Publications by authors named "Simon R Best"

51 Publications

Laryngeal disorders in people living with HIV.

Am J Otolaryngol 2021 Sep 20;43(1):103234. Epub 2021 Sep 20.

Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, United States of America.

Objectives: Several studies have shown that HIV infected individuals are at higher risk compared to the general population of developing non-AIDS defining conditions such as some types of cancer, kidney disease, liver disease and others. In this case-control study, we compared the incidence of laryngeal disorders between a treatment-seeking HIV-positive population and uninfected controls. We aimed to investigate whether there are any laryngeal disorders that are overrepresented in HIV-positive individuals.

Methods: This was a case-control study based on retrospective chart review, comparing the incidence of laryngeal, airway, and swallowing disorders in sixty-nine HIV positive individuals and 4178 HIV negative controls treated between January 1, 2016 and December 31, 2017, at the Johns Hopkins Voice Center.

Results: A majority of HIV-infected patients (59.4%) had at least one diagnosis belonging to the Vocal cord pathology category compared to 48.2% of controls (OR 1.57, p = 0.065). Compared to the entire treatment-seeking population, HIV patients were more likely to present with laryngeal cancer (15.9% vs. 3.4% in controls, OR 5.43, p < 0.001) and chronic laryngitis (17.4% vs. 4.2%, OR 4.79, p < 0.001). Fungal and ulcerative laryngitis were also overrepresented in HIV-positive individuals (OR 9.45, p < 0.001 and 6.29, p < 0.001, respectively). None of the diagnoses categorized as functional voice disorders, swallowing, or airway problems showed a significant difference between groups. Laryngeal papillomatosis, which is an HPV-dependent disease, had similar prevalence in both groups.

Conclusions: Treatment-seeking HIV-positive patients presenting to a laryngology clinic suffer significantly more often from laryngeal squamous cell carcinoma as well as chronic, fungal, and ulcerative laryngitis compared to HIV-negative individuals.

Level Of Evidence: 4.
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http://dx.doi.org/10.1016/j.amjoto.2021.103234DOI Listing
September 2021

Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement.

Laryngoscope 2021 06 6;131(6):E1941-E1949. Epub 2021 Jan 6.

Department of Otolaryngology-Head and Neck Surgery, University of Texas (UT) Southwestern Medical Center, Dallas, Texas, U.S.A.

Objectives/hypothesis: The purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality.

Study Design: Delphi method-based survey series.

Methods: A multidisciplinary, multi-institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work-up.

Results: The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18).

Conclusion: This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best-practice applications of systemic bevacizumab for patients with early-onset or less-severe disease phenotypes.

Level Of Evidence: 5 Laryngoscope, 131:E1941-E1949, 2021.
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http://dx.doi.org/10.1002/lary.29343DOI Listing
June 2021

Laryngeal Injury and Upper Airway Symptoms After Endotracheal Intubation During Surgery: A Systematic Review and Meta-analysis.

Anesth Analg 2021 04;132(4):1023-1032

Department of Emergency Medicine.

Laryngeal injury from intubation can substantially impact airway, voice, and swallowing, thus necessitating multidisciplinary interventions. The goals of this systematic review were (1) to review the types of laryngeal injuries and their patient-reported symptoms and clinical signs resulting from endotracheal intubation in patients intubated for surgeries and (2) to better understand the overall the frequency at which these injuries occur. We conducted a search of 4 online bibliographic databases (ie, PubMed, Embase, Cumulative Index of Nursing and Allied Health Literature [CINAHL], and The Cochrane Library) and ProQuest and Open Access Thesis Dissertations (OPTD) from database inception to September 2019 without restrictions for language. Studies that completed postextubation laryngeal examinations with visualization in adult patients who were endotracheally intubated for surgeries were included. We excluded (1) retrospective studies, (2) case studies, (3) preexisting laryngeal injury/disease, (4) patients with histories of or surgical interventions that risk injury to the recurrent laryngeal nerve, (5) conference abstracts, and (6) patient populations with nonfocal, neurological impairments that may impact voice and swallowing function, thus making it difficult to identify isolated postextubation laryngeal injury. Independent, double-data extraction, and risk of bias assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Collaboration's criteria. Twenty-one articles (1 cross-sectional, 3 cohort, 5 case series, 12 randomized controlled trials) representing 21 surgical studies containing 6140 patients met eligibility criteria. The mean patient age across studies reporting age was 49 (95% confidence interval [CI], 45-53) years with a mean intubation duration of 132 (95% CI, 106-159) minutes. Studies reported no injuries in 80% (95% CI, 69-88) of patients. All 21 studies presented on type of injury. Edema was the most frequently reported mild injury, with a prevalence of 9%-84%. Vocal fold hematomas were the most frequently reported moderate injury, with a prevalence of 4% (95% CI, 2-10). Severe injuries that include subluxation of the arytenoids and vocal fold paralysis are rare (<1%) outcomes. The most prevalent patient complaints postextubation were dysphagia (43%), pain (38%), coughing (32%), a sore throat (27%), and hoarseness (27%). Overall, laryngeal injury from short-duration surgical intubation is common and is most often mild. No uniform guidelines for laryngeal assessment postextubation from surgery are available and hoarseness is neither a good indicator of laryngeal injury or dysphagia. Protocolized screening for dysphonia and dysphagia postextubation may lead to improved identification of injury and, therefore, improved patient outcomes and reduced health care utilization.
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http://dx.doi.org/10.1213/ANE.0000000000005276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969363PMC
April 2021

Dysphonia and dysphagia as early manifestations of autoimmune inflammatory myopathy.

Am J Otolaryngol 2021 Jan - Feb;42(1):102747. Epub 2020 Oct 3.

Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, 601 N Caroline Street, Baltimore, MD, USA. Electronic address:

Purpose: While dysphagia is a recognized manifestation of autoimmune inflammatory myopathy, a relationship between myositis and dysphonia or laryngeal pathology is not well-documented. We therefore sought to describe the spectrum of laryngeal disorders present in myositis patients, evaluate whether any specific conditions are overrepresented among these patients compared to a large treatment-seeking population, and examine the clinical course and outcomes of these symptoms.

Materials And Methods: This was a retrospective chart review, including all patients seen at the Johns Hopkins Voice Center between January 2016 and December 2017. Demographic data, comorbidities, and laryngeal diagnoses were extracted from the electronic medical record. The charts of patients with myositis were reviewed further to ascertain details of their laryngeal symptoms and myositis disease course. Associations between myositis and dysphonia/dysphagia were evaluated using binary regression and multinomial logistic regression models to adjust for age, sex, race, and smoking status.

Results: Of 4252 patients, sixteen had myositis. Compared to 4236 controls, these patients had significantly higher odds of presenting with muscular voice disorders (adjusted odds ratio (OR*) = 4.503, p* = 0.005) and dysphagia (OR* = 6.823, p* < 0.001). A majority (64.3%, CI:35.6-93.0%) of myositis patients had laryngeal pathology among the presenting symptoms of their myositis. Across all diagnostic categories, there was a non-significant trend towards better outcomes in patients receiving specific interventions for their laryngeal symptoms.

Conclusions: Muscular voice disorders and dysphagia are significantly overrepresented in myositis patients presenting to a laryngology clinic, and in these patients, both are frequently among the presenting symptoms of myositis.
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http://dx.doi.org/10.1016/j.amjoto.2020.102747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722093PMC
April 2021

Nonepithelial Tumors of the Larynx: Single-Institution 13-Year Review with Radiologic-Pathologic Correlation.

Radiographics 2020 Nov-Dec;40(7):2011-2028. Epub 2020 Oct 9.

From the Russell H. Morgan Department of Radiology and Radiological Science (A.C.O., E.H.H., A.J.M., N.A., M.A.K.), Department of Pathology (L.M.R.), and Department of Otolaryngology-Head and Neck Surgery (L.M.A., S.R.B.), Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore. MD 21287.

Nonepithelial tumors of the larynx are rare and represent a minority of all laryngeal neoplasms. Imaging has an important role in the diagnosis, treatment planning, and surveillance of these entities. However, unfamiliarity with these neoplasms can cause diagnostic difficulties for radiologists, especially because many of the imaging findings are nonspecific. By using a systematic approach based on clinical history, patient age and gender, lesion location, endoscopic results, and specific imaging findings, the differential diagnosis can often be narrowed. These tumors typically affect the submucosal layer, so if a tumor has an intact mucosa at endoscopy, a nonepithelial neoplasm is the most likely diagnosis. Nonepithelial tumors of the larynx can arise from the laryngeal cartilage or muscle or from the surrounding lymphoid tissue or blood vessels. Consequently, imaging findings typically correspond to the specific cell type from which it originated. Recognizing specific features (eg, metaplastic bone formation, macroscopic fat, or enhancement pattern) can often help narrow the differential diagnosis. In addition, identification of noncircumscribed borders of the lesion and invasion of the adjacent structures is key to diagnosis of a malignant process rather than a benign neoplasm. Understanding the pathologic correlation is fundamental to understanding the radiologic manifestations and is ultimately crucial for differentiation of nonepithelial laryngeal neoplasms. RSNA, 2020.
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http://dx.doi.org/10.1148/rg.2020190210DOI Listing
July 2021

Multidisciplinary Safety Recommendations After Tracheostomy During COVID-19 Pandemic: State of the Art Review.

Otolaryngol Head Neck Surg 2021 05 22;164(5):984-1000. Epub 2020 Sep 22.

Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA; Global Tracheostomy Collaborative, Raleigh, North Carolina, USA.

Objective: In the chronic phase of the COVID-19 pandemic, questions have arisen regarding the care of patients with a tracheostomy and downstream management. This review addresses gaps in the literature regarding posttracheostomy care, emphasizing safety of multidisciplinary teams, coordinating complex care needs, and identifying and managing late complications of prolonged intubation and tracheostomy.

Data Sources: PubMed, Cochrane Library, Scopus, Google Scholar, institutional guidance documents.

Review Methods: Literature through June 2020 on the care of patients with a tracheostomy was reviewed, including consensus statements, clinical practice guidelines, institutional guidance, and scientific literature on COVID-19 and SARS-CoV-2 virology and immunology. Where data were lacking, expert opinions were aggregated and adjudicated to arrive at consensus recommendations.

Conclusions: Best practices in caring for patients after a tracheostomy during the COVID-19 pandemic are multifaceted, encompassing precautions during aerosol-generating procedures; minimizing exposure risks to health care workers, caregivers, and patients; ensuring safe, timely tracheostomy care; and identifying and managing laryngotracheal injury, such as vocal fold injury, posterior glottic stenosis, and subglottic stenosis that may affect speech, swallowing, and airway protection. We present recommended approaches to tracheostomy care, outlining modifications to conventional algorithms, raising vigilance for heightened risks of bleeding or other complications, and offering recommendations for personal protective equipment, equipment, care protocols, and personnel.

Implications For Practice: Treatment of patients with a tracheostomy in the COVID-19 pandemic requires foresight and may rival procedural considerations in tracheostomy in their complexity. By considering patient-specific factors, mitigating transmission risks, optimizing the clinical environment, and detecting late manifestations of severe COVID-19, clinicians can ensure due vigilance and quality care.
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http://dx.doi.org/10.1177/0194599820961990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198753PMC
May 2021

Characterization of Geriatric Dysphagia Diagnoses in Age-Based Cohorts.

OTO Open 2020 Jul-Sep;4(3):2473974X20939543. Epub 2020 Jul 8.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Objective: An aging population requires increased focus on geriatric otolaryngology. Patients aged ≥65 years are not a homogenous population, and important physiologic differences have been documented among the young-old (65-74 years), middle-old (75-84), and old-old (≥85). We aim to analyze differences in dysphagia diagnoses and swallowing-related quality-of-life among these age subgroups.

Study Design: Retrospective chart review.

Setting: Tertiary care laryngology clinic.

Subjects And Methods: We identified chief complaint, diagnosis, and self-reported swallowing handicap (Eating Assessment Tool [EAT-10] score) of all new patients aged ≥65 years presenting to the Johns Hopkins Voice Center between April 2015 and March 2017. Dysphagia diagnoses were classified by physiologic etiology and anatomic source. Diagnostic categories and EAT-10 score were evaluated as functions of patient age and sex.

Results: Of 839 new patients aged ≥65 years, 109 (13.0%) reported a chief complaint of dysphagia and were included in this study. The most common dysphagia etiologies were neurologic and esophageal. Most common diagnoses were diverticula (15.6%), reflux (13.8%), and radiation induced (8.3%). Diverticula, cricopharyngeal hypertonicity, and radiation-induced changes were associated with higher EAT-10 score ( < .001). Significant differences by sex were found in anatomic source of dysphagia, as men and women were more likely to present with oropharyngeal and esophageal disease, respectively ( = .023). Dysphagia etiology and EAT-10 score were similar across age subgroups.

Conclusion: Important differences among dysphagia diagnosis and EAT-10 score exist among patients aged ≥65 years. Knowledge of these differences may inform diagnostic workup, management, and further investigations in geriatric otolaryngology.
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http://dx.doi.org/10.1177/2473974X20939543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346702PMC
July 2020

Laryngeal Pathologies and Their Associations With Mental Health Disorders.

Laryngoscope 2021 01 8;131(1):E231-E239. Epub 2020 Jun 8.

Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, Sweden.

Objectives: Mental health disorders are very common. Understanding their clinical manifestations in terms of voice and laryngeal disorders (VLD) is important because they constitute a significant proportion of all patients seen by otolaryngology-head and neck surgery. In this study, we examine different mental disorders (MDs) and their presenting symptoms and diagnoses of VLD.

Methods: Case series study, retrospective chart review of patients seen between January 2016 and December 2017 at the Johns Hopkins Voice Center. Diagnoses, demographic data, and comorbidities were collected. VLD were grouped into categories (laryngeal pathology, functional voice disorders, airway, swallowing, other) for statistical analysis.

Results: Of a total 4,249 patients, 836 patients (19.7%) suffered from at least one MD. Those patients presented more frequently with swallowing problems (24.9% of all diagnoses in MD compared to 21.2% in control group; adjusted odds ratio [aOR] 1.280, 95% confidence interval [CI] 1.107-1.480, P = .001) and less frequently with vocal cord pathology (30.9% of all diagnoses in MD compared to 33.9% in control group, aOR 0.793, 95% CI 0.694-0.907, P = .001). Patients suffering from depression had significantly increased odds for dysphagia (aOR 1.570, 95% CI 1.216-2.026, P = .001). VLD clinical presentation profile was created for every MD studied.

Conclusion: Patients suffering from mental health disorders present more frequently with swallowing complaints, in particular for dysphagia. Awareness of this can guide appropriate referrals. Objective laryngeal findings are common in patients with substance abuse disorders. They should be screened with careful diagnostic laryngoscopy.

Level Of Evidence: 4 Laryngoscope, 131:E231-E239, 2021.
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http://dx.doi.org/10.1002/lary.28755DOI Listing
January 2021

Chronic Pain Syndromes and Their Laryngeal Manifestations.

JAMA Otolaryngol Head Neck Surg 2020 06;146(6):543-549

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland.

Importance: Fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), and chronic fatigue syndrome (CFS) are traditionally considered as distinct entities grouped under chronic pain syndrome (CPS) of an unknown origin. However, these 3 disorders may exist on a spectrum with a shared pathophysiology.

Objective: To investigate whether the clinical presentation of FMS, IBS, and CFS is similar in a population presenting with voice and laryngeal disorders.

Design, Setting, And Participants: This case series was a retrospective review of the medical records and clinical notes of patients treated between January 1, 2016, and December 31, 2017, at the Johns Hopkins Voice Center in Baltimore, Maryland. Patients with at least 1 CPS of interest (FMS, IBS, or CFS) were included (n = 215), along with patients without such diagnoses (n = 4034). Diagnoses, demographic, and comorbidity data were reviewed. Diagnoses related to voice and laryngeal disorders were subdivided into 5 main categories (laryngeal pathology, functional voice disorders, airway problems, swallowing problems, and other diagnoses).

Main Outcomes And Measures: Prevalence and odds ratios of 45 voice and laryngeal disorders were reviewed. Odds ratios (ORs) were calculated by comparing patients with CPS with control patients.

Results: In total, 4249 individuals were identified; 215 (5.1%) had at least 1 CPS and 4034 (94.9%) were control participants. Patients with CPS were 3 times more likely to be women compared with the control group (173 of 215 [80.5%] vs 2318 of 4034 [57.5%]; OR, 3.156; 95% CI, 2.392-4.296), and the CPS group had a mean (SD) age of 57.80 (15.30) years compared with the mean (SD) age of 55.77 (16.97) years for the control group. Patients with CPS were more likely to present with functional voice disorders (OR, 1.812; 95% CI, 1.396-2.353) and less likely to present with laryngeal pathology (OR, 0.774; 95% CI, 0.610-0.982) or airway problems (OR, 0.474; 95% CI, 0.285-0.789).

Conclusions And Relevance: The voice and airway presentation of patients with FMS, IBS, and/or CFS appears to be indistinguishable from each other. This finding suggests that these 3 diseases share upper airway symptoms.
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http://dx.doi.org/10.1001/jamaoto.2020.0530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193518PMC
June 2020

CT Lung Screening in Patients with Laryngeal Cancer.

Sci Rep 2020 03 13;10(1):4676. Epub 2020 Mar 13.

Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA.

Laryngeal cancer (LC) patients who meet the age and smoking criteria of the U.S. Preventive Services Task Force (USPSTF) for annual CT lung screening were analysed for pulmonary nodules (PN) detection and secondary lung cancer (SLC) diagnosis. This is a retrospective chart review of LC patients treated at Johns Hopkins Hospital from January 2010 to December 2017. The study population included patients who met USPSTF criteria by age and smoking history for annual chest screening and were followed for at least 3 consecutive years. A total of 998 LC patients' records were reviewed, of which 151 met the inclusion criteria. Inadequate follow-up period (37% of excluded cases) was the most common reason for exclusion, followed by not meeting USPSTF age criteria (27% excluded cases). In seventy-eight patients (n = 78, 52% of analysed patients) PN were reported. Nine individuals (6% of analysed patients) were diagnosed with SLC. Age over 70 (p = 0.003) was an independent predictor of malignancy. White race and smoking history over 40 pack-years were positively associated with a pulmonary nodule detection (p = 0.037 and p = 0.044, respectively). The incidence of PN and SLC in patients with LC is high. Many patients with laryngeal cancer meet the formal guidelines for USPSTF screening, and should be screened annually according to evidence-based medicine for the early detection of secondary lung cancers.
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http://dx.doi.org/10.1038/s41598-020-61511-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070077PMC
March 2020

Paraganglioma of the recurrent laryngeal nerve.

Laryngoscope 2020 12 29;130(12):E782-E785. Epub 2019 Nov 29.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Paragangliomas of the head and neck are rare, and most frequently benign, slow growing, and nonsecretory. The most frequent locations these tumors arise in the head and neck include the carotid body, jugular bulb, vagus nerve, tympanic branch of the glossopharyngeal nerve, and sympathetic chain. Here we present, to our knowledge, the second reported case of paraganglioma of the recurrent laryngeal nerve. This case is unique given the patient presentation due to ipsilateral vocal fold paralysis, which has not previously been reported, lack of previous surgery, and demonstration of loss of succinate dehydrogenase iron-sulfur subunit B expression. Laryngoscope, 2019.
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http://dx.doi.org/10.1002/lary.28430DOI Listing
December 2020

Evaluating the Utility and Prevalence of HPV Biomarkers in Oral Rinses and Serology for HPV-related Oropharyngeal Cancer.

Cancer Prev Res (Phila) 2019 10 16;12(10):689-700. Epub 2019 Aug 16.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 "at-risk" people (screening) and 133 "high-risk" people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each < 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88% for DEIA, Cobas, and E6 antibodies, respectively), but specificity was reduced (93%-97%). Aptima had poor sensitivity (23%). Sensitivity decreased when cotesting HPV16 oral rinse DNA and E6 antibodies (37%-48%), or multiple E antibodies (69%-72%). HPV16 DNA were detected in ∼2% of the at-risk by either DEIA or Cobas and up to 15% of the high-risk population. HPV16 E6 seroprevalence was 2.3% and 2.4% in the at-risk and high-risk populations, respectively. Oral rinse HPV testing had moderate-to-poor sensitivity for HPV-OPC, suggesting many true positives would be missed in a potential screening scenario. HPV16 E6 serum antibody was the most promising biomarker evaluated.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029397PMC
October 2019

HPV RNA in-situ hybridization as a diagnostic aid in papillary laryngeal lesions.

Laryngoscope 2020 04 8;130(4):955-960. Epub 2019 Jul 8.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, U.S.A.

Objectives: In the larynx, differentiating squamous papillomas from de-novo papillary squamous dysplasias or squamous cell carcinomas (SCC) has significant consequences for management. Overlapping clinical presentations and cytologic changes across the spectrum of papillary lesions presents diagnostic challenges for otolaryngologists and pathologists. In this study, we evaluate whether ribonucleic acid (RNA) in-situ hybridization (ISH) for low-risk and high-risk human papillomavirus (HPV) can help distinguish these lesions.

Methods: We constructed tissue microarrays from 97 papillary laryngeal lesions, including 61 squamous papillomas, two papillomas with dysplasia, two SCCs-ex papilloma, 14 papillary squamous dysplasias, and 18 papillary SCCs identified at the Johns Hopkins Hospital between 2000 and 2017. We performed RNA ISH using probes for low-risk and high-risk HPV types.

Results: Low-risk HPV RNA was identified in 55 benign papillomas (90%), two papillomas with dysplasia (100%), and two SCCs-ex papilloma (100%) but was absent in de-novo papillary dysplasias and SCCs (0%). High-risk HPV RNA ISH was positive only in four papillary SCC (22%). Overall, low-risk HPV RNA ISH was 90% sensitive and 89% specific for benign papillomas with a positive predictive value of 93% and negative predictive value of 84%. In contrast, high-risk HPV was 20% sensitive for SCC.

Conclusion: Low-risk HPV RNA ISH is a useful diagnostic adjunct for distinguishing laryngeal squamous papillomas from papillary squamous dysplasia and SCC. However, it is not entirely specific for benign processes as it is also retained in papillomas with dysplasia and SCCs-ex papilloma. Because high-risk HPV is rare in papillary laryngeal lesions, high-risk HPV RNA ISH has limited utility.

Level Of Evidence: Level 4 Laryngoscope, 130:955-960, 2020.
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http://dx.doi.org/10.1002/lary.28159DOI Listing
April 2020

Infectivity of murine papillomavirus in the surgical byproducts of treated tail warts.

Laryngoscope 2020 03 1;130(3):712-717. Epub 2019 May 1.

Department of Otolaryngology-Head and Neck Surgery, The Voice and Swallowing Institute, Columbia University Medical Center, New York Presbyterian Hospital, New York, New York, U.S.A.

Objectives/hypothesis: Human papillomavirus (HPV) is a highly stable DNA virus that causes disease in human organ systems, including the larynx and oropharynx. The treatment of HPV-associated diseases with scalpels, lasers, and other surgical instruments has the potential to release infectious particles, placing healthcare workers at risk. The objectives of this study were to create a reproducible in vivo animal model of papillomavirus infectivity and to compare the infectivity of byproducts of surgically treated mouse papillomavirus (MmuPV1) warts.

Study Design: Animal study.

Methods: Nude laboratory mice (Mus musculus) with established MmuPV1 tail warts were treated with scalpel excision, potassium titanyl phosphate (KTP) laser ablation, and coblator treatment. Uninfected nude mice were challenged with surgical byproducts, including ablated and heated tissue, and surgical smoke products. The incidence and time course of the appearance of warts was recorded.

Results: There was rapid transmission of virus in mice challenged with scalpel-treated warts, with 50% penetrance of infection at day 13 and 100% at day 32. For KTP-treated warts, there was the slower development of infection (50% by day 35) but 100% penetrance by day 52. Coblator-treated tissue reached 50% penetrance at day 59 and a maximum of 73% penetrance. Smoke plume captured during treatment with the KTP laser and coblator was highly infectious, as was the material captured in a laser filter.

Conclusions: MmuPV1 remains infectious in all modes of surgically treated tissue, and the smoke plume is capable of transmitting infection. Healthcare workers should use appropriate precautions to lower their risk of infection when treating papillomavirus-associated diseases.

Level Of Evidence: NA Laryngoscope, 130:712-717, 2020.
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http://dx.doi.org/10.1002/lary.28026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884657PMC
March 2020

Clinical practice patterns in laryngeal cancer and introduction of CT lung screening.

Am J Otolaryngol 2019 Jul - Aug;40(4):520-524. Epub 2019 Apr 12.

Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, United States of America. Electronic address:

Objectives: After the publication of large clinical trials, in January 2014 The U.S. Preventive Services Task Force (USPSTF) recommended annual lung cancer screening with low-dose CT in a well-defined group of high-risk smokers. A significant proportion of patients with laryngeal cancer (LC) meet the introduced criteria, and we hypothesized that clinical practice would change as a result of these evidence-based guidelines.

Methods: Retrospective chart review of patients diagnosed with LC and treated at Johns Hopkins Hospital who met USPSTF criteria for annual chest screening and were followed for at least 3 consecutive years in the years surrounding the introduction of screening guidelines (January 2010 to December 2017) was performed to identify those who had recommended screening CT chest.

Results: A total of 151 patients met the inclusion criteria of the study and were followed for a total of 746 patient-years. 184/332 (55%) patient-years in the pre-guidelines period and 246/414 (59%) in the post-guidelines period included at least one recommended chest imaging (CT or PET-CT; p = 0.27). 248/332 (75%) patient-years in the pre-guidelines period and 314/414 (76%) in the post-guidelines period included any radiological chest imaging (X-ray, CT or PET-CT; p = 0.72). Screening scans were ordered by OHNS (45%), Medical Oncology (31%), Radiation Oncology (8%), and primary care (14%) with 70% of patients missing at least one year of indicated screening.

Conclusions: The implementation of new lung cancer screening guidelines did not change clinical practice in the management of patients with LC and many patients do not receive recommended screening. Further study concerning potential barriers to effective evidence-based screening and coordination of care is warranted.
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http://dx.doi.org/10.1016/j.amjoto.2019.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570546PMC
December 2019

Geriatric Dysphonia: Characteristics of Diagnoses in Age-Based Cohorts in a Tertiary Voice Clinic.

Ann Otol Rhinol Laryngol 2019 May 24;128(5):384-390. Epub 2019 Jan 24.

1 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Objective: An aging population has increased focus on geriatric otolaryngology. Those ≥65 years old are not a uniform population, however, and recent gerontology literature recognizes important physiologic differences between the young-old (ages 65-74 years), middle-old (75-84), and old-old (≥85). This study evaluates differences within these groups among dysphonia patients ≥65 years relative to diagnosis and voice-related quality of life (V-RQOL).

Methods: Chart review of all new patients ≥65 years presenting to the Johns Hopkins Voice Center between April 2015 and March 2017 identified chief complaint, diagnosis, and self-reported voice handicap. Etiology of dysphonia diagnoses were classified. Diagnostic categories and V-RQOL were evaluated as functions of patient age and gender.

Results: Of 839 new patients ≥65 years, 463 (55.2%) reported chief complaint of dysphonia, with the most common etiologies being vocal fold immobility (28.3%) and atrophy (21.6%). Younger cohorts were more likely to present with benign vocal fold lesion and vocal fold immobility, while older cohorts were more likely to present with atrophy ( P = .016). The odds of having a diagnosis of vocal fold atrophy increased 7% with each year of life (odds ratio = 1.07; 95% CI, 1.03-1.11). V-RQOL scores were similar across gender and age categorization.

Conclusion: Dysphonia patients ≥65 years are not a uniform group, and important differences exist in terms of diagnosis as a function of age. Knowledge of these differences may inform further investigations in the growing field of geriatric otolaryngology.
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http://dx.doi.org/10.1177/0003489419826133DOI Listing
May 2019

Voice Outcomes in Laryngotracheal Stenosis: Impact of the Montgomery T-tube.

Clin Surg 2018 Jan 10;3. Epub 2018 Jan 10.

Department of Otolaryngology, Johns Hopkins University, USA.

Objectives: Montgomery T-tubes enable patients with laryngotracheal stenosis to maintain airway patency. They also restore the ability to phonate in many patients. The primary objective is to compare voice quality of life outcomes in patients before and after Montgomery T-tube placement. The secondary objective is evaluating complications associated with T-tube placement.

Methods: Retrospective chart review of patients with T-tubes for laryngotracheal stenosis from 2012-2016. Patient demographics, Voice-Related Quality of Life (VRQoL) scores, indication for t-tube placement, t-tube duration and complications were analyzed.

Results: Thirteen patients were included. The most common indication for T- tube placement was grade III-IV stenosis with aphonia/significant dysphonia (n=7, 54%). Other indications were grade III/IV stenosis who desired T-tube over tracheostomy (n=2, 15%), primary glottic stenosis (n=3, 23%), and primary tracheomalacia (n=1, 8%). There was a statistically significant improvement (p<0.05) in VRQoL after T-tube placement. Five patients (38%) went from aphonia to voicing. Granulation tissue was the most common complication related to T tube placement. There were no deaths related to T-tube placement after two years.

Conclusion: Montgomery T-tubes can restore phonation in a population of patients with iatrogenic high grade stenosis who are aphonic/severely dysphonic with traditional tracheotomies. The complication rate must be considered, with granulation tissue formation the most common.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291003PMC
January 2018

Molecular and immunologic analysis of laryngeal squamous cell carcinoma in smokers and non-smokers.

Am J Otolaryngol 2019 Mar - Apr;40(2):213-217. Epub 2018 Nov 22.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Laryngeal squamous cell carcinoma (LSCC) is strongly associated with tobacco use, but recent reports suggest an increasing incidence of LSCC in patients without traditional risk factors, suggesting an alternative etiology of tumorigenesis. The purpose of this study is to characterize this non-smoking population and to compare immunohistochemical markers in tumor specimens from non-smokers and smokers with LSCC.

Methods: A retrospective chart review of patients with LSCC at Johns Hopkins Hospital (JHH) was performed. A tissue microarray (TMA) was constructed with tumor specimen from non-smokers with stage and age-matched smokers and stained for a variety of immunologic and molecular targets.

Results: In the JHH cohort of 521 patients, 12% (n = 63) were non-smokers. Non-smokers were more likely to be <45 years old at time of diagnosis (OR 4.13, p = 0.001) and to have glottic tumors (OR 2.46, p = 0.003). The TMA was comprised of tumors from 34 patients (14 non-smokers, 20 smokers). Only 2 patients (6%) were human-papillomavirus (HPV) positive by high-risk RNA in situ hybridization (ISH). There was no correlation between smoking status and p16 (p = 0.36), HPV-ISH positivity (p = 0.79), phosphatase and tensin homolog (PTEN, p = 0.91), p53 (p = 0.14), or programmed death-ligand 1 (PD-L1, p = 0.27) expression.

Conclusions: Non-smokers with LSCC are more likely to be younger at the time of diagnosis and have glottic tumors than smokers with LSCC. In TMA analysis of stage and age-matched specimens from smoker and non-smokers with LSCC, the pattern of expression for common molecular and immunologic markers is similar. Further, HPV does not appear to be a major causative etiology of LSCC in either smokers or non-smokers in our cohort of patients.
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http://dx.doi.org/10.1016/j.amjoto.2018.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485418PMC
June 2019

I dream of Gini: Quantifying inequality in otolaryngology residency interviews.

Laryngoscope 2019 03 8;129(3):627-633. Epub 2018 Nov 8.

Department of Otolaryngology-Head and Neck Surgery, Baltimore, Maryland, U.S.A.

Objectives: Otolaryngology applicants routinely decry conflicting interview dates because this limits the number of interviews that one can attend, despite being offered an interview. Conversely, applicants also perceive that a large number of interviews are offered to a minority of applicants. We sought to verify and quantify the inequality in distribution of interviews attended.

Study Design: Retrospective analysis of the National Resident Matching Program (NRMP) 2016 Charting Outcomes in the Match and Electronic Residency Application Service (ERAS) historic specialty data.

Methods: The Gini coefficient, a commonly used indicator of economic inequality, was calculated using data from the 2016 Charting Outcomes in the Match to estimate the distribution of interviews attended. This data was compared to nine other specialties, comprising a wide range of competitiveness and specialty size.

Results: 26% (110 of 416) of otolaryngology applicants accounted for half (1,721 of 3,426) of all possible interview positions. The Gini coefficient ranged from 0.43 to 0.84 across 10 specialties, with a higher coefficient indicating higher inequality. The Gini coefficient among otolaryngology applicants was 0.43, indicating lower inequality than most other specialties. When including only applicants who interviewed, the Gini coefficient was 0.23.

Conclusion: There is an unequal distribution of interview invitations, which likely reflects the reality of asymmetry in applicant competitiveness. Otolaryngology demonstrates the greatest equality in distribution, which may stem from a greater burden of hoarding. The specialty's perceived competitiveness mitigates factors such as cost and time, essentially encouraging more people to take as many interviews as they can.

Level Of Evidence: NA Laryngoscope, 129:627-633, 2019.
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http://dx.doi.org/10.1002/lary.27521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883635PMC
March 2019

Outcomes in Bilateral Vocal Fold Immobility: A Retrospective Cohort Analysis.

Otolaryngol Head Neck Surg 2018 Sep 18:194599818800462. Epub 2018 Sep 18.

3 Department of Otolaryngology-Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective To test the hypothesis that the etiologies of bilateral vocal fold mobility impairment (BLVFI), bilateral vocal fold paralysis (BVFP), and posterior glottis stenosis (PGS) have distinct clinical outcomes. To identify patient-specific and procedural factors that influence tracheostomy-free survival. Study Design Retrospective cohort study. Setting Johns Hopkins Medical Center from 2004 to 2015. Subjects and Methods Case series with chart review of 68 patients with PGS and 17 patients with BVFP. Multiple logistic regression analysis determined factors associated with airway prosthesis dependence at last follow-up and the procedural burden (defined as number of operative procedures per year). Results PGS comprised the majority of BLVFI (76%). PGS injury arose primarily after endotracheal intubation (91%), while BVFP most commonly was due to iatrogenic surgical injury to bilateral recurrent laryngeal nerves (88%, P < .001). Overall in BLVFI, 66% were tracheostomy free at last follow-up (62% in PGS, 82% in BVFP). Of those who underwent an operative intervention to be decannulated, 88% were decannulated (90% PGS, 80% BVFP). Patients with PGS required higher procedural burden to achieve decannulation compared with the BVFP cohort (3.1 ± 5.2 vs 0.71 ± 1.4, P = .002). In multivariate analysis of PGS, smoking was a risk factor for tracheostomy dependence ( P = .026). Conclusions BLVFI is primarily an iatrogenic complication. There are high rates of tracheostomy dependence in BLVFI, with procedural intervention needed for decannulation. Compared with BVFP, patients with PGS had a higher procedural burden overall and to achieve decannulation. Patients with PGS should be counseled that smoking, a modifiable risk factor, may increase the risk of tracheostomy dependence.
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http://dx.doi.org/10.1177/0194599818800462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422766PMC
September 2018

Laryngeal Injury and Upper Airway Symptoms After Oral Endotracheal Intubation With Mechanical Ventilation During Critical Care: A Systematic Review.

Crit Care Med 2018 12;46(12):2010-2017

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD.

Objectives: To systematically review the symptoms and types of laryngeal injuries resulting from endotracheal intubation in mechanically ventilated patients in the ICU.

Data Sources: PubMed, Embase, CINAHL, and Cochrane Library from database inception to September 2017.

Study Selection: Studies of adult patients who were endotracheally intubated with mechanical ventilation in the ICU and completed postextubation laryngeal examinations with either direct or indirect visualization.

Data Extraction: Independent, double-data extraction and risk of bias assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias assessment followed the Cochrane Collaboration's criteria.

Data Synthesis: Nine studies (seven cohorts, two cross-sectional) representing 775 patients met eligibility criteria. The mean (SD; 95% CI) duration of intubation was 8.2 days (6.0 d; 7.7-8.7 d). A high prevalence (83%) of laryngeal injury was found. Many of these were mild injuries, although moderate to severe injuries occurred in 13-31% of patients across studies. The most frequently occurring clinical symptoms reported post extubation were dysphonia (76%), pain (76%), hoarseness (63%), and dysphagia (49%) across studies.

Conclusions: Laryngeal injury from intubation is common in the ICU setting. Guidelines for laryngeal assessment and postextubation surveillance do not exist. A systematic approach to more robust investigations could increase knowledge of the association between particular injuries and corresponding functional impairments, improving understanding of both time course and prognosis for resolution of injury. Our findings identify targets for future research and highlight the long-known, but understudied, clinical outcomes from endotracheal intubation with mechanical ventilation in ICU.
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http://dx.doi.org/10.1097/CCM.0000000000003368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219530PMC
December 2018

Voice and Swallowing Dysfunction in Neurofibromatosis 2.

Otolaryngol Head Neck Surg 2018 03 21;158(3):505-510. Epub 2017 Nov 21.

2 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Objective Neurofibromatosis 2 (NF2) is a neuro-oncologic condition that presents with bilateral vestibular schwannomas of the cerebellopontine angle (CPA). Voice and swallowing impairment can occur from direct involvement or compression of the vagus nerve or as the result of surgical excision of CPA tumors. The objectives in this study are to (1) assess the prevalence of voice and swallowing impairments and (2) analyze the effects of vagal dysfunction in patients with NF2. Study Design Cross-sectional. Setting Academic tertiary care center. Subjects and Methods Patients at a neurofibromatosis center were mailed Voice Handicap Index and Sydney Swallow Questionnaire surveys. Stroboscopic, voice, and swallowing evaluations were performed for patients who elected to participate in screening exams. Results There were high rates of self-assessed and objective voice and swallowing handicaps in this population. Fourteen of 40 (35%) patients had a self-assessed voice handicap, and 20 of 40 (50%) patients had a self-assessed swallow handicap. Vocal fold motion impairment (VFMI) was observed in 22 of 31 (71%) patients examined, with 27 of 62 (44%) possible vocal cords affected. Velopharyngeal insufficiency (45%) and piriform sinus pooling or residue (39%) were seen in a significant percentage of patients. There was a significant relationship between vocal cord motion impairment and CPA surgical intervention ipsilateral to the impairment ( P = .002). The presence of VFMI was strongly associated with voice ( P = .002) and swallowing ( P = .01) impact on quality of life. Conclusion Speech and swallowing impairments are highly prevalent in patients with NF2, cause significant impact on quality of life, and are most commonly related to surgical interventions in the CPA region.
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http://dx.doi.org/10.1177/0194599817741839DOI Listing
March 2018

The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis.

Laryngoscope 2018 01 22;128(1):E27-E32. Epub 2017 Sep 22.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.

Objectives/hypothesis: Generation of an immunosuppressive microenvironment may enable a persistent human papillomavirus infection in the setting of an otherwise normal immune system. We hypothesized that expression of the T-lymphocyte co-inhibitory receptor programmed death 1 (PD-1) and its ligand PD-L1 would be increased in the recurrent respiratory papillomatosis (RRP) microenvironment compared to normal controls.

Study Design: Case-control study.

Methods: Formalin-fixed paraffin-embedded respiratory papilloma and normal controls were obtained under institutional review board approval, stained for CD4, CD8, FoxP3, and PD-1, and scored by automated cell count. PD-L1 staining was scored by a blinded pathologist using an adjusted inflammation score that accounted for epithelial and immune infiltrate.

Results: Thirty-nine RRP cases and seven controls were studied. All immunologic markers demonstrated significantly increased staining in RRP specimens compared to normal controls (all P < .01). PD-1 correlated with both CD4 (P < .0001) and CD8 (P < .001) cell counts. Epithelial staining for PD-L1 (68%) and PD-L1+ infiltrating immune cells (76%) were observed in the majority of papilloma samples. The strongest staining for PD-L1 was usually observed in the basal papilloma layer adjacent to the immunologic infiltrate in the vascular core. Disease severity inversely correlated with CD8 cell counts (P = .01). A correlation between disease severity and other immunologic markers was not observed.

Conclusions: Most RRP specimens demonstrate PD-1 T-lymphocyte infiltration and PD-L1 expression on both papilloma and infiltrating immune cells. This study suggests that this checkpoint pathway may be contributing to local immunosuppression in RRP, and opens the door for clinical trials utilizing PD-blocking monoclonal antibodies.

Level Of Evidence: NA Laryngoscope, 128:E27-E32, 2018.
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http://dx.doi.org/10.1002/lary.26847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771441PMC
January 2018

Prophylactic immunization with human papillomavirus vaccines induces oral immunity in mice.

Laryngoscope 2018 01 4;128(1):E16-E20. Epub 2017 Sep 4.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.

Objective: Although it has been shown that prophylactic vaccination can induce genital immunity, there is inadequate information on human papillomavirus (HPV) vaccine-induced oral immunity, which is of particular interest due to HPV-associated oropharyngeal malignancies and recurrent respiratory papillomatosis. Therefore, we assessed the efficacy of various HPV vaccines against oral HPV pseudovirus (PsV) infection in mice.

Study Design: Preclinical scientific investigation.

Methods: C57BL/6 mice were vaccinated three times at 2-week intervals with either Gardasil (Merck, Kenilworth, NJ) (50 µL intramuscular injection) or a candidate pan-HPV L2 vaccine with alum adjuvant (25 µg subcutaneous injection). Additional mice were immunized with passive transfer of either Gardasil (Merck) human antisera or nonimmunized sera (100 µL intraperitoneal injection). All vaccinated and naïve control mice were then challenged with HPV16 E6E7 luciferase PsV in the oral mucosa. Visualization of HPV PsV infection was monitored through in vivo luciferase imaging.

Results: Oral luciferase-expressing HPV16 PsV infection was not detected in Gardasil (Merck), L2 vaccine, and Gardasil (Merck) antisera-immunized mice, whereas robust luciferase expression was observed in all control mice. An in vitro neutralization assay from sera of Gardasil-vaccinated (Merck) mice confirmed that vaccine efficacy was due to neutralizing antibodies.

Conclusion: Oral HPV16 PsV infection in mice was completely prevented with all methods of prophylactic HPV immunization. These findings provide preliminary evidence that human vaccines induce protection against oral HPV infection, which has significant public health implications for HPV-associated oropharyngeal malignancies.

Level Of Evidence: NA. Laryngoscope, 128:E16-E20, 2018.
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http://dx.doi.org/10.1002/lary.26772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739972PMC
January 2018

Immunologic responses to a novel DNA vaccine targeting human papillomavirus-11 E6E7.

Laryngoscope 2017 12 17;127(12):2713-2720. Epub 2017 Jul 17.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.

Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a benign disease caused by human papillomavirus (HPV) types 6 and 11. Although a prophylactic vaccine against RRP is available, a therapeutic vaccine is needed to treat those already infected. The objective of our study was to design and test a DNA vaccine targeting HPV11 proteins.

Study Design: Preclinical scientific investigation.

Methods: A DNA vaccine encoding the HPV11 E6 and E7 genes linked to calreticulin (CRT) was generated. Immunologic response to the HPV11 CRT/E6E7 vaccine was measured by vaccinating C57BL/6 mice via electroporation and measuring CD8 + T cell responses from harvested splenocytes. A tumor cell line containing HPV11-E6E7 was created, and the ability of novel DNA vaccine to control tumor growth was measured in vivo.

Results: Our vaccine generated a significant and specific CD8 + T-cell response against the HPV11-E6aa41-70 peptide. The CD8 + T-cell responses did not recognize E7 epitopes, indicating E6 immunodominance. CD8 + responses were augmented in the CRT-linked vaccine compared to a control non-CRT vaccine. The HPV11 CRT/E6E7 vaccine was used to treat mice inoculated with a HPV11 E6E7 expressing tumor cell line after temporary CD3 depletion to facilitate tumor growth. Vaccinated mice had a significantly lower tumor growth rate (P = .029) and smaller tumor volumes compared to control mice, indicating an augmented immunologic response in vaccinated mice.

Conclusions: A DNA vaccine targeting HPV11 E6E7 generates a specific HPV11 CD-8 + T-cell response capable of reducing the growth of HPV11-expressing tumors. DNA vaccines are a promising immunologic strategy for treating RRP.

Level Of Evidence: NA. Laryngoscope, 127:2713-2720, 2017.
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http://dx.doi.org/10.1002/lary.26737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687988PMC
December 2017

Evaluating Post-Radiotherapy Laryngeal Function with Laryngeal Videostroboscopy in Early Stage Glottic Cancer.

Front Oncol 2017 12;7:124. Epub 2017 Jun 12.

Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Objective: Dysphonia is common among patients with early stage glottic cancer. Laryngeal videostroboscopy (LVS) has not been routinely used to assess post-radiotherapy (RT) voice changes. We hypothesized that LVS would demonstrate improvement in laryngeal function after definitive RT for early-stage glottic cancer.

Study Design: Blinded retrospective review of perceptual voice and stroboscopic parameters for patients with early glottic cancer and controls.

Setting: High-volume, single-institution academic medical center.

Subjects And Methods: Fifteen patients underwent RT for Tis-T2N0M0 glottic cancer and were evaluated with serial LVS exams pre- and post-RT. Stroboscopic assessment included six parameters: vocal fold (VF) vibration, VF mobility, erythema/edema, supraglottic compression, glottic closure, and secretions. Grade, roughness, breathiness, asthenia, strain (GRBAS) voice perceptual scale was graded in tandem with LVS score. Assessments were grouped by time interval from RT: pre-RT, 0-4, 4-12, and >12 months post-RT.

Results: 60 LVS exams and corresponding GRBAS assessments were reviewed. There were significant improvements in ipsilateral VF motion ( = 0.03) and vibration ( = 0.001) and significant worsening in contralateral VF motion ( < 0.001) and vibration ( = 0.008) at >12 months post-RT. Glottic closure significantly worsened, most prominent >12 months post-RT ( = 0.01). Composite GRBAS scores were significantly improved across all post-RT intervals.

Conclusion: LVS proved to be a robust tool for assessing pre- and post-RT laryngeal function. We observed post-RT improvement in ipsilateral VF function, a decline in contralateral VF function, and decreased glottic closure. These results demonstrate that LVS can detect meaningful changes in VF and glottic function and support its use for post-RT evaluation of glottic cancer patients.
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http://dx.doi.org/10.3389/fonc.2017.00124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467001PMC
June 2017

Systemic bevacizumab for recurrent respiratory papillomatosis: A national survey.

Laryngoscope 2017 10 28;127(10):2225-2229. Epub 2017 Jun 28.

Pediatric Otolaryngology, The Children's Hospital of Philadelphia, The University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Objectives/hypothesis: Aggressive laryngeal, tracheal, and pulmonary papilloma is an extremely challenging clinical problem without proven treatment options. A recent German report documented promising results with systemic bevacizumab. The objective of this study is to report the initial experience of this novel treatment in the United States for recurrent respiratory papillomatosis (RRP).

Study Design: Cases series.

Methods: Electronic survey of the RRP Task Force of the American Society of Pediatric Otolaryngology, American Broncho-Esophagological Association, and physicians known to the authors to have used systemic bevacizumab for RRP.

Results: Eleven completed surveys were obtained. In three cases, systemic bevacizumab was considered clinically but not administered. Eight patients were treated with systemic bevacizumab, all for aggressive papillomatosis uncontrolled by surgical and adjuvant therapy, including seven of eight with pulmonary disease. Treatment dosing ranged from 5 to 10 mg/kg every 2 to 4 weeks, with all patients responding (7/8 partial response, 1/8 complete response). In four patients who had postbevacizumab chest imaging, three demonstrated improvement of disease and one stabilization. Treatment interval could be lengthened in seven patients and clinical response maintained. One patient with long-standing pulmonary disease (>10 years) was diagnosed with malignant transformation while on treatment, and bevacizumab was discontinued in lieu of other chemotherapeutic agents. All other patients continue on systemic bevacizumab with minimal complications (hemoptysis n = 1, proteinuria n = 1).

Conclusions: Systemic bevacizumab appears to have significant promise in the most treatment-resistant and aggressive forms of papillomatosis with a low complication profile. These results suggest bevacizumab should be studied in a formal clinical trial for RRP.

Level Of Evidence: 4. Laryngoscope, 127:2225-2229, 2017.
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http://dx.doi.org/10.1002/lary.26662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607082PMC
October 2017

Spontaneous and Vaccine-Induced Clearance of Mus Musculus Papillomavirus 1 Infection.

J Virol 2017 08 12;91(15). Epub 2017 Jul 12.

Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, USA

Mus musculus papillomavirus 1 (MmuPV1/MusPV1) induces persistent papillomas in immunodeficient mice but not in common laboratory strains. To facilitate the study of immune control, we sought an outbred and immunocompetent laboratory mouse strain in which persistent papillomas could be established. We found that challenge of SKH1 mice (Crl:SKH1-Hrhr) with MmuPV1 by scarification on their tail resulted in three clinical outcomes: (i) persistent (>2-month) papillomas (∼20%); (ii) transient papillomas that spontaneously regress, typically within 2 months (∼15%); and (iii) no visible papillomas and viral clearance (∼65%). SKH1 mice with persistent papillomas were treated by using a candidate preventive/therapeutic naked-DNA vaccine that expresses human calreticulin (hCRT) fused in frame to MmuPV1 E6 (mE6) and mE7 early proteins and residues 11 to 200 of the late protein L2 (hCRTmE6/mE7/mL2). Three intramuscular DNA vaccinations were delivered biweekly via electroporation, and both humoral and CD8 T cell responses were mapped and measured. Previously persistent papillomas disappeared within 2 months after the final vaccination. Coincident virologic clearance was confirmed by hybridization and a failure of disease to recur after CD3 T cell depletion. Vaccination induced strong mE6 and mE7 CD8 T cell responses in all mice, although they were significantly weaker in mice that initially presented with persistent warts than in those that spontaneously cleared their infection. A human papillomavirus 16 (HPV16)-targeted version of the DNA vaccine also induced L2 antibodies and protected mice from vaginal challenge with an HPV16 pseudovirus. Thus, MmuPV1 challenge of SKH1 mice is a promising model of spontaneous and immunotherapy-directed clearances of HPV-related disease. High-risk-type human papillomaviruses (hrHPVs) cause 5% of all cancer cases worldwide, notably cervical, anogenital, and oropharyngeal cancers. Since preventative HPV vaccines have not been widely used in many countries and do not impact existing infections, there is considerable interest in the development of therapeutic vaccines to address existing disease and infections. The strict tropism of HPV requires the use of animal papillomavirus models for therapeutic vaccine development. However, MmuPV1 failed to grow in common laboratory strains of mice with an intact immune system. We show that MmuPV1 challenge of the outbred immunocompetent SKH1 strain produces both transient and persistent papillomas and that vaccination of the mice with a DNA expressing an MmuPV1 E6E7L2 fusion with calreticulin can rapidly clear persistent papillomas. Furthermore, an HPV16-targeted version of the DNA can protect against vaginal challenge with HPV16, suggesting the promise of this approach to both prevent and treat papillomavirus-related disease.
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http://dx.doi.org/10.1128/JVI.00699-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512245PMC
August 2017

The Changing Impact of Gastroesophageal Reflux Disease in Clinical Practice.

Ann Otol Rhinol Laryngol 2017 Mar 10;126(3):229-235. Epub 2017 Jan 10.

4 Department of Otolaryngology-Head & Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.

Objectives: The National Ambulatory Medical Care Survey (NAMCS) database was utilized to understand evolving national trends in diagnosis and management of reflux.

Methods: The NAMCS database was queried for visits related to gastroesophageal reflux diagnosis and management. Analysis performed for time periods 1998-2001, 2002-2005, and 2006-2009 was weighted to provide national estimates of care. Results were compared to previously reported time periods from 1990 to 2001 to evaluate patterns in overall visits, age and ethnicity of patients, provider type, and prescriptions provided.

Results: The number of ambulatory visits for reflux increased from 8 684 000 in 1998-2001 to 15 750 000 in 2006-2009. Visits increased across each time period for internal medicine, family, and gastroenterology physicians. Among otolaryngologists, absolute visits increased from 1998-2001 to 2002-2005 but decreased in 2006-2009; difference between these time periods did not reach statistical significance. From 1998-2001 to 2006-2009, reflux medication use increased 233%, with continuing trends toward increased proton pump inhibitor use.

Conclusions: Reflux visits have increased across all demographic subgroups studied. Knowledge of these trends may inform further paradigm shifts in diagnosis and management of reflux.
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http://dx.doi.org/10.1177/0003489416686586DOI Listing
March 2017
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