Faculty Bibliography

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.

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.

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.

Nasal bone and nasal septal fractures are common facial traumas. The proper management of these injuries and their associated complications can both functionally improve nasal breathing and also lead to improved cosmetic outcomes. Closed reduction of these fractures can often be performed at bedside if within the appropriate time window; regardless of whether reduction is performed under local anesthesia, these patients can follow-up in clinic to discuss further management, which might include delayed septorhinoplasty in the operating room.

We present a case highlighting innominate vein reconstruction for resection of Hurthle cell carcinoma with complex vascular invasion. A 69-year-old man presented with a rapidly enlarging neck mass, dysphagia and dysphonia. Workup demonstrated a 11.2 × 7.0 × 6.5 cm Hurthle cell carcinoma invading the oropharynx and superior mediastinum. We proceeded with left thyroid lobectomy and modified left radical neck dissection. Median sternotomy, resection of the left clavicular head, and partial resection of the left manubrium were performed to circumferentially expose the innominate vein. Tumor thrombus was extruded from the innominate vein followed by patch angioplasty, which remains patent 14 months postoperatively.

Tumors of the paranasal sinus and nasal cavity (PNS/NC) are rare and exhibit diverse histology, anatomic subsite, and malignant potential. Early-stage disease is typically managed with surgery, and locally advanced disease is treated with a combination of surgery, radiotherapy, and chemotherapy. Clinical decision-making is commonly guided by limited retrospective evidence. To address this limitation, we performed a systematic review to inform evidence-based consensus for the management of common clinical scenarios, including the potential roles of radiation and systemic therapy to promote structural preservation, elective neck management, and radiation technique considerations. A librarian-mediated literature search identified 39 studies of adult patients with PNS/NC tumors treated with curative intent that met the study inclusion criteria. Search results were reported using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) methodology. A modified-Delphi process was used to guide consensus for the appropriate use of various management strategies. Strong consensus existed for the appropriateness of primary surgery for early-stage disease, approaches to locally advanced disease with minimal periorbital fat invasion, and the use of induction chemotherapy with response-directed local therapy. Consensus regarding nodal treatment and the use of proton therapy in the adjuvant setting was less robust. The rarity and diversity of PNS/NC tumors limit randomized phase III trials to guide management. As such, this systematic review and appropriate-use consensus statements provide clinical guidance for the management of this challenging disease spectrum.

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.

BACKGROUND/OBJECTIVES/OBJECTIVE:Vocal fold (VF) muscle atrophy, often associated with neuromuscular disorders and aging, can lead to voice-related disability. Myostatin is well-known to mediate skeletal muscle atrophy via Smad2/3 signaling, whereas TGF-β1, a potent inducer of Smad2/3 signaling, is upregulated following VF injury. However, the impact of Smad2/3 signaling on laryngeal muscles remains unclear. This study provides foundational insight regarding Smad2/3-dependent atrophic responses of VF skeletal muscle cells, to ultimately develop novel therapeutic strategies for VF muscle atrophy. STUDY DESIGN/METHODS:In vitro. METHODS:Myoblasts isolated from the rat thyroarytenoid muscle were differentiated into myotubes in myogenic differentiation medium ±500 ng/mL myostatin or 10 ng/mL TGF-β1, in the presence or absence of an ALK4/5 inhibitor or siRNA targeting Smad2 and Smad3. Myotube formation and activation of Smad2/3 (nuclear localization of Smad2/3) were assessed via immunofluorescence. Transcription related to myotube differentiation and Smad2/3 signaling was quantified by qRT-PCR. RESULTS:Both myostatin and TGF-β1 suppressed myogenic differentiation, increased Smad2/3 nuclear intensity, downregulated Myh2, and upregulated downstream targets of Smad2/3 (Ccn2 and Serpine1) and Fbox32, an atrophy-related gene. These effects were more pronounced with TGF-β1 than with myostatin and were reversed by inhibition of ALK4/5. Furthermore, Smad2/3 knockdown via siRNA promoted myogenic differentiation, further supporting the role of Smad2/3 signaling in the atrophic response in VF myoblasts. CONCLUSIONS:Smad2/3 signaling mediates differentiation of VF myoblasts and TGF-β1, a potent mediator of fibrosis, elicited a more pronounced atrophic response than myostatin. Smad2/3 may be an attractive therapeutic target for VF muscle atrophy. LEVEL OF EVIDENCE/METHODS:NA.

OBJECTIVES/OBJECTIVE:) and PRO scores; (3) explore how changes across individual PROs align with changes in DIGEST pre- to six weeks post- surgery. METHODS:) pharyngeal total score and the DIGEST. PROs included the Bazaz Dysphagia Scale, the Eating Assessment Tool (EAT-10), the Swallowing Quality of Life Questionnaire (SWAL-QoL), and the Hospital for Special Surgery Dysphagia Index (HSS-DDI). RESULTS:Statistical models for all outcome measures revealed a significant effect of operative timepoint, indicating worse outcomes postoperatively. There were greater postoperative increases in point prevalence and incidence rates using PROs compared with DIGEST. Rates of clinically meaningful change were similar across PROs and DIGEST, but not consistently across the same individual cases. CONCLUSION/CONCLUSIONS:This study highlights the difference between physical function and patient experience, suggesting the presence or absence of dysphagia symptoms may not correspond with observed physical impairments after ACDF. LEVEL OF EVIDENCE/METHODS:Level III.