71.4% (60/84) reported that they did not know the frequency of delays starting PORT among patients with HNC nationally, and 63.1% (53/84) did not know the frequency of delays at their institution. CONCLUSIONS: In this national landscape survey, we identified that PN is already widely used in clinical practice to help patients with HNC start timely, guideline-adherent PORT. To enhance and scale PN within this area and improve the quality and equity of HNC care delivery, organizations could focus on providing better education and support for their navigators as well as specialization in HNC.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Free Flap Outcomes for Head and Neck Surgery in Patients with COVID-19.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) affects the vascular system, subjecting patients to a hypercoagulable state. This is of particular concern for the success of microvascular free flap reconstruction. This study aims to report head and neck free flap complications in patients with COVID-19 during the perioperative period. We believe these patients are more likely to experience flap complications given the hypercoagulable state. METHODS: This is a multi-institutional retrospective case series of patients infected with COVID-19 during the perioperative period for head and neck free flap reconstruction from March 2020 to January 2022. RESULTS: Data was collected on 40 patients from 14 institutions. Twenty-one patients (52.5%) had a positive COVID-19 test within 10 days before surgery and 7 days after surgery. The remaining patients had a positive test earlier than 10 days before surgery. A positive test caused a delay in surgery for 16 patients (40.0%) with an average delay of 44.7 days (9-198 days). Two free flap complications (5.0%) occurred with no free flap deaths. Four patients (10.0%) had surgical complications and 10 patients had medical complications (25.0%). Five patients (12.5%) suffered from postoperative COVID-19 pneumonia. Three deaths were COVID-19-related and one from cancer recurrence during the study period. CONCLUSION: Despite the heightened risk of coagulopathy in COVID-19 patients, head and neck free flap reconstructions in patients with COVID-19 are not at higher risk for free flap complications. However, these patients are at increased risk of medical complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 2023.

Neighborhood socioeconomic status and race are associated with incidence disparities in oral cavity cancers.

OBJECTIVES: To determine the association between neighborhood socioeconomic status (nSES), race and incidence rate trends of oral cavity cancer (OCC). MATERIALS AND METHODS: We used data from the SEER (Surveillance, Epidemiology, and End Results) 18 Census Tract-level SES and Rurality Database (2006-2018) database of the National Cancer Institute to create cohorts of OCC patients between 2006 and 2018. Annual incidence rates were calculated and trends in rates were estimated using joinpoints regression. RESULTS: The incidence of OCC is the highest among low nSES White Americans (2.86 per 100 000 persons) and the lowest among high nSES Black Americans (1.17 per 100 000 persons). Incidence has significantly increased among Asian Americans (annual percent change [APC]: low nSES-2.4, high nSES-2.6) and White Americans (APC: low nSES-1.4, high nSES-1.6). Significant increases in the incidence of oral tongue cancer in these groups primarily drive this increase. Other increases were noted in alveolar ridge cancer among White Americans and hard palate cancer among Asian Americans. OCC incidence decreased significantly in Hispanic Americans of high nSES (APC: -2.5) and Black Americans of low nSES (APC: -2.7). Floor of mouth cancer incidence decreased among most groups. CONCLUSION: Despite the overall decreasing incidence of OCC, these trends are inconsistent among all OCC subsites. Differences are seen by race, nSES, and subsite, indicating intersectional barriers that extend beyond nSES and race and ethnicity alone. Further research on risk factors and developing interventions targeting vulnerable groups is needed.

Immune Cell Deconvolution Reveals Possible Association of γδ T Cells with Poor Survival in Head and Neck Squamous Cell Carcinoma.

(1) Background: The role of rare immune cell subtypes in many solid tumors, chief among them head and neck squamous cell carcinoma (HNSCC), has not been well defined. The objective of this study was to assess the association between proportions of common and rare immune cell subtypes and survival outcomes in HNSCC. (2) Methods: In this cohort study, we utilized a deconvolution approach based on the CIBERSORT algorithm and the LM22 signature matrix to infer proportions of immune cell subtypes from 517 patients with untreated HPV-negative HNSCC from The Cancer Genome Atlas. We performed univariate and multivariable survival analysis, integrating immune cell proportions with clinical, pathologic, and genomic data. (3) Results: We reliably deconvolved 22 immune cell subtypes in most patients and found that the most common immune cell types were M0 macrophages, M2 macrophages, and memory resting CD4 T cells. In the multivariable analysis, we identified advanced N stage and the presence of γδ T cells as independently predictive of poorer survival. (4) Conclusions: We uncovered that γδ T cells in the tumor microenvironment were a negative predictor of survival among patients with untreated HNSCC. Our findings underscore the need to better understand the role of γδ T cells in HNSCC, including potential pro-tumorigenic mechanisms, and whether their presence may predict the need for alternative therapy approaches.

Functional considerations between flap and non-flap reconstruction in oral tongue cancer: A systematic review.

This systematic review aims to provide insight into the ideal reconstructive approach of the oral tongue in oral tongue cancer (OTC) by investigating the relationship between functional outcomes and the extent of tongue resection. A structured search was performed in Ovid MEDLINE, EMBASE, and Web of Science. Studies comparing patient-reported and objective measurements of the oral tongue function between flap vs. non-flap reconstruction were included. Functional outcomes of interest were speech production, deglutition efficiency, tongue mobility, overall quality of life, and postoperative complications. A total of nine studies were retrieved and critically appraised. Patients with 20 % or less of oral tongue resected had superior swallowing efficiency and speech intelligibility with a non-flap reconstruction while patients with a tongue defect of 40-50 % self-reported or demonstrated better swallowing function with a flap repair. The data in intermediate tongue defects (20-40 % tongue resected) was inconclusive, with several studies reporting comparable functional outcomes between approaches. A longitudinal multi-institutional prospective study that rigidly controls the extent of tongue resected and subsites involved is needed to determine the percentage of tongue resected at which a flap reconstruction yields a superior functional result in OTC.

Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Targeted Proteomic Quantitation of NRF2 Signaling and Predictive Biomarkers in HNSCC.

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min.

Acute Taste Dysfunction in Oropharyngeal Cancer Patients after Transoral Robotic Surgery.

OBJECTIVES: To compare taste changes after transoral robotic surgery (TORS) to taste changes in healthy controls. METHODS: Oropharyngeal cancer patients receiving TORS and healthy controls were recruited. Participants underwent posterolateral and whole-mouth psychophysical taste testing (identification, intensity, and hedonics) at baseline and at 2 weeks postoperatively (patients) or follow-up (controls). Surgeons reported suspension time and glossopharyngeal nerve injury (GNI) based on the identification and sacrifice of the nerve. A Clinical Global Impression (CGI) of taste symptoms was completed at each session ("My sense of taste bothers me" on a 5-point scale from Never [1] to Always [5]). A taste disorder (TD) was a CGI of 3 (Sometimes) or worse. Within-subject changes in CGI and psychophysical scores were computed. "Worsened taste" was a CGI increase by ≥1 point at follow-up. RESULTS: Of 69 participants, most (33/37 tumor, 31/32 controls) had normal baseline taste (CGI < 3). 14/33 (42%) TORS patients and no controls developed new TDs at follow-up. More smokers (7/9) had worsened taste than nonsmokers (19/60, difference = 46% [95% CI 16%-76%]). More patients without GNI (6/22) than with GNI (0/15) had postoperative phantogeusia (difference = 27% [95% CI 9-45%]). Tumor-ipsilateral taste identification (TI) decreased more in patients (-11.3%) than controls (0.8%, difference = 12.2% [95% CI 5.0-19.3%]). Suspension time was not associated with worsened taste symptoms or psychophysical changes. CONCLUSIONS: Patient-reported taste changes after TORS are frequent. Compared to healthy controls, TORS patients have decreased tumor-ipsilateral TI. Suspension time and GNI are unlikely to cause symptomatic TDs. Further investigations of the etiology and long-term symptom burden of TORS-associated TDs will aid in the management of oropharyngeal cancer patients. LEVEL OF EVIDENCE: 3 (non-randomized controlled cohort study) Laryngoscope, 133:3520-3528, 2023.

Memory-like Differentiation, Tumor-Targeting mAbs, and Chimeric Antigen Receptors Enhance Natural Killer Cell Responses to Head and Neck Cancer.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy-refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC. EXPERIMENTAL DESIGN: We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells. RESULTS: Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets. CONCLUSIONS: These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.

Epigenetic regulation of hybrid epithelial-mesenchymal cell states in cancer.

Epithelial-to-mesenchymal transition (EMT) is a process by which cells lose their epithelial characteristics and gain mesenchymal phenotypes. In cancer, EMT is thought to drive tumor invasion and metastasis. Recent efforts to understand EMT biology have uncovered that cells undergoing EMT attain a spectrum of intermediate "hybrid E/M" states, which exist along an epithelial-mesenchymal continuum. Here, we summarize recent studies characterizing the epigenetic drivers of hybrid E/M states. We focus on the histone-modification writers, erasers, and readers that assist or oppose the canonical hybrid E/M transcription factors that modulate hybrid E/M state transitions. We also examine the role of chromatin remodelers and DNA methylation in hybrid E/M states. Finally, we highlight the challenges of targeting hybrid E/M pharmacologically, and we propose future directions that might reveal the specific and targetable mechanisms by which hybrid E/M drives metastasis in patients.

Margins in Stage I and II Oral Cavity Squamous Cell Carcinoma: A Review From the American Head and Neck Society.

Importance: The assessment and management of surgical margins in stage I and II oral cavity squamous cell carcinoma is one of the most important perioperative aspects of oncologic care, with profound implications for patient outcomes and adjuvant therapy. Understanding and critically reviewing the existing data surrounding margins in this context is necessary to rigorously care for this challenging group of patients and minimize patient morbidity and mortality. Observations: This review discusses the data related to the definitions related to surgical margins, methods for assessment, specimen vs tumor bed margin evaluation, and re-resection of positive margins. The observations presented emphasize notable controversy within the field about margin assessment, with early data coalescing around several key aspects of management, although studies are limited by their design. Conclusions and Relevance: Stage I and II oral cavity cancer requires surgical resection with negative margins to obtain optimal oncologic outcomes, but controversy persists over margin assessment. Future studies with improved, well-controlled study designs are required to more definitively guide margin assessment and management.