Publications by authors named "Nithin D Adappa"

205 Publications

A National Cancer Database Analysis of Sinonasal Malignant Myoepithelial Carcinoma Outcomes.

Am J Rhinol Allergy 2022 Aug 15:19458924221121419. Epub 2022 Aug 15.

Department of Otorhinolaryngology - Head and Neck Surgery, 6572University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

Objectives: Myoepithelial carcinoma (MECA) is a rare salivary gland tumor that can occur in the sinonasal cavity with poor outcomes. There are limited data on sinonasal outcomes to guide management. We sought to use the National Cancer Database (NCDB) to better define treatment outcomes in MECA.

Methods: We conducted a retrospective analysis of the NCDB from 2004 to 2016 for patients with MECA of the sinonasal cavity. Patient demographic, treatment, and survival information were extracted from the database. Unadjusted Kaplan-Meier estimates, log-rank tests, and a multivariable Cox proportional hazard model were used to assess overall survival (OS).

Results: A total of 38 patients were included. The average age was 60.7 ± 18.2 years and male patients represented 47.4% of the cohort. Most patients were White (n = 26, 68.4%) and the majority of patients had either private insurance (n = 20, 52.6%) or Medicare (n = 15, 39.5%). The primary site of most tumors was nasal cavity (n = 19, 50%), followed by maxillary sinus (n = 16, 42.1%). Most tumors were >4 cm (n = 17, 44.7%). The 1-, 5-, and 10-year OS was 89.7% (95% confidence interval [CI]: 80.7%-99.8%), 63.6% (95% CI: 49.4%-82%), and 46.4% (95% CI: 31%-69.5%), respectively. The median survival for the overall cohort was 85.8 months. Medicare insurance was associated with a decreased OS (hazard ratio [HR]: 8.2; 95% CI: 2.88-23.4,  < .001). Patients who underwent surgery had a significant survival benefit (HR: 0.04, 95% CI: 0.01-0.21,  < .001).

Discussion: MECA of the sinonasal cavity is a rare tumor with poorly understood behavior. Data from the NCDB suggests that it is a relatively aggressive tumor with surgical management associated with better outcomes. This analysis is limited by the small sample size and further research into optimal treatment regimens is needed.
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http://dx.doi.org/10.1177/19458924221121419DOI Listing
August 2022

In-Hospital Costs for Open versus Endoscopic Endonasal Approach for Craniopharyngioma Resection.

Laryngoscope 2022 Aug 5. Epub 2022 Aug 5.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: To determine the in-hospital cost implications of an expanded endoscopic endonasal approach (EEEA) for craniopharyngioma resection relative to the traditional open transcranial approach.

Methods: All craniopharyngioma surgeries performed at a single institution over a period from January 1st 2001 to October 31th 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate regression analysis was performed using R software.

Results: Thirty-six patients met study criteria, including 22 undergoing an open approach and 14 undergoing an EEEA. There was a significantly longer average length of stay among patients undergoing open resection (21.5 vs. 10.6 days, p = 0.024). The average total in-hospital cost of a patient undergoing an EEEA was $58979.3 compared to $89142.3 for an open approach (p = 0.127). On univariate regression analysis, the total in-hospital cost for a patient undergoing an open approach relative to an EEEA was $30163.0 (p = 0.127). The open approach was exclusively performed from study onset until April 2010 (16 patients). From April 2010 to August 2013, 6 open approaches and 5 EEEA were performed. The EEEA has been exclusively performed from August 2013 until the conclusion of our study period (9 patients).

Conclusions: There has been a shift toward surgical resection of craniopharyngioma via an EEEA approach for amenable tumors. Our study demonstrates that the EEEA has become the preferred surgical approach at our institution, and shows that the EEEA is associated with shorter postoperative length of stay and lower total in-hospital cost. Laryngoscope, 2022.
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http://dx.doi.org/10.1002/lary.30313DOI Listing
August 2022

Rhinologic Innovation and Advancement Come in All Forms of Investigation.

Authors:
Nithin D Adappa

Am J Rhinol Allergy 2022 09;36(5):556-558

University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1177/19458924221116173DOI Listing
September 2022

Odontogenic Sinusitis is a Common Cause of Operative Extra-Sinus Infectious Complications.

Am J Rhinol Allergy 2022 Jul 25:19458924221114941. Epub 2022 Jul 25.

Department of Otolaryngology-Head & Neck Surgery, 2971Henry Ford Health, Detroit, Michigan.

Background: Orbital, intracranial, and osseous extra-sinus complications can arise from bacterial or fungal sinusitis. Odontogenic sinusitis (ODS) can cause extra-sinus complications, but its prevalence remains poorly characterized.

Objective: To determine the frequency of ODS as a cause of operative extra-sinus infectious complications and describe clinical features of all complicated sinusitis cases.

Methods: A multi-institutional retrospective review was performed on all operative sinusitis-related extra-sinus complications from 2011 to 2020. ODS was diagnosed by sinus computed tomography (CT) and dental evaluations when available. Demographics, complication types, sinusitis etiologies, and various clinical features were analyzed.

Results: Forty-five patients were included (mean age 55.5 years, 56% male). Of the extra-sinus complications, 40% were orbital only, 22% intracranial only, 13% osseous only, and 25% involved combined complications. The 2 most common causes of extra-sinus complications were ODS (40%) and mucopyocele (27%). When invasive fungal etiologies were excluded, and only unilateral maxillary opacification on CT was considered, nearly 60% of extra-sinus complications were due to ODS. Unilateral maxillary sinus opacification on CT was present in 100% of complicated ODS compared to 44% of nonodontogenic cases, and oral anaerobes were only identified in ODS cases. No complicated ODS patients underwent dental interventions during hospitalization.

Conclusion: ODS was the most common cause of operative extra-sinus infectious complications. Clinicians should consider ODS high on the differential diagnosis of all patients presenting with complicated sinusitis, especially when sinusitis is unilateral and invasive fungal infection is not suspected.
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http://dx.doi.org/10.1177/19458924221114941DOI Listing
July 2022

Image-Guided Surgical Device Failures in Functional Endoscopic Sinus Surgery: A MAUDE Analysis.

Laryngoscope 2022 Jul 14. Epub 2022 Jul 14.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Objective: Image-guided surgery (IGS) devices have become widely used for anatomic localization during functional endoscopic sinus surgery (FESS). However, there are no studies that analyze the post-market complications associated with IGS device use during FESS. The objective of this study was to better characterize post-market complications associated with the use of IGS devices during sinus surgery.

Methods: The US Food and Drug Administration's Manufacturer and User Facility Device Experience database was queried for event reports associated with neurological stereotaxic devices utilized in IGS between the dates of January 1, 2016 and December 31, 2020. Medical device reports that were analyzed for this study pertained strictly to FESS.

Results: There were 1873 reports involving IGS devices for FESS included in this study. Fifty-five reports involved adverse events to patients (2.9%) and 1818 (97.1%) involved device malfunctions. Of the adverse events to patients, the most common included cerebrospinal fluid leakage (45.6%), tissue damage (12.7%), and nervous system injury (3.6%). The most commonly reported device malfunction was imprecision (21.1%).

Conclusion: IGS devices are widely utilized in FESS. Of the medical device reports between 2016 and 2020, less than 3% resulted in adverse events. Further studies of the infrequent post-market complications of IGS devices used in FESS can help guide surgeons on the risks of their clinical use.

Level Of Evidence: 4-Retrospective database survey without controls Laryngoscope, 2022.
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http://dx.doi.org/10.1002/lary.30296DOI Listing
July 2022

Prognosis of Distant Metastatic Sites in Anterior Skull Base Malignancies.

J Neurol Surg B Skull Base 2022 Jun 10;83(Suppl 2):e459-e466. Epub 2021 Jun 10.

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States.

 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).  The National Cancer Database was queried for patients with anterior skull base malignant neoplasms with DM.  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).  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).  Tumor histology, metastatic sites, and several disease factors affected prognosis in anterior skull base malignancies with DM.
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http://dx.doi.org/10.1055/s-0041-1731031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272307PMC
June 2022

Sinonasal Acinic Cell Carcinoma: A Review of the National Cancer Database.

Am J Rhinol Allergy 2022 Jun 14:19458924221107206. Epub 2022 Jun 14.

Department of Otorhinolaryngology - Head and Neck Surgery, 6572University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Background: Acinic cell carcinoma (ACC) is a salivary gland malignancy that rarely can involve the sinonasal cavity. There are limited outcomes data available to guide management.

Objective: We sought to use the National Cancer Database (NCDB) to characterize treatment outcomes in sinonasal ACC.

Methods: A retrospective analysis of the NCDB from 2004 to 2016 for patients with ACC involving the sinonasal cavity was conducted. Demographic, treatment, and survival information were obtained. Unadjusted Kaplan-Meier estimates, log-rank tests, and a multivariable Cox proportional hazard model were used to assess overall survival (OS).

Results: A total of 28 patients were included in the analysis with an average age of 58.6 ± 15.5 years. Half the patients (n = 14, 50%) were male, mostly white (n = 23, 82.1%), and with private insurance (n = 16, 57.1%). The nasal cavity was the most common subsite (n = 18, 64.3%), followed by the maxillary sinus (n = 5, 17.9%). Most patient received surgery alone (n = 17, 60.7%), with the remaining patients undergoing surgery followed by radiation (n = 8, 28.6%), radiation alone (n = 1, 3.6%), and no treatment (n = 2, 7.1%). The 1-, 5-, and 10-year survival in this cohort was 100% (95% CI: 100%-100%), 84.3% (95% CI: 71.2%-99.7%), and 72.2% (95% CI: 55%-94.8%), respectively. On multivariate analysis, older age was associated with worse OS (hazard ratio (HR): 1.27; 95% CI: 1.11-1.46,  < .001). Disease of the sphenoid sinus correlated with worse survival (HR: 198, 95% CI: 10.4-3,739,  < .001) and large tumor size was associated with worse OS on log-rank test, but not on multivariate analysis.

Conclusion: Sinonasal ACC is a rare entity with relatively good long-term outcomes. Older age and primary disease of the sphenoid sinus are associated with worse outcomes. Most patients are treated with surgical resection. Future research is needed to assess the optimal timing and indications for radiation therapy.
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http://dx.doi.org/10.1177/19458924221107206DOI Listing
June 2022

Novel intraoperative fast anatomic mapping as teaching adjunct in endoscopic sinus surgery.

Int Forum Allergy Rhinol 2022 Jun 10. Epub 2022 Jun 10.

Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania Health System, Philadelphia, PA.

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http://dx.doi.org/10.1002/alr.23046DOI Listing
June 2022

Postoperative protocols following endoscopic skull base surgery: An evidence-based review with recommendations.

Int Forum Allergy Rhinol 2022 Jun 9. Epub 2022 Jun 9.

Department of Otolaryngology, Head and Neck Surgery, University of California Irvine, Orange, California, USA.

Background: Postoperative management strategies for endoscopic skull base surgery (ESBS) vary widely because of limited evidence-based guidance.

Methods: The PubMed, EMBASE, and Cochrane databases were systematically reviewed from January 1990 through February 2022 to examine 18 postoperative considerations for ESBS. Nonhuman studies, articles written in a language other than English, and case reports were excluded. Studies were assessed for levels of evidence, and each topic's aggregate grade of evidence was evaluated.

Results: A total of 74 studies reporting on 18 postoperative practices were reviewed. Postoperative pain management, prophylactic antibiotics, and lumbar drain use had the highest grades of evidence (B). The literature currently lacks high quality evidence for a majority of the reviewed ESBS precautions. There were no relevant studies to address postoperative urinary catheter use and medical intracranial pressure reduction.

Conclusion: The evidence for postoperative ESBS precautions is heterogeneous, scarce, and generally of low quality. Although this review identified the best evidence available in the literature, it suggests the urgent need for more robust evidence. Therefore, additional high-quality studies are needed in order to devise optimal postoperative ESBS protocols.
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http://dx.doi.org/10.1002/alr.23041DOI Listing
June 2022

Sinonasal Inverted Papilloma and Squamous Cell Carcinoma: Contemporary Management and Patient Outcomes.

Cancers (Basel) 2022 Apr 28;14(9). Epub 2022 Apr 28.

Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Inverted papillomas (IP) are the most common sinonasal tumor with a tendency for recurrence, potential attachment to the orbit and skull base, and risk of malignant degeneration into squamous cell carcinoma (SCC). While the overall rate of recurrence has decreased with the widespread adoption of high-definition endoscopic optics and advanced surgical tools, there remain challenges in managing tumors that are multiply recurrent or involve vital neurovascular structures. Here, we review the state-of-the-art diagnostic tools for IP and IP-degenerated SCC, contemporary surgical management, and propose a surveillance protocol.
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http://dx.doi.org/10.3390/cancers14092195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102473PMC
April 2022

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

Cells 2022 04 27;11(9). Epub 2022 Apr 27.

Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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 , leading to Ca-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 Ca- 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 and pHrodo-. 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 Ca 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.
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http://dx.doi.org/10.3390/cells11091478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9101439PMC
April 2022

Outcomes of endoscopic endonasal resection of pediatric craniopharyngiomas.

Int Forum Allergy Rhinol 2022 Apr 29. Epub 2022 Apr 29.

Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania, Health System, Philadelphia, Pennsylvania, USA.

Background: Craniopharyngiomas have traditionally been treated via open transcranial approaches. More recent, endoscopic endonasal approaches have been increasingly used; however, there has been limited evaluation of long-term outcomes for this approach.

Methods: A retrospective review was performed to analyze patients with pediatric craniopharyngioma undergoing endonasal endoscopic resection from 2012 to 2020. Demographic information, clinicopathologic factors, and outcomes including follow-up and recurrences were analyzed.

Results: All 42 patients, with a mean age of 8.0 years, were included. The median follow-up time was 49 months. Mean tumor diameter was 3.6 cm. All of the tumors had sellar and suprasellar components. The most common presenting symptoms were headaches (64.3%), visual changes (59.5%), and nausea/vomiting (38.1%). Most patients (73.3%) had resolution of their presenting symptoms by their first postoperative visit. Vision improved or remained normal in 69.0% of patients. Postoperatively, incidence of panhypopituitarism or diabetes insipidus developed in 89.7% and 77.8% of patients, respectively. The postoperative cerebrospinal fluid leak rate was 7.1%. The recurrence rate was 9.5%.

Conclusion: Endoscopic endonasal resection for pediatric craniopharyngiomas can achieve high rates of resection with low rates of disease recurrence when compared with the outcomes of open transcranial resection reported in the literature. However, hypothalamic-pituitary dysfunction remains a significant postoperative morbidity in both approaches.
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http://dx.doi.org/10.1002/alr.23009DOI Listing
April 2022

Cilia Stimulatory and Antibacterial Activities of T2R Bitter Taste Receptor Agonist Diphenhydramine: Insights into Repurposing Bitter Drugs for Nasal Infections.

Pharmaceuticals (Basel) 2022 Apr 6;15(4). Epub 2022 Apr 6.

Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

T2R bitter taste receptors in airway motile cilia increase ciliary beat frequency (CBF) and nitric oxide (NO) production. Polymorphisms in some T2Rs are linked to disease outcomes in chronic rhinosinusitis (CRS) and cystic fibrosis (CF). We examined the expression of cilia T2Rs during the differentiation of human nasal epithelial cells grown at air-liquid interface (ALI). The T2R expression increased with differentiation but did not vary between CF and non-CF cultures. Treatment with Pseudomonas aeruginosa flagellin decreased the expression of diphenhydramine-responsive T2R14 and 40, among others. Diphenhydramine increased both NO production, measured by fluorescent dye DAF-FM, and CBF, measured via high-speed imaging. Increases in CBF were disrupted after flagellin treatment. Diphenhydramine impaired the growth of lab and clinical strains of , a major pathogen in CF and CF-related CRS. Diphenhydramine impaired biofilm formation of , measured via crystal violet staining, as well as the surface attachment of to CF airway epithelial cells, measured using colony-forming unit counting. Because the T2R agonist diphenhydramine increases NO production and CBF while also decreasing bacterial growth and biofilm production, diphenhydramine-derived compounds may have potential clinical usefulness in CF-related CRS as a topical therapy. However, utilizing T2R agonists as therapeutics within the context of infection may require co-treatment with anti-inflammatories to enhance T2R expression.
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http://dx.doi.org/10.3390/ph15040452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025516PMC
April 2022

International consensus statement on allergy and rhinology: Olfaction.

Int Forum Allergy Rhinol 2022 04;12(4):327-680

Neurology Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania, USA.

Background: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O).

Methods: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus.

Results: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies.

Conclusion: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.
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http://dx.doi.org/10.1002/alr.22929DOI Listing
April 2022

Pediatric Pituitary Surgery.

Otolaryngol Clin North Am 2022 Apr 4;55(2):477-491. Epub 2022 Mar 4.

Division of Neurosurgery, Children's Hospital of Philadelphia, Wood Building, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Lesions of the pituitary and sellar region in children comprise a wide variety of pathologic conditions, but advances in surgical technology and techniques have enabled both biopsy and resection of such lesions despite age-dependent anatomic constraints. In this article, the authors discuss the common pathologic conditions encountered, perioperative management of these patients, surgical techniques required to address these lesions and repair the pediatric skull base, points of controversy, and future areas of work.
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http://dx.doi.org/10.1016/j.otc.2021.12.017DOI Listing
April 2022

Long-term outcomes in sinonasal squamous cell carcinoma arising from inverted papilloma: Systematic review.

Head Neck 2022 04 9;44(4):1014-1029. Epub 2022 Feb 9.

Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, California, USA.

Long-term survival and recurrence patterns of squamous cell carcinoma arising from inverted papilloma (IP-SCC) have not been thoroughly investigated. Four electronic databases were searched and primary studies describing overall survival (OS), recurrence, and mean time to recurrence of patients with IP-SCC were included for review. Our search yielded 662 studies. The 28 studies selected for inclusion identified 663 patients with IP-SCC. In 596 patients with reported T classification, 439 (73.7%) were T3/T4 on presentation. Of the 650 participants with recurrence data (local, regional, and distant), 155 (23.8%) experienced a recurrence, with an aggregate mean time-to-recurrence of 24.3 months. In 565 patients with 5-year OS rates, the aggregate 5-year OS was 62%. Based on the literature to date, IP-SCC is associated with a 5-year OS rate of 62%. 23.8% of patients experienced recurrence at a mean time of 24.3 months, suggesting the need for long-term surveillance.
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http://dx.doi.org/10.1002/hed.26995DOI Listing
April 2022

Similarities between allergen sensitivity patterns of central compartment atopic disease and allergic rhinitis.

Int Forum Allergy Rhinol 2022 Feb 7. Epub 2022 Feb 7.

Division of Rhinology, Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1002/alr.22983DOI Listing
February 2022

Steroid affected cytokines in aspirin-exacerbated respiratory disease.

Int Forum Allergy Rhinol 2022 Jan 14. Epub 2022 Jan 14.

Department of Otorhinolaryngology-Head and Neck Surgery, Division of Rhinology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Background: Patients with aspirin-exacerbated respiratory disease (AERD) are among the most challenging rhinologic patients to treat. AERD has a complex inflammatory milieu of lipid mediators and cytokines. In this study we evaluated cytokine differences in the complex AERD environment at the mucus, epithelial, and tissue levels.

Methods: Samples were acquired at the time of sinus surgery from 21 patients (seven steroid-treated, 14 untreated) with aspirin challenge-confirmed AERD. Three methods (sponge adsorption, epithelial brushing, tissue biopsy) were used to acquire samples from the respective sinus sampling sites (mucus, polyp epithelium, and full-thickness polyp) of each patient. We measured and compared 16 cytokine concentrations in AERD patients with or without prednisone treatment using the Luminex platform.

Results: In most sampling sites, IL-5, IL-6, IL-10, IL-13, IL-33, CCL20, and TNF-α were detected at higher concentrations than IFN-γ, IL-1β, IL-17A, IL-4, IL-22, IL-17E/IL25, and GM-CSF. Each sampling site had a different pattern of cytokine levels, and except for IL-5 and IL-25 there was no correlation among sampling methods for each cytokine tested. The most notable and significant decreases in cytokines from those treated with prednisone were observed in the epithelium for IL-5, IL-10, IL-33, and IFN-γ.

Conclusions: In the epithelial samples, type 2-associated cytokines IL-5 and IL-33, the anti-inflammatory cytokine IL-10, and IFN-γ were lower in AERD patients treated with prednisone. This work serves as a basis to assess therapeutic-induced mucosal cytokine responses in AERD and indicates that the site of cytokine measurement is an important consideration when assessing results.
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http://dx.doi.org/10.1002/alr.22977DOI Listing
January 2022

Association between the HLA-DQA1 rs1391371 risk allele and chronic rhinosinusitis.

Int Forum Allergy Rhinol 2022 Aug 25;12(8):1075-1077. Epub 2022 Jan 25.

Department of Otorhinolaryngology - Head and Neck Surgery, Division of Rhinology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1002/alr.22960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9256855PMC
August 2022

Deep learning classification of inverted papilloma malignant transformation using 3D convolutional neural networks and magnetic resonance imaging.

Int Forum Allergy Rhinol 2022 Aug 18;12(8):1025-1033. Epub 2022 Jan 18.

Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA.

Background: Distinguishing benign inverted papilloma (IP) tumors from those that have undergone malignant transformation to squamous cell carcinoma (IP-SCC) is important but challenging to do preoperatively. Magnetic resonance imaging (MRI) can help differentiate these 2 entities, but no established method exists that can automatically synthesize all potentially relevant MRI image features to distinguish IP and IP-SCC. We explored a deep learning approach, using 3-dimensional convolutional neural networks (CNNs), to address this challenge.

Methods: Retrospective chart reviews were performed at 2 institutions to create a data set of preoperative MRIs with corresponding surgical pathology reports. The MRI data set included all available MRI sequences in the axial plane, which were used to train, validate, and test 3 CNN models. Saliency maps were generated to visualize areas of MRIs with greatest influence on predictions.

Results: A total of 90 patients with IP (n = 64) or IP-SCC (n = 26) tumors were identified, with a total of 446 images of distinct MRI sequences for IP (n = 329) or IP-SCC (n = 117). The best CNN model, All-Net, demonstrated a sensitivity of 66.7%, specificity of 81.5%, overall accuracy of 77.9%, and receiver-operating characteristic area under the curve of 0.80 (95% confidence interval, 0.682-0.898) for test classification performance. The other 2 models, Small-All-Net and Elastic-All-Net, showed similar performance levels.

Conclusion: A deep learning approach with 3-dimensional CNNs can distinguish IP and IP-SCC with moderate test classification performance. Although CNNs demonstrate promise to enhance the prediction of IP-SCC using MRIs, more data are needed before they can reach the predictive value already established by human MRI evaluation.
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http://dx.doi.org/10.1002/alr.22958DOI Listing
August 2022

Editorial: Emerging frontiers in rhinology and skull base surgery.

Curr Opin Otolaryngol Head Neck Surg 2022 02;30(1):1-2

Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine Medical Center, Orange, California, USA.

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http://dx.doi.org/10.1097/MOO.0000000000000785DOI Listing
February 2022

The management of cystic fibrosis chronic rhinosinusitis: An evidenced-based review with recommendations.

Int Forum Allergy Rhinol 2021 Dec 21. Epub 2021 Dec 21.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Irving Medical Center, New York, NY.

Background: Cystic fibrosis (CF) chronic rhinosinusitis (CRS) has emerged as a distinct diagnostic entity, unique from other endotypes of CRS in its presentation, pathophysiology, diagnosis, treatment, and outcomes. As the sinonasal health of this patient population may have broad effects on pulmonary health and quality of life, a comprehensive understanding of the diagnostic and therapeutic approach to CF CRS is essential. In recognizing recent scientific advances and unique treatment modalities specific to this challenging patient population, in this review we systematically evaluate the scientific literature and provide an evidenced-based review with recommendations (EBRR) for fundamental management principles of CF CRS.

Methods: A systematic review of the literature was performed. Studies evaluating interventions for the management of CF CRS were included. An iterative review process was implemented in accordance with EBRR guidelines. A treatment recommendation was generated based on an assessment of the benefits, harms, and the overall grade of evidence.

Results: We evaluated the published literature on 5 unique topics. Each of the following therapeutic categories was investigated explicitly for treatment outcomes in patients with CF CRS: (1) nasal saline; (2) intranasal corticosteroids (INCS); (3) topical antibiotics; (4) cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy; and (5) endoscopic sinus surgery (ESS).

Conclusion: Based on the currently available evidence, nasal saline, ESS, and CFTR modulators are recommended in the management of CF CRS when appropriate. INCS and topical antibiotics are options. Clinical judgment and experience are essential in caring for patients with this uniquely challenging disorder.
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http://dx.doi.org/10.1002/alr.22953DOI Listing
December 2021

Dupilumab Adverse Events in Nasal Polyp Treatment: Analysis of FDA Adverse Event Reporting System.

Laryngoscope 2021 Dec 16. Epub 2021 Dec 16.

Department of Otolaryngology-Head and Neck Surgery, Kaiser Permanente, Oakland, California, U.S.A.

Objectives: Dupilumab was the first biologic approved to treat chronic rhinosinusitis with nasal polyps (CRSwNP). While the risk of adverse events in phase-III clinical trials was low, dupilumab-associated adverse reactions (DAR) with real-world use is unknown and potentially under-reported. We aimed to evaluate DAR for CRSwNP treatment (CRSwNP-tx) using the FDA Adverse Event Reporting System (FAERS).

Study Design: Retrospective database study.

Methods: FAERS was queried for DAR from 2019Q1 to 2021Q2. Individual DAR (iDAR) were categorized and quantitatively compared between treatment groups (CRSwNP, asthma, atopic dermatitis). Zero-truncated Poisson regression was modeled to predict the number of iDAR, and logistic regression was modeled to predict serious DARs.

Results: There were 15,411 DAR observations; 911 for CRSwNP-tx, of which 121 (13.3%) had serious reactions and 3 died. Common CRSwNP-tx iDAR were dermatologic (13.9%), generalized (13.3%), and injection-site (10.8%) symptoms. The number of CRSwNP-tx iDAR was 2.99 [2.81, 3.17], compared to 3.44 [3.32, 3.56] for asthma and 3.18 [3.13, 3.24] for atopic dermatitis (Kruskal-Wallis test, P < .001). For CRSwNP-tx, iDAR reported-risk-ratio was 0.84 [0.77, 0.92] among men and 1.12 [1.04, 1.22] among older adults (>50). Serious DAR reported-odds-ratio was 1.37 [0.91, 2.04] among men and 1.39 [0.93, 2.08] among older adults.

Conclusions: While there are limitations with FAERS, this analysis suggests CRSwNP-tx is associated with fewer iDAR compared with other treatment indications. More iDAR are experienced among women and older adults, but men tend to have more serious DAR.

Level Of Evidence: III Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29992DOI Listing
December 2021

Comparison of aspirin desensitization outcomes between men and women with AERD.

Int Forum Allergy Rhinol 2022 Jun 5;12(6):872-875. Epub 2022 Jan 5.

Division of Rhinology, Department of Otorhinolaryngology, Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1002/alr.22933DOI Listing
June 2022

The bitter end: T2R bitter receptor agonists elevate nuclear calcium and induce apoptosis in non-ciliated airway epithelial cells.

Cell Calcium 2022 01 8;101:102499. Epub 2021 Nov 8.

Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. Electronic address:

Bitter taste receptors (T2Rs) localize to airway motile cilia and initiate innate immune responses in retaliation to bacterial quorum sensing molecules. Activation of cilia T2Rs leads to calcium-driven NO production that increases cilia beating and directly kills bacteria. Several diseases, including chronic rhinosinusitis, COPD, and cystic fibrosis, are characterized by loss of motile cilia and/or squamous metaplasia. To understand T2R function within the altered landscape of airway disease, we studied T2Rs in non-ciliated airway cell lines and primary cells. Several T2Rs localize to the nucleus in de-differentiated cells that typically localize to cilia in differentiated cells. As cilia and nuclear import utilize shared proteins, some T2Rs may target to the nucleus in the absence of motile cilia. T2R agonists selectively elevated nuclear and mitochondrial calcium through a G-protein-coupled receptor phospholipase C mechanism. Additionally, T2R agonists decreased nuclear cAMP, increased nitric oxide, and increased cGMP, consistent with T2R signaling. Furthermore, exposure to T2R agonists led to nuclear calcium-induced mitochondrial depolarization and caspase activation. T2R agonists induced apoptosis in primary bronchial and nasal cells differentiated at air-liquid interface but then induced to a squamous phenotype by apical submersion. Air-exposed well-differentiated cells did not die. This may be a last-resort defense against bacterial infection. However, it may also increase susceptibility of de-differentiated or remodeled epithelia to damage by bacterial metabolites. Moreover, the T2R-activated apoptosis pathway occurs in airway cancer cells. T2Rs may thus contribute to microbiome-tumor cell crosstalk in airway cancers. Targeting T2Rs may be useful for activating cancer cell apoptosis while sparing surrounding tissue.
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http://dx.doi.org/10.1016/j.ceca.2021.102499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752513PMC
January 2022

Determinants of Survival in Skull Base Chondrosarcoma: A National Cancer Database Study.

World Neurosurg 2022 Feb 20;158:e766-e777. Epub 2021 Nov 20.

Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Orange, California, USA. Electronic address:

Objective: Chondrosarcomas of the skull base are rare tumors most commonly treated surgically with or without adjuvant radiation therapy. Using the National Cancer Database (NCDB), we analyzed overall survival (OS), treatment modalities, and prognosticators.

Methods: The NCDB was queried for all cases of histologically confirmed skull base chondrosarcoma treated between 2004 and 2015, excluding patients with more than 1 malignant tumor, on palliative care, receiving unrelated concurrent treatments, or having less than 1 month of follow-up. The χ test for categorical variables, Cox proportional hazards models, and Kaplan-Meier log-rank analysis were used to test associations with the use of adjuvant radiation, OS, and survival time.

Results: A total of 498 patients with skull base chondrosarcoma were identified in the NCDB. Of them, 224 (45.0%) and 198 (39.8%) were treated with either surgery alone or surgery with adjuvant radiation therapy, respectively. Patients more likely to undergo surgery with adjuvant radiation had higher tumor grade (P = 0.008), later year of diagnosis (P = 0.002), positive surgical margins (P < 0.001), and treatment at an academic institution (P = 0.02). Patient, tumor, and socioeconomic factors associated with worse OS on multivariate analysis included the Charlson/Deyo Comorbidity Score ≥2 (P = 0.017), as well as clear cell (P = 0.02) and dedifferentiated (P = 0.006) histology. Age, tumor grade, tumor size, treatment modality, insurance status, facility type, and urban/rural population did not show a statistically significant impact on OS.

Conclusion: The mainstay of treatment for skull base chondrosarcoma is surgery, with consideration of adjuvant radiation. This study demonstrated worse overall survival associated with more frail patients and aggressive histology types. It is important to consider these factors when planning the clinical management of these patients.
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http://dx.doi.org/10.1016/j.wneu.2021.11.066DOI Listing
February 2022

Neuropeptide Y Reduces Nasal Epithelial T2R Bitter Taste Receptor-Stimulated Nitric Oxide Production.

Nutrients 2021 Sep 27;13(10). Epub 2021 Sep 27.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Bitter taste receptors (T2Rs) are G-protein-coupled receptors (GPCRs) expressed on the tongue but also in various locations throughout the body, including on motile cilia within the upper and lower airways. Within the nasal airway, T2Rs detect secreted bacterial ligands and initiate bactericidal nitric oxide (NO) responses, which also increase ciliary beat frequency (CBF) and mucociliary clearance of pathogens. Various neuropeptides, including neuropeptide tyrosine (neuropeptide Y or NPY), control physiological processes in the airway including cytokine release, fluid secretion, and ciliary beating. NPY levels and/or density of NPYergic neurons may be increased in some sinonasal diseases. We hypothesized that NPY modulates cilia-localized T2R responses in nasal epithelia. Using primary sinonasal epithelial cells cultured at air-liquid interface (ALI), we demonstrate that NPY reduces CBF through NPY2R activation of protein kinase C (PKC) and attenuates responses to T2R14 agonist apigenin. We find that NPY does not alter T2R-induced calcium elevation but does reduce T2R-stimulated NO production via a PKC-dependent process. This study extends our understanding of how T2R responses are modulated within the inflammatory environment of sinonasal diseases, which may improve our ability to effectively treat these disorders.
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http://dx.doi.org/10.3390/nu13103392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538228PMC
September 2021

Small-molecule Akt-activation in airway cells induces NO production and reduces IL-8 transcription through Nrf-2.

Respir Res 2021 Oct 19;22(1):267. Epub 2021 Oct 19.

Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Background: The non-cancerous functions of Akt in the airway are understudied. In some tissues, Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO) that has anti-inflammatory effects. NO production has antibacterial and antiviral effects in the airway, and increasing NO may be a useful anti-pathogen strategy. Akt also stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2) transcription factor, which transcribes antioxidant genes. Therefore, we hypothesized that activation of the Akt/eNOS pathway, which also activates Nrf-2, may have protective effects in human airway cells against injury.

Methods: To directly test the effects of Akt signaling in the airway, we treated A549 and 16HBE cells as well as primary bronchial, nasal, and type II alveolar epithelial cells with small molecule Akt activator SC79. We examined the effects of SC79 on eNOS activation, NO production, Nrf-2 target levels, and interleukin-8 (IL-8) transcription during exposure to TNF-α or Pseudomonas flagellin (TLR5 agonist). Additionally, air-liquid interface bronchial cultures were treated with cadmium, an oxidative stressor that causes airway barrier breakdown.

Results: SC79 induced a ~ twofold induction of p-eNOS and Nrf-2 protein levels blocked by PI3K inhibitor LY294002. Live cell imaging revealed SC79 increased acute NO production. Quantitative RT-PCR showed a ~ twofold increase in Nrf-2 target gene transcription. TNF-α or flagellin-induced IL-8 levels were also significantly reduced with SC79 treatment. Moreover, the transepithelial electrical resistance decrease observed with cadmium was ameliorated by SC79, likely by an acute increase in tight junction protein ZO-1 levels.

Conclusions: Together, the data presented here demonstrate SC79 activation of Akt induces potentially anti-pathogenic NO production, antioxidant gene transcription, reduces IL-8 transcription, and may protect against oxidative barrier dysfunction in a wide range of airway epithelial cells.
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http://dx.doi.org/10.1186/s12931-021-01865-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525858PMC
October 2021

A Systematic Review of Definitive Treatment for Inverted Papilloma Attachment Site and Associations With Recurrence.

Otolaryngol Head Neck Surg 2021 Oct 12:1945998211051975. Epub 2021 Oct 12.

Department of Otolaryngology-Head and Neck Surgery, University of California-Irvine, Orange, California, USA.

Objective: Inverted papilloma (IP) is the most common benign neoplasm of the nasal cavity with known risk of recurrence. There is no standardized approach to definitive treatment for attachment sites. This systematic review aims to determine whether surgeon choice of technique differs by anatomic attachment site and whether different surgical techniques contribute to reduced rates of recurrence.

Data Sources: PubMed and Ovid Medline.

Review Methods: A systematic review was conducted for studies reporting on IP. Those that included IP recurrence rates and primary tumor attachment site were reviewed.

Results: Of 122 published studies, 14 met eligibility criteria, representing 585 patients and a recurrence rate of 5.8%. The maxillary sinus (50.9%) was the most common primary attachment site, and the sphenoid sinus was associated with the highest rate of recurrence (10.4%). The most utilized technique included debulking the tumor, removing mucosa over the attachment site, and drilling the underlying bone. The most common Krouse stage represented was T3 (53.3%). No single technique predicted a propensity for recurrence, but certain techniques are favored depending on IP attachment site. Finally, frozen sections to obtain evidence of clear margins intraoperatively significantly reduced rates of recurrence (3.4% vs 7.3%, = .045).

Conclusion: Based on the current literature, the most common technique to address site of attachment involves resecting mucosa and drilling the tumor base. Choice of technique appears to differ for various sites of attachment. Use of intraoperative frozen section analysis appears to be associated with decreased recurrence overall.

Level Of Evidence: 3.
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http://dx.doi.org/10.1177/01945998211051975DOI Listing
October 2021
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