Faculty Bibliography

OBJECTIVES/OBJECTIVE:To determine the relationships between the number and class of xerogenic medications on whole stimulated salivary flow rates and oral health-related quality of life (OH-QOL) measures in patients who received high-dose external beam radiation therapy (RT) for head and neck cancer (HNC). STUDY DESIGN/METHODS:Complete medication lists were generated using patient electronic health records from every attended study visit for 146 HNC patients. Whole stimulated salivary flow was measured before RT, and 6 and 18-months after RT. Ten single-item questions and two composite scales of swallowing problems and senses problems (taste and smell) were assessed at baseline and at 6-month intervals up to 24 months after RT. Linear mixed-effects models examined associations between the total number and class of medications and stimulated salivary flow and OH-QOL. RESULTS:There was no detected association between the total number of medications and stimulated salivary flow (p-value = .18). Only antidepressant usage was significantly associated with stimulated salivary flow (P = .006). Number of medications, narcotic analgesic, and antidepressant usage were significantly associated with a clinically meaningful decrease in OH-QOL. CONCLUSION/CONCLUSIONS:Antidepressants were associated with reduced stimulated salivary flow, but no cumulative negative effect on whole stimulated salivary flow was identified. Polypharmacy was associated with worse OH-QOL.

INTRODUCTION/BACKGROUND:Prior studies have demonstrated that comorbid conditions can negatively impact cochlear implantation (CI) outcomes in elderly patients, but few have examined how comorbidities affect younger adult CI recipients. This study examines the relationship between comorbidities and CI outcomes in adults under 60 years old. METHODS:We reviewed all CI recipients between 20 and 60 years old from 2015 to 2019 at a tertiary academic medical center. Patient data were collected including comorbidities, demographics, etiology, and length of deafness (LOD). Patients' Charlson Comorbidity Index (CCI) was calculated. The primary outcome was speech perception scores at 1 year on the consonant-nucleus-consonant (CNC) word test. RESULTS:There were 118 patients who underwent CI (20-29 years [15%], 30-39 years [22%], 40-49 years [21%], 50-60 years [42%]), averaging 1.8 comorbidities. Mean LOD was 19.7 years, and most etiologies were unknown (53.4%). 34% had no comorbidities, and the most frequent comorbidities were hypertension (14%), asthma (10%), anxiety (8%), acoustic neuroma (8%), and arthritis (7%). Comorbidity frequency was similar across ages, but cardiovascular comorbidities varied by patient decade (50-60 years: 41% vs. 20-49 years: 12-22%, p = 0.004). Compared to studies on elderly CI outcomes, our cohort had fewer comorbidities with reduced cardiac events and neurological conditions. We did not find differences in 1-year CNC scores or complications based on the number of comorbidities or any single comorbidity. However, there was a difference in individual improvement in CNC word scores by age group (p = 0.024). Patients' CCI did not correlate to post-op scores. CONCLUSION/CONCLUSIONS:Subjects showed improved speech understanding post-CI. The number and type of comorbidities were not meaningful predictors of 1-year speech perception scores, suggesting adult CI users under 60 years with comorbidities can expect comparable outcomes to those without comorbidities.

PURPOSE/OBJECTIVE:Bevacizumab treatment is associated with imaging and hearing responses in progressive vestibular schwannoma (VS) caused by NF2-related schwannomatosis (NF2-SWN). However, its effect on co-existing intracranial non-vestibular schwannomas (NVS) and meningiomas is unclear. METHODS:We retrospectively analyzed tumor volumes of non-target intracranial NVS and meningiomas in patients with NF2-SWN and progressive VS who were prospectively treated with bevacizumab for two years on the Neurofibromatosis Clinical Trials Consortium (NFCTC) trial NF104 (NCT01767792). Radiographic response (RR) or progression (PD) were defined as ≥ 20% decrease or ≥ 20% increase in tumor volume compared to baseline, respectively. All other responses were defined as stable disease. RESULTS:A total of 40 meningiomas in eight patients and 12 NVS in six patients were evaluated across 22 enrolled trial participants. On best response analysis, RR occurred in 13% (5/40) of meningiomas and in 42% (5/12) of NVS. On a per-patient basis, RR for meningioma occurred in 38% (3/8) of patients and for NVS in 67% (4/6) of patients. RR in two NVS were durable throughout the study period. During two years of treatment, PD occurred in 55% (22/40) of meningiomas and in 8% (1/12) of NVS. Median time to tumor progression was 15 months for meningiomas and was not reached for NVS. CONCLUSIONS:We observed greater activity of bevacizumab against intracranial NVS compared to meningioma, evidenced by more favorable RR rates, durability of response, and rates of PD. Potential biological differences between meningiomas and schwannomas that underlie this differential response to bevacizumab warrant further investigation.

OBJECTIVE:To evaluate the long-term safety and clinical effect of INO-3107 immunotherapy in adults with recurrent respiratory papillomatosis (RRP). METHODS:RRP-002 was a retrospective, observational extension study that followed patients enrolled in the 52-week RRP-001 study. Patients with moderate to severe juvenile or adult-onset RRP who had undergone ≥ 2 surgical interventions in the year preceding dosing were eligible for enrollment in RRP-001. Participants underwent surgical debulking within 14 days prior to initial dosing and then received INO-3107 on Day 0, Weeks 3, 6, and 9. Efficacy assessments during RRP-002 follow-up were the frequency of surgical interventions and alternative medication use. The safety evaluation included reported severe adverse events (SAEs). RESULTS:Twenty-eight (28) of 32 participants from the 52-week RRP-001 study were enrolled in RRP-002. The median follow-up time for RRP-002 was 1.8 years (range: 1.2-2.4 years) for a total median assessment time of 2.8 years (range: 1.0-3.5 years). There were no SAEs or long-term safety concerns identified. The mean number of surgeries was reduced from 4.1 in the pre-treatment period to 1.7 in the first year post-INO-3107 treatment (Year 1) to 0.9 in the second year (Year 2). The complete response rate (0 surgeries per year) increased from 28% (9/32) in Year 1 to 50% (14/28) in Year 2. CONCLUSION/CONCLUSIONS:INO-3107 is well tolerated and provides a continued clinical effect against HPV-6 and 11 RRP that results in further reduction of the surgical burden observed in Year 1. These data support the role of INO-3107 immunotherapy for adult patients with RRP. LEVEL OF EVIDENCE/METHODS:III.

Epigenetic changes drive gene expression alterations, contributing to oncogenesis and drug resistance. Lysosomes play a key role in cell signaling and sequestering toxins, including chemotherapeutic agents, which are then expelled through lysosomal exocytosis-a process linked to drug resistance. However, the epigenetic regulation of lysosomal exocytosis is poorly understood. We hypothesize that epigenetic modifier drugs (epidrugs) inhibiting this exocytosis could serve as potential cancer therapeutics. To explore this, we screened more than 150 epidrugs targeting various epigenetic proteins for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and lysosomal biogenesis. Two type I PRMT inhibitors, MS023 and GSK3368715, showed synergy with cisplatin, reduced cell viability, and inhibited lysosomal exocytosis without altering lysosomal biogenesis gene expression. RNA-seq analysis revealed differentially expressed genes involved in vesicular trafficking and lysosome dynamics, suggesting novel regulatory mechanisms. These inhibitors also synergized with other lysosome-sequestered drugs, indicating a broader application in overcoming drug resistance. Analysis of patient data further linked lower type I PRMT levels to better responses, highlighting their potential as combination therapy candidates to enhance chemotherapy efficacy and improve cancer survival rates.

Cochlear implants are neuroprosthetic devices that restore hearing and speech comprehension to profoundly deaf humans, and represent an exemplar application of biomedical engineering and research to clinical conditions. However, the utility of these devices in many subjects is limited, largely due to lack of information about how neural circuits respond to implant stimulation. Recently we showed that deafened rats can use cochlear implants to recognize sounds, and that this training refined the responses of single neurons in the primary auditory cortex. Here we asked how local populations of cortical neurons represent acute implant stimuli, using electrode arrays we developed for cortical surface recordings for micro-electrocorticography (μECoG), a form of intracranial electroencephalography (iEEG). We found that there was a limited tonotopic organization across recording sites, relative to a clearer tonotopic spatial representation in normal-hearing rats. Single-trial iEEG responses to acoustic inputs were more reliable than responses to cochlear implant stimulation, although stimulus identity could be successfully decoded in both cases. However, the spatio-temporal response profiles to acoustic vs cochlear implant stimulation were substantially different. Decoders trained on acoustic responses showed essentially zero information transfer when tested on electrical stimulation responses in the same animals after deafening and cochlear implant stimulation. Thus while acute cochlear implant stimulation might activate the auditory cortex in a cochleotopic manner, the dynamics of network activity are quite distinct, suggesting that pitch percepts from acoustic and electrical stimulation are fundamentally different.

Vocal fold (VF) fibrosis, often resulting from phonosurgery, radiation, or trauma, causes irreversible voice dysfunction due to excessive ECM deposition and increased tissue stiffness. No FDA-approved treatments for VF fibrosis exist, highlighting the need for novel antifibrotic therapies. TGF-β1 contributes to fibroblast-to-myofibroblast activation, leading to increased ACTA2 expression and collagen production via SMAD3, YAP1, and integrin signaling pathways. Leveraging the principle that local cells respond to tissue-specific signals, our ECM hydrogel, derived from decellularized vocal fold lamina propria (VFLP-ECM), reduced ACTA2 expression in TGF-β1-stimulated VF fibroblasts, showcasing antifibrotic potential. This study evaluates the therapeutic potential of VFLP-ECM hydrogel in a rabbit VF injury model. VFLP-ECM hydrogel or bovine type I collagen injections were administered 7 days post-injury and evaluated on day 28. We compared two VFLP-ECM formulations: a manual process (VFLP (man)) and an accelerated automated method (VFLP (au)). VFLP (man) modulated fibrosis-associated gene expressions more effectively than controls. Proteomics identified 229 proteins uniquely preserved in VFLP (man), including vitronectin, crucial in TGF-β1 signaling and ECM remodeling. Transcriptomic analysis suggests downregulation of fibrotic markers and inhibition of SMAD3, YAP1, and MRTFA, alongside upregulation of SMAD7, an inhibitor of TGF-β signaling. Notably, VFLP (man) treatment recovered stiffness comparable to uninjured controls (1.84 vs. 1.94 mN), whereas collagen-treated tissues remained stiff (2.7 mN), similar to the injury group (2.6 mN), indicating incomplete mechanical recovery. These in vivo data show that manually decellularized VFLP-ECM hydrogel attenuates fibrosis by disrupting key biochemical and mechanical cues driving myofibroblast activation.

Fish actively control posture in the pitch axis (nose-up/nose-down) to counter instability and regulate their elevation in the water column. To test the hypothesis that environmental cues shape strategies fish use to control posture, we leveraged a serendipitous finding: larval zebrafish (Danio rerio) lose swim bladder volume and sink mildly after acute loss of lateral line hair cells. Using long-term (48 h) recordings of unrestrained swimming, we discovered that sinking larvae compensated differently depending on light conditions. In the dark, they swim more frequently with an increased nose-up posture. In contrast, larvae in the light do not swim more frequently, but do climb more often. Finally, after lateral line regeneration, larvae returned to normal buoyancy and swam comparably to control siblings. We conclude that larvae can switch postural control strategies depending on the availability of visual information. Our findings complement and extend morphological and kinematic analyses of locomotion. More broadly, by quantifying the variation in strategies our work speaks to the evolutionary substrate for different balance behaviors.

OBJECTIVE:Surgical treatment of recurrent respiratory papillomatosis (RRP) has been shown to aerosolize human papillomavirus (HPV), putting healthcare workers at risk for exposure, infection, and disease. Knowledge of HPV infection risk among otolaryngologists who treat HPV-related diseases is limited. We sought to characterize the prevalence of oral HPV infection in otolaryngologists treating RRP. METHODS:This observational cohort study enrolled otolaryngologists at a national meeting. Participants completed a survey concerning HPV vaccination, disease history, and practice techniques for patients with RRP. An oral rinse was collected from participants; DNA was extracted and analyzed using commercially available kits. RESULTS:laser (N = 78), microdebrider (N = 80), and cold steel (N = 21). Oral rinses from three participants (2.2%) tested positive for HPV, including Subtypes 6 (N = 2) and 16 (N = 1). All three were male with no history of HPV vaccination. CONCLUSION/CONCLUSIONS:Otolaryngologists treating HPV-related diseases do not seem to be at a higher risk of HPV infection compared to the general adult population. Vaccination, the use of N95 masks, and minimizing aerosol-generating techniques are likely protective for healthcare workers dealing with HPV-related conditions.

INTRODUCTION/UNASSIGNED:for head and neck cancer (HNC), a patient-reported symptom measure available only in English. METHODS/UNASSIGNED: = 4) diagnosed with HNC. RESULTS/UNASSIGNED:The translation was acceptable in cultural relevance (average CVI score = 0.95) and equivalence (average CVI score = 0.84). Cognitive interviews revealed 9 problematic items that differed in words and meaning, primarily addressing pain and swallowing symptoms. These items were refined and included in the final translation of the Spanish ePVA. CONCLUSION/UNASSIGNED:These study findings underscore the need for survey instrument translations that account for variations in shared languages spoken across countries.