A Consistent Endoscopic Landmark to Identify the Anterior Ethmoidal Artery.

OBJECTIVE: The anterior ethmoidal artery (AEA) is an important structure to identify during endoscopic sinus surgery. Although identification on imaging is easily taught, a consistent endoscopic landmark for the AEA, independent of anatomic ethmoid cell variation, is lacking, leaving many surgeons unclear about the exact location without dependence on navigation. Here, we describe a consistent endoscopic landmark, regardless of anatomical ethmoid variation. METHODS: We prospectively enrolled adult patients undergoing endoscopic surgery involving frontal and ethmoid sinuses in this observational study. The AEA landmark was defined simply as the septation or ridge one step back along the ethmoid skull base from the posterior table of the frontal sinus. The gold standard to calculate the sensitivity of our endoscopic landmark was an image-navigation system, registered to within 1.5 mm accuracy, locating the AEA within three planes. Both endoscopic and computerized tomography (CT) images of the pointer at the landmark were taken simultaneously. The concordance of endoscopic to navigation images was independently assessed by three blinded rhinologists. RESULTS: Forty patients were included in our study with 73 sides analyzed. Diagnoses included chronic rhinosinusitis without polyps (52.5%), with polyps (22.5%), recurrent acute sinusitis (15%), sinonasal tumors (7.5%), and odontogenic sinusitis (2.5%). The AEA was accurately identified using our endoscopic landmark in 97.3% of the cases (71/73). Of the two cases in which the AEA was not found within the landmark, the artery was located ≤1 mm posteriorly. CONCLUSION: We describe a consistent endoscopic landmark to identify the AEA, conserved across various clinical diagnoses and anatomic variations in sinus structure. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1096-1099, 2024.

Chronic Rhinosinusitis After Maxillary Advancement Orthognathic Surgery.

INTRODUCTION: Maxillomandibular advancement (MMA) remains an effective procedure for the management of obstructive sleep apnea (OSA). Maxillary advancement may lead to anatomical changes that impair paranasal sinus drainage, leading to chronic sinus inflammation. The aim of this study was to describe the clinical features and outcomes of patients suffering from chronic rhinosinusitis (CRS) following MMA. METHODS: This is a retrospective case series study. Our study included subjects diagnosed with CRS following MMA from January 1992 to October 2018 at Stanford Hospital. We screened 730 patients undergoing MMA and identified a total of 57 with CRS after MMA. A descriptive analysis was performed using clinical data including patient demographics, comorbidities, prior surgical history, physical exam manifestations, CT findings, and quality of life outcomes (SNOT-22). RESULTS: Out of 730 patients undergoing MMA, 57(7.8%) were found to have CRS after orthognathic surgery. Presenting symptoms included facial pain (92.5%), nasal drainage (75%), nasal obstruction (67.5%), and hyposmia (20%). Endoscopic examination revealed recirculation (30.5%), purulent discharge (27.7%), polypoid changes (22.2%), and scarring (13.8%). Preoperative CT prior to undergoing endoscopic sinus surgery (ESS) demonstrated mucosal thickening in maxillary (64.2%), anterior ethmoid (39.2%), frontal (14.2%), posterior ethmoid (10.7%), sphenoid sinus (14.2%), and ostiomeatal complex (55.3%). Average Lund-Mackay score was 5.5(±3.8). Additional CT findings included secondary ostium in the inferior meatus (42.8%). Forty patients (70.1%) underwent ESS at a mean of 4.6 years after MMA. Patients undergoing ESS experienced significant improvement in SNOT-22 scores at 12-months post-surgery (P = .018). CONCLUSION: Patients undergoing maxillary advancement surgery are at risk of developing CRS postoperatively and should be advised of the risk of CRS associated with this procedure. Surgical treatment can be an option for medically refractory CRS related to MMA surgery.

Characterizing Trends in Diagnosis and Management of Sinusitis in a Large Health Care System: From Primary Care to Otolaryngology.

OBJECTIVES: Variations in management of sinusitis in primary care settings can be associated with inappropriate antibiotic prescriptions and delays in treatment. The objective of this study was to identify patient and provider characteristics associated with possible inaccurate diagnosis and management of sinusitis. METHODS: We performed a cross-sectional retrospective analysis using an established regional healthcare database of patients who received a diagnosis of sinusitis between 2011 and 2022 from a non-otolaryngologist provider. Patient's comorbidities, insurance status, chronicity of sinusitis, and prescriptions were included. We noted if patients were referred to an otolaryngology practice and if they received a diagnosis of sinusitis from an otolaryngologist. RESULTS: We analyzed 99 581 unique patients and 168 137 unique encounters. The mean age was 41.5 (±20.4 years) and 35.7% were male. Most patients had private insurance (88.5%), acute sinusitis (81.2%), and were seen at a primary care office (97.8%). Approximately 30% of patients were referred to an otolaryngology practice for sinusitis. Of referred patients, 50.6% did not receive a diagnosis of sinusitis from an otolaryngology practice. Patients without a sinusitis diagnosis by an otolaryngology practice received significantly more mean courses of antibiotics (5.04 vs 2.39, P < .0001) and oral steroids (3.53 vs 2.08, P < .0001). CONCLUSIONS: Over half of the patients referred to an otolaryngology practice from primary care for sinusitis did not receive a diagnosis of sinusitis from an otolaryngology practice. Further research should investigate implications for increased healthcare costs and inappropriate prescription trends associated with the management of sinusitis.

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.

Prognostic Factors and Treatment Impact on Overall Survival in Adult Craniopharyngioma.

OBJECTIVE: To examine the demographics, tumor characteristics, treatments, and clinical outcomes of a large adult craniopharyngioma population. METHODS: The 2004-2018 National Cancer Database was queried to investigate adult patients with craniopharyngioma. Univariable and multivariable Cox hazard ratio analysis was conducted to analyze the overall survival (OS) impact of demographic and clinical variables. RESULTS: A total of 666 adult patients with craniopharyngioma were identified with a mean age of 51 years (standard deviation 16 years). On multivariable analysis, independent of demographic and clinical variables, increased age, uninsured status, Medicaid, Medicare, Charlson-Deyo Comorbidity Index of 2, and tumor size greater than 40 mm were independently associated with worse OS. There was no significant difference in survival between histologic subtypes. Gross total resection (GTR) (hazard ratio [HR] 0.602, 95% confidence interval [CI] 0.384-0.942, P = 0.026) and subtotal resection (STR) with adjuvant radiotherapy (HR 0.316, 95% CI 0.140-0.710, P = 0.005) were independently associated with improved OS. GTR with radiotherapy trended towards improved OS (HR 0.601, 95% CI 0.334-1.083, P =0.090), but STR alone and radiotherapy alone demonstrated no significant difference in survival compared with no treatment on multivariable analysis. Kaplan-Meier survival models demonstrated improved survival with GTR, GTR + radiation therapy, and STR + radiation therapy. Patients undergoing endoscopic resection had significantly lower GTR rates and greater rates of adjuvant radiotherapy compared with open approaches but no difference in OS. CONCLUSION: Adult patients with craniopharyngioma who underwent GTR or STR with adjuvant radiotherapy had significantly improved overall survival. Endoscopic approaches had lower rates of GTR but no difference in OS.

Estimating Risk of Pituitary Apoplexy after Resection of Giant Pituitary Adenomas.

Background Pituitary apoplexy after resection of giant pituitary adenomas is a rare but often cited morbidity associated with devastating outcomes. It presents as hemorrhage and/or infarction of residual tumor in the postoperative period. Because of its rarity, its incidence and consequences remain ill defined. Objective The aim of this study is to estimate the rate of postoperative pituitary apoplexy after resection of giant pituitary adenomas and assess the morbidity and mortality associated with apoplexy. Methods A systematic review of literature was performed to examine extent of resection in giant pituitary adenomas based on surgical approach, rate of postoperative apoplexy, morbidities, and mortality. Advantages and disadvantages of each approach were compared. Results Seventeen studies were included in quantitative analysis describing 1,031 cases of resection of giant pituitary adenomas. The overall rate of subtotal resection (<90%) for all surgical approaches combined was 35.6% (95% confidence interval: 28.0-43.1). Postoperative pituitary apoplexy developed in 5.65% ( n = 19) of subtotal resections, often within 24 hours and with a mortality of 42.1% ( n = 8). Resulting morbidities included visual deficits, altered consciousness, cranial nerve palsies, and convulsions. Conclusion Postoperative pituitary apoplexy is uncommon but is associated with high rates of morbidity and mortality in subtotal resection cases. These findings highlight the importance in achieving a maximal resection in a time sensitive fashion to mitigate the severe consequences of postoperative apoplexy.

Outcomes for recurrent oral cavity squamous cell carcinoma.

OBJECTIVES: We sought to determine overall survival (OS), prognostic factors, cost, and functional outcomes after surgery for locally recurrent oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS: We retrospectively reviewed 399 cases of locally recurrent OCSCC from 1997 to 2011, of which 259 patients were treated with salvage surgery. Survival and prognostic factors were evaluated using univariable and multivariable Cox regression, the Kaplan-Meier method, and the log-rank test. RESULTS: The 5-year OS for patients undergoing surgical salvage, nonsurgical therapy, or supportive care was 44.2%, 1.5%, and 0%, respectively. For patients who underwent surgical salvage, 133 (51%) patients experienced a second recurrence at a median of 17 months. Factors associated with OS included disease-free interval ≤ 6 months (P =.0001), recurrent stage III-IV disease (P <.0001), and prior radiation (P =.0001). Patients with both advanced stage and prior radiation had a 23% 5-year OS, compared with 70% for those with neither risk (P <.001). Functionally, 85% of patients had > 80% speech intelligibility and 81% were able to eat by mouth following salvage surgery. Of the patients who required tracheostomy, 78% were decannulated. The adjusted median hospital and professional charges for patients were $129,696 (range $9,238-$956,818). CONCLUSIONS: Patients with recurrent OCSCC who underwent salvage surgery have favorable functional outcomes with half of alive at 5 years but poorer OS for advanced disease, disease-free interval ≤ 6 months, and prior radiation. Additionally, treatment is associated with high cost, and about half of patients ultimately develop another recurrence.

A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma.

Glioblastoma multiforme is a primary malignancy of the central nervous system that is universally fatal due to its disseminated nature. Recent investigations have focused on the unique tumor-tropic properties of stem cells as a novel platform for targeted delivery of anticancer agents to the brain. Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) both have the potential to function as cell carriers for targeted delivery of a glioma restricted oncolytic virus to disseminated tumor due to their reported tumor tropism. In this study, we evaluated NSCs and MSCs as cellular delivery vehicles for an oncolytic adenovirus in the context of human glioma. We report the first preclinical comparison of the two cell lines and show that, while both stem cell lines are able to support therapeutic adenoviral replication intracellularly, the amount of virus released from NSCs was a log higher than the MSC (p < 0.001). Moreover, only virus loaded NSCs that were administered intracranially in an orthotopic glioma model significantly prolonged the survival of tumor bearing animals (median survival for NSCs 68.5 days vs 44 days for MSCs, p < 0.002). Loading oncolytic adenovirus into NSCs and MSCs also led to expression of both pro- and anti-inflammatory genes and decreased vector-mediated neuroinflammation. Our results indicate that, despite possessing a comparable migratory capacity, NSCs display superior therapeutic efficacy in the context of intracranial tumors. Taken together, these findings argue in favor of NSCs as an effective cell carrier for antiglioma oncolytic virotherapy.

Bone marrow mesenchymal stem cells loaded with an oncolytic adenovirus suppress the anti-adenoviral immune response in the cotton rat model.

Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer. However, following intratumoral injections, oncolytic viruses fail to efficiently migrate away from the injection site and are rapidly cleared by the immune system. We have previously demonstrated enhanced viral delivery and replicative persistence in vivo using human bone marrow-derived mesenchymal stem cells (MSCs) as delivery vehicles. In this study, we evaluated the immune response to adenovirus (Ad)-loaded MSCs using the semipermissive cotton rat (CR) model. First, we isolated MSCs from CR bone marrow aspirates. Real-time quantitative PCR analysis revealed that CR MSCs supported the replication of Ads in vitro. Moreover, we observed similar levels of suppression of T-cell proliferation in response to mitogenic stimulation, by MSCs alone and virus-loaded MSCs. Additionally, we found that MSCs suppressed the production of interferon-γ (IFN-γ) by activated T cells. In our in vivo model, CR MSCs enhanced the dissemination and persistence of Ad, compared to virus injection alone. Collectively, our data suggest that the use of MSCs as a delivery strategy for oncolytic Ad potentially offers a myriad of benefits, including improved delivery, enhanced dissemination, and increased persistence of viruses via suppression of the antiviral immune response.

Revisiting the controversy: The role of fungi in chronic rhinosinusitis.

In the last two decades, the development of culture-independent genomic techniques has facilitated an increased appreciation of the microbiota-immunity interactions and their role in a multitude of chronic inflammatory diseases such as chronic rhinosinusitis (CRS), asthma, inflammatory bowel disease and dermatitis. While the pathologic role of bacteria in chronic inflammatory diseases is generally accepted, the understanding of the role of fungi remains controversial. Chronic rhinosinusitis, specifically the phenotype linked to nasal polyps, represents a spectrum of chronic inflammatory diseases typically characterized by a type 2 immune response. Studies on the microbiota within sinus cavities from healthy and diseased patients have focused on the bacterial community, mainly highlighting the loss of diversity associated with sinus inflammation. Within the various CRS with nasal polyps (CRSwNP) phenotypes, allergic fungal rhinosinusitis presents an opportunity to investigate the role of fungi in chronic type 2 immune responses as well as the antifungal immune pathways designed to prevent invasive fungal diseases. In this review, we examine the spectrum of fungi-associated sinus diseases highlighting the interaction between fungal species and host immune status on disease presentation. With a focus on fungi and type 2 immune response, we highlight the current knowledge and its limitations of the sinus mycobiota along with cellular interactions and activated molecular pathways linked to fungi.

Current Concepts in the Management of Allergic Fungal Rhinosinusitis.

Allergic fungal rhinosinusitis (AFRS) represents a subtype of chronic rhinosinusitis with nasal polyposis that exhibits a unique, often striking clinical presentation. Since its initial description more than a quarter century ago, a more sophisticated understanding of the pathophysiology of AFRS has been achieved and significant advancements in improving clinical outcomes made. This review focuses on the latest developments involving the pathophysiology and clinical management of this fascinating disease.

Nasal vestibular body treatment for recalcitrant nasal obstruction.

BACKGROUND: The nasal vestibular body (NVB) is a recently reported dynamic swell body present in the inferolateral internal nasal valve. The contribution of NVB presence to persistent nasal obstruction, and effects of NVB treatment, are undefined. METHODS: Thirty-five patients with recalcitrant nasal obstruction and NVB presence were retrospectively reviewed between 2013 and 2019, including 25 patients (48 sides) who had NVBs reduced via radiofrequency ablation (RFA) and 10 patients (20 sides) who had untreated NVBs. Posttreatment healing and complications were reviewed at early (<1 month) and late (mean, 7.3 months) time-points after RFA of the NVB. A subset of the NVB-treatment patients (18 of 25 patients) were compared with 10 NVB-control patients for pre-/posttreatment outcomes using 22-item Sino-Nasal Outcome Test (SNOT-22) and subdomain scoring. RESULTS: NVBs were successfully reduced in 100% of cases (48 of 48 sides) over both time-points. Early sequelae of NVB treatment, such as local crusting (22 of 23, 95.6%) and bone exposure (4 of 23, 17.3%), resolved by the late time-point, with complete remucosalization (23 of 23, 100%) of all NVB treatment sites. No persistent pain, sensory loss, or pyriform aperture stenosis was noted from any patient/side. Significant reductions between mean pre- and postoperative SNOT-22 (-24, p = 0.001) and individual subdomain (-2, p = 002) scores were seen in the NVB-treatment patients compared to the reductions in NVB-controls (-8 and -1, respectively, both p > 0.001). CONCLUSION: NVB treatment using RFA is safe and highly effective, providing complete swell body reduction with only transient local morbidity. NVB presence contributes to persistent/recalcitrant nasal obstruction, with significant improvement in nasal airway function noted after NVB soft tissue reduction.

Long-term quality of life after definitive treatment of sinonasal and nasopharyngeal malignancies.

OBJECTIVE: To evaluate long-term global and site-specific health-related quality of life (HRQoL) in patients treated for sinonasal and nasopharyngeal malignancies. STUDY DESIGN: Cross-sectional. METHODS: One hundred fourteen patients with sinonasal and nasopharyngeal malignancies received surgery, radiation, systemic chemotherapy, or a combination thereof, with curative intent. Validated global ([EuroQol-5D] Visual Analogue Scale [EQ-5D VAS]) and disease-specific instruments (MD Anderson Symptom Inventory-Head and Neck [MDASI-HN], Anterior Skull Base Questionnaire [ASBQ]) were administered to patients who were both free of disease and had completed treatment at least 12 months previously. Associations between instruments, instrument domains, and specific clinical parameters were analyzed. RESULTS: The median age was 55 years. The mean EQ-5D VAS, MDASI-22 composite score, and ASBQ score were 74 (standard deviation [SD] 21), 48 (SD 36), and 130 (SD 27), respectively. The most frequently reported high-severity items in MDASI-HN were dry mouth and difficulty tasting food. The most frequently reported high-severity items in ASBQ were difficulty with smell and nasal secretions. Advanced Tumor (T) classification was associated with worse overall ASBQ sum score (P = 0.02). ASBQ performance at home and MDASI-HN drowsy symptom items independently predicted worse global HRQoL as measured by the EQ-5D VAS (P < 0.001). CONCLUSION: Global HRQoL for survivors of sinonasal and nasopharyngeal malignancies after multimodality treatment approximates that of the U.S. population for the same age group. ASBQ and MDASI-HN correlate well with global HRQoL outcomes as measured by EQ-5D VAS. MDASI-HN and ASBQ elicited unique symptoms, highlighting the complex symptom burden experienced by these patients. Further studies should identify patients predisposed to reduced long-term QOL. LEVEL OF EVIDENCE: 3 Laryngoscope, 130:86-93, 2020.

ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers.

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.

Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma.

Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4-5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4-5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4-5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma.

Oncologic management of sinonasal undifferentiated carcinoma.

PURPOSE OF REVIEW: This article reviews the latest treatment paradigms in sinonasal undifferentiated carcinoma (SNUC). RECENT FINDINGS: The aggressive biology and associated advanced presentation of SNUC make successful treatment a challenge shared across medical specialties. Still, studies reporting outcomes in SNUC indicate that an aggressive treatment strategy consisting of surgery, radiation and chemotherapy offers the best chance of prolonged survival. SUMMARY: Successful treatment of SNUC requires highly specialized care at tertiary cancer treatment facilities. A better understanding of the biology of the disease coupled with increasing outcome reporting will lead to optimized treatment regimens.