Faculty Bibliography

An increasing number of elderly patients are seeking hearing rehabilitation strategies, including cochlear implantation. Elderly patient who are frail or those with significant pre-existing comorbidities have a higher risk of perioperative morbidity after undergoing surgery with general anesthesia. Additionally, there is a growing concern that general anesthesia could increase the risk of dementia or postoperative cognitive decline. In patients who wish to avoid the perceived medical and cognitive risks attributed to general anesthesia or for those who are deemed medically unfit for general anesthesia, surgery under local anesthesia with conscious sedation may be offered. This article details the surgical technique of local anesthesia with conscious sedation and describes the modifications and technical nuances which may be employed for executing a successful surgery.

Fibrosis of the vocal folds poses a substantive clinical challenge potentially underlying the rapid proliferation of direct steroid injections into the upper airway. The variable clinical response to glucocorticoids (GCs) in the vocal folds is likely related to diversity inherent to GCs and both patient-specific, and upstream, cell-specific responses to GCs. Broadly, we hypothesize the disparity in clinical outcomes are due to undesirable effects of GCs on resident fibroblasts. Transcriptome analysis identified significant GC-mediated modulation of Hippo signaling, a known regulator of fibrotic gene expression. Subsequent analysis confirmed GC-mediated YAP activation, a transcriptional co-factor in the Hippo signaling pathway. YAP inhibition attenuated ACTA2 expression in GC-treated human vocal fold fibroblasts. Nuclear localization and phosphorylation at Ser211, however, was not affected by YAP inhibition, suggesting nuclear translocation of YAP is indirectly driven by GR. RNA-seq analysis confirmed the influence of GCs on Wnt signaling, and canonical Wnt signaling target genes were upregulated by GCs. These data implicate YAP and its downstream targets as putative mediators of a pro-fibrotic response to GCs. Therapeutic YAP inhibition may ultimately be clinically relevant and warrants further consideration.

OBJECTIVE:To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. METHODS:Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). RESULTS:A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1β secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. CONCLUSION/CONCLUSIONS:We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Menopause adversely affecs power and endurance of the limb muscles. However, despite clinical observations that menopause corresponds to negative changes of the voice, the direct effects of estrogen deprivation on the thyroarytenoid muscles are unknown. The purpose of this study was to investigate the effects of estrogen deprivation via ovariectomy on three neuromuscular parameters of the thyroarytenoid muscles using a rat model. STUDY DESIGN/METHODS:Animal model. METHODS:Cryosections of vocal folds of 20 (10 control and 10 ovariectomized) female rats were stained to label neuromuscular junctions, fiber size, or parvalbumin levels using immunohistochemical techniques and compared between experimental groups. RESULTS:The neuromuscular junctions, thyroarytenoid fiber sizes, and parvalbumin levels of the vocal folds were similar between experimental groups. CONCLUSIONS:The loss of estrogen did not change neuromuscular parameters of the vocal folds of adult female rats; therefore, vocal changes within the outer vibratory layers of the vocal folds may primarily be responsible for clinically observed menopausal vocal changes. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2020.

Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P < 0.0001). Among mutation-positive cfDNAs, the corresponding gDNA was frequently negative (44.6%; 25/55) or failed sequencing (17.8%; 9/55). Routine molecular profiling of cfDNA is superior to gDNA from CSF, facilitating the capture of mutations at high variant allele frequency, even in the context of a negative cytology.

Introduction Photobiomodulation therapy has been shown to be an effective treatment for reducing the incidence and severity of oral mucositis (OM). The objective of this study is to determine the range of effective PBM dose, and review the adequacy of reporting irradiation parameters. Methods Online databases were searched to compare efficacy of PBM versus controls for preventing or treating cancer therapy-induced OM. Irradiation parameters were reviewed for accuracy. Results A total of 53 clinical trials were identified and 29 papers were excluded, leaving 24 papers for review. Only 1 study reported all parameters accurately. Seven studies reported a difference in OMgrade >= 3 (WHO) between the placebo and PBM groups greater than 40% when PBM was used prophylactically with greater irradiation parameters (mean energy dose 50%, beam area 58%, irradiance 246%, and treatment time per point 290% greater than the overall mean values).Aplot of effect size (%) vs. total energy per session was created using studies that reported adequate information to determine both total energy per session and the difference in the percent of patients with OMgrade >= 3 between the study group and placebo group. These data points were fit with a quadratic curve to evaluate if the data may resemble the parabolic relationship observed in previous studies. Conclusions This review has reconfirmed the lack of accurate reporting of PBM parameters. Total energy per session may be used to guide PBM dose parameters

OBJECTIVES/OBJECTIVE:The role of locoregional radiotherapy for metastatic oropharyngeal squamous cell cancer (OPSCC) is unclear. We investigated the impact of head and neck radiotherapy on survival in de novo metastatic OPSCC patients who received systemic therapy. METHODS:We queried the NCDB from 2004-2015 for metastatic OPSCC patients at diagnosis with known HPV-status who received systemic therapy. The association of head and neck radiotherapy with overall survival was analyzed using the Kaplan-Meier method, Cox proportional hazards model, and propensity score-matched analysis adjusting for demographic and disease-specific prognostic factors. RESULTS:Of the 2,139 patients with metastatic OPSCC who presented with metastases and received systemic treatment, we identified 556 patients with known HPV-status. Among these 556 patients, 49% were HPV-positive and 56% received head and neck radiotherapy. With a median follow-up of 17.5 months (IQR 6.0-163.4 months), radiotherapy was associated with significantly improved 1-year OS (67% vs 58%, log-rank P < .001) which remained significant on MVA (HR 0.78 95% CI 0.62-0.97 P = .029). In HPV-status subgroup analysis, a survival benefit was identified in HPV-positive patients (1-year OS 77% vs 67%, log-rank P < .001) but not in HPV-negative patients. Results were consistent on a propensity score-matched analysis of 212 HPV-positive matched patients (HR 0.66, 95% CI 0.49-0.83, P < .001). CONCLUSION/CONCLUSIONS:The survival of metastatic OPSCC remains limited. In this large series of patients with known HPV-status, head and neck radiotherapy was associated with longer survival in those with HPV-associated disease. These data could guide management of this challenging group of patients for head and neck cancer practitioners. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2020.