Faculty Bibliography

OBJECTIVES/OBJECTIVE:Recurrent respiratory papillomatosis (RRP), caused by chronic HPV-6/11 infection, leads to repeated papilloma growth requiring frequent surgical removal. DNA immunotherapy INO-3107 aims to induce HPV antigen-specific T-cell responses and reduce surgical burden. This analysis evaluated HPV-specific immune responses after INO-3107 and their association with long-term clinical outcomes. METHODS:Adults with HPV-6/11-associated RRP received INO-3107 in a Phase 1/2 trial and were followed for one year, with additional clinical follow-up in a long-term extension. Number of surgeries in Years 1 and 2 was compared with the pre-treatment year. Blood and laryngotracheal tissue collected at Day 0 and Year 1 were analyzed for treatment-related changes in T-cell activity. Safety was assessed throughout. RESULTS:Thirty-two patients were treated; 28 continued into Year 2. At Year 1, most evaluable patients showed increased T-cell activity: 73% (19/26) demonstrated persistent expanded T-cell populations in blood, 71% (12/17) showed higher T-cell clone counts in laryngotracheal tissue, indicating site-specific immune infiltration. Antiviral T-cell signatures were enriched in 88% for CD4+ Th1 and CD8+ cytotoxic, and 71% for CD8+ effector memory, suggesting durable proinflammatory and memory responses in airway tissue. Mean annual surgeries decreased over time in the overall population (Baseline: 4.1, Year 1: 1.7, Year 2: 0.9). Similar durable reductions were observed in Responder subgroups. INO-3107 was well-tolerated, with no treatment-related serious adverse events. CONCLUSION/CONCLUSIONS:INO-3107 generates increased HPV-directed T-cell responses and substantially reduced surgical procedures over two years, supporting its ability to provide long-term clinical benefit in RRP without requiring additional surgeries during the dosing window.

Oral cancer patients suffer pain that is patient-specific and heterogeneous at the site of the tumor. Protease-activated receptor 2 (PAR₂), a G-protein coupled receptor and an oral cancer mediator, is activated by protease cleavage of an N-terminal ligand. Once cleaved, the receptor is retained at the plasma membrane or re-distributed (trafficking) to internal sites followed by downstream protease-specific signaling. The oral cancer tumor microenvironment (TME) is replete with protases that activate PAR₂, potentially evoking PAR₂ trafficking and signaling that is unique to each cancer and reflecting the protease composition of the individual TMEs. To measure PAR₂ cleavage activity in oral cancer samples, an array of overlapping peptides spanning the PAR₂ N-terminus was assembled. In this feasibility study, we assayed the cleavage activity of individual PAR₂-activating proteases and mixtures of proteases modeling the oral cancer TME. Additionally, we confirmed that PAR₂-cleaving proteases are active in oral cancer patient saliva, a sample that can be collected non-invasively to measure PAR₂ cleavage in patients when they are experiencing pain prior to surgery. Further studies should elucidate the utility of the peptide array to measure PAR₂-activating proteolysis in cancer samples.

BACKGROUND:Major breakthroughs in the clinical application of liquid biopsies, such as the use of salivary samples to detect biomarkers for the early detection of diseases and conditions, are on the horizon. Historically, late detection of oral cancer has contributed to high morbidity and mortality, making scientific advancements in this field particularly impactful. This guideline evaluates and provides recommendations for commercially available salivary adjunct tests in the United States designed specifically for screening adults without mucosal abnormalities and for determining the need for biopsy among adults with mucosal abnormalities of the oral cavity or lip. TYPES OF STUDIES REVIEWED/METHODS:The researchers used living systematic review methodology to identify evidence on the benefits and harms of salivary adjunct tests. They also conducted a scoping review of patient and clinician values and preferences regarding the use of these adjuncts and evaluated data on other contextual factors, including costs, equity, acceptability, and feasibility of these tests. The guideline panel formulated a recommendation after applying the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework. RESULTS:The panel issued 2 research-only recommendations, limiting the use of salivary adjunct tests for early oral cancer detection to research settings: 1 for adults with oral mucosal or lip abnormalities, and 1 for adults without mucosal abnormalities. Three good practice statements were also formulated: 2 recommending the performance of clinical oral examinations for all adult patients, and 1 recommending biopsy or referral for adult patients with persistent oral mucosal abnormalities. PRACTICAL IMPLICATIONS/CONCLUSIONS:All adult patients should receive a clinical oral examination. When a mucosal abnormality is identified, biopsy remains the reference standard for establishing a definitive diagnosis. Salivary diagnostic adjuncts, whether used to screen asymptomatic adults or to determine the need for biopsy in adults with mucosal abnormalities, should not be used in regular clinical practice or as a public health screening measure outside of a research setting. Further research is needed to establish the potential role of salivary adjunct tests in clinical practice.

Cochlear implants (CIs) stimulate auditory neurons with electric pulse trains whose amplitudes are modulated using envelopes extracted from different frequency bands, conveying essential speech cues. This study investigated how the rate of stimulation pulses affects envelope processing and speech perception in ten post-lingually deaf CI users. Amplitude modulation (AM) detection and consonant identification were examined using acoustic stimuli processed by multi-channel and single-channel strategies, with pulse rates ranging from 125 to 2000 pulses per second (pps) for multi-channel stimulation and from 125 to 4000pps for single-channel stimulation. The single-channel conditions encoded the overall broad-band speech envelope by a single electrode and were used to isolate within-electrode temporal modulation coding. For AM detection, the modulation frequency was 25 Hz ensuring sufficient modulation sampling across all carrier rates tested. Even at 125pps, the 25-Hz modulation was represented by five pulses per modulation cycle. Results revealed a significant decline in both AM detection and consonant identification at 125pps, suggesting that poorer speech recognition at low rates may be partly attributable to limitations in temporal modulation processing rather than solely to a restricted range of representable envelope frequencies. Consonant recognition performance remained stable across clinically relevant pulse rates (250-2000pps), though significant listener- and feature-specific effects were observed. Notably, while AM detection and consonant recognition were not significantly correlated within this small cohort, significant correlations were found between single-channel and multi-channel performance in both tasks. These findings support an important role for within-electrode temporal coding in CI speech perception and highlight the clinical relevance of individual variability in pulse rate effects.

Diagnostic adjuncts for oral potentially malignant disorders such as leukoplakia or erythroplakia can aid the clinician in triaging abnormal lesions and facilitate both biopsy site selection and surgical management. No adjuncts replace gold standard biopsy and histopathological examination, and their optimal use requires training and experience. This article covers the potential applications, both in primary and expert settings, of adjuncts, such as tissue autofluorescence, toluidine blues staining, and cytopathology. It covers new and emerging adjuncts such as confocal microscopy, liquid biopsy, oral microbiome testing, and the role of artificial intelligence. Incisional biopsy site selection and techniques will also be discussed.

The locus coeruleus (LC) brainstem cell group is evolutionarily conserved across vertebrates and influences both mind (cognition) and body (cardiorespiratory, metabolic, and immune functions) via two-putatively distinct-spontaneous activity patterns. Yet, the degree to which spontaneous LC firing rates and patterns are homogeneous across species has never been assessed due to inherently limited sample sizes. To remedy this, we pooled cross-species data from 20 laboratories to show that firing rates differ across species and are modulated by sex, age, and type of in vitro or in vivo preparation. Contrary to the prevailing dual-mode firing pattern schema, we observed patterns spread across a low-dimensional manifold, with subregions enriched for specific biological factors and neurodegenerative disease models. Our findings show considerable diversity in an ancestral vertebrate neuromodulatory system.

BACKGROUND:Evaluation of otolaryngology resident technical performance has historically relied on subjective perioperative feedback. Despite various assessment tools attempting to provide consistent surgical skill evaluations, current methods remain inherently subjective. AIM/OBJECTIVE:This proof-of-concept pilot study aimed to assess if a 3-dimensional surgical navigation system could capture objective surgical data during endoscopic sinus surgery (ESS). A secondary aim was to analyze if there were any differences between novice and practiced trainees. METHODS:Navigation System. Prior to the surgery, surgical landmarks were defined with sensory beacons in the navigation system using the patient's preoperative computed tomography (CT) scan. Metrics included time to reach beacons, number of alerts at each beacon, and instrument speed. RESULTS: < .001). IMPACT/CONCLUSIONS:This study demonstrates the feasibility of collecting objective, navigation-based intraoperative metrics during live surgery and is a first step toward building a comprehensive objective assessment tool in ESS. We hope this report encourages further research into this technology's application in objective resident skill assessment and correlation with concurrent faculty assessments.

OBJECTIVE:Pregnancy produces physiologic adaptations that may affect laryngeal tissues, respiratory support for phonation, and voice quality. We performed a scoping review exploring the influence of pregnancy on voice and laryngeal outcomes. DATA SOURCES/METHODS:PubMed, CINAHL, and Web of Science. REVIEW METHODS/METHODS:A scoping review was conducted per PRISMA-ScR guidelines. Searches of PubMed, CINAHL, and Web of Science yielded 1350 studies screened in Covidence by two reviewers. Of 107 full texts reviewed, 22 met inclusion criteria. We included human studies in which pregnancy was the primary exposure and voice-related outcomes were measured. Pregnancy-specific animal studies were included when modeling mechanisms of laryngeal change. RESULTS:Twenty-two studies met inclusion criteria and were grouped into domains: acoustic/aerodynamic (n = 16), patient-reported/perceptual (n = 12), physiologic laryngeal (n = 5), mechanistic animal studies (n = 4), singing voice (n = 4), and respiratory (n = 1); several studies contributed to multiple domains. Acoustic measures (fundamental frequency, jitter, shimmer) were generally unchanged, while multiple studies reported reduced maximum phonation time (MPT) during pregnancy. Subjective voice measures tended to worsen, and singer studies reported reduced vocal range and timbre changes. Physiologic studies noted increased vocal fold edema and reduced motility, most prominent in the third trimester. Mechanistic models supported hormone-associated mucosal changes and altered laryngeal protein expression. CONCLUSIONS:The literature on voice changes during pregnancy is limited and heterogeneous, with evidence concentrated in late pregnancy. Pregnancy is more consistently associated with reduced phonatory efficiency and worse perceived voice function than with major acoustic vocal changes. LEVEL OF EVIDENCE/METHODS:N/A.

BACKGROUND:Mild autonomous cortisol secretion causes substantial cardiometabolic morbidity, yet evidence for benefits following adrenalectomy remains mixed. Prior studies are limited by small sample sizes and heterogeneous definitions. This study evaluates the metabolic impact of adrenalectomy compared with nonoperative management in mild autonomous cortisol secretion using standardized biochemical criteria from the Epic Cosmos database. METHODS:Mild autonomous cortisol secretion was defined biochemically using dexamethasone suppression test cortisol 1.8-10 μg/dL, dexamethasone, and adrenocorticotropic hormone levels. Surgical patients underwent unilateral adrenalectomy with biochemical resolution of hypercortisolism. Inverse probability of treatment weighting was performed, adjusting for demographics, baseline cardiometabolic parameters, dexamethasone suppression test cortisol level, and glucagon-like peptide-1 receptor agonist use. The starting time point was the adrenalectomy date or, for nonoperative patients, the dexamethasone suppression test date plus the median time to surgery. Follow-up outcomes (A1C, lipid profile, body mass index, and blood pressure) were assessed for categorical improvement at last follow-up within 3 years using a weighted logistic regression model. RESULTS:From 2018 to 2025, 395 patients met inclusion criteria (54 surgical, 341 nonoperative). Surgical patients had a higher adjusted likelihood of categorical improvements in A1C (25.6% vs 9.5%, odds ratio, 3.30; P = .002), total cholesterol (14.6% vs 3.9%, odds ratio, 4.25; P = .004), and body mass index (24.9% vs 12.1%, odds ratio, 2.42; P = .018). There were no differences in blood pressure between groups (28.4% vs 26.7%, odds ratio, 1.09; P = .803). CONCLUSION/CONCLUSIONS:This is the largest cohort study to date evaluating metabolic outcomes after surgery for mild autonomous cortisol secretion. Adrenalectomy was associated with categorical improvement in A1C, body mass index, and total cholesterol, supporting more widespread consideration for selective operative management.