Elective Neck Dissection in cT1-4 N0M0 Head and Neck Basaloid Carcinoma.

OBJECTIVE: To investigate the survival benefit of elective neck dissection (END) over neck observation in surgically resected cT1-4 N0M0 head and neck basaloid carcinoma (HNBC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2006 to 2017 hospital-based National Cancer Database. METHODS: Patients with surgically resected cT1-4 N0M0 HNBC were selected. Linear, binary logistic, Kaplan-Meier, and Cox proportional hazards regression models were implemented. RESULTS: Of 857 patients satisfying inclusion criteria, the majority were male (77.0%) and white (88.1%) with disease of the oral cavity (21.5%) or oropharynx (42.9%) classified as high grade (76.9%) and cT1-2 (72.9%). 389 (45.4%) patients underwent END. END utilization between 2006 and 2017 increased for cT1-2 disease (33.3% vs 56.9%, R2 = .699) but remained relatively constant for cT3-4 disease (66.7% vs 57.9%, R2 = .062). One-hundred and fifteen (29.6%) ENDs detected occult nodal metastases (ONMs). The 5-year overall survival (OS) of patients undergoing neck observation and END was 65.6% and 66.8%, respectively (P = .652). END was not associated with improved OS in survival analyses stratified by patient demographics, clinicopathologic features, and adjuvant therapy. Compared with surgery alone, adjuvant radiotherapy (adjusted hazard ratio: 0.74, 95% confidence interval [CI]: 0.57-0.97, P = .031) was associated with improved OS. END (hazard ratio [HR]: 0.96, 95% CI: 0.71-1.28, P = .770) and ONM (HR: 1.12, 95% CI: 0.78-1.61, P = .551) were not associated with OS. CONCLUSION: END is performed in nearly half of patients with HNBC but is not associated with improved OS, even after stratifying survival analyses by patient demographics, clinicopathologic features, and adjuvant therapy. The rate of ONM approaching 30%, however, justifies inclusion of END in the surgical management of HNBC.

Surgical Resection Improves Overall Survival in cT4b Major Salivary Gland Cancer.

OBJECTIVE: To compare surgical and nonsurgical definitive treatment in cT4b major salivary gland cancer (MSGC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2004 to 2019 National Cancer Database. METHODS: The NCDB was queried for patients with cT4b MSGC (N = 976). Patients undergoing definitive treatment with (1) surgical resection + adjuvant therapy, (2) radiotherapy (RT) alone, or (3) chemoradiotherapy (CRT) were included in Kaplan-Meier and Cox survival analyses. RESULTS: Of 219 patients undergoing definitive treatment, 148 (67.6%) underwent surgical resection + adjuvant therapy and 71 (32.4%) underwent RT or CRT. There were no documented mortalities within 90 days of surgical resection. Tumor diameter and nodal metastasis were associated with decreased odds of undergoing definitive treatment (P < 0.025). Patients with positive surgical margins (PSM) had higher 5-year overall survival (OS) than those undergoing definitive RT or CRT (48.5% vs 30.1%, P = 0.018) and similar 5-year OS as those with negative margins (48.5% vs 54.0%, P = 0.205). Surgical resection + adjuvant therapy (adjusted hazard ratio: 0.55, 95% confidence interval [CI]: 0.37-0.84) was associated with higher OS than definitive RT or CRT (P < 0.025). A separate cohort of 961 patients with cT4a tumors undergoing surgical resection + adjuvant therapy was created; cT4a and cT4b (hazard ratio: 1.02, 95% CI: 0.80-1.29, P = 0.896) tumors had similar OS. CONCLUSION: A minority of patients with cT4b MSGC undergo definitive treatment. Surgical resection + adjuvant therapy was safe and associated with higher OS than definitive RT or CRT, despite high rate of PSM. In the absence of clinical trial data, appropriately selected patients with cT4b MSGC may benefit from surgical resection.

Choice of Adjuvant Radiotherapy Facility in Major Salivary Gland Cancer.

OBJECTIVE: Undergoing surgery and adjuvant radiotherapy (aRT) at the same facility has been associated with higher overall survival (OS) in head and neck squamous cell carcinoma. Our study investigates whether undergoing surgery and aRT at the same academic facility is associated with higher OS in major salivary gland cancer (MSGC). METHODS: The 2006-2018 National Cancer Database was queried for patients with MSGC undergoing surgery at an academic facility and then aRT. Multivariable binary logistic and Cox proportional hazards regression models were implemented. RESULTS: Of 2801 patients satisfying inclusion criteria, 2130 (76.0%) underwent surgery and aRT at the same academic facility. Residence in a less populated area (adjusted odds ratio [aOR] 1.69, 95% confidence interval [CI] 1.16-2.45), treatment without adjuvant chemotherapy (aOR 1.97, 95% CI 1.41-2.76), and aRT duration (aOR 1.02, 95% CI 1.01-1.04) were associated with undergoing surgery and aRT at different facilities on multivariable logistic regression adjusting for patient demographics, clinicopathologic features, and adjuvant therapy (p < 0.01). Five-year OS was higher in patients undergoing surgery and aRT at the same academic facility (68.8% vs. 61.9%, p < 0.001). Undergoing surgery and aRT at different facilities remained associated with worse OS on multivariable Cox regression (aHR 1.41, 95% CI 1.10-1.81, p = 0.007). CONCLUSION: Undergoing surgery and aRT at the same academic facility is associated with higher OS in MSGC. Although undergoing surgery and aRT at the same academic facility is impractical for all patients, academic physicians should consider same-facility treatment for complex patients who would most benefit from clear multidisciplinary communication. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Primary Site Surgery in Distantly Metastatic Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES: Determine if intensive local therapy (i.e., local surgery or radiation) has a survival benefit for patients presenting with distantly metastatic oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Retrospective population-based cohort study of patients in the National Cancer Database presenting with distantly metastatic OPSCC. Overall survival (OS) was compared for patients receiving systemic therapy alone or in combination with local surgery or curative dose radiation, controlling for various clinicodemographic factors. RESULTS: Between 2010 and 2015, 627 patients presented with newly diagnosed, metastatic OPSCC and an initial treatment course including systemic chemotherapy. Multivariable analysis demonstrated that local radiation therapy was independently associated with improved OS (OR 0.64, CI [0.51-0.81]); local surgery was not independently associated with improved OS (OR 0.99, CI [0.65-1.53]). Higher T stages were associated with worse OS (OR 1.69, CI [1.14-2.50] for T3 and OR 1.77, CI [1.22-2.58] for T4 compared to T1). HPV-positive (HPV+) tumors were associated with improved OS compared to HPV- (OR 0.79, CI [0.64-0.97]). Multiagent chemotherapy was associated with improved OS compared to single-agent (OR 0.78, CI [0.62-1.00]). The best survival for the entire cohort and for HPV+ patients was for radiation with systemic therapy and the worst survival for systemic therapy alone. CONCLUSIONS: Curative dose local radiotherapy in addition to systemic therapy is associated with improved OS compared to systemic therapy alone in patients presenting with distantly metastatic OPSCC. There is not a significant survival benefit for local surgery in addition to systemic therapy in this patient population, regardless of HPV status. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2243-2251, 2024.

Nodal Metastasis in Surgically Treated Oral Cavity Squamous Cell Carcinoma.

INTRODUCTION: Management of the neck in oral cavity squamous cell carcinoma (OCSCC) is essential to oncologic control and survival. The rates of lymph node metastasis (LNM) vary based on oral cavity tumor site and stage and influence treatment decisions. The aim of this paper was to describe clinical LNM for different tumor subsites and stages of surgically managed OCSCC. METHODS: We conducted a retrospective analysis of 25,846 surgically managed OCSCC patients from the National Cancer Database (NCDB) stratified by tumor subsite and clinical T-stage. For cN + patients, rates of pathologic LNM and absence of pathologic LNM were determined. For cN0 patients, outcomes included the rates of elective neck dissection (END) and occult LNM and predictors of occult LNM determined by a multivariable logistic regression model. RESULTS: A total of 25,846 patients (59.1% male, mean age 61.9 years) met inclusion criteria with primary tumor sites including oral tongue (50.8%), floor of mouth (21.2%), lower alveolus (7.6%), buccal mucosa (6.7%), retromolar area (4.9%), upper alveolus (3.6%), hard palate (2.7%), and mucosal lip (2.5%). Among all sites, clinical N+ rates increased with T-stage (8.9% T1, 28.0% T2, 51.6% T3, 52.5% T4); these trends were preserved across subsites. Among patients with cN + disease, the overall rate of concordant positive pathologic LNM was 80.1% and the rate of discordant negative pathologic LNM was 19.6%, which varied based on tumor site and stage. In the overall cohort of cN0 patients, 59.9% received END, and the percentage of patients receiving END increased with higher tumor stage. Occult LNM among those cN0 was found in 25.1% of END cases, with the highest rates in retromolar (28.8%) and oral tongue (27.5%) tumors. Multivariable regression demonstrated significantly increased rates of occult LNM for higher T stage (T2 OR: 2.1 [1.9-2.4]; T3 OR: 3.0 [2.5-3.7]; T4 OR: 2.7 [2.2-3.2]), positive margins (OR: 1.4 [1.2-1.7]), and positive lymphovascular invasion (OR: 5.1 [4.4-5.8]). CONCLUSIONS: Management of the neck in OCSCC should be tailored based on primary tumor factors and considered for early-stage tumors.

Lidocaine induces apoptosis in head and neck squamous cell carcinoma through activation of bitter taste receptor T2R14.

Head and neck squamous cell carcinomas (HNSCCs) have high mortality and significant treatment-related morbidity. It is vital to discover effective, minimally invasive therapies that improve survival and quality of life. Bitter taste receptors (T2Rs) are expressed in HNSCCs, and T2R activation can induce apoptosis. Lidocaine is a local anesthetic that also activates bitter taste receptor 14 (T2R14). Lidocaine has some anti-cancer effects, but the mechanisms are unclear. Here, we find that lidocaine causes intracellular Ca2+ mobilization through activation of T2R14 in HNSCC cells. T2R14 activation with lidocaine depolarizes mitochondria, inhibits proliferation, and induces apoptosis. Concomitant with mitochondrial Ca2+ influx, ROS production causes T2R14-dependent accumulation of poly-ubiquitinated proteins, suggesting that proteasome inhibition contributes to T2R14-induced apoptosis. Lidocaine may have therapeutic potential in HNSCCs as a topical gel or intratumor injection. In addition, we find that HPV-associated (HPV+) HNSCCs are associated with increased TAS2R14 expression. Lidocaine treatment may benefit these patients, warranting future clinical studies.

Nodal metastasis in surgically treated laryngeal squamous cell carcinoma.

BACKGROUND: Management of the neck in laryngeal squamous cell carcinoma (LSCC) is essential to oncologic control and survival. We aim to describe patterns and rates of clinical/pathologic lymph node disease, elective neck dissection (END), and occult lymph node metastasis (LNM) in patients with surgically-managed LSCC. METHODS: Retrospective cohort study of patients in the National Cancer Database (NCDB) diagnosed with LSCC between January 2004 and December 2016 who underwent primary surgery. RESULTS: Seven thousand eight hundred and seventy-six patients met inclusion criteria. For cN0 patients, the rates of END and occult LNM both increased with tumor stage and were highest for supraglottic tumors. Predictors of occult LNM included supraglottic site, pathologic T3 and T4 stage, positive margins, and presence of lymphovascular invasion (p < 0.05). CONCLUSIONS: The propensity for cervical LNM in surgically-managed LSCC varies based on primary tumor site and stage, and a variety of disease factors increase risk of occult LNM.

Determinants of Patient Refusal of Postoperative Radiation Therapy in Sinonasal Squamous Cell Carcinoma.

Objectives Although adjuvant radiotherapy may be indicated in patients with sinonasal squamous cell carcinoma (SNSCC) following primary surgery, some patients choose to forgo recommended postoperative radiation therapy (PORT). This study aimed to elucidate factors associated with patient refusal of recommended PORT in SNSCC and examine overall survival. Methods Retrospective analysis of patients with SNSCC treated with primary surgery from the National Cancer Database diagnosed between 2004 and 2016. A multivariable logistic regression model was created to determine the association between clinical or demographic covariates and likelihood of PORT refusal. Unadjusted Kaplan-Meier estimates, log-rank tests, and a multivariable Cox proportional hazard model were used to assess overall survival. Results A total of 2,231 patients were included in the final analysis, of which 1,456 (65.3%) were males and 73 (3.3%) refused recommended PORT. Patients older than 74 years old were more likely to refuse PORT than those younger than 54 (odds ratio [OR] 3.43, 95% confidence interval [CI]: 1.84-6.62). Median survival among the entire cohort, those who received recommended PORT, and those who refused PORT was 83.0 months (95% CI: 74.6-97.1), 83.0 months (95% CI: 74.9-98.2), and 63.6 months (95% CI: 37.3-101.4), respectively. Refusal of PORT was not associated with overall survival (hazard ratio: 0.99, 95% CI: 0.69-1.42). Conclusions PORT refusal in patients with SNSCC is rare and was found to be associated with several patient factors. The decision to forgo PORT is not independently associated with overall survival in this cohort. Further study is required to determine the clinical implications of these findings as the treatment decisions are complex.

Postoperative Radiation Therapy Refusal in Major Salivary Gland Cancers.

OBJECTIVE: Major salivary gland cancers (MSGCs) are often treated with primary surgery followed by adjuvant therapy for high-risk pathology. Patients with these cancers may opt out of recommended postoperative radiation therapy (PORT) for many reasons and consequently may suffer worse outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database. METHODS: Patients diagnosed with MSGC from 2004 to 2016 were identified, and overall survival and risk factors for refusal of recommended PORT were analyzed based on demographic, socioeconomic, and clinical factors. Multivariable logistic regression and a Cox model were used to conduct the analysis. RESULTS: 211 out of 4704 qualifying patients (4.5%) refused recommended PORT. Multivariable analysis demonstrated increased PORT refusal for age >74 years (odds ratio OR 4.34, confidence interval [CI] [2.43-7.85]), Asian race (OR 2.25, CI [1.10-4.23]), and certain facility types (comprehensive cancer center, OR 2.39, CI [1.08-6.34]; academic research program, OR 3.29, CI [1.49-8.74]; and integrated network cancer program, OR 2.75, CI [1.14-7.7]). N2 stage was associated with decreased PORT refusal (OR 0.67, CI [0.45-0.98]). The 5-year overall survival for patients who received and refused PORT were significantly different at 65.8% and 53.8%, respectively (p < .001). When controlling for several factors, PORT refusal was independently associated with significantly lower overall survival (HR 1.54, CI [1.21-1.98]). CONCLUSION: Patient refusal of recommended PORT in MSGC is rare, associated with various disease and socioeconomic factors, and may decrease overall survival. Our findings can assist clinicians in counseling patients and identifying those who may be more likely to opt out of recommended PORT.

Loss of CFTR function is associated with reduced bitter taste receptor-stimulated nitric oxide innate immune responses in nasal epithelial cells and macrophages.

Introduction: Bitter taste receptors (T2Rs) are G protein-coupled receptors identified on the tongue but expressed all over the body, including in airway cilia and macrophages, where T2Rs serve an immune role. T2R isoforms detect bitter metabolites (quinolones and acyl-homoserine lactones) secreted by gram negative bacteria, including Pseudomonas aeruginosa, a major pathogen in cystic fibrosis (CF). T2R activation by bitter bacterial products triggers calcium-dependent nitric oxide (NO) production. In airway cells, the NO increases mucociliary clearance and has direct antibacterial properties. In macrophages, the same pathway enhances phagocytosis. Because prior studies linked CF with reduced NO, we hypothesized that CF cells may have reduced T2R/NO responses, possibly contributing to reduced innate immunity in CF. Methods: Immunofluorescence, qPCR, and live cell imaging were used to measure T2R localization, calcium and NO signaling, ciliary beating, and antimicrobial responses in air-liquid interface cultures of primary human nasal epithelial cells and immortalized bronchial cell lines. Immunofluorescence and live cell imaging was used to measure T2R signaling and phagocytosis in primary human monocyte-derived macrophages. Results: Primary nasal epithelial cells from both CF and non-CF patients exhibited similar T2R expression, localization, and calcium signals. However, CF cells exhibited reduced NO production also observed in immortalized CFBE41o- CF cells and non-CF 16HBE cells CRISPR modified with CF-causing mutations in the CF transmembrane conductance regulator (CFTR). NO was restored by VX-770/VX-809 corrector/potentiator pre-treatment, suggesting reduced NO in CF cells is due to loss of CFTR function. In nasal cells, reduced NO correlated with reduced ciliary and antibacterial responses. In primary human macrophages, inhibition of CFTR reduced NO production and phagocytosis during T2R stimulation. Conclusions: Together, these data suggest an intrinsic deficiency in T2R/NO signaling caused by loss of CFTR function that may contribute to intrinsic susceptibilities of CF patients to P. aeruginosa and other gram-negative bacteria that activate T2Rs.

Association of Head and Neck Anatomic Zones with Microvascular Reconstruction Outcomes.

Background: Head and neck free flap survival relies on adequate tissue perfusion from the external carotid artery (ECA), and vessel length is inversely proportional to blood flow rate. Objective: Investigate whether distance from the ECA (as a proxy for pedicle vessel length) predicts flap survival or complications. Methods: Retrospective review of free flaps performed at three academic centers from 9/2006 to 8/2021. Flaps were categorized by distance from the ECA: orbit and above (zone 1), maxilla to parotid (zone 2), and mandible and below (zone 3). Secondary analysis assessed flap outcomes stratified by average historical pedicle length. Results: A total of 2,369 flaps were identified in zones 1 (n = 109), 2 (n = 1878), and 3 (n = 382). Rates of flap failure (4.9%) and perioperative complications (36.3%) did not differ by zone or pedicle length. Zone 3 flaps, most commonly located in the larynx and hypopharynx, had significantly higher rates of fistula and infection. Conversely, 30-day readmission rates were significantly lower in patients with zone 2 flaps (p < 0.001). Rates of all other complications did not differ significantly between zones. Conclusions: Proximity to mucosal anatomic sites was a more powerful predictor of free flap viability than pedicle length or ECA proximity.

Postoperative analysis of osseous midface reconstructions: The value of imaging and a novel scoring system for complexity and operative success.

BACKGROUND: Few standardized methods exist for evaluating the postoperative outcomes of osteocutaneous free flaps. We propose an anatomic-based scoring system for midface free flap reconstruction. METHODS: One hundred and twelve patients across four institutions underwent osteocutaneous reconstruction of the midface. Postoperative scans were scored based on the number of independent osseous subunits reconstructed (Subunit Score), the number of different bony appositions with bony contact (Contact Score), and the number of osseous segments in anatomic position (Position Score). These were added together to create a Total Score. RESULTS: Osteocutaneous radial forearm flaps had the lowest Subunit Score (p = 0.001). Fibula flaps had the highest Contact Score (p = 0.0008) and Position Score (p = 0.001). Virtual surgical planning was associated with an increased Subunit Score (p = 0.02) and Total Score (p = 0.04). CONCLUSIONS: We propose a novel scoring system for osseous midface reconstruction based on postoperative imaging scans. This can help guide management decisions and create a common language to compare outcomes.

Post-operative Monitoring for Head and Neck Microvascular Reconstruction in the Era of Resident Duty Hour Restrictions: A Retrospective Cohort Study Comparing 2 Monitoring Protocols.

OBJECTIVES: To determine whether 2 different methods of post-operative head and neck free flap monitoring affect flap failure and complication rates. METHODS: A retrospective chart review of 803 free flaps performed for head and neck reconstruction by the same microvascular surgeon between July 2013 and July 2020 at 2 separate hospitals within the same healthcare system. Four-hundred ten free flaps (51%) were performed at Hospital A, a medical center where flap checks were performed at frequent, scheduled intervals by in-house resident physicians and nurses; 393 free flaps (49%) were performed at Hospital B, a medical center where flap checks were performed regularly by nursing staff with resident physician evaluation as needed. Total free flap failure, partial free flap failure, and complications (consisting of wound infection, fistula, and reoperation within 1 month) were assessed. RESULTS: There were no significant differences between Hospitals A and B when comparing rates of total free flap failure, partial free flap failure, complication, or re-operation (P = .27, P = .66, P = .65, P = .29, respectively). There were no significant differences in urgent re-operation rates for flap compromise secondary to thrombosis and hematoma (P = .54). CONCLUSIONS: In our series, free flap outcomes did not vary based on the degree of flap monitoring by resident physicians. This data supports the ability of a high-volume, well-trained, nursing-led flap monitoring program to detect flap compromise in an efficient fashion while limiting resident physician obligations in the age of resident duty hour restrictions.

Use of the O-Z flap as an alternative to free tissue transfer for reconstruction of large scalp defects.

Objective: The reconstruction of large scalp defects poses both functional and cosmetic challenges. While free tissue transfer remains the standard for defects larger than 30 cm2, prolonged anesthesia and postoperative complications remain significant limitations. The purpose of this study is to evaluate the use of O-Z flaps for the reconstruction of large scalp defects and to describe the techniques employed. Methods: This is a retrospective analysis of ten patients who underwent reconstructive surgery using an O-Z flap approach for large scalp defects between July 2017 and June 2019. The parameters included in this study were patient demographics, tumor characteristics, and postoperative management, collected for at least a year after surgery. Results: In this cohort, the mean age was 76.1 years and 90% were male. All patients were treated for neoplastic skin lesions, with 70% located on the vertex and 30% located on the temporoparietal region. The mean size of defect was 52.0 cm2 (range: 38.6 to 63.8 cm2). The maximum hospital stay was two days, and no patients were readmitted within 30 days of surgery. There were no cases of wound infection or flap necrosis. All patients reported pain control with acetaminophen and ibuprofen. Four patients received adjuvant radiation, and there was no delay to receiving treatment following surgery. Conclusions: The O-Z flap is a reliable alternative for the reconstruction of non-irradiated scalp defects in the vertex and temporoparietal regions up to 63 cm2. This technique provides advantages for patients, including hairline preservation, shorter hospital stays, and decreased postoperative complications.

Prognosis of Distant Metastatic Sites in Anterior Skull Base Malignancies.

Objective This study aimed to provide information regarding the prognosis of patients presenting with metastatic anterior skull base malignancies based upon histology and site of distant metastasis (DM). Patients and Methods The National Cancer Database was queried for patients with anterior skull base malignant neoplasms with DM. Outcomes Prognosis was compared between site of DM and tumor histologies. A multivariable Cox proportional hazards model was used to identify prognostic factors for overall survival (OS). Results A total of 481 patients were identified. Lung was the most common site of DM (24.9%), followed by bone (22.2%), liver (5.6%), and brain (2.5%). Lung was the most common site for squamous cell carcinoma (SCCa) (28.3%), melanoma (37.7%), and adenoid cystic carcinoma (ACC; 31.4%). The median survival for patients presenting with metastatic disease regardless of tumor histology was 9.0 months (95% confidence interval [CI]: 8.2-10.3), and patients with metastasis to the liver had the best median survival at 15.5 months (95% CI: 10.5-25.6). The median survivals for the most common histologies, SCCa, melanoma, and ACC were 8.2 months (95% CI: 5.5-10.2), 10.5 months (95% CI: 8.7-14.1), and 15.0 months (95% CI: 11.1-61.1), respectively. Multivariable analysis demonstrated worse overall survival (OS) for older patients, higher Charlson-Deyo comorbidity scores, and tumors with higher grade and T stage. Compared with metastasis to bone, lung metastasis had better OS on multivariable analysis (hazard ratio [HR]: 0.70, 95% CI: 0.51-97). Adenoid cystic carcinoma had improved OS compared with SCCa (HR: 0.62, 95% CI: 0.39-99). Conclusion Tumor histology, metastatic sites, and several disease factors affected prognosis in anterior skull base malignancies with DM.

HSP90 Modulates T2R Bitter Taste Receptor Nitric Oxide Production and Innate Immune Responses in Human Airway Epithelial Cells and Macrophages.

Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two innate immune cell types are activated by bitter products, including those secreted by Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO enhances mucociliary clearance and has direct antibacterial effects in ciliated epithelial cells. NO also increases phagocytosis by macrophages. Using biochemistry and live-cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). Immunofluorescence showed that H441 cells express eNOS and T2Rs and that the bitter agonist denatonium benzoate activates NO production in a Ca2+- and HSP90-dependent manner in cells grown either as submerged cultures or at the air-liquid interface. In primary sinonasal epithelial cells, we determined that HSP90 inhibition reduces T2R-stimulated NO production and ciliary beating, which likely limits pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves as an innate immune modulator by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream Ca2+ signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases such as chronic rhinosinusitis, asthma, or cystic fibrosis.

Impact of sweet, umami, and bitter taste receptor (TAS1R and TAS2R) genomic and expression alterations in solid tumors on survival.

Originally identified on the tongue for their chemosensory role, the receptors for sweet, umami, and bitter taste are expressed in some cancers where they regulate important cellular processes including apoptosis and proliferation. We examined DNA mutations (n = 5103), structural variation (n = 7545), and expression (n = 6224) of genes encoding sweet or umami receptors (TAS1Rs) and bitter receptors (TAS2Rs) in 45 solid tumors subtypes compared to corresponding normal tissue using The Cancer Genome Atlas and the Genotype Tissue Expression Project databases. Expression of TAS1R and TAS2R genes differed between normal and cancer tissue, and nonsilent mutations occurred in many solid tumor taste receptor genes (~ 1-7%). Expression levels of certain TAS1Rs/TAS2Rs were associated with survival differences in 12 solid tumor subtypes. Increased TAS1R1 expression was associated with improved survival in lung adenocarcinoma (mean survival difference + 1185 days, p = 0.0191). Increased TAS2R14 expression was associated with worse survival in adrenocortical carcinoma (-1757 days, p < 0.001) and esophageal adenocarcinoma (-640 days, p = 0.0041), but improved survival in non-papillary bladder cancer (+ 343 days, p = 0.0436). Certain taste receptor genes may be associated with important oncologic pathways and could serve as biomarkers for disease outcomes.

A benchmark for oncologic outcomes and model for lethal recurrence risk after transoral robotic resection of HPV-related oropharyngeal cancers.

OBJECTIVES: Increasing use of transoral robotic surgery (TORS) is likely to impact outcomes for HPV+ oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to describe oncologic outcomes for a large HPV+ OPSCC cohort after TORS and develop a risk prediction model for recurrence under this treatment paradigm. MATERIALS AND METHODS: 634 HPV+ OPSCC patients receiving TORS-based therapy at a single institution were reviewed retrospectively to describe survival across the entire cohort and for patients suffering recurrence. Risks for distant metastatic recurrence (DMR) and locoregional recurrence (LRR) were modeled using multivariate logistic regression analyses of case-control sub-cohorts. RESULTS: 5-year overall and recurrence-free survival were 91.2% and 86.1%, respectively. 5-year overall survival was 52.5% following DMR and 83.3% after isolated LRR (P = .01). In case-control analyses, positive surgical margins were associated with DMR (adjusted OR 5.8, CI 2.1-16.0, P = .001), but not isolated LRR, and increased DMR risk 4.2 fold in patients with early clinical stage disease. By contrast, LRR was associated with not receiving recommended adjuvant therapy (OR 13.4, CI 6.3-28.5, P < .001). CONCLUSIONS: This study sets a benchmark for oncologic outcomes from HPV+ OPSCC after TORS-based therapy. Under this treatment paradigm, margins are relevant for assessing lethal recurrence risk during clinical trial design and post-treatment surveillance.

Reconstruction following transoral robotic surgery for head and neck cancer: Systematic review.

We performed a systematic review to characterize reconstructive modalities and postoperative surgical outcomes following TORS resection. A search of the PubMed, SCOPUS, and EMBASE databases was conducted to identify studies describing patients undergoing reconstruction of TORS defects. Twenty-six studies met inclusion criteria, consisting of 260 patients who underwent TORS resection followed by reconstruction. Twenty-one studies reported tumor classification information, with TORS performed for 44 (23.0%) T1, 86 (45.0%) T2, 33 (17.3%) T3, and 28 (14.7%) T4 tumors. Eighteen distinct reconstructive modalities were described in the studies identified, including nine unique free flap types. The most commonly performed reconstruction was the radial forearm free flap (RFFF), accounting for 121/260 (46.5%) of reconstructions performed. Reported surgical complications included 5 pharyngocutaneous fistulae, 13 hemorrhagic complications, 24 infectious complications, and 5 free flap failures. Our findings demonstrate favorable surgical outcomes but minimal quantitative functional data to compare reconstructive options following TORS.