Faculty Bibliography

OBJECTIVE:To evaluate the safety, immunogenicity, and efficacy of INO-3107, a DNA immunotherapy designed to elicit targeted T-cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433). METHODS:Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO-3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post-INO-3107 and cellular immune responses. RESULTS:An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain (n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO-3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO-3107 induced durable cellular responses against HPV-6 and HPV-11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential. CONCLUSION/CONCLUSIONS:The data suggest that INO-3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2023.

OBJECTIVE:Children with high-frequency severe-to-profound hearing loss and low-frequency residual hearing who do not derive significant benefit from hearing aids are now being considered for cochlear implantation. Previous research shows that hearing preservation is possible and may be desirable for the use of electroacoustic stimulation (EAS) in adults, but this topic remains underexplored in children. The goal of this study was to explore factors relating to hearing preservation, acceptance, and benefits of EAS for children. STUDY DESIGN:Retrospective review. SETTING:Tertiary academic medical center. PATIENTS:Forty children (48 ears) with preoperative low-frequency pure-tone averages of 75 dB HL or less at 250 and 500 Hz (n = 48). INTERVENTION:All patients underwent cochlear implantation with a standard-length electrode. MAIN OUTCOME MEASURE:Low-frequency audiometric thresholds, speech perception, and EAS usage were measured at initial stimulation, and 3 and 12 months postoperatively. Outcomes were compared between children with and without hearing preservation, and between EAS users and nonusers. RESULTS:Hearing was preserved at similar rates as adults but worse for children with an enlarged vestibular aqueduct. Fewer than half of children who qualified to use EAS chose to do so, citing a variety of audiologic and nonaudiologic reasons. No differences were detected in speech perception scores across the groups for words, sentences, or sentences in noise tests. CONCLUSIONS:Neither hearing preservation nor EAS use resulted in superior speech perception in children with preoperative residual hearing; rather, all children performed well after implantation.

OBJECTIVES/OBJECTIVE:Head and neck cancer patients that require major reconstruction often have advanced-stage disease. Discharge disposition of patients can vary and impact time to adjuvant treatment. We sought to examine outcomes in patients discharged to skilled nursing facilities (SNF) compared to those discharged home, including the impact on adjuvant therapy initiation and treatment package time (TPT). METHODS:Patients with head and neck squamous cell carcinoma treated with surgical resection and microvascular free flap reconstruction from 2019 to 2022 were included. Retrospective review was conducted to evaluate the impact of disposition on time to radiation (RT) and TPT. RESULTS:230 patients were included, with 165 (71.7%) discharged to home and 65 (28.3%) discharged to SNF. 79.1% of patients were recommended adjuvant therapy. Average time to RT was 59 days for patients discharged to home compared to 70.1 days for patients discharged to SNF. Disposition was an independent risk factor for delays to starting RT (p = 0.03). TPT was 101.7 days for patients discharged to home versus 112.3 days for those who discharged to SNF. Patients discharged to SNF had higher rates of readmission (p < 0.005) compared to patients discharged home in an adjusted multivariate logistic regression. CONCLUSIONS:Patients discharged to an SNF had significantly delayed time to initiation of adjuvant treatment and higher rates of readmission. Timeliness to adjuvant treatment has recently been established as a quality measure, thus identifying delays to adjuvant treatment initiation should be a priority. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2023.

PURPOSE:Neoadjuvant targeted therapy provides a brief, preoperative window of opportunity that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS:A pooled analysis of treatment-naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009 to 2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n = 83) or anti-ErbB3 antibody therapy (n = 9) within 28 days of surgery. Clinical to pathologic stage migration was compared with disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed. RESULTS:92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared with control cohort (P = 0.048). Patients with pathologic downstage migration had the highest OS [89.5%; 95% confidence interval (CI), 75.7-100] compared with those with no stage change (58%; 95% CI, 46.2-69.8) or upstage (40%; 95% CI, 9.6-70.4; P = 0.003). Downstage migration remained a positive prognostic factor for OS (HR, 0.22; 95% CI, 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P = 0.0078). CONCLUSIONS:Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.

OBJECTIVE:To assess the validity of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) for evaluating thyroid nodules in children. METHODS:Patients aged <19 years with thyroid nodule(s) evaluated by ultrasound (US) from 2007-2018 at a tertiary children's hospital were included. Two radiologists scored de-identified thyroid US images using ACR TI-RADS (from 1, "benign" to 5, "highly suspicious"). The radiologists recorded size and rated vascularity for each nodule. Ultrasound findings were compared to pathology results (operative cases, n = 91) and clinical follow-up without disease progression (non-operative cases, n = 15). RESULTS:Thyroid images from 115 patients were reviewed. Nine patients were excluded due to the absence of an evaluable nodule. Forty-seven benign and 59 malignant nodules were included. Median age at ultrasound was 15 years (range 0.9-18 years). Twenty (18.9%) patients were male. There was moderate agreement between TI-RADS levels assigned by the two raters (kappa = 0.57, p < 0.001). When the raters' levels were averaged, >3 as the threshold for malignancy correctly categorized the greatest percentage of nodules (68.9%). Eleven (18.6%) malignant nodules received a TI-RADS level of 2 (n = 3) or 3 (n = 8). Sensitivity, specificity, and positive and negative predictive values were 81.4%, 53.2%, 68.6%, and 69.4%, respectively. Although not part of TI-RADS, vascularity was similar between benign and malignant nodules (p = 0.56). CONCLUSION/CONCLUSIONS:In a pediatric population, TI-RADS can help distinguish between benign and malignant nodules with comparable sensitivity and specificity to adults. However, the positive and negative predictive values suggest TI-RADS alone cannot eliminate the need for FNA. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2022.

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

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.

OBJECTIVES:To determine rates of hearing preservation and performance in patients who met candidacy for electroacoustic stimulation (EAS) and were implanted with a slim modiolar electrode (CI532 or CI632). DESIGN:Adult patients meeting Food and Drug Administration criteria for electroacoustic stimulation (preoperative low-frequency pure-tone average [LFPTA] less than 60 dB at 125, 250, and 500 Hz and monosyllabic word scores between 10% and 60% in the ear to be implanted), who received a slim modiolar electrode were included. Main outcome measures included rates of hearing preservation, defined as a LFPTA ≤80 dB at 125, 250, and 500 Hz, as well as postoperative low-frequency pure-tone threshold shifts, consonant-Nucleus-Consonant (CNC) word scores and AzBio sentences in noise scores. RESULTS:Forty-six patients met inclusion criteria during a 4-year period. Mean (standard deviation) preoperative LFPTA was 34.5 (13.0) dB, and 71.7% had preserved hearing at initial activation. The mean LFPTA shift in patients who preserved hearing at initial activation was 19.7 (14.6) dB, compared with 62.6 (17.7) dB in patients who did not preserve hearing as per our definition. Perioperative steroid use was not different in patients with and without preserved hearing (X 2 (1, N = 46) = 0.19, p = .67, V = 0.06). One year after surgery, 57% of patients had a decline in LFPTA >80 dB and were no longer considered candidates for EAS, with 34.7% still retaining low-frequency thresholds ≤80 dB. CNC word scores at 1 year were 69.9% and 61.4% among individuals with and without preserved low-frequency hearing respectively, measured in their CI ear alone, in their regular listening condition of EAS or electric only ( t (32) = 1.13, p = 0.27, d = 0.39, 95% CI = -6.51, 22.86). Device use time did not differ between groups. Among adults with preserved residual hearing at 1 year (n = 16), 44% used EAS, although there was no significant difference in performance between EAS users and nonusers with preserved hearing. Loss of residual hearing over time did not result in a decline in speech perception performance. CONCLUSION:The present study demonstrated favorable early rates of hearing preservation with a slim modiolar array. Performance was not significantly different in individuals with and without preserved low-frequency acoustic hearing, independent of EAS use. Compared with reports of short electrode use, the loss of residual hearing in patients implanted with this array did not impact speech perception performance.