Efficacy of Systemic Bevacizumab for Recurrent Respiratory Papillomatosis with Pulmonary Involvement.

OBJECTIVES: Pulmonary papillomatosis is a rare but severe manifestation of recurrent respiratory papillomatosis (RRP). Efficacy data of systemic bevacizumab for pulmonary RRP are limited. This study's objective was to characterize disease response of pulmonary RRP to systemic bevacizumab. METHODS: A retrospective review was performed to identify patients with pulmonary RRP seen at three medical institutions. Clinical symptoms, CT findings, and disease response were compared before and after initiation of systemic bevacizumab therapy. Disease response was categorized as complete response, partial response, stabilization, or progression for each subsite involved by papilloma. RESULTS: Of the 12 pulmonary RRP patients treated with systemic bevacizumab, 4 (33.3%) were male, and 11 (91.7%) were juvenile-onset RRP patients. All presented with laryngeal, tracheal, and pulmonary RRP. The median (range) age at first bevacizumab infusion was 48.1 (19.5-70.2) years. Progression to pulmonary malignancy was identified in 3 (25.0%) patients, 2 before initiation of and 1 after complete cessation of bevacizumab therapy. Clinical symptoms such as dyspnea (75.0% vs. 25.0%; p = 0.01) and dysphagia and/or odynophagia (33.3 vs. 0.0%; p = 0.03) were significantly decreased following bevacizumab therapy. Compared with pre-treatment baseline, 9 (75.0%) patients experienced a stable-to-partial response in the lungs to systemic bevacizumab, and 10 (83.3%) experienced partial-to-complete responses in the larynx and trachea. CONCLUSION: Systemic bevacizumab is effective in stabilizing progression in even the most severe cases of RRP, with both a dramatic reduction in laryngeal and tracheal disease as well as a stable-to-partial response of pulmonary involvement in a majority of patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:577-581, 2024.

Otolaryngologic Symptom Severity Post SARS-CoV-2 Infection.

OBJECTIVE(S): To assess laryngologic symptomatology following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and determine whether symptom severity correlates with disease severity. METHODS: Single-institution survey study in participants with documented SARS-CoV-2 infection between March 2020 and February 2021. Data acquired included demographic, infection severity characteristics, comorbidities, and current upper aerodigestive symptoms via validated patient reported outcome measures. Primary outcomes of interest were scores of symptom severity questionnaires. Coronavirus disease of 2019 (COVID-19) severity was defined by hospitalization status. Descriptive subgroup analyses were performed to investigate differences in demographics, comorbidities, and symptom severity in hospitalized participants stratified by ICU status. Multivariate logistical regression was used to evaluate significant differences in symptom severity scores by hospitalization status. RESULTS: Surveys were distributed to 5300 individuals with upper respiratory infections. Ultimately, 470 participants with COVID-19 were included where 352 were hospitalized and 118 were not hospitalized. Those not hospitalized were younger (45.87 vs. 56.28 years), more likely female (74.17 vs. 58.92%), and less likely white (44.17 vs. 52.41%). Severity of dysphonia, dyspnea, cough, and dysphagia was significantly worse in hospitalized patients overall and remained worse at all time points. Cough severity paradoxically worsened in hospitalized respondents over time. Dyspnea scores remained abnormally elevated in respondents even 12 months after resolution of infection. CONCLUSIONS: Results indicate that laryngologic symptoms are expected to be worse in patients hospitalized with COVID-19. Dyspnea and cough symptoms can be expected to persist or even worsen by 1-year post infection in those who were hospitalized. Dysphagia and dysphonia symptoms were mild. Nonhospitalized participants tended to have minimal residual symptoms by 1 year after infection.

Long-Term Follow-up of Parenteral Bevacizumab In Patients with Recurrent Respiratory Papillomatosis.

OBJECTIVE: The clinical course of recurrent respiratory papillomatosis (RRP) varies from spontaneous remission to severe airway obstruction with wide variability in recurrence. Standard treatment involves debulking to improve voice and/or breathing. Non-surgical therapies are emerging in hopes of non-operative disease control. This retrospective review analyzes long-term safety, efficacy, and durability of clinical control in the largest reported series of parenteral bevacizumab in adults with RRP. METHODS: Twenty-three patients with known RRP who have been receiving off-label systemic bevacizumab were included. Dosage, infusion interval, number of cycles, debulking requirements, subjective outcomes, adverse events, and reasons for treatment termination were investigated. RESULTS: Patients have been followed for an average of 791.43 (21-1468) days. The most common starting dosing regimen was 15 mg/kg at 3 weeks in 11 followed by 10 mg/kg at 6 weeks intervals in 6 individuals. Long-term maintenance dosage varied with the least intensive regimen being 10 mg/kg at 14-week intervals. Subjective improvement of voice and/or breathing was reported in 18/23 subjects. The median time for patients that needed a procedure after treatment was 634 days. Procedures after infusions decreased from 3.08 ± 2.48 procedures in the year prior to 0.52 ± 1.12 during systemic Bevacizumab, and to 0.86 ± 2.05 after stopping bevacizumab. Therapy termination occurred in 8 subjects where only 3 were due to adverse events. CONCLUSION: Parenteral bevacizumab remains a well-tolerated treatment for patients with recalcitrant RRP. There appears to be a durable reduction in the frequency of debulking surgery requirements although on a maintenance regimen. Laryngoscope, 133:2725-2733, 2023.

The Upper Esophageal Sphincter Distensibility Index Measured Using Functional Lumen Imaging Probe Identifies Defective Barrier Function of the Upper Esophageal Sphincter.

Background/Aims: The mechanism via which supra-esophageal symptoms are generated is unclear. We assessed upper esophageal sphincter (UES) function in novel fashion using functional lumen imaging probe (FLIP) topography. We hypothesize that symptoms related to aspiration of esophageal contents may be associated with a more distensible UES. Methods: FLIP and reflux symptom index score data from patients undergoing diagnostic evaluation for an esophageal complaint over a 10-month period were analyzed retrospectively. UES distensibility on FLIP was studied at 40-70 mL volumes with in-depth analysis at 50 and 60 mL. Symptoms were compared between patients with low, middle, and high UES-distensibility index (UES-DI). Receiver-operating characteristic analysis was performed to determine associations between the UES-DI and individual reflux symptom index symptom item scores. Results: One hundred and eleven subjects were included. Overall, the associations between UES-DI and symptoms that could be related to supra-esophageal aspiration were strongest at the 50 mL FLIP volume. Choking item score was highest in the high UES-DI group (2.8) vs 1.4 (P < 0.001) in the middle UES-DI and 1.1 (P = 0.004) in the low UES-DI groups. Similarly, the cough item score was highest in the high UES-DI group (2.7) vs 1.5 (P = 0.009) and 0.9 (P = 0.002) groups. Conclusion: A higher UES-DI measures defective barrier function which could may be the main pathophysiology that generates supra-esophageal symptoms.

Parenteral Bevacizumab for the Treatment of Severe Respiratory Papillomatosis in an Adult Population.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a rare, potentially life-threatening, disease that impacts the voice, breathing, and quality of life of patients. Frequent surgical interventions may be needed to control symptoms. We examined the safety and efficacy of utilizing parenteral bevacizumab in the management of severe RRP in adults. STUDY DESIGN: This is a retrospective review of clinical management approaches in a group of patients with severe RRP defined as having a high disease burden, frequent need for debridement, and/or tracheobronchial disease. Patients were initially treated with 15 mg/kg of bevacizumab at 3-week intervals. Bevacizumab dosing and frequency was then individually titrated down. RESULTS: Fourteen adults received a median of 8.5 (range 2-17) bevacizumab infusions over approximately 24 months. All had a history of laryngeal RRP with 6/14 having additional tracheobronchial lesions. Patients required a median of 4 (range 2-11) procedures in the year prior to treatment. Only 3/10 (30%) patients who continued therapy required any additional procedures. Bevacizumab administration was generally well tolerated, with four patients discontinuing therapy. Medical reasons included severe epistaxis and hypertension and thrombocytopenia in an individual with systemic lupus erythematosus. Common side effects included hypertension (grade 2), headache (grades 1-2), elevated creatinine (grades 1-2), and epistaxis (grade 3). CONCLUSIONS: Intravenous bevacizumab for the primary treatment of severe RRP in adults appears clinically effective and safe. Expected and typically mild side effects related to bevacizumab were observed. Continued investigation of bevacizumab through a prospective clinical trial is warranted. LEVEL OF EVIDENCE: 4. Laryngoscope, 131:E921-E928, 2021.

GFI1 functions to repress neuronal gene expression in the developing inner ear hair cells.

Despite the known importance of the transcription factors ATOH1, POU4F3 and GFI1 in hair cell development and regeneration, their downstream transcriptional cascades in the inner ear remain largely unknown. Here, we have used Gfi1cre;RiboTag mice to evaluate changes to the hair cell translatome in the absence of GFI1. We identify a systematic downregulation of hair cell differentiation genes, concomitant with robust upregulation of neuronal genes in the GFI1-deficient hair cells. This includes increased expression of neuronal-associated transcription factors (e.g. Pou4f1) as well as transcription factors that serve dual roles in hair cell and neuronal development (e.g. Neurod1, Atoh1 and Insm1). We further show that the upregulated genes are consistent with the NEUROD1 regulon and are normally expressed in hair cells prior to GFI1 onset. Additionally, minimal overlap of differentially expressed genes in auditory and vestibular hair cells suggests that GFI1 serves different roles in these systems. From these data, we propose a dual mechanism for GFI1 in promoting hair cell development, consisting of repression of neuronal-associated genes as well as activation of hair cell-specific genes required for normal functional maturation.

Semaphorin-5B Controls Spiral Ganglion Neuron Branch Refinement during Development.

During nervous system development, axons often undergo elaborate changes in branching patterns before circuits have achieved their mature patterns of innervation. In the auditory system, type I spiral ganglion neurons (SGNs) project their peripheral axons into the cochlear epithelium and then undergo a process of branch refinement before forming synapses with sensory hair cells. Here, we report that Semaphorin-5B (Sema5B) acts as an important mediator of this process. During cochlear development in mouse, immature hair cells express Sema5B, whereas the SGNs express both PlexinA1 and PlexinA3, which are known Sema5B receptors. In these studies, genetic sparse labeling and three-dimensional reconstruction techniques were leveraged to determine the morphologies of individual type I SGNs after manipulations of Sema5B signaling. Treating cultured mouse cochleae with Sema5B-Fc (to activate Plexin-As) led to type I SGNs with less numerous, but longer terminal branches. Conversely, cochleae from Sema5b knock-out mice showed type I SGNs with more numerous, but shorter terminal branches. In addition, conditional loss of Plxna1 in SGNs (using Bhlhb5Cre) led to increased type I SGN branching, suggesting that PlexinA1 normally responds to Sema5B in this process. In these studies, mice of either sex were used. The data presented here suggest that Sema5B-PlexinA1 signaling limits SGN terminal branch numbers without causing axonal repulsion, which is a role that distinguishes Sema5B from other Semaphorins in cochlear development.SIGNIFICANCE STATEMENT The sensorineural components of the cochlea include hair cells, which respond mechanically to sound waves, and afferent spiral ganglion neurons (SGNs), which respond to glutamate released by hair cells and transmit auditory information into the CNS. An important component of synapse formation in the cochlea is a process of SGN "debranching" whereby SGNs lose extraneous branches before developing unramified bouton endings that contact the hair cells. In this work, we have found that the transmembrane ligand Semaphorin-5B and its receptor PlexinA1 regulate the debranching process. The results in this report provide new knowledge regarding the molecular control of cochlear afferent innervation.

A Novel Device for Placement of a Secondary Tracheoesophageal Voice Prosthesis: A Preliminary Feasibility Study.

BACKGROUND: Tracheoesophageal puncture (TEP) for post-laryngectomy speech rehabilitation can be performed at the time of laryngectomy (primary) or at a subsequent time (secondary). Traditionally, the secondary procedure is performed using a rigid esophagoscope. Diseases like esophageal stricture, limited neck extension, and soft-tissue fibrosis can make this procedure technically challenging or impossible. We developed a novel device to perform a secondary tracheoesophageal puncture using a flexible esophagoscope. OBJECTIVE: To test the feasibility of a novel device used to create a secondary TEP in post-laryngectomy cadavers. METHODS: In this study, we performed a total laryngectomy on 3 fresh cadavers to establish the feasibility of our prototype. In each cadaver, a flexible esophagoscope was passed into the pharynx with the prototype. The prototype was passed through a working port and deployed to distend the esophagus. The puncture was visualized and a wire was passed via the newly established fistula. The device was activated, securing the wire, and then the esophagoscope and device were removed. RESULTS: There was 100% successful deployment of the prototype device, allowing rapid creation of the puncture and security of the guide wire in each cadaver. There was no evidence of collateral mucosal injury or esophageal perforation. CONCLUSIONS: The prototype device offers an alternative method to safely and efficiently perform a secondary TEP without the requirement of rigid esophagoscopy which can sometimes be technically impossible in this patient population.

Cystic Lesions of the Jaw in Children: A 15-Year Experience.

IMPORTANCE: Pediatric jaw cysts represent a rarely symptomatic clinical entity and are not well addressed in the otolaryngology literature. It is important that otolaryngologists should be familiar with these lesions, which can manifest as jaw swelling or as paranasal sinus abnormalities. OBJECTIVE: To review the clinical presentation, radiologic features, management, and outcomes of jaw cysts in children treated at a single academic institution. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review at a tertiary care children's hospital among patients 16 years and younger who were seen with a cystic jaw lesion. MAIN OUTCOMES AND MEASURES: Medical records were reviewed for data on symptoms, physical examination findings, imaging, pathology, interventions, and outcomes among children who were seen at the Department of Oral and Maxillofacial Surgery or the Department of Otorhinolaryngology-Head and Neck Surgery at the University of Maryland Medical Center between January 1997 and December 2012 and were diagnosed as having a jaw cyst. RESULTS: Fifty-seven patients were identified who were diagnosed as having a true cystic jaw lesion and whose complete medical records were available for review. The most common cystic lesions were keratocystic odontogenic tumors (n = 19) and dentigerous cysts (n = 17). Fifty-six percent (32 of 57) of all cystic lesions were asymptomatic on presentation and were identified by imaging. The second most common presentation was local swelling (n = 15), followed by dental irregularities (n = 6). All patients, except for 1 with an eruption cyst, required surgical intervention, including biopsy, enucleation, curettage, or ostectomy, with reconstruction as indicated. Keratocystic odontogenic tumors tended to require more treatment (median, 2 procedures) for metachronous lesions or recurrence. CONCLUSIONS AND RELEVANCE: Pediatric jaw cysts are unusual, and data are scarce regarding their presentation and management. Many of these cysts are asymptomatic and are identified incidentally on orthopantomography. Keratocystic odontogenic tumors were the most common lesion seen in our series, followed by dentigerous cysts. Surgical intervention is required in most patients with a cystic lesion of the jaw.

Tumors of the pediatric maxillofacial skeleton: a 20-year clinical study.

IMPORTANCE: Pediatric jaw tumors are a rare clinical entity and are not well addressed in the otolaryngology literature. It is important that otolaryngologists be familiar with the clinical features, management, and outcomes associated with these lesions. OBJECTIVE: To review the clinical presentation, management, and outcomes of jaw tumors in children treated at a tertiary care academic center. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of children 16 years or younger who presented to the departments of Oral-Maxillofacial Surgery and Otorhinolaryngology at the University of Maryland Medical Center between 1992 and 2012 and were diagnosed as having a jaw tumor. A PubMed review of literature from 1992 to 2013 on jaw tumors in children was also conducted. MAIN OUTCOMES AND MEASURES: Medical records were reviewed for data on symptoms, physical findings, pathologic diagnosis, intervention, and outcomes. RESULTS: The medical records of 76 patients evaluated for a jaw mass were reviewed, and 20 were found to have a diagnosis of a jaw tumor. The 2 most common pathologic diagnoses were ameloblastoma (n = 5) and juvenile ossifying fibroma (n = 4). Two tumors were malignant, a rhabdomyosarcoma and a teratoma. Thirteen patients presented with evidence of a mass or swelling, 5 patients were asymptomatic with a lesion found on surveillance panoramic radiography, and 1 patient presented with epistaxis and 1 with facial weakness and pain. All tumors excluding a lymphangioma and a rhabdomyosarcoma were managed surgically. Eight patients underwent more than 1 procedure including secondary reconstruction prior to a satisfactory outcome. CONCLUSIONS AND RELEVANCE: Pediatric jaw tumors are rare lesions most commonly presenting with a swelling or mass. Patients can be asymptomatic with the lesion identified on routine imaging. Certain clinical features such as age, location of tumor, and presence or absence of bone and soft tissue can narrow the differential diagnosis and identify tumors that may be malignant. Incisional biopsy is an important first step. A majority of jaw tumors are benign but require surgical intervention for eradication of disease. Multiple procedures, including reconstruction, may be required for certain lesions prior to cure.

Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults.

OBJECTIVES: The aim of this study was to evaluate the association between physical activity and changes in levels of highly sensitive troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the subsequent risk of the development of heart failure (HF) in community-dwelling older adults. BACKGROUND: Higher baseline levels of cTnT and NT-proBNP and increases over time correlate with the risk of HF in older adults. Factors modifying these levels have not been identified. METHODS: NT-proBNP and cTnT were measured at baseline and 2 to 3 years later in adults 65 years of age and older free of HF participating in the Cardiovascular Health Study. Self-reported physical activity and walking pace were combined into a composite score. An increase was prespecified for NT-proBNP as a >25% increment from baseline to ≥190 pg/ml and for cTnT as a >50% increment from baseline in participants with detectable levels (≥3 pg/ml). RESULTS: A total of 2,933 participants free of HF had NT-proBNP and cTnT measured at both time points. The probability of an increase in biomarker concentrations between baseline and follow-up visits was inversely related to the physical activity score. Compared with participants with the lowest score, those with the highest score had an odds ratio of 0.50 (95% confidence interval: 0.33 to 0.77) for an increase in NT-proBNP and an odds ratio of 0.30 (95% confidence interval: 0.16 to 0.55) for an increase in cTnT, after adjusting for comorbidities and baseline levels. A higher activity score associated with a lower long-term incidence of HF. Moreover, at each level of activity, an increase in either biomarker still identified those at higher risk. CONCLUSIONS: These findings suggest that moderate physical activity has protective effects on early heart failure phenotypes, preventing cardiac injury and neurohormonal activation.