Faculty Bibliography

A new study has identified the periaqueductal gray as an important brain region for play and tickle behavior in rats.

Bilaterally organized brain regions are often simultaneously active in both humans¹

BACKGROUND AND OBJECTIVES/OBJECTIVE:Advances in targeted therapies and wider application of stereotactic radiosurgery (SRS) have redefined outcomes of patients with brain metastases. Under modern treatment paradigms, there remains limited characterization of which aspects of disease drive demise and in what frequencies. This study aims to characterize the primary causes of terminal decline and evaluate differences in underlying intracranial tumor dynamics in patients with metastatic brain cancer. These fundamental details may help guide management, patient counseling, and research priorities. METHODS:Using NYUMets-Brain-the largest, longitudinal, real-world, open data set of patients with brain metastases-patients treated at New York University Langone Health between 2012 and 2021 with SRS were evaluated. A review of electronic health records allowed for the determination of a primary cause of death in patients who died during the study period. Causes were classified in mutually exclusive, but collectively exhaustive, categories. Multilevel models evaluated for differences in dynamics of intracranial tumors, including changes in volume and number. RESULTS:Of 439 patients with end-of-life data, 73.1% died secondary to systemic disease, 10.3% died secondary to central nervous system (CNS) disease, and 16.6% died because of other causes. CNS deaths were driven by acute increases in intracranial pressure (11%), development of focal neurological deficits (18%), treatment-resistant seizures (11%), and global decline driven by increased intracranial tumor burden (60%). Rate of influx of new intracranial tumors was almost twice as high in patients who died compared with those who survived (P < .001), but there was no difference in rates of volume change per intracranial tumor (P = .95). CONCLUSION/CONCLUSIONS:Most patients with brain metastases die secondary to systemic disease progression. For patients who die because of neurological disease, tumor dynamics and cause of death mechanisms indicate that the primary driver of decline for many may be unchecked systemic disease with unrelenting spread of new tumors to the CNS rather than failure of local growth control.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Dose selection for brain metastases stereotactic radiosurgery (SRS) classically has been based on tumor diameter with a reduction of dose in the settings of prior brain irradiation, larger tumor volumes, and critical brain location. However, retrospective series have shown local control rates to be suboptimal with reduced doses. We hypothesized that lower doses could be effective for specific tumor biologies with concomitant systemic therapies. This study aims to report the local control (LC) and toxicity when using low-dose SRS in the era of modern systemic therapy. METHODS:We reviewed 102 patients with 688 tumors managed between 2014 and 2021 who had low-margin dose radiosurgery, defined as ≤14 Gy. Tumor control was correlated with demographic, clinical, and dosimetric data. RESULTS:The main primary cancer types were lung in 48 (47.1%), breast in 31 (30.4%), melanoma in 8 (7.8%), and others in 15 patients (11.7%). The median tumor volume was 0.037cc (0.002-26.31 cm3), and the median margin dose was 14 Gy (range 10-14). The local failure (LF) cumulative incidence at 1 and 2 years was 6% and 12%, respectively. On competing risk regression analysis, larger volume, melanoma histology, and margin dose were predictors of LF. The 1-year and 2-year cumulative incidence of adverse radiation effects (ARE: an adverse imaging-defined response includes increased enhancement and peritumoral edema) was 0.8% and 2%. CONCLUSION/CONCLUSIONS:It is feasible to achieve acceptable LC in BMs with low-dose SRS. Volume, melanoma histology, and margin dose seem to be predictors for LF. The value of a low-dose approach may be in the management of patients with higher numbers of small or adjacent tumors with a history of whole brain radio therapy or multiple SRS sessions and in tumors in critical locations with the aim of LC and preservation of neurological function.

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.

OBJECTIVE:Military drill instructors have extreme vocal demands that place them at risk for phonotrauma. Characterization of laryngeal pathology and vibratory characteristics among drill instructors presenting for specialized voice care is lacking. METHODS:A retrospective review in a specialized voice clinic over a two-year period was conducted. Patients identified as current drill instructors between the ages of 28-43 with a diagnosis of dysphonia were included. Laryngeal pathology was diagnosed by a fellowship trained laryngologist and vibratory characteristics were evaluated utilizing the Voice-Vibratory Assessment with Laryngeal Imaging (VALI) rating form. All patients were also evaluated by a speech-language pathologist. Patient reported outcome measures were collected along with perceptual voice evaluations utilizing the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V). RESULTS:Twelve current drill instructors were identified, and all had phonotraumatic lesions. Lesions were categorized as vocal fold hemorrhage (8%), ectasia (25%), unilateral epithelial thickening (33.3%), bilateral epithelial thickening (58.3%), ventricular cyst (8%), polyp (25%), and sulcus vocalis (25%). Vibratory abnormalities were assessed with the VALI rating scale and correlated to CAPE-V perceptual ratings with 83% having reduced mucosal wave, 75% reduced amplitude of lateral excursion, 50% aperiodic vibrations, 50% asymmetric or chasing wave, 58% glottal insufficiency, 100% supraglottic hyperfunction, and an average CAPE-V overall severity of 50% with severe perceptual dysphonia. The average Voice Handicap Index (VHI-10) and Reflux Symptom Index (RSI) score was 15.5 and 14.7, respectively. CONCLUSION/CONCLUSIONS:Phonotraumatic lesions were universally present in drill instructors complaining of hoarseness, suggesting early referral, and intervention may be warranted in this population. LEVEL OF EVIDENCE/METHODS:4.

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.

OBJECTIVES:To explore factors influencing research interest and productivity and perceived barriers to conducting research in Oral Medicine (OM). METHODS:Invitations to participate in an online survey were e-mailed to a network of international OM practitioners and related professional organizations. Questions captured respondents' demographic/professional variables and gauged research interest, productivity, and perceived barriers to conducting research specifically in OM. Statistical analysis was conducted via descriptive, logistic regression, and multivariate modeling. RESULTS:Five hundred and ninety-three OM practitioners from 55 countries completed the survey, with 54%, 25%, and 21% practicing in high, upper-middle, and lower-middle-income countries, respectively. Eighty-six percent of respondents were interested in conducting research. Age (less interest with an increase in age), working in academia, and practicing in a lower-middle vs high-income country were significant predictors of research interest. Self-reported research productivity was significantly greater among males, those working in academia, and those who graduated from programs that mandated research presentation/publication. Obtaining research funding was a significant barrier among respondents from lower and upper-middle-income countries, whereas finding time for research was a reported barrier by respondents from high-income countries. CONCLUSION:The results of this survey identified perceived barriers to conducting research in OM and highlighted solutions to address such barriers.

OBJECTIVE:The diversity of glucocorticoid (GC) properties may underlie variability of clinical efficacy for vocal fold (VF) disease. Optimized therapeutic approaches must account for tissue complexity as well as interactions between cell types. We previously reported that reduced GC concentrations inhibited inflammation without eliciting fibrosis in mono-cultured VF fibroblasts and macrophages. These data suggested that a refined approach to GC concentration may improve outcomes. In the current study, co-culture of VF fibroblasts and macrophages was employed to investigate the effects of different concentrations of methylprednisolone on fibrotic and inflammatory response genes in VF fibroblasts to optimize management paradigms. STUDY DESIGN/METHODS:In vitro. METHODS:THP-1 monocyte-derived macrophages were stimulated with interferon-γ (IFN-γ), lipopolysaccharide (LPS), or transforming growth factor-β (TGF-β) to induce inflammatory (M(IFN/LPS)) and fibrotic (M(TGF)) phenotypes. Macrophages were then co-cultured with a human VF fibroblast cell line using a 0.4 μm pore membrane with or without 0.1-3000 nM methylprednisolone. Inflammatory (CXCL10, TNF, and PTGS2) and fibrotic (ACTA2, CCN2, and COL1A1) gene expression was quantified in fibroblasts. RESULTS:Incubating VF fibroblasts with M(IFN/LPS) macrophages increased expression of TNF and PTGS2, and this effect was inhibited by methylprednisolone. Incubation of VF fibroblasts with M(TGF) macrophages increased expression of ACTA2, CCN2, and COL1A1, and this effect was enhanced by methylprednisolone. The concentration of methylprednisolone required to downregulate inflammatory genes (TNF and PTGS2) was lower than that to upregulate fibrotic genes (ACTA2, CCN2, and COL1A1). CONCLUSION/CONCLUSIONS:Reduced concentration of methylprednisolone effectively suppressed inflammatory genes without enhancing fibrotic genes, suggesting that a refined approach to GC concentration may improve clinical outcomes. LEVEL OF EVIDENCE/METHODS:N/A Laryngoscope, 2023.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Myofiber culture has been employed to investigate muscle physiology in vitro and is well-established in the rodent hind limb. Thyroarytenoid (TA) myofiber culture has not been described, providing an opportunity to employ this method to investigate distinct TA myofiber functions. The purpose of this study was to assess the feasibility of a TA myofiber culture model. STUDY DESIGN/METHODS:In vitro. METHODS:for 2 h. Myofiber specificity was determined via immunolabeling for desmin and myosin heavy chain (MHC). Myofibers viability was assessed over 7 days via esterase assay. Additional myofibers were immunolabeled for satellite cell marker Pax-7. Glucocorticoid (GC) receptor (GR) was immunolabeled following GC treatment. RESULTS:The harvest technique yielded ~120 myofibers per larynx. By day 7, ~60% of the fibers remained attached and were calcein AM-positive/ethidium homodimer-negative, indicating viability. Myofibers were positive for desmin and MHC, indicating muscle specificity. Cells surrounding myofibers were positive for Pax-7, indicating the presence of myogenic satellite cells. Myofibers also responded to GC treatment as determined by GR nuclear translocation. CONCLUSION/CONCLUSIONS:TA myofibers remained viable in culture for at least 7 days with a predictable response to exogenous stimuli. This technique provides novel investigative opportunities regarding TA structure and function. LEVEL OF EVIDENCE/METHODS:N/A Laryngoscope, 2023.