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T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, we assessed samples for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18-86 years old, approximately half of whom were considered at high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4+ and CD8+ T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4+ T cell and CD8+ T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4+ and CD8+ T cells during acute COVID-19.

ObjectivesA subset of laryngeal squamous cell carcinoma (LSCC) patients undergoing larynx preserving treatment ultimately require total laryngectomy (TL) for oncologic or functional reasons. This study aims to identify TL risk factors in these patients.MethodsRetrospective cohort study using Veterans Affairs (VA) database. T1-T4 LSCC cases treated with primary radiotherapy (XRT) or chemoradiotherapy (CRT) were assessed for TL and recurrence. Binary logistic and Cox regression and Kaplan-Meier analyses were implemented.ResultsOf 5390 cases, 863 (16.0%) underwent TL. On multivariable analysis, age (adjusted odds ratio: 0.97 [0.96-0.98]; p T1 disease (T2, 1.76 [1.44-2.17]; p

ObjectivesMost transoral robotic surgery (TORS) literature for HPV-positive oropharyngeal squamous cell carcinoma (HPV-OPC) derives from high-volume tertiary-care centers. This study aims to describe long-term recurrence and survival outcomes among Veterans Health Administration patients.Materials and methodsUsing the US Veterans Affairs database, we identified patients with HPV-OPC treated with TORS between January 2010 and December 2016. Patients were stratified in risk categories: low (0-1 metastatic nodes, negative margins), intermediate (close margins, 2-4 metastatic nodes, lymphovascular or perineural invasion, pT3-pT4 tumor), or high (positive margins, extranodal extension (ENE), and/or ≥5 metastatic nodes). Primary outcomes included overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS).ResultsThe cohort included 161 patients of which 29 (18%) were low-risk, 45 (28%) intermediate-risk, and 87 (54%) high-risk. ENE was present in 41% of node-positive cases and 24% had positive margins. Median follow-up was 5.6 years (95% CI, 3.0-9.3). The 5-year DSS for low, intermediate, and high-risk groups were: 100%, 90.0% (95% CI, 75.4-96.1%), and 88.7% (95% CI, 78.3-94.2%). Pathologic features associated with poor DSS on univariable analysis included pT3-T4 tumors (HR 3.81, 95% CI, 1.31-11; p = 0.01), ≥5 metastatic nodes (HR 3.41, 95% CI, 1.20-11; p = 0.02), and ENE (HR 3.53, 95% CI, 1.06-12; p = 0.04). Higher 5-year cumulative incidences of recurrence were observed in more advanced tumors (pT3-T4, 33% [95% CI, 14-54%] versus pT1-T2, 13% [95% CI, 8-19%]; p = 0.01).ConclusionsIn this nationwide study, patients with HPV-OPC treated with TORS followed by adjuvant therapy at Veterans Affairs Medical Centers demonstrated favorable survival outcomes comparable to those reported in high-volume academic centers and clinical trials.Level of evidence4 Laryngoscope, 134:207-214, 2024.

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

OBJECTIVES: This study aimed to evaluate the outcomes of a hands-on simulation-based course with emphasis on procedural techniques, clinical reasoning, and communication skills developed to improve junior Otolaryngology - Head and Neck Surgery (OHNS) residents preparedness in managing otolaryngologic emergencies. METHODS: Junior OHNS residents and faculty from residency programs in California, Nevada, and Arizona participated in this workshop in 2020 and 2021. The stations featured airway management techniques, ultrasound-guided needle aspiration, nasoseptal hematoma evacuation, and facial fracture repair using various models and cadavers. Participants completed a pre-workshop survey, post-workshop survey, and 2-month follow-up survey that assessed resident anxiety and confidence in three OHNS emergency situations across knowledge, manual skills, and teamwork using a 5-point Likert scale. RESULTS: Pre-workshop surveys reported the least anxiety and most confidence in teamwork, but the most anxiety and least confidence in technical skills and knowledge related to foreign body retrieval and airway management. Immediately post-workshop participants reported significant reductions in anxiety and increases in confidence, largest in the manual skills domain, in foreign body retrieval (anxiety: -0.99, confidence: +0.95, p

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, β1AR and β2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs-DREADD to activate CD8-restricted Gαs signaling and show that a Gαs-PKA signaling axis promotes CD8+ T cell dysfunction and immunotherapy failure. These data indicate that Gαs-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.

Despite the widespread use of SARS-CoV-2-specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2-specific T cell responses has been unknown, resulting in uncertainty as to whether anti-SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2-specific mAb may enhance adaptive immunity to SARS-CoV-2 via a "vaccinal effect." Bamlanivimab (Eli Lilly and Company) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2-specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with bamlanivimab versus placebo. SARS-CoV-2-specific T cell responses were evaluated using activation-induced marker assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 developed SARS-CoV-2-specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2-specific T cell memory were not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2-specific cellular immunity.

Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphatics and develop models for regional lymphablation with surgery or radiation. We find that lymphablation eliminates the tumor ICI response, worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observe an upregulation of conventional type I dendritic cells and type I interferon signaling and show that both are necessary for the ICI response and lost with lymphablation. Ultimately, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational, lymphatic-preserving treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, control regional metastatic disease, and confer durable antitumor immunity.

Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of HNSCC patients respond to recently approved immune checkpoint inhibitors. The Hippo signaling pathway, originally discovered as a mechanism regulating tissue growth and organ size, transduces intracellular and extracellular signals to regulate the transcriptional co-activators YAP and TAZ. Alterations in the Hippo pathway resulting in persistent YAP and TAZ activation have emerged as major oncogenic drivers. Our analysis of the human HNSCC oncogenome revealed multiple genomic alterations impairing Hippo signaling and activating YAP and TAZ, which in turn contribute to HNSCC development. This includes mutations and deletions of the FAT1 gene (29%) and amplification of the WWTR1 (encoding TAZ, 14%) and YAP1 genes (8%), together representing one of the most genetically altered signaling mechanisms in this malignancy. Here, we discuss key elements of the mammalian Hippo pathway, detail mechanisms by which perturbations in Hippo signaling promote HNSCC initiation and progression and outline emerging strategies to target Hippo signaling vulnerabilities as part of novel multimodal precision therapies for HNSCC.

ObjectiveThe purpose of this study was to evaluate the utility of ICD-O-3-classified local tumor behavior as a prognosticator of head and neck paraganglioma (HNP) outcomes.Study designRetrospective cohort study.SettingNational Cancer Database between 2004 and 2016.MethodsThis study included patients aged ≥18 years who were diagnosed with HNP. Clinical outcomes and clinicopathologic features were compared with regard to local tumor behavior.ResultsOur study included 525 patients, of which the majority had HNP classified as locally invasive (45.9%) or borderline (37.9%). The most common anatomic sites involved were the carotid body (33.7%), intracranial regions (29.0%), or cranial nerves (25.5%). Carotid body tumors were exclusively locally invasive, whereas intracranial and cranial nerve HNP were overwhelmingly benign or borderline (94% and 91%, respectively). One-fourth of patients underwent pathologic analysis of regional lymph nodes, of which the majority were positive for metastasis (80.6%). Metastasis to distant organs was twice as common in patients with locally invasive tumors vs benign (15% vs 7.1). For benign disease, surgery with radiotherapy (adjusted hazard ratio [aHR], 40.45; P = .006) and active surveillance (aHR, 24.23; P = .008) were associated with worse survival when compared with surgery alone. For locally invasive tumors, greater age (aHR, 1.07; P < .0001) and positive surgical margins (aHR, 4.13; P = .010) were predictors of worse survival, while combined surgery and radiotherapy were predictors of improved survival vs surgery alone (aHR, 0.31; P = .027).ConclusionWhile criteria for tumor behavior could not be defined, our results suggest that such a classification system could be used to enhance HNP risk stratification and guide clinical management decisions.

In a preregistered, cross-sectional study, we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n = 4148) or negative (C19-; n = 546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean ± SD, C19+: -82.5 ± 27.2 points; C19-: -59.8 ± 37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC = 0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4 < OR < 10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable.

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± standard deviation), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.

BackgroundRapid spread of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and concern for viral transmission by ambulatory patients with minimal to no symptoms underline the importance of identifying early or subclinical symptoms of coronavirus disease 2019 (COVID-19) infection. Two such candidate symptoms include anecdotally reported loss of smell and taste. Understanding the timing and association of smell/taste loss in COVID-19 may help facilitate screening and early isolation of cases.MethodsA single-institution, cross-sectional study evaluating patient-reported symptoms with a focus on smell and taste was conducted using an internet-based platform on adult subjects who underwent testing for COVID-19. Logistic regression was employed to identify symptoms associated with COVID-19 positivity.ResultsA total of 1480 patients with influenza-like symptoms underwent COVID-19 testing between March 3, 2020, and March 29, 2020. Our study captured 59 of 102 (58%) COVID-19-positive patients and 203 of 1378 (15%) COVID-19-negative patients. Smell and taste loss were reported in 68% (40/59) and 71% (42/59) of COVID-19-positive subjects, respectively, compared to 16% (33/203) and 17% (35/203) of COVID-19-negative patients (p < 0.001). Smell and taste impairment were independently and strongly associated with COVID-19 positivity (anosmia: adjusted odds ratio [aOR] 10.9; 95% CI, 5.08-23.5; ageusia: aOR 10.2; 95% CI, 4.74-22.1), whereas sore throat was associated with COVID-19 negativity (aOR 0.23; 95% CI, 0.11-0.50). Of patients who reported COVID-19-associated loss of smell, 74% (28/38) reported resolution of anosmia with clinical resolution of illness.ConclusionIn ambulatory individuals with influenza-like symptoms, chemosensory dysfunction was strongly associated with COVID-19 infection and should be considered when screening symptoms. Most will recover chemosensory function within weeks, paralleling resolution of other disease-related symptoms.

BackgroundRapid spread of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus has left many health systems around the world overwhelmed, forcing triaging of scarce medical resources. Identifying indicators of hospital admission for coronavirus disease 2019 (COVID-19) patients early in the disease course could aid the efficient allocation of medical interventions. Self-reported olfactory impairment has recently been recognized as a hallmark of COVID-19 and may be an important predictor of clinical outcome.MethodsA retrospective review of all patients presenting to a San Diego Hospital system with laboratory-confirmed positive COVID-19 infection was conducted with evaluation of olfactory and gustatory function and clinical disease course. Univariable and multivariable logistic regression were performed to identify risk factors for hospital admission and anosmia.ResultsA total of 169 patients tested positive for COVID-19 disease between March 3 and April 8, 2020. Olfactory and gustatory data were obtained for 128 (75.7%) of 169 subjects, of which 26 (20.1%) of 128 required hospitalization. Admission for COVID-19 was associated with intact sense of smell and taste, increased age, diabetes, and subjective and objective parameters associated with respiratory failure. On adjusted analysis, anosmia was strongly and independently associated with outpatient care (adjusted odds ratio [aOR] 0.09; 95% CI, 0.01-0.74), whereas positive findings of pulmonary infiltrates and/or pleural effusion on chest radiograph (aOR 8.01; 95% CI, 1.12-57.49) was strongly and independently associated with admission.ConclusionNormosmia is an independent predictor of admission in COVID-19 cases. Smell loss in COVID-19 may be associated with a milder clinical course.

ObjectiveThe use of standing electronic scooters associated with micromobility applications (e-scooters) has risen nationally. The aim of this study was to obtain a detailed view of soft tissue and bony craniofacial injury associated with e-scooter-related trauma.MethodsSingle-institution retrospective case series of patients presenting to a level 1 trauma center emergency department or trauma unit with documented e-scooter-related craniofacial injury.ResultsOf 203 included patients, 188 (92.6%) patients sustained craniofacial injury. One hundred thirty-one (64.5%) had exclusively soft tissue injury, 3 (1.5%) exclusively bony injury, 51 (25.1%) both soft and bony injuries, and twenty-five (12.3%) patients sustained dental injury. Aesthetic units most frequently sustaining acute soft tissue injury were the forehead (n = 106, 34.6%), scalp (n = 36, 11.8%), chin (n = 34, 11.1%), upper lip (n = 32, 10.5%), and cheek (n = 31, 10.1%). Aesthetic subunits most often sustaining acute soft tissue injury included the brow (42, 13.7%), central forehead (39, 12.7%), lateral forehead (n = 25, 8.2%), and upper lip vermillion (n = 23, 7.5%). Craniofacial osseous fracture most often occurred in the orbit (n = 42, 24.6%) and maxilla (n = 40, 23.4%). Individual osseous segments most frequently sustaining acute fracture included the anterior maxillary sinus wall (n = 22, 12.9%), nasal bone (n = 20, 11.7%), lateral orbital wall (n = 16, 9.4%), orbital floor (n = 15, 8.8%), and zygomatic bone (13, 7.6%).ConclusionsOur analysis demonstrates that most patients presenting to our center with craniofacial trauma sustained acute bony fracture, most often to the midface. Our data of common injuries associated with e-scooter trauma could inform implementation in the form of facial safety equipment or safety skills training for e-scooter riders.Level of evidence4.