Faculty Bibliography

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.

BACKGROUND AND PURPOSE/OBJECTIVE:Skeletal-related events (SRE) are a major source of morbidity and mortality across cancer types. Identification of risk factors for SRE and association with survival would facilitate more targeted preventive treatment. MATERIALS AND METHODS/METHODS:This retrospective cohort study included patients with bone metastases from solid tumors undergoing systemic imaging from February-March 2022 who had not received radiation within one year. Survival was analyzed using Cox models, and multi-state models assessed factors linked to SRE with death as a competing risk. Outcomes were SRE (including radiation for pain) and all-cause death. Variables included tumor type, metastasis site, and trial eligibility. RESULTS:Among 410 patients (median age 67 years; 48 % male), 162 (40 %) experienced SRE over a median follow-up of 26.8 months. Seventy-five (18.3 %) received radiation for pain alone. Experiencing any type of SRE (HR 1.98, 95 % CI 1.47-2.67, p < 0.001) or radiation for pain alone (HR 2.14, 95 % CI 1.57-2.92, p < 0.001) were both associated with increased mortality. Patients eligible for a trial of early radiation were more likely to develop SRE (HR 1.67, 95 % CI 1.18-2.37, p = 0.004). Prostate cancer histology (HR 1.70, p = 0.02) and metastases to the hip/acetabulum (HR 2.55, p = 0.02) were associated with SRE. CONCLUSION/CONCLUSIONS:Patients treated with radiation for pain alone demonstrated similar risk of death as those experiencing any type of SRE, supporting the inclusion of radiation in endpoint definitions. Prostate cancer type and hip/acetabulum metastasis location may help identify patients and lesions at elevated SRE risk, informing future preventive strategies.

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.

A key treatment for patients with multiple myeloma is high-dose melphalan followed by autologous stem cell transplant (ASCT). It can provide a deep response with long-term remission. However, some patients progress quickly, and it is not clear why that is. Here, we performed single-cell RNA and T-cell receptor (TCR) sequencing of the immune microenvironment of 40 patients before and after ASCT to determine if differences in the immune composition could define those who would progress. Clear differences in cell populations were identified in progressors, including increased T-cell infiltration, decreased TCR diversity, and decreased frequency of monocytes and CD56bright NK cells. We identified cell interactions that predicted progression including increased frequency of CD8+ exhausted T cells and stromal cells and decreased frequency of CD56bright NK cells and plasmacytoid dendritic cells. We propose and validate a model of progression that can also be determined by flow cytometry. Together these data highlight the importance of the immune microenvironment in understanding responses to ASCT.

BACKGROUND:Fistulous and cystic neck lesions that cannot be categorized into traditional classification schemes at presentation are challenging to manage and often manifest as recurrently draining fistulas after primary surgery. Work up with traditional cross-sectional imaging techniques with computed tomography (CT) or magnetic resonance imaging (MRI) may not provide adequate fine details of small channels. Characterization of fistula tracts is necessary for identification and definitive management of atypical or recurrent congenital neck anomalies. METHODS:A retrospective review of the electronic medical record from 2 institutions between 2016 and 2023 identifying cases of atypical or recurrent congenital neck anomalies for which CT and MR fistulogram, a novel interventional imaging technique, identified and characterized atypical fistula tracts. Imaging protocol, fistulogram technique, imaging-anatomic correlation, and follow up are reported. RESULTS:We identified 5 patients aged 8-14 years who presented with a draining pit in the head and neck who underwent CT or MRI fistulograms. Diagnoses include first branchial cleft anomalies (n = 3), deep branchial cleft fistula containing ectopic salivary tissue (n = 1), and a recurrent thyroglossal duct cyst (n = 1). Three patients had prior surgery to address these anomalies with recurrences, and one patient had an associated Kabuki syndrome. Complete resection was performed in all cases, with no recurrence to date. CONCLUSION/CONCLUSIONS:CT and MRI fistulograms are minimally invasive, safe, efficacious, and feasible techniques that can be performed before surgery and facilitated on the same day in a single anesthesia encounter. The technique allows for complete visualization of atypical and/or recurrent cystic and fistulous neck anomalies. It facilitates preoperative planning and aids in the characterization of the lesion so that a complete surgical excision can be executed.

OBJECTIVE:Observe if metal artifact reduction (MAR) techniques applied to magnetic resonance imaging (MRI) performed on patients with cochlear implants (CI) or auditory brainstem implants (ABI) improves image quality. STUDY DESIGN/METHODS:Retrospective review. SETTING/METHODS:Tertiary care center. PATIENTS/METHODS:Patients with auditory implants who underwent clinical MRI before and after the application of MAR techniques previously described. INTERVENTIONS/METHODS:From September 2022 to March 2023, patients who underwent brain or internal auditory canal (IAC) MRI with and without MAR were identified. Sequences included T1 and T2 weighted with turbo-spin-echo (TSE) correction and fluid-attenuation inversion recovery (FLAIR). Images were analyzed for visualization of intracranial structures by two neuroradiologists. MAIN OUTCOME MEASURES/METHODS:Visibility of 14 structures graded on a four-point Likert scale. Average scores per structure and sequence were compared using paired two-tailed t-tests and change in mode score. RESULTS:Ten patients underwent pre- and post-MAR MRI. Six had a unilateral CI, three had a unilateral ABI, and one had an ABI and CI. Three patients had four devices with the internal magnet removed for both scans. All structures had significantly improved visibility on post-MAR scan except ipsilateral parietal and occipital lobes and contralateral inner ear. Mode score increased from 2 to 4 for the ipsilateral occipital lobe and from 3 to 4 for the ipsilateral semicircular canals, brainstem, and cerebellar peduncles. Significant improvement was seen in all sequences except for ipsilateral structures on T1w axial precontrast and contralateral structures on T1w coronal postcontrast. ABIs did not improve as much as CIs because they scored better on the pre-MAR scan. CONCLUSIONS:MAR techniques improve image quality for patients with MRI-compatible implants with magnets. Benefits may be more evident in CIs than ABIs.

OBJECTIVES/OBJECTIVE:To investigate the added value of steroid injection following office-based blue laser therapy of benign lesions of the vocal folds. STUDY DESIGN/METHODS:Retrospective cohort analysis. METHODS:The medical records and video-recordings of patients with benign lesions of the vocal folds who underwent office-based blue laser therapy in a tertiary referral center between February 2020 and October 2022 were reviewed. Patients were divided into two subgroups, those who underwent office-based blue laser therapy alone (n = 23) and those who underwent office-based blue laser therapy with steroid injection (n = 19). Disease regression and voice outcome measures included Voice Handicap Index-10 score, perceptual voice evaluation using the GRB grading, jitter, shimmer, noise to harmonic ratio, voice turbulence index, and maximum phonation time were reviewed. RESULTS:A total of 42 patients were included. The mean age was 54.7 ± 10.1 years. Lesions included polyps (n = 21), Reinke's edema (n = 19), and cysts (n = 2). There was partial or complete disease regression in all patients who presented for follow-up (n = 37). In patients who underwent blue laser therapy alone (n = 19), 42.1% had complete regression and 57.9% had partial regression. In those who underwent blue laser therapy followed by steroid injection (n = 18), 77.7% had complete disease regression and 22.3% had partial regression. The difference in disease regression between the two subgroups was statistically significant (P = 0.027). The decrease in the mean Voice Handicap Index-10 score was also statistically significant with a higher mean being noted in the subgroup who underwent blue laser therapy followed by steroid injection (-10.5 ± 6.9 vs. -17.3 ± 11.8, P = 0.031). There was no significant difference in the decrease in the perceptual evaluation scores nor in the decrease in jitter, shimmer, noise to harmonic ratio, and voice turbulence index between the two subgroups. There was also no significant increase in the maximum phonation time. CONCLUSION/CONCLUSIONS:Steroid injection after blue laser therapy improves disease regression and voice outcome of laser therapy.

OBJECTIVE:The videofluoroscopic swallow study (VFSS) is an evaluation of the anatomy and physiology of swallowing, and often includes a screening evaluation of the esophagus. How the esophageal screen translates to esophageal pathology remains unknown. The purpose of this study was to determine if abnormal esophageal clearance (EC) on VFSS correlates with esophageal function on high-resolution esophageal manometry (HREM). MATERIALS AND METHODS/METHODS:This is a retrospective review of 115 adult patients who underwent both VFSS with esophageal screen and HRM. EC on VFSS was scored with the modified barium swallow impairment profile (MBSImP) component 17. Motility was characterized using HRM metrics according to the Chicago Classification Version 4.0 (CCv4.0). Predictive metrics were calculated for the esophageal screen. RESULTS:An EC score o greater than or equal to 1 had a sensitivity of 66%, specificity of 57%, PPV of 52%, NPV of 70%, and OR of 2.55 (p = 0.027). EC weakly correlated with incomplete bolus clearance (rho = 0.331, p = 0.0004) and did not correlate with bolus transit time (rho = 0.17, p = 0.105). CONCLUSIONS:The esophageal screen as characterized by the MBSImP is not an effective predictor of esophageal function on HREM as defined by the CCv4.0. Future work may focus on a defining a standardized VFSS protocol for the esophageal screen and potentially a more nuanced assessment of esophageal findings on VFSS that may enhance the sensitivity of the modality to motility disorders.

OBJECTIVES/OBJECTIVE:To examine the effects of short-term and long-term engagement with structured choral singing on vocal function and quality of life outcomes in older adults. METHODS:Two groups of older adult singers over 55 years, one with fewer than 4 semesters and one with 4 or more semesters singing in a chorale, were assessed at 3 time points: baseline, after 1 semester of singing, and either after 1 semester of rest or after 1 semester of rest and 1 semester more of singing. Acoustic and aerodynamic measures, voice-related quality of life ratings, and measures of singing accuracy were obtained. Percent change between time points were calculated to determine three outcomes: improvement, lack of change, or worsening of measures across time. RESULTS:Long-term average spectrum (LTAS), difference in first and second harmonics and estimated subglottic pressure were significantly more likely to improve after a semester of singing with less experience singers, and LTAS continued to improve after a semester of rest. Flow was significantly more likely to improve with more singing experience after a semester of singing. Aerodynamic variables consistently changed in more experienced singers and improvement was maintained over the three visits. No significant changes occurred over time for singing accuracy for any singer type. Self-perception of singing voice continued to improve with more singing experience. CONCLUSIONS:This study demonstrated that for older adults in good health, regular singing provided a mechanism for maintaining speaking voice over time.