Publications by authors named "Jonathan B Overdevest"

25 Publications

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COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Brain 2021 Apr 15. Epub 2021 Apr 15.

Department of Pathology and Cell Biology, Division of Neuropathology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, and the New York Presbyterian Hospital, New York, NY, 10032, USA.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms, though, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical center. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit (ICU). Hospital-associated complications were common, including 8 (20%) with deep vein thrombosis/pulmonary embolism (DVT/PE), 7 (17%) patients with acute kidney injury requiring dialysis, and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 hours of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischemic changes in all brains, both global and focal; large and small infarcts, many of which appeared hemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, though none had evidence of vasculitis. Eighteen (44%) contained pathologies of neurodegenerative diseases, not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR (qRT-PCR), RNAscope, and immunocytochemistry with primers, probes, and antibodies directed against the spike and nucleocapsid regions. qRT-PCR revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in nasal epithelia. RNAscope and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in COVID-19 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but rather likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischemia. Further studies are needed to define whether these pathologies, if present in patients who survive COVID-19, might contribute to chronic neurological problems.
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http://dx.doi.org/10.1093/brain/awab148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083258PMC
April 2021

Telemedicine lessons learned during the COVID-19 pandemic: The augmented outpatient otolaryngology teleconsultation.

Am J Otolaryngol 2021 Feb 15;42(4):102960. Epub 2021 Feb 15.

Department of Otolaryngology-Head & Neck Surgery, New York-Presbyterian/Columbia University Medical Center, New York, NY, United States of America.

Purpose: Telemedicine use in otolaryngology waxed and waned during the COVID-19 pandemic outbreak in the U.S. Assessing the patterns of telemedicine use and its perceived limitations during the COVID-19 outbreak in 2020 allows identification and correction of impediments to consistent telemedicine use by otolaryngologists.

Materials And Methods: Full-time faculty of 2 academic otolaryngology departments in New York City were surveyed regarding their telemedicine use from March through August 2020 during the "first wave" of the COVID-19 pandemic. Based on these findings, a method of "augmented outpatient otolaryngology teleconsultation" designed to enhance the quality of the physical examination was developed and employed from August to December 2020. Patients receiving this augmented teleconsult were anonymously surveyed about their telemedical experience.

Results: Telemedicine use by faculty was minimal prior to the pandemic, but as total outpatient volume decreased 65-84% across subspecialties, it was used by all otolaryngologists during COVID-19. Physicians were less confident in making a telemedical diagnosis at all phases of the study in all subspecialties. Patients who had an augmented otolaryngology teleconsultation were satisfied with it, believed it facilitated earlier care, limited the time and cost of travel to the physician's office and felt their physician was able to perform a sufficient physical examination.

Conclusions: During the COVID-19 crisis, physicians utilized teleotolaryngology to provide care but were less satisfied with their ability to make an accurate diagnosis. Inexpensive direct-to-consumer digital otoscopes can improve the quality of the physical examination provided and can address both patient and physician needs.
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http://dx.doi.org/10.1016/j.amjoto.2021.102960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883738PMC
February 2021

Disruption of nuclear architecture as a cause of COVID-19 induced anosmia.

bioRxiv 2021 Feb 9. Epub 2021 Feb 9.

Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.
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http://dx.doi.org/10.1101/2021.02.09.430314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885920PMC
February 2021

Race in Rhinology Clinical Trials: A Decade of Disparity.

Laryngoscope 2021 Jan 25. Epub 2021 Jan 25.

Department of Otolaryngology Head and Neck Surgery, Columbia University Irving Medical Center, New York, New York, U.S.A.

Objective/hypothesis: The aim of this study is to assess the ethnic and racial demographics of patients enrolled in prospective chronic rhinosinusitis (CRS) studies relative to the corresponding geographic demographics of the United States (U.S.) census data.

Study Design: Systematic Review and Population analysis.

Methods: A systematic review was performed to identify CRS clinical trials, conducted in the U.S. and published between 2010 and 2020 in which patients were prospectively enrolled. Pooled racial and ethnicity data were compared to national and corresponding regional census data.

Results: Eighty-three studies were included, comprising 12,027 patients. 50.4% were male and the average age was 49.2 years. 8,810 patients underwent a surgical procedure. Of the 12,027 patients, 81.67% were identified as White, 5.35% as Black, 1.27% as Asian, 0.02% as Pacific Islander, 0.12% as American Indian, and 11.57% were classified as Other. The racial and ethnic composition of the pooled study population differs significantly from the national U.S. census data with the underrepresentation of each minority population (P ≤ .0002). Regional sub-analyses yield variable results. In the Northeast and West, there was an underrepresentation of all minority populations. In the South and Midwest, Black enrollment was similar to the U.S. census data, while all other minorities were underrepresented.

Conclusions: The racial and ethnic composition of patients enrolled in prospective CRS clinical trials differs significantly from the demographics of the U.S.

Population: The generalizability and external validity of findings derived from studies comprised of demographically mismatched populations has not been established. Future efforts to enroll more representative populations should be emphasized by the research community, funding bodies, and editorial boards.

Level Of Evidence: N/A Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29371DOI Listing
January 2021

Gender as a Predictor of Complications in Endoscopic Sinus Surgery.

Ann Otol Rhinol Laryngol 2021 Jan 8:3489420987418. Epub 2021 Jan 8.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA.

Background: Understanding patient-specific risk factors for complications of functional endoscopic sinus surgery (ESS) is critical. Previous work has investigated such risk factors, but a population-based analysis has not been performed to date.

Objectives: This study analyzes the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database to identify patient-specific risk factors associated with complications following ESS.

Methods: A retrospective cohort study of patients who underwent ESS was conducted using the NSQIP database from 2011 to 2017. Patients were identified using CPT-codes for ESS procedures. The primary outcome analyzed was any postoperative complication. Simultaneous procedures with ESS were controlled for with regression analysis. Post-operative complications and 30-day readmission were evaluated using multivariate logistic regression controlling for age, gender, race, comorbidities (diabetes mellitus, hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, steroid use, and cancer history), smoking history, and intraoperative factors.

Results: A total of 1279 patients who underwent ESS were identified. The average age of patients was 46.1 (SD = 16.8). Most patients (58.2%) had no major comorbidities. 594 (46.4%) patients had a tonsillectomy, adenoidectomy, or uvulopharyngoplasty at the same time as ESS. 101 (7.9%) patients experienced a complication post-operatively. 46 (3.6%) patients experienced a readmission postoperatively. The most common complication was reoperation (N = 40, 3.1%). Regression analysis revealed that gender was the only demographic factor associated with risk of post-operative complications, with women having a significantly lower risk than men (OR = 0.61, 95% CI 0.37-0.99,  = .046).

Conclusions: ESS is typically performed on a relatively young and healthy population. Women have a significantly lower risk of complications after controlling for comorbidities. Further analysis of gender-specific differences in surgical outcomes should be evaluated to understand this phenomenon.
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http://dx.doi.org/10.1177/0003489420987418DOI Listing
January 2021

Gross Total Versus Subtotal Surgical Resection in the Management of Craniopharyngiomas.

Allergy Rhinol (Providence) 2020 Jan-Dec;11:2152656720964158. Epub 2020 Oct 29.

Department of Otolaryngology - Head and Neck Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, NewYork-Presbyterian Hospital, New York, New York.

Craniopharyngiomas (CP) are suprasellar tumors that can grow into vital nearby structures and thus cause significant visual, endocrine, and hypothalamic dysfunction. Debate persists as to the optimal treatment strategy for these benign lesions, particularly with regards to the extent of surgical resection. The goals of tumor resection are to eliminate the compressive effect of the tumor on surrounding structures and minimize recurrence. It remains unclear whether a gross total resection (GTR) or subtotal resection (STR) with adjuvant therapy confers a better prognosis. Chemotherapy and radiation therapy (RT) have been explored as both neoadjuvant and adjuvant treatments to decrease tumor burden and prevent recurrence. The objective of this paper is to review the risks and benefits of GTR versus STR, specifically with regard to risk of recurrence and postoperative morbidity. Aggregated data suggest that STR monotherapy is associated with higher rates of recurrence relative to GTR (50.6% ± 22.1% vs 20.2% ± 13.5%), while STR combined with RT leads to recurrence rates similar to GTR. However, both GTR and RT are independently associated with higher rates of comorbidities including panhypopituitarism, diabetes insipidus, and visual deficits. The treatment strategy for CPs should ultimately be tailored to each patient's individual tumor characteristics, risk, symptoms, and therapeutic goals.
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http://dx.doi.org/10.1177/2152656720964158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675910PMC
October 2020

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

Nat Commun 2020 10 28;11(1):5453. Epub 2020 Oct 28.

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

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.
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http://dx.doi.org/10.1038/s41467-020-19145-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595232PMC
October 2020

Bilateral "Rescue Strip" Technique for Endoscopic Endonasal Approaches to the Clivus.

Oper Neurosurg (Hagerstown) 2021 Jan;20(2):E112-E115

Division of Rhinology and Anterior Skull Base Surgery, Department of Otolaryngology - Head and Neck Surgery, New York-Presbyterian Hospital, New York, New York.

Background: The vascularized nasoseptal flap (NSF) is a pillar of contemporary endoscopic skull base reconstruction. The pedicle for the NSF is supplied by the posterior septal branch of the sphenopalatine artery, which courses along the arch of the choana and sphenoid rostrum before entering the nasal septum. Resection or mobilization of this region is necessary for surgical access to the clivus.

Objective: To describe a technique for preserving bilateral NSF pedicles during endoscopic endonasal resection of the clivus, thereby safeguarding availability of the flaps for future skull base repair needs.

Methods: Report of operative technique with video demonstration.

Results: This technique for NSF preservation allows for wide access to the clivus while saving the future option for vascularized flap repairs of skull base defects. The patient in whom we demonstrate this technique underwent complete resection of her clivus without cerebrospinal fluid leak and with preservation of both NSF pedicles.

Conclusion: The "rescue strip" technique for endonasal endoscopic clival surgery preserves the bilateral NSF pedicles for future use without compromising surgical access to the clivus.
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http://dx.doi.org/10.1093/ons/opaa304DOI Listing
January 2021

Diagnostic dilemma - sinonasal organizing hematoma.

SAGE Open Med Case Rep 2020 30;8:2050313X20945843. Epub 2020 Jul 30.

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

Sinonasal organizing hematomas are benign lesions often mistaken for malignancy due to their aggressive appearance on diagnostic imaging and endoscopic findings that favor advanced disease. The destructive nature of this pathology paired with the rarity of the presentation often results in diagnostic deception that may escalate intervention planning and affect discussion of prognosis with patients. Herein, we present a case of a 56-year-old male with left-sided nasal obstruction and daily epistaxis, where computed tomography imaging revealed heterogeneous opacification of the left maxillary sinus, erosion of the left inferior orbital wall and extension into the nasal cavity. Although clinical and radiographic presentations of sinonasal organizing hematomas can be managed definitively with endoscopic intervention, there is a need to increase awareness of this entity among clinicians to improve our prognostic counseling with patients.
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http://dx.doi.org/10.1177/2050313X20945843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412905PMC
July 2020

Treatment Strategies and Outcomes of Pediatric Esthesioneuroblastoma: A Systematic Review.

Front Oncol 2020 24;10:1247. Epub 2020 Jul 24.

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

Esthesioneuroblastoma, also known as olfactory neuroblastoma, is a small round blue cell tumor of nasal neuroepithelium first described in 1924. Though this tumor is especially rare in the pediatric population with an incidence of <0.1 per 100,000, it is the most common pediatric nasal cavity neoplasm. The purpose of this systematic review is to examine the treatment modalities utilized for pediatric esthesioneuroblastoma and overall survival. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pubmed, EMBASE, and Ovid MEDLINE databases were queried for studies pertinent to treatment modalities for pediatric esthesioneuroblatoma and survival outcomes. Two hundred and seventy-sixth articles were identified, with seven meeting inclusion criteria. Ninety-four patients with an age range of 0.9-21 years old with esthesioneuroblastoma were included. Nearly 90% of patients were of stage Kadish B or C at time of presentation, while 20% presented with cervical lymphadenopathy. Only about 10% of patients underwent single modality therapy. Overall, 5-year survival ranged from 44 to 91% with a median follow-up of 3-13 years. Children with esthesioneuroblastoma usually present at an advanced stage and undergo multi-modality therapy at a higher rate than adult patients. There is a wide range of documented overall survival though this lack of precision could be due to a paucity of patients.
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http://dx.doi.org/10.3389/fonc.2020.01247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393231PMC
July 2020

Recent smell loss is the best predictor of COVID-19: a preregistered, cross-sectional study.

medRxiv 2020 Jul 26. Epub 2020 Jul 26.

Background: COVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19.

Methods: This preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery.

Results: Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing no significant model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ~50% of participants and was best predicted by time since illness onset.

Conclusions: As smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (10
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http://dx.doi.org/10.1101/2020.07.22.20157263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386529PMC
July 2020

Pediatric sinonasal and skull base lesions.

World J Otorhinolaryngol Head Neck Surg 2020 Jun 8;6(2):118-124. Epub 2020 Apr 8.

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

Pediatric skull base lesions are complex and challenging disorders. Safe and comprehensive management of this diverse group of disorders requires the expertise of an experienced multidisciplinary skull base team. Adult endoscopic skull base surgery has evolved due to technologic and surgical advancements, multidisciplinary team approaches, and continued innovation. Similar principles continue to advance the care delivered to the pediatric population. The approach and management of these lesions varies considerably based on tumor anatomy, pathology, and surgical goals. An understanding of the nuances of skull base reconstruction unique to the pediatric population is critical for successful outcomes.
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http://dx.doi.org/10.1016/j.wjorl.2020.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296510PMC
June 2020

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.

medRxiv 2020 May 12. Epub 2020 May 12.

Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan.

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.
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http://dx.doi.org/10.1101/2020.05.08.20092866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273284PMC
May 2020

Hemodynamic changes in patients undergoing office-based sinus procedures under local anesthesia.

Int Forum Allergy Rhinol 2020 01 5;10(1):114-120. Epub 2019 Nov 5.

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

Background: The objective of this study is to characterize changes in hemodynamics, pain, and anxiety during office-based endoscopic sinus procedures performed under local anesthesia.

Methods: We conducted a prospective study of adults undergoing in-office endoscopic sinus procedures under local anesthesia. Patients with American Society of Anesthesiologists (ASA) Physical Status Classification System class 1 or 2 were included. Anesthesia was administered by topical 4% lidocaine/oxymetazoline and submucosal injection of 1% lidocaine/1:200,000 epinephrine. Vital signs and pain were measured at baseline, postinjection, and 5-minute intervals throughout the procedure. Anxiety levels were scored using the State-Trait Anxiety Inventory (STAI). Univariate and multivariate regression analyses were performed to identify factors significantly associated with changes in each hemodynamic metric.

Results: Twenty-five patients were studied. This cohort was 52% male, mean age of 57.8 ± 14.4 years, and Charlson Comorbidity Index (CCI) median of 2. Mean procedure duration was 25.0 ± 10.3 minutes. Mean maximal increase in systolic blood pressure (SBP) was 24.6 ± 17.8 mmHg from baseline. Mean maximal heart rate increase was 22.8 ± 10.8 beats per minute (bpm) from baseline. In multivariate regression analysis, when accounting for patient age, cardiac comorbidity, CCI, and ASA, older age was significantly associated with an increase of >20 mmHg in SBP (p = 0.043). Mean pain score during procedures was 1.5 ± 1.3 with a mean maximum of 4.0 ± 2.6. STAI anxiety scores did not change significantly from preprocedure to postprocedure (32.8 ± 11.6 to 31.0 ± 12.6, p = 0.46). No medical complications occurred.

Conclusion: Although patients appear to tolerate office procedures well, providers should recognize the potential for significant fluctuations in blood pressure during the procedure, especially in older patients.
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http://dx.doi.org/10.1002/alr.22460DOI Listing
January 2020

Nasopharyngeal Angiofibroma Staging with a Novel Nominal Basis: An 18-Year Study in a Tertiary Center.

Otolaryngol Head Neck Surg 2019 08 23;161(2):352-361. Epub 2019 Apr 23.

2 Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Objective: To develop a systematic method for anatomic mapping of juvenile nasopharyngeal angiofibroma (JNA) tumors to standardize communication, facilitate surgical planning, and convey prognosis.

Study Design: Retrospective cohort.

Setting: Tertiary referral center.

Subjects And Methods: Following Institutional Review Board approval, we performed a retrospective review of radiologic and angiographic data of patients with JNA presenting to the Department of Otolaryngology-Head and Neck Surgery, Mansoura University, from 2001 to 2017. All patients underwent angiography with embolization and had >1-year follow-up. Based on frequently involved anatomic sites and factors predictive of prognosis, the NSF-COR staging system (nose/nasopharynx, sinus, fossa-cranium, orbit, residual internal carotid artery supply) was developed to explicitly convey anatomic site of involvement and presence of residual vascularity. We validated the NSF-COR staging system against other systems with Pearson chi-square test based on risk factors and clinical outcomes of blood transfusion volume, recurrence, and JNA resectability.

Results: Fifty-four patients met inclusion criteria, where all primary cases (100%) demonstrated nose/nasopharynx involvement, followed by sinus (85.2%), natural fossae (85.2%), intracranial (26%), and orbital involvement (16.7%). These sites, with assessment of residual internal carotid artery vascular supply, were used to develop the NSF-COR anatomically based staging system. The components COR showed significant association with clinical outcomes of blood transfusion and recurrence. Contingency coefficients between the NSF-COR staging system and available staging systems showed significant correlations ( < .05) for prognosis.

Conclusion: The NSF-COR staging system conveys a communicable anatomic map of JNA tumors that integrates residual vascularity of the tumor and demonstrates strong concordance with current staging systems to assess clinical outcomes.
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http://dx.doi.org/10.1177/0194599819842155DOI Listing
August 2019

Therapeutic use of steroids in non-chronic rhinosinusitis olfactory dysfunction: a systematic evidence-based review with recommendations.

Int Forum Allergy Rhinol 2019 02 24;9(2):165-176. Epub 2018 Nov 24.

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

Background: Olfactory loss is a common and debilitating disease with limited treatment options, particularly for olfactory dysfunction not related to sinonasal inflammation. Both topical and systemic steroids have been used as treatments for olfactory loss. This study systematically reviews the literature on the efficacy of steroids for non-chronic rhinosinusitis (CRS)-related olfactory loss and provides recommendations.

Methods: A literature search of PubMed, Ovid, EMBASE, and the Cochrane Database was performed according to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Inclusion criteria included original data, English-language articles on steroid treatment (topical and systemic) for olfactory loss unrelated to sinonasal inflammation. Data was collected on study design, olfaction dysfunction etiology, clinical outcomes, and level of evidence. Two investigators reviewed all articles independently, with a third acting as a mediator for any disagreements in recommendation.

Results: Of 866 abstracts identified, only 15 studies met inclusion criteria and were systematically reviewed. Level 4 evidence suggests oral steroids can improve olfactory loss. Level 1B evidence demonstrates topical steroid rinses improve olfactory dysfunction in a select group of patients. Topical steroid sprays show no improvement across several levels of evidence.

Conclusion: There is a paucity of high-quality studies demonstrating efficacy of either topical or oral steroids for olfactory dysfunction unrelated to sinonasal disease. The only level 1 evidence suggests using steroid rinses to improve olfactory outcomes in select patients, with weaker evidence supporting use of oral steroids. Topical steroid sprays do not improve olfactory dysfunction in this patient population and are not recommended.
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http://dx.doi.org/10.1002/alr.22240DOI Listing
February 2019

Patterns of vascularization and surgical morbidity in juvenile nasopharyngeal angiofibroma: A case series, systematic review, and meta-analysis.

Head Neck 2018 02 11;40(2):428-443. Epub 2017 Nov 11.

Department of Otolaryngology - Head and Neck Surgery, Division of Rhinology, San Francisco, California.

Background: Vascular patterns of juvenile nasopharyngeal angiofibroma (JNA) are poorly defined. We performed both institutional and systematic literature reviews to characterize the relationship between arterial supply patterns of JNA with intraoperative blood loss and tumor recurrence.

Methods: A retrospective review of 26 patients with JNA treated at our institution from 1995 to 2015 with available angiograms, and systematic reviews and meta-analyses of 828 JNA cases undergoing angiographic embolization published between 1995 and 2015 were completed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results: The systematic review (828 cases) found internal carotid artery (ICA) supply in 35.6% of tumors, and 30.8% of tumors received bilateral vascular supply. Our institutional data (n = 26) indicated 69% had bilateral supply. Meta-analysis of data from 5 studies demonstrated ICA/bilateral arterial supply is predictive of increased operative blood loss (P < .01).

Conclusion: Complex vascular contributions to JNA are frequent, underreported, and portends increased blood loss. This information can justifiably be included in staging systems to enhance prognostic counseling of patients.
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http://dx.doi.org/10.1002/hed.24987DOI Listing
February 2018

Tinnitus following treatment for sporadic Acoustic neuroma.

Laryngoscope 2016 07 25;126(7):1639-43. Epub 2015 Sep 25.

Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California, U.S.A.

Objectives/hypothesis: To evaluate the impact of treatment modality, tumor size, time from therapy, and demographic features on tinnitus distress, as measured by the Tinnitus Functional Index (TFI) in patients treated for sporadic acoustic neuroma.

Study Design: Cross-sectional observation study.

Methods: A Web-based 44-question online survey was made available on the Acoustic Neuroma Association Web site for 3 months. Of 154 unique surveys that were completed in entirety, further screening netted 143 study participants. Questions included the TFI, treatment modality, tumor size, time from therapy, demographic features, and hearing status of both ears.

Results: Tinnitus distress following treatment for acoustic neuroma is independent of treatment type, tumor size, tumor laterality, time after treatment, age, and gender. Tinnitus Functional Index scores closely mirror severity profile of the study population as reported in the pivotal TFI instrument validation study by Meikle et al.(17) Tinnitus is "not a problem" in 20% of respondents, a "small problem" in 20%, a "moderate problem" in 11%, a "big problem" in 22%, and a "very big problem" in 27%. Subscale analysis suggests that acoustic tumor patients struggle most with tinnitus intrusiveness and loss of control.

Conclusions: Whereas tinnitus is a common symptom in acoustic neuroma patients in both the pre- and posttreatment settings, clinicians can provide counsel that choice of treatment modality, tumor size, age, and gender have little to no bearing on severity of posttreatment tinnitus distress. Tinnitus severity does not differ among the treatment choices of open microsurgery, stereotactic radiosurgery, external beam radiation, and observation.

Level Of Evidence: NA Laryngoscope, 126:1639-1643, 2016.
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http://dx.doi.org/10.1002/lary.25672DOI Listing
July 2016

Fatty Acid binding protein 7 is a molecular marker in adenoid cystic carcinoma of the salivary glands: implications for clinical significance.

Transl Oncol 2014 Dec;7(6):780-7

Head and Neck Cancer Research Laboratory, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA, USA. Electronic address:

Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the salivary glands. Its diagnosis is difficult due to overlapping features with other salivary tumors. Gene expression analysis may complement traditional diagnostic methods. We searched gene expression patterns in the Gene Expression Omnibus (GEO) database and in our tumor and normal samples. The biologic and prognostic potential of the identified genes was analyzed. The GEO data set of primary xenografted ACCs revealed that expression of five genes, engrailed homeobox 1 (EN1), fatty acid binding protein 7 (FABP7), hemoglobin epsilon 1, MYB, and versican (VCAN), was dramatically increased. mRNA expression of EN1, FABP7, MYB, and VCAN distinguished our sporadic ACCs from normal tissues and benign tumors. FABP7 expression appeared to be regulated differently from EN1 and MYB and was crossly correlated with poor prognosis in our ACC cohort. Immunohistochemistry showed that FABP7 protein was predominantly expressed in the nucleus of myoepithelial cells of both tubular and cribriform subtypes. In contrast, in the solid subtype, which is often associated with a lower survival rate, FABP7 protein was uniformly expressed in cancerous cells. One case with cribriform architecture and the highest level of FABP7 mRNA showed strong FABP7 staining in both duct-type epithelial and myoepithelial cells, suggesting that diffuse expression of FABP7 protein might be related to aggressive tumor behavior and poor prognosis. We propose FABP7 as a novel biomarker in ACC. The molecule may be useful in diagnosis and for identifying more effective therapies targeting this protein or upstream molecules that regulate it.
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http://dx.doi.org/10.1016/j.tranon.2014.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311037PMC
December 2014

c-Kit Expression is Rate-Limiting for Stem Cell Factor-Mediated Disease Progression in Adenoid Cystic Carcinoma of the Salivary Glands.

Transl Oncol 2014 Oct 24;7(5):537-45. Epub 2014 Oct 24.

Head and Neck Cancer Research Laboratory, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA ; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA.

Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the salivary glands in which c-Kit is overexpressed and activated, although the mechanism for this is as yet unclear. We analyzed 27 sporadic ACC tumor specimens to examine the biologic and clinical significance of c-Kit activation. Mutational analysis revealed expression of wild-type c-Kit in all, eliminating gene mutation as a cause of activation. Because stem cell factor (SCF) is c-Kit's sole ligand, we analyzed its expression in the tumor cells and their environment. Immunohistochemistry revealed its presence in c-Kit-positive tumor cells, suggesting an activation of autocrine signaling. We observed a significant induction of ERK1/2 in the cells. SCF staining was also found in other types of non-cancerous cells adjacent to tumors within salivary glands, including stromal fibroblasts, neutrophils, peripheral nerve, skeletal muscle, vascular endothelial cells, mucous acinar cells, and intercalated ducts. Quantitative PCR showed that the top quartile of c-Kit mRNA expression distinguished ACCs from normal salivary tissues and was cross-correlated with short-term poor prognosis. Expression levels of SCF and c-Kit were highly correlated in the cases with perineural invasion. These observations suggest that c-Kit is potentially activated by receptor dimerization upon stimulation by SCF in ACC, and that the highest quartile of c-Kit mRNA expression could be a predictor of poor prognosis. Our findings may support an avenue for c-Kit-targeted therapy to improve disease control in ACC patients harboring the top quartile of c-Kit mRNA expression.
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http://dx.doi.org/10.1016/j.tranon.2014.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225653PMC
October 2014

CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated.

Proc Natl Acad Sci U S A 2012 Dec 25;109(51):E3588-96. Epub 2012 Sep 25.

Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.

Overexpression of CD24, a glycosyl phosphatidylinositol-linked sialoglycoprotein, is associated with poor outcome in urothelial carcinoma and contributes to experimental tumor growth and metastasis. However, the requirement for CD24 (Cd24a in mice) in tumorigenesis and spontaneous metastasis from the orthotopic site remains uncharacterized. Using N-butyl-N-(4-hydroxybutyl) nitrosamine induction of invasive and metastatic bladder cancer, we show that Cd24a-deficient male mice developed fewer bladder tumors than C57BL/6 control male mice. Evaluating only mice with evidence of primary tumors, we observed that Cd24a-deficient male mice also had fewer metastases than wild-type counterparts. In parallel observations, stratification of patients based on CD24 immunohistochemical expression in their tumors revealed that high levels of CD24 are associated with poor prognosis in males. In female patients and mice the above observations were not present. Given the significant role of CD24 in males, we sought to assess the relationship between androgen and CD24 regulation. We discovered that androgen receptor knockdown in UM-UC-3 and TCCSUP human urothelial carcinoma cell lines resulted in suppression of CD24 expression and cell proliferation. Androgen treatment also led to increased CD24 promoter activity, dependent on the presence of androgen receptor. In vivo, androgen deprivation resulted in reduced growth and CD24 expression of UM-UC-3 xenografts, and the latter was rescued by exogenous CD24 overexpression. These findings demonstrate an important role for CD24 in urothelial tumorigenesis and metastasis in male mice and indicate that CD24 is androgen regulated, providing the foundation for urothelial bladder cancer therapy with antiandrogens.
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http://dx.doi.org/10.1073/pnas.1113960109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529071PMC
December 2012

CD24 is an effector of HIF-1-driven primary tumor growth and metastasis.

Cancer Res 2012 Nov 27;72(21):5600-12. Epub 2012 Aug 27.

Departments of Urology, University of Virginia, Charlottesville, Virginia, USA.

Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor hypoxia inducible factor-1α (HIF-1α) in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here, we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. Short hairpin RNA-mediated attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α-depleted cancer cells rescued this decrease, whereas HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their coexpression to decreased patient survival. Our results establish a mechanistic linkage between 2 critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biologic effector, strengthening the rationale to target CD24 for cancer therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-3666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488144PMC
November 2012

CD24 offers a therapeutic target for control of bladder cancer metastasis based on a requirement for lung colonization.

Cancer Res 2011 Jun 11;71(11):3802-11. Epub 2011 Apr 11.

Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.

Metastasis is lethal in most bladder cancer patients. Expression of CD24, a glycosyl phosphatidylinositol (GPI)-linked sialoglycoprotein and cancer stem cell marker, is associated with metastatic progression in multiple cancer types, yet the role of CD24 in this process remains unclear. While developing a murine model of human metastatic bladder cancer, we observed that tumor cell CD24 expression correlated with a propensity to metastasize to the lung. Our immunohistochemical evaluation of 60 paired primary and metastatic human bladder cancer samples revealed increased intensity (P < 0.001) and frequency (P < 0.001) of CD24 expression in metastases. To directly evaluate the role of CD24 in metastatic colonization, we manipulated CD24 expression in human bladder cancer cell lines using short hairpin RNA depletion, cDNA overexpression, and fluorescence-activated cell sorting selection. Although suppression of CD24 reduced acute tumor cell retention in the lungs of mice inoculated intravenously with cancer cells, this differential retention was no longer apparent after 24 hours, prompting us to evaluate the role of CD24 in lung colonization. Here, CD24 was found necessary for subsequent development of lung metastases. We next treated clinically detectable lung metastases in mice with anti-CD24 antibody and observed reduced tumor growth and prolonged survival. These findings suggest that CD24 is a lynchpin of metastatic progression and a promising therapeutic target for antimetastatic therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-0519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283788PMC
June 2011

Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer.

Cancer Res 2011 Feb 10;71(3):832-41. Epub 2010 Dec 10.

Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.

In bladder cancer, increased caveolin-1 (Cav-1) expression and decreased Src expression and kinase activity correlate with tumor aggressiveness. Here, we investigate the clinical and functional significance, if any, of this reciprocal expression in bladder cancer metastasis. We evaluated the ability of tumor Cav-1 and Src RNA and protein expression to predict outcome following cystectomy in 257 patients enrolled in two independent clinical studies. In both, high Cav-1 and low Src levels were associated with metastasis development. We overexpressed or depleted Cav-1 and Src protein levels in UMUC-3 and RT4 human bladder cancer cells and evaluated the effect of this on actin stress fibers, migration using Transwells, and lung metastasis following tail vein inoculation. Cav-1 depletion or expression of active Src in metastatic UMUC-3 cells decreases actin stress fibers, cell migration, and metastasis, while Cav-1 overexpression or Src depletion increased the migration of nonmetastatic RT4 cells. Biochemical studies indicated that Cav-1 mediates these effects via its phosphorylated form (pY14), whereas Src effects are mediated through phosphorylation of p190RhoGAP and these pathways converge to reduce activity of RhoA, RhoC, and Rho effector ROCK1. Treatment with a ROCK inhibitor reduced UMUC-3 lung metastasis in vivo, phenocopying the effect of Cav-1 depletion or expression of active Src. Src suppresses whereas Cav-1 promotes metastasis of bladder cancer through a pharmacologically tractable common downstream signaling pathway. Clinical evaluation of personalized therapy to suppress metastasis development based on Cav-1 and Src profiles seems warranted.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-0730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306590PMC
February 2011

Utilizing the molecular gateway: the path to personalized cancer management.

Clin Chem 2009 Apr 26;55(4):684-97. Epub 2009 Feb 26.

Departments of Molecular Physiology and Biological Physics; and Public Health Sciences, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.

Background: Personalized medicine is the provision of focused prevention, detection, prognostic, and therapeutic efforts according to an individual's genetic composition. The actualization of personalized medicine will require combining a patient's conventional clinical data with bioinformatics-based molecular-assessment profiles. This synergistic approach offers tangible benefits, such as heightened specificity in the molecular classification of cancer subtypes, improved prognostic accuracy, targeted development of new therapies, novel applications for old therapies, and tailored selection and delivery of chemotherapeutics.

Content: Our ability to personalize cancer management is rapidly expanding through biotechnological advances in the postgenomic era. The platforms of genomics, proteomics, single-nucleotide polymorphism profiling and haplotype mapping, high-throughput genomic sequencing, and pharmacogenomics constitute the mechanisms for the molecular assessment of a patient's tumor. The complementary data derived during these assessments is processed through bioinformatics analysis to offer unique insights for linking expression profiles to disease detection, tumor response to chemotherapy, and patient survival. Together, these approaches permit improved physician capacity to assess risk, target therapies, and tailor a chemotherapeutic treatment course.

Summary: Personalized medicine is poised for rapid growth as the insights provided by new bioinformatics models are integrated with current procedures for assessing and treating cancer patients. Integration of these biological platforms will require refinement of tissue-processing and analysis techniques, particularly in clinical pathology, to overcome obstacles in customizing our ability to treat cancer.
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http://dx.doi.org/10.1373/clinchem.2008.118554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529063PMC
April 2009