Faculty Bibliography

OBJECTIVE:To assess a series of patients receiving teprotumumab therapy and objectively quantify the rates of otologic adverse events. STUDY DESIGN:A prospective cohort study of adult patients receiving teprotumumab between May 2020 and January 2022. SETTING:Tertiary referral center. METHODS:Prior to treatment initiation, an ototoxicity-specific audiometric battery was completed, which included conventional audiometry (frequencies 250-8000 Hz), ultrahigh-frequency audiometry (9000-20,000 Hz), tympanometry, speech discrimination scores, and distortion product otoacoustic emissions (DPOAEs). Testing was then repeated after treatment completion. RESULTS:In total, 35 patients were recruited, with a median (range) age of 48.5 years (21-74), and 8 (22.8%) were male. The most common subjective symptom reported was a hearing decline (25.7%), followed by aural fullness (17.1%) and tinnitus (14.3%). Fourteen patients had both pre- and posttreatment audiometric data. Among them, 3 patients (21.4%) were found to have changes in standard frequency audiometry, and 10 (71.4%) had changes in high-frequency audiometry, with 2 patients having changes in both. Less than half (n = 5) of the 11 patients with changes in standard or high-frequency pure tone hearing noted subjective hearing decline. Changes in DPOAE were noted in 4 patients out of 13 (30.7%). Two patients discontinued treatment due to hearing decline. Finally, 3 patients (8.6%) were diagnosed with patulous eustachian tube (PET) by an otolaryngologist, and another 3 patients are suspected to have PET based on symptom description during ophthalmologic follow-up. CONCLUSION:In our cohort, a high incidence of otologic symptoms was found to be associated with teprotumumab usage. Subjective hearing decline, changes in ultrahigh-frequency hearing as well as eustachian tube dysfunction may be encountered and suggest the potential ototoxicity of teprotumumab.

While motor cortical circuits contain information related to specific movement parameters¹, long-range inputs also have a critical role in action execution^2,3. Thalamic projections can shape premotor activity^2-6 and have been suggested⁷ to mediate the selection of short, stereotyped actions comprising more complex behaviours⁸. However, the mechanisms by which thalamus interacts with motor cortical circuits to execute such movement sequences remain unknown. Here we find that thalamic drive engages a specific subpopulation of premotor neurons within the zebra finch song nucleus HVC (proper name) and that these inputs are critical for the progression between vocal motor elements (that is, 'syllables'). In vivo two-photon imaging of thalamic axons in HVC showed robust song-related activity, and online perturbations of thalamic function caused song to be truncated at syllable boundaries. We used thalamic stimulation to identify a sparse set of thalamically driven neurons within HVC, representing ~15% of the premotor neurons within that network. Unexpectedly, this population of putative thalamorecipient neurons is robustly active immediately preceding syllable onset, leading to the possibility that thalamic input can initiate individual song components through selectively targeting these 'starter cells'. Our findings highlight the motor thalamus as a director of cortical dynamics in the context of an ethologically relevant behavioural sequence.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

PURPOSE/OBJECTIVE:Head and neck cancer (HNC) treatment results in morbidity impacting quality of life (QOL) in survivorship. This analysis evaluated changes in oral health-related QOL (OH-QOL) up to 2 years after curative intent radiation therapy (RT) for HNC patients and factors associated with these changes. METHODS:572 HNC patients participated in a multicenter, prospective observational study (OraRad). Data collected included sociodemographic, tumor, and treatment variables. Ten single-item questions and 2 composite scales of swallowing problems and senses problems (taste and smell) from a standard QOL instrument were assessed before RT and at 6-month intervals after RT. RESULTS:The most persistently impacted OH-QOL variables at 24 months included: dry mouth; sticky saliva, and senses problems. These measures were most elevated at the 6-month visit. Aspects of swallowing were most impacted by oropharyngeal tumor site, chemotherapy, and non-Hispanic ethnicity. Problems with senses and dry mouth were worse with older age. Dry mouth and sticky saliva increased more among men and those with oropharyngeal cancer, nodal involvement, and use of chemotherapy. Problems with mouth opening were increased by chemotherapy and were more common among non-White and Hispanic individuals. A 1000 cGy increase in RT dose was associated with a clinically meaningful change in difficulty swallowing solid food, dry mouth, sticky saliva, sense of taste, and senses problems. CONCLUSIONS:Demographic, tumor, and treatment variables impacted OH-QOL for HNC patients up to 2 years after RT. Dry mouth is the most intense and sustained toxicity of RT that negatively impacts OH-QOL of HNC survivors. GOV IDENTIFIER/UNASSIGNED:NCT02057510; first posted February 7, 2014.

OBJECTIVE:To determine if metal reduction magnetic resonance imaging sequences and changes in implant placement minimize artifact from cochlear implants and improve visualization of intracranial structures. STUDY DESIGN/METHODS:Cadaveric study. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Five cadaveric heads. INTERVENTIONS/METHODS:Specimens were implanted with Advanced Bionics HiRes Ultra3D devices at nasion-external auditory canal angles of 90, 120, and 160 degrees, and distances from the external auditory canal of 9 or 12 cm. Standard brain/internal auditory canal (IAC) sequences with metal artifact reducing technique were acquired in a 1.5T scanner. MAIN OUTCOME MEASURES/METHODS:The primary outcome was visibility of 14 intracranial structures graded on a 4-point scale (1, structures <50% visible; 2, >50% visible with some areas nonvisible from artifact; 3, artifact present but adequate for diagnosis; and 4, high quality). Scores were determined by experienced head and neck radiologists and compared with one-way analysis of variance. RESULTS:Imaging sequences included axial 5-mm whole-brain turbo spin echo (TSE) T2 with right to left and anterior to posterior encoding, fluid-attenuation inversion recovery high bandwidth, axial 5-mm whole-brain slice-encoding metal artifact correction (SEMAC), axial IAC constructive interference in steady state, and axial 3-mm T1 IAC with and without fat saturation. T1 IACs in axial and coronal planes were best for ipsilateral structures overall (mean [standard deviation {SD}], 3.8 [0.6] and 3.8 [0.5]). SEMAC (mean [SD], 3.5 [0.8]) was superior to TSE with anterior to posterior encoding (mean [SD], 3.5 [0.9) for ipsilateral cortex, cerebellopontine angle, and brainstem/cerebellum, and equivalent for the inner ear. Constructive interference in steady state and T1 with fat saturation were poor for all ipsilateral structures (mean, 2.8 [ p < 0.01]; mean, 3.1 [ p < 0.01]). The 120 degrees/12 cm position was overall best, although the 120 degrees/9 cm position still afforded visualization of ipsilateral structures; other angles and distances conferred slight advantages for specific structures of interest. CONCLUSIONS:SEMAC and T2 TSE with anterior to posterior encoding sequences provide artifact suppression while retaining excellent image quality. Different placement angles did not confer improvement in visualization, although placement distances provided slight advantages for some structures.

Background: Survivors of oral cavity and oropharyngeal cancer frequently experience difficulties in swallowing; tasting; speaking; chewing; and maintaining comfortable movements of the head, neck, and shoulder. Engagement in regular self-care can reduce further loss of function and mitigate late effects. Despite the substantial self-care requirements, there are no empirically based interventions to enhance the skills and confidence of these survivors in managing their ongoing care. Objective: The aim of this study is to describe the rationale and methodology for a randomized controlled trial evaluating Empowered Survivor (ES) versus Springboard Beyond Cancer, a general web-based program for cancer survivors, on self-efficacy in managing care, preparedness for managing survivorship, and health-related quality of life (QOL). Methods: This study will recruit a total of 600 individuals who were diagnosed with oral cavity or oropharyngeal cancer in the past 3 years and are currently cancer free primarily from state cancer registries; these individuals will be randomly assigned to either the ES or Springboard Beyond Cancer condition. The participants complete measures of self-efficacy in managing care, preparedness for survivorship, health-related QOL, and engagement in oral self-examination and head and neck strengthening and flexibility exercises at baseline and 2 and 6 months after baseline. The primary aim of this study is to evaluate the impact of ES versus Springboard Beyond Cancer on self-efficacy, preparedness, and health-related QOL. The secondary aim is to examine the mediators and moderators of ES"™s impact on self-efficacy in managing care, preparedness, and health-related QOL at 6 months. The exploratory aim is to conduct a process evaluation of ES to identify potential oncology or community settings for future implementation. Results: Multilevel modeling will be used to examine whether there are significant differences between the ES and Springboard Beyond Cancer interventions over time. Mediational models will evaluate the indirect effects of ES on outcomes. Quantitative analyses will evaluate the predictors of ES use, and qualitative analyses will evaluate the preferred timing and settings for the implementation of ES. Conclusions: This randomized controlled trial evaluates a completely web-based intervention, ES, versus a general web-based program for cancer survivors, Springboard Beyond Cancer, on self-efficacy in managing care, preparedness for managing survivorship, and health-related QOL and identifies the putative mediators and moderators of the intervention"™s effects. If an effect on the primary outcomes is illustrated, the next step could be an implementation trial to evaluate the intervention"™s uptake in and impact on an oncology care setting or nonprofit organizations.

3D models of airway lumens were created from CT scans of 19 patients with laryngotracheal stenosis. Computational fluid dynamics (CFD) simulations were completed for each, and results were compared to measured peak inspiratory flow rate, grade of lumen constriction, and measures of airway geometry. Results demonstrate flow resistance and shear stress correlate with degree of lumen constriction and absolute cross-sectional area as well as flow rate. Flow recirculation depends on airway constriction but does not vary with flow rate. Resistance and wall shear stress did not correlate well with functional measures. Flow recirculation did differ between subjects with higher functional measures and subjects with lower functional measures. This analysis provides mathematical models to predict airway resistance, wall shear stress, and flow reversal according lumen constriction and inspiratory flow rate. It suggests aerodynamic factors such as flow recirculation play a role in differences in functional performance between patients with similar airway measures.

OBJECTIVE:To compare treatment outcomes for T4b head and neck adenoid cystic carcinoma (ACC). STUDY DESIGN/METHODS:Historical cohort study. SETTING/METHODS:National Cancer Database (NCDB). METHODS:Identified all T4b ACC of head and neck origin diagnosed 2004 to 2019 in the NCDB. Demographics, clinical characteristics, treatment details, and survival were analyzed. Treatment outcomes were analyzed using univariable and multivariable Cox regression. RESULTS:We identified 606 cases of T4b ACC. Less than half (284, 47.0%) underwent curative-intent treatment. Among these, most were treated with primary surgery: surgery + radiotherapy (RT) (122, 43.0%) or surgery + chemoradiotherapy (CRT) (42, 14.8%). The positive margin rate was 78.7%, and 90-day postoperative mortality was zero. Nonsurgical patients were treated with definitive RT (60, 21.1%) or definitive CRT (60, 21.1%). The median follow-up was 51.5 months. Overall survival was 77.8% at 3 years. Three-year survival was higher for patients treated with surgery compared to those treated nonsurgically (84% vs 70%; p = .005). Surgical treatment remained associated with higher survival on multivariable analysis (hazard ratio [HR]: 0.47, p = .005). This effect was most pronounced for oral cavity tumors (HR: 0.17, p = .01). Among matched cohorts of surgically treated patients, there was no difference in 3-year survival between clinical T4a and T4b tumors (83.3% vs 83.0%, p = .99). CONCLUSION/CONCLUSIONS:Long-term survival for T4b ACC of the head and neck could be expected. Primary surgical treatments can be performed safely and are associated with longer survival. A carefully selected subset of patients with very advanced ACC might benefit from the consideration of surgical treatments.