SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming.

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.

Ethacridine inhibits SARS-CoV-2 by inactivating viral particles.

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 µM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.

Targeted replacement of full-length CFTR in human airway stem cells by CRISPR-Cas9 for pan-mutation correction in the endogenous locus.

Cystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the CF transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR-Cas9 and two adeno-associated viruses (AAVs) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial epithelial cells (HBECs). The modified cells were enriched to obtain 60%-80% tCD19+ UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies.

Inflammatory molecular endotypes of nasal polyps derived from White and Japanese populations.

BACKGROUND: Emerging evidence suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with disparate inflammatory characteristics between different racial groups and geographies. Currently, little is known about possible underlying distinguishing factors between these inflammatory differences. OBJECTIVE: Our aim was to interrogate differences in CRSwNP disease between White/non-Asian patients and Japanese patients by using whole transcriptome and single-cell RNA gene expression profiling of nasal polyps (NPs). METHODS: We performed whole transcriptome RNA sequencing with endotype stratification of NPs from 8 White patients (residing in the United States) and 9 Japanese patients (residing in Japan). Reproducibility was confirmed by quantitative PCR in an independent validation set of 46 White and 31 Japanese patients. Single-cell RNA sequencing (scRNAseq) was used to stratify key cell types for contributory transcriptional signatures. RESULTS: Unsupervised clustering analysis identified 2 major endotypes that were present within both cohorts of patients with NPs and had previously been reported at the cytokine level: (1) type 2 endotype and (2) non-type 2 endotype. Importantly, there was a statistically significant difference in the proportion of these endotypes between these geographically distinct subgroups with NPs (P = .03). Droplet-based single-cell RNA sequencing further identified prominent type 2 inflammatory transcript expression: C-C motif chemokine ligand 13 (CCL13) and CCL18 in M2 macrophages, as well as cystatin SN (CST1) and CCL26 in basal, suprabasal, and secretory epithelial cells. CONCLUSION: NPs from both racial groups harbor the same 2 major endotypes, which we have determined to be present in differing ratios between each cohort with CRSwNP disease. Distinct inflammatory and epithelial cells contribute to the type 2 inflammatory profiles observed.

Evidence for altered levels of IgD in the nasal airway mucosa of patients with chronic rhinosinusitis.

BACKGROUND: IgD is an enigmatic antibody isotype best known when coexpressed with IgM on naive B cells. However, increased soluble IgD (sIgD) levels and increased IgD+IgM- B-cell populations have been described in the human upper respiratory mucosa. OBJECTIVE: We assessed whether levels of sIgD and IgD+ B cell counts are altered in nasal tissue from patients with chronic rhinosinusitis (CRS). We further characterized IgD+ B-cell populations and explored clinical and local inflammatory factors associated with tissue sIgD levels. METHODS: sIgD levels were measured by means of ELISA in nasal tissues, nasal lavage fluid, sera, and supernatants of dissociated nasal tissues. IgD+ cells were identified by using immunofluorescence and flow cytometry. Inflammatory mediator levels in tissues were assessed by using real-time PCR and multiplex immunoassays. Bacterial cultures from the middle meatus were performed. Underlying medical history and medicine use were obtained from medical records. RESULTS: sIgD levels and numbers of IgD+ cells were significantly increased in uncinate tissue (UT) of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with that of control subjects (4-fold, P < .05). IgD+ cells were densely scattered in the periglandular regions of UT from patients with CRSsNP. We also found that IgD+CD19+CD38bright plasmablast numbers were significantly increased in tissues from patients with CRSsNP compared with control tissues (P < .05). Among numerous factors tested, IL-2 levels were increased in UT from patients with CRSsNP and were positively correlated with tissue IgD levels. Additionally, supernatants of IL-2-stimulated dissociated tissue from patients with CRSsNP had significantly increased sIgD levels compared with those in IL-2-stimulated dissociated control tissue ex vivo (P < .05). Tissue from patients with CRS with preoperative antibiotic use or those with pathogenic bacteria showed higher IgD levels compared with tissue from patients without these variables (P < .05). CONCLUSION: sIgD levels and IgD+CD19+CD38bright plasmablast counts were increased in nasal tissue of patients with CRSsNP. IgD levels were associated with increased IL-2 levels and the presence of pathogenic bacteria. These findings suggest that IgD might contribute to enhancement mucosal immunity or inflammation or respond to bacterial infections in patients with CRS, especially CRSsNP.

Wnt Signaling in Chronic Rhinosinusitis with Nasal Polyps.

The signaling pathways that sustain the disease process of chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly understood. We sought to determine the expression levels of Wnt signaling genes in CRSwNP and to study the role of the Wnt pathway in inflammation and epithelial remodeling in the nasal mucosa. Microarrays and real time-quantitative polymerase chain reaction comparing gene expression in matched NPs and inferior turbinates revealed that WNT2B, WNT3A, WNT4, WNT7A, WNT7B, and FZD2 were up-regulated and that FZD1, LRP5, LRP6, and WIF1 were down-regulated in NPs. Immunolabeling showed robust expression of Wnt ligands, nuclear ß-catenin, and Axin-2 in NP tissue, suggesting that Wnt/ß-catenin signaling is activated in NPs. We used primary human nasal epithelial cell (HNEpC) cultures to test the functional consequences of Wnt pathway activation. Monolayer HNEpCs treated with recombinant human WNT (rhWNT) 3A, but not with rhWNT4, had altered epithelial morphology and decreased adhesion, without loss of viability. We found that neither rhWNT3A nor rhWNT4 treatment induced proliferation. The expression and release of inflammatory cytokines IL-6 and granulocyte-macrophage colony-stimulating factor were increased after rhWNT3A exposure of HNEpCs. When differentiated at an air-liquid interface, rhWNT3A- and WNT agonist-, but not rhWNT4-treated HNEpCs, had abnormal epithelial architecture, failed to undergo motile ciliogenesis, and had defective noncanonical Wnt (planar cell polarity) signaling. On the basis of these results, we propose a model in which Wnt/ß-catenin signaling sustains mucosal inflammation and leads to a spectrum of changes consistent with those seen during epithelial remodeling in NPs.

Selective expansion of human regulatory T cells in nasal polyps, and not adjacent tissue microenvironments, in individual patients exposed to steroids.

Severe forms of chronic rhinosinusitis (CRS), a common upper airway inflammatory disorder, are associated with nasal polyps (NPs). NP disease is ameliorated by glucocorticoid (GC) treatment, whose cellular effects are poorly understood. We therefore assessed the influence of GC therapy on NPs in CRS patients, focusing on regulatory T (Treg) cells. Treg cell populations were analyzed by flow cytometry in NPs and control tissues from GC-treated CRS patients and controls. After GC exposure, selective expansion of Treg cells was seen within NPs, and not blood or adjacent ethmoid tissues. To confirm direct GC effects, NPs from the same patients were biopsied prior to, and following, 1week of oral GC exposure. Direct expansion of Tregs into the same NP bed was detected in 4/4 CRS patients following GC exposure. Treg cell spikes into NPs were secondary to cellular recruitment given limited Ki67 expression within these regulatory cells. Chemokine gene expression profiling identified several chemokines, notably CCL4, induced within NPs upon GC treatment. Neutralization of chemokine receptor/ligand interactions using CCR4 small molecule antagonists reduced Treg migration towards GC-treated NPs in an ex vivo migration assay. Our findings suggest that the common use of GCs in the treatment of NP disease leads to recruitment of Treg cells from peripheral sites into NP tissues, which may be critical to the anti-inflammatory effect of GCs. Mechanistically Treg expansion appears to be conferred, in part, by chemokine receptor/ligand interactions induced following corticosteroid therapy.

Use of Pedicled Nasoseptal Flap for Pathologic Oroantral Fistula Closure.

Oroantral fistula (OAF) is a pathologic, epithelialized communication between the oral cavity and the maxillary sinus. OAF most commonly results from posterior maxillary tooth or molar extraction owing to proximity of the dental roots to the maxillary antrum and the thinness of the adjacent antral floor. It also can arise secondary to implant and orthognathic surgeries, cyst and tumor removal, dental infection, trauma, or as a sequela of radiation therapy. Communications larger than 5 mm are less likely to heal spontaneously and can epithelialize, forming an OAF. When locoregional flaps and grafts are not ideal or have failed, but primary OAF closure is mandated, surgical options are unclear. This report describes a novel method for autologous tissue flap coverage from the nasal septum, pedicled off the posterior septal artery, for successful extension to, and closure of, OAFs.

The nasal vestibular body: anatomy, clinical features, and treatment considerations.

Nasal obstruction is a common presenting complaint, with many possible etiologies. Herein, we provide an introductory anatomic description, clinical relevance, and proposed nomenclature for an underappreciated soft tissue focus in the nasal vestibule-the nasal vestibular body (NVB)-that can contribute to nasal obstruction in a subset of patients. This is a small mound of dynamic soft tissue in the lateral aspect of the internal nasal valve, situated inferior and anterior to the head of the inferior turbinate that can be missed on routine examination for many salient reasons. In well-selected patients, whose symptoms of nasal obstruction may in part be secondary to the presence of this soft tissue focus, directed testing and tissue reduction can be performed.

Experience with intraoperative navigation and imaging during endoscopic transnasal spinal approaches to the foramen magnum and odontoid.

OBJECT: In this study the authors share their experience using intraoperative spinal navigation and imaging for endoscopic transnasal approaches to the odontoid in 5 patients undergoing C1-2 surgery for basilar invagination at Stanford Hospital and Clinics from 2010 to 2013. METHODS: Of these 5 patients undergoing C1-2 surgery for basilar invagination, 4 underwent a 2-tiered anterior C1-2 resection with posterior occipitocervical fusion during a first stage surgery, followed by endoscopic endonasal odontoidectomy in a separate setting. Intraoperative stereotactic navigation was performed using a surgical navigation system in all cases. Navigation accuracy, characterized as target registration error, ranged between 0.8 mm and 2 mm, with an average of 1.2 mm. Intraoperative imaging using a CT scanner was also performed in 2 patients. RESULTS: Endoscopic decompression of the brainstem was achieved in all patients, and no intraoperative complications were encountered. All patients were extubated within 24 hours after surgery and were able to swallow within 48 hours. After appropriate initial reconstruction of the defect at the craniocervical junction, no postoperative CSF leakage, arterial injury, or need for reoperation was encountered; 1 patient developed mild postoperative velopharyngeal insufficiency that resolved by the 6-month follow-up evaluation. There were no deaths and no patients required tracheostomy placement. The average inpatient stay after surgery varied between 72 and 96 hours, without extended intensive care unit stays for any patient. CONCLUSIONS: Technologies such as intraoperative CT scanning and merged MRI/CT can provide the surgeon with detailed, virtual real-time information about the extent of complex endoscopic vertebral segment resection and brainstem decompression and lessens the prospect of revision or secondary procedures in this challenging surgical corridor. Moreover, patients experience limited morbidity and can tolerate early oral intake after transnasal endoscopic odontoidectomy. Essential to the successful undertaking of these endoscopic adventures is 1) an understanding of the endoscopic nasal, skull base, and neurovascular anatomy; 2) advanced and extended-length instrumentation including navigation; and 3) a team approach between experienced rhinologists and spine surgeons comfortable with endoscopic skull base techniques.

Delayed orbital floor implant complications: Case report and review of the literature.

Purpose: Foreign body reaction to non-absorbable alloplastic orbital implants utilized for bony reconstruction are infrequently documented in the literature. We present the workup and surgical management of a giant cystic mass encapsulating a patient's alloplastic orbital implant, which was ultimately deemed to be a result of foreign body reaction. Observations: A 41-year-old male patient with distant history of a right orbital floor fracture had undergone repair with the placement of a nylon foil implant. The patient presented twenty years later with progressive ipsilateral globe proptosis and was found to have a giant inferior orbital cyst. Surgical exploration and removal of the implant and capsule were performed. Histopathology confirmed a delayed foreign body reaction around the patient's alloplastic implant. Conclusions: Alloplastic implants may result foreign body reaction and cyst encapsulation as a delayed complication.

Incidence of hypocortisolism with long-term budesonide irrigation for chronic rhinosinusitis.

BACKGROUND: Budesonide irrigations (BIs) are commonly used to control inflammation in chronic rhinosinusitis (CRS). In 2016 we reported an analysis of long-term BI with regard to hypothalamic-pituitary-adrenal axis function. We present a follow-up analysis in a larger cohort of patients with longer follow-up. METHODS: Patients were candidates for stimulated cortisol testing after regularly performing BI for CRS at least daily for ≥6 months. We retrospectively evaluated all patients who received stimulated cortisol testing at our center between 2012 and 2022. We correlated cortisol levels with the use of BI and other forms of corticosteroids. RESULTS: We analyzed 401 cortisol test results in 285 patients. The mean duration of use was 34 months. Overall, 21.8% of patients were hypocortisolemic (<18 ug/dL) at first test. In patients who used only BI, the rate of hypocortisolemia was 7.5%, whereas in patients who also used concurrent oral and inhaled corticosteroids, the rate was 40% to 50%. Lower cortisol levels were associated with male sex (p < 0.0001) and concomitant use of oral and inhaled steroids (p < 0.0001). Duration of BI use was not significantly associated with lower cortisol levels (p = 0.701), nor was greater dosing frequency (p = 0.289). CONCLUSION: Prolonged use of BI alone is not likely to cause hypocortisolemia in the majority of patients. However, concomitant use of inhaled and oral steroids and male sex may be associated with hypocortisolemia. Surveillance of cortisol levels may be considered in vulnerable populations who use BI regularly, particularly in patients using other forms of corticosteroids with known systemic absorption.

The Serpentine Sign: A Reliable Endoscopic and Radiographic Finding in Empty Nose Syndrome.

OBJECTIVE: Empty nose syndrome (ENS) is a relatively uncommon disease that greatly impacts the quality of life and presents diagnostic challenges. We sought to identify objective clinical findings unique to patients with ENS, and in doing so identified compensatory mucosal hypertrophy in an alternating, undulating swelling on endoscopy and coronal computerized tomography (CT) that we have termed the "Serpentine Sign." Here, we investigated whether this radiographic finding is a reliable manifestation in ENS patients. METHODS: Retrospective review was undertaken to identify ENS patients with past turbinoplasty, an ENS6Q score of at least 11/30, and symptomatic improvement with the cotton placement test. Control patients without complaints of ENS symptoms (ENS6Q < 11) were identified for comparison. ENS and control patients had coronal CT imaging available to evaluate for the Serpentine Sign, as well as ENS6Q scores, and histologic analysis of nasal tissue. RESULTS: 34 ENS and 74 control patients were evaluated for the presence of the Serpentine Sign. Of the 34 patients with ENS, 18 exhibited this radiographic finding on CT imaging (52.9%) compared to 0 of the 74 control patients (p < 0.0001). Further analysis demonstrated that ENS patients with the Serpentine Sign had lower median scores on ENS6Q than ENS patients without (17.5 vs. 22, p = 0.033). Histology revealed disorganized subepithelium rich in seromucinous glands similar to the nasal septum swell body. CONCLUSION: The "Serpentine Sign" is a unique presentation of hypertrophic change to the nasal septum soft tissue that is specific to ENS patients and may serve as a reliable radiographic and endoscopic finding in diagnosis. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1089-1095, 2024.

Eustachian tube dysfunction symptoms after endonasal skull base surgery.

KEY POINTS: ETD symptoms are present in 16% patients with underlying skull base pathology. Preoperative ETD symptoms improve following surgical treatment of skull base pathology. ETD symptoms may worsen in patients with central, posterior, or malignant skull base pathology.

Surgical Correction of Nasal Obstruction and Its Effect on Eustachian Tube Dysfunction Symptoms.

OBJECTIVES: To investigate how eustachian tube dysfunction symptoms change following surgical treatment of nonsinusitis-related nasal obstruction. STUDY DESIGN: Retrospective chart review. SETTING: Single academic center. METHODS: We assessed patients who underwent septoplasty, turbinate reduction, or both for nasal obstruction. Chronic sinusitis patients were excluded. Eustachian tube dysfunction (ETD) symptoms were studied using the Eustachian Tube Dysfunction Questionnaire (ETDQ-7), collected preoperatively and postoperatively (1 week, 1 month, 3 months, 6 months postop). Patients with preoperative ETDQ-7 > 14.5 were considered to have clinically significant symptoms. Sinonasal outcomes test scores were also assessed. Pre- and postoperative ETDQ-7 scores were compared using t test. Multivariate linear regression analysis identified factors associated with ETDQ-7 change. RESULTS: We analyzed 259 patients. Preoperatively, 37.5% of patients with nasal obstruction had clinically significant ETD symptoms. These patients exhibited significant improvement in ETDQ-7 at all postoperative timepoints from 23.3 ± 7.6 at baseline to 19.1 ± 9.1 at 1 week, 16.5 ± 8.0 at 1 month, 16.2 ± 7.8 at 3 months, and 16.7 ± 10.4 at 6 months (all P < .01). In patients without baseline ETD symptoms, (baseline ETDQ-7: 9.1 ± 2.3) ETDQ-7 scores did not change significantly at postoperative timepoints, except for an acute worsening at 1 week postoperatively (10.7 ± 5.1, P < .001). Regression analysis showed that higher preoperative ETDQ-7 score (ß = -0.84, 95% confidence interval [CI]: -1.10 to -0.59) and postoperative antihistamine spray usage (ß = -8.70, 95% CI: -14.20 to -3.20) were associated with ETDQ-7 improvement, while comorbid GERD (ß = 7.50, 95% CI: 3.42-11.58) and asthma (ß = 5.62, 95% CI: 0.80-10.45) were negatively associated with improvement. CONCLUSION: Surgical correction of nasal obstruction may improve ETD symptoms.

The Utility of a "Second-Look" Debridement Following Endonasal Skull Base Surgery in the Pediatric Population.

Background Sinonasal debridement is typically performed in the weeks following endonasal skull base surgery (ESBS). In the pediatric population, this second-look procedure may require general anesthesia; however, there is currently little evidence assessing the benefit of this practice. Methods This was a multicenter retrospective study of pediatric patients (age <18 years) undergoing a planned second-look debridement under general anesthesia following ESBS. Intraoperative findings, interventions performed, and perioperative complications were reviewed. Multivariate regression analysis was performed to identify associations between intraoperative findings and clinical factors. Results We reviewed 69 cases of second-look debridements (age mean 8.6 ± 4.2 years, range: 2-18 years), occurring a mean of 18.3 ± 10.3 days following ESBS. All abnormal findings were noted in patients age ≤12 years. Synechiae were noted in 8.7% of cases, bacterial rhinosinusitis in 2.9%, and failed reconstruction with cerebrospinal fluid leak in 4.5% (two cases of flap malposition and one case of flap necrosis). All failed reconstructions were noted following expanded endonasal cases for craniopharyngioma, and in each case, a revision reconstruction was performed during the second-look surgery. Synechiae were not significantly associated with younger age, revision cases, or cases with reconstructive flaps. There were no perioperative complications. Conclusion Second-look debridement under general anesthesia may be useful in the identification and intervention of sinonasal pathology following endoscopic skull base surgery, particularly in children ≤12 years old or those with pedicled flap reconstructions. Larger controlled studies are warranted to validate this practice and refine indications and timing of this second procedure.

Stepwise Empty Nose Syndrome Evaluation (SENSE) test-A modified cotton test for reduced bias in office diagnosis of empty nose syndrome.

INTRODUCTION: Diagnosis of empty nose syndrome (ENS) relies on the ENS six-item questionnaire (ENS6Q) with a score of ≥11, followed by a "positive" cotton test yielding seven-point reduction from baseline ENS6Q score via cotton placement to the inferior meatus (IM). Given the intricacies of diagnosing ENS and the propensity for false positives with the standard cotton test, we modified the classic single-step cotton test into a four-part Stepwise Empty Nose Syndrome Evaluation (SENSE) cotton test to reduce bias and evaluate the placebo effect. METHODS: Individuals diagnosed with ENS underwent the SENSE test, a single-blinded, four-step, office-based cotton test, without topical anesthesia or decongestants. Conditions included: (1) placebo/no cotton placed; (2) complete cotton-blockade of nasal vestibule; (3) cotton placed medially against the nasal septum; and (4) cotton placed laterally in the IM (site of inferior turbinate tissue loss). With each condition, patients completed an ENS6Q. RESULTS: Forty-eight ENS patients were included. Twenty-nine percent demonstrated a placebo effect (p < 0.001), 40.4% had a positive response to complete cotton-blockade (p < 0.001), 64.4% to septum-placed cotton, and 79.1% to IM-placed cotton (p < 0.001), corresponding to a mean ENS6Q reduction of 11.9 points (p < 0.001). Notably, the mean difference in ENS6Q scores between septum and IM placement was 1.7 (p < 0.001). CONCLUSIONS: The SENSE test offers further insight into subtleties of nasal breathing experienced by ENS patients. The placebo effect can be prominent and important to consider with individual patients. While most ENS patients prefer any intranasal cotton placement over baseline, blinded testing reveals these patients can accurately discriminate minimal changes in nasal aerodynamics.

Comparative analysis of traditional machine learning and automated machine learning: advancing inverted papilloma versus associated squamous cell carcinoma diagnosis.

KEY POINTS: Inverted papilloma conversion to squamous cell carcinoma is not always easy to predict. AutoML requires much less technical knowledge and skill to use than traditional ML. AutoML surpassed the traditional ML algorithm in differentiating IP from IP-SCC.

Predictive factors for decreased baseline quality of life in patients with sinonasal malignancies.

BACKGROUND: The impact of sinonasal malignancies (SNMs) on quality of life (QOL) at presentation is poorly understood. The Sinonasal Outcome Test (SNOT-22) and University of Washington Quality of Life (UWQOL) are validated QOL instruments with distinctive subdomains. This study aims to identify factors impacting pretreatment QOL in SNM patients to personalize multidisciplinary management and counseling. METHODS: Patients with previously untreated SNMs were prospectively enrolled (2015-2022) in a multicenter observational study. Baseline pretreatment QOL instruments (SNOT-22, UWQOL) were obtained along with demographics, comorbidities, histopathology/staging, tumor involvement, and symptoms. Multivariable regression models identified factors associated with reduced baseline QOL. RESULTS: Among 204 patients, presenting baseline QOL was significantly reduced. Multivariable regression showed worse total SNOT-22 QOL in patients with skull base erosion (p = 0.02). SNOT-rhinologic QOL was worse in women (p = 0.009), patients with epistaxis (p = 0.036), and industrial exposure (p = 0.005). SNOT extranasal QOL was worse in patients with industrial exposure (p = 0.016); worse SNOT ear/facial QOL if perineural invasion (PNI) (p = 0.027). Squamous cell carcinoma pathology (p = 0.037), palate involvement (p = 0.012), and pain (p = 0.017) were associated with worse SNOT sleep QOL scores. SNOT psychological subdomain scores were significantly worse in patients with palate lesions (p = 0.022), skull base erosion (p = 0.025), and T1 staging (p = 0.023). Low QOL was more likely in the presence of PNI on UW health (p = 0.019) and orbital erosion on UW overall (p = 0.03). UW social QOL was worse if palatal involvement (p = 0.023) or PNI (p = 0.005). CONCLUSIONS: Our findings demonstrate a negative impact on baseline QOL in patients with SNMs and suggest sex-specific and symptom-related lower QOL scores, with minimal histopathology association. Anatomical tumor involvement may be more reflective of QOL than T-staging, as orbital and skull base erosion, PNI, and palate lesions are significantly associated with reduced baseline QOL.