Faculty Bibliography

Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m² and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9-11.4) and 8.9 (90% CI = 2.7-15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6-40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8⁺ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.

Introduction: While cochlear implants (CI) prior to 12 months of age have become common, the prevalence and impact of issues that either arise or were not evident prior to implantation is unknown. Methods: Retrospective chart review of children implanted under 12 months of age with minimum 3 years follow up. The children were divided into three groups: those with no identified additional disabilities, those with no known disabilities at time of implantation but diagnosed with additional disabilities following implantation, and those that had known anticipated additional disabilities at time of implantation. Results: 108 children under the age of 12 months were implanted at our Center between 2000 and 2013 with an average age of 9 months at time of implantation and n = 93 met inclusion criteria. In 79.6% (74/93) of children, there were no additional issues detected. In 11.8% (11/93), additional issues were known at the time of implantation while in 8.6% (8/93) of the children were diagnosed with additional issues that were not evident prior to implantation. The auditory and linguistic benefits vary commensurate with the severity of their disabilities. Those with anticipated issues preoperatively did not perform as well. Conclusions: Children implanted below one year of age but diagnosed with additional disabilities following implantation obtained substantial though varying degrees of benefit. In none of these cases would knowledge of the disability have altered the decision to offer early CI. It is important to address these potential issues when counseling families about outcomes.

In recent years there has been an increasing percentage of cochlear implant (CI) users who have usable residual hearing in the contralateral, nonimplanted ear, typically aided by acoustic amplification. This raises the issue of the extent to which the signal presented through the cochlear implant may influence how listeners process information in the acoustically stimulated ear. This multicenter retrospective study examined pre- to postoperative changes in speech perception in the nonimplanted ear, the implanted ear, and both together. Results in the latter two conditions showed the expected increases, but speech perception in the nonimplanted ear showed a modest yet meaningful decrease that could not be completely explained by changes in unaided thresholds, hearing aid malfunction, or several other demographic variables. Decreases in speech perception in the nonimplanted ear were more likely in individuals who had better levels of speech perception in the implanted ear, and in those who had better speech perception in the implanted than in the nonimplanted ear. This raises the possibility that, in some cases, bimodal listeners may rely on the higher quality signal provided by the implant and may disregard or even neglect the input provided by the nonimplanted ear.

Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity.

Excitation in neural circuits must be carefully controlled by inhibition to regulate information processing and network excitability. During development, cortical inhibitory and excitatory inputs are initially mismatched but become co-tuned or balanced with experience. However, little is known about how excitatory-inhibitory balance is defined at most synapses or about the mechanisms for establishing or maintaining this balance at specific set points. Here we show how coordinated long-term plasticity calibrates populations of excitatory-inhibitory inputs onto mouse auditory cortical pyramidal neurons. Pairing pre- and postsynaptic activity induced plasticity at paired inputs and different forms of heterosynaptic plasticity at the strongest unpaired synapses, which required minutes of activity and dendritic Ca²⁺ signaling to be computed. Theoretical analyses demonstrated how the relative rate of heterosynaptic plasticity could normalize and stabilize synaptic strengths to achieve any possible excitatory-inhibitory correlation. Thus, excitatory-inhibitory balance is dynamic and cell specific, determined by distinct plasticity rules across multiple excitatory and inhibitory synapses.

OBJECTIVES/OBJECTIVE:The current analysis queries rhinologists' attitudes about the use of telemedicine, including the degree to which it has impacted practice patterns during the COVID-19 pandemic. Our objective was to survey rhinologists and understand the extent to which telemedicine serves as a rejoinder to in-person consultation: appreciation of relevant factors may be important in planning for present and future considerations. METHODS:A 14-question anonymous survey sent out to the American Rhinologic Society (ARS) membership in April 2020. It included demographic factors and detailed questions examining the extent of telemedicine use. Numerous topics including the degree of use, satisfaction with services, and utility of services were evaluated. RESULTS:There were 134 respondents. Most reported seeing ≤30% of typical in-person volume, with 14.8% not seeing any patients at all. 88.1% used telemedicine; 82.0% reported some level of satisfaction with telemedicine. The vast majority utilized platforms employing audio and video (83.3%), and a plurality reported spending 5-15 min on calls. Numerous reasons were cited for the use of telemedicine, including significant public health benefits amid the crisis (89.7%). Only 12.0% of respondents reported using telemedicine for hospital consultation. CONCLUSION/CONCLUSIONS:Rhinologists have embraced telemedicine during the COVID-19 pandemic in an attempt to improve accessibility, patient satisfaction, and revenue stream. When utilized appropriately, this technology obviates the need for seeing at-risk patients and performing procedures such as nasal endoscopy. Only a minority of rhinologists was dissatisfied, viewing this as a temporary fix during the pandemic.

OBJECTIVES/OBJECTIVE:To evaluate the impact of the novel coronavirus pandemic on practice patterns, clinical behavior, personal health, and emotional/psychological concerns of rhinologists. METHODS:A 15-question survey was sent out to the American Rhinologic Society's (ARS) membership to determine the impact of COVID-19 during the crisis. Demographic factors and practice patterns were collected and evaluated. RESULTS:There were 224 total respondents out of 835 ARS members queried (26.8% response rate). Study queries were sent in April 2020. Notably, 17.8% reported illness in themselves or their staff and 74.4% noted a psychological/emotional impact. A plurality of rhinologists noted their practice volume and in-office procedure volume has become 20.0% and 0.0% of their prior volumes, respectively. In addition, 96.2% were noted to be using telemedicine in our subspecialty. CONCLUSION/CONCLUSIONS:In addition to severely impacting volume and the perception of future decreases in patients and revenue, the COVID-19 pandemic has had a physical and emotional impact on rhinologists in ways that need to be further studied. These data include significantly novel and objective information. The COVID-19 crisis also reveals the important role of telemedicine in rhinology. Guidelines regarding personal protective equipment for in-office visits, nasal endoscopy, and other in-office and operating room procedures would be particularly helpful as future waves are expected.

Importance/UNASSIGNED:The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists-head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. Observations/UNASSIGNED:A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Conclusions and Relevance/UNASSIGNED:Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19.

Importance/UNASSIGNED:The fibula free flap donor site is associated with both short-term and long-term morbidity. Split-thickness skin graft (STSG) loss can lead to long delays in donor site healing and is associated with significant adverse sequelae. Patients may experience initial good STSG uptake after bolster removal but may have subsequent partial or total loss related to contact pressure or shearing. Objective/UNASSIGNED:To determine if increased duration of bolster use is associated with increased STSG uptake rates following fibula free flap reconstruction. Design, Setting, and Participants/UNASSIGNED:This retrospective cohort study included patients 18 years and older undergoing fibula free flap reconstruction following head and neck extirpative surgery at a tertiary care academic medical center from May 2013 to March 2019. The donor sites were photographed 4 weeks postoperatively, and areas of graft uptake were measured using image processing software. The baseline demographic, comorbidity, and operative characteristics were also collected. Interventions/UNASSIGNED:A fine mesh gauze with 3% bismuth tribromophenate and petrolatum blend bolster was sutured over leg STSGs placed on fibula free flap donor sites intraoperatively, and the ankle and lower leg were immobilized for 5 days in a plaster splint. Bolsters were either removed on postoperative day 5 or 14. Thereafter, the STSGs were covered with a petroleum and bismuth gauze and a cotton dressing. Main Outcomes and Measures/UNASSIGNED:Rates of donor site infection and STSG percentage uptake at 4 weeks. Results/UNASSIGNED:Of the 42 included patients, 31 (74%) were male, and the mean (SD) age was 62.1 (13.1) years. A total of 20 patients were included in the 5-day group, and 22 were included in the 14-day group. The 14-day bolster group had a higher mean percentage skin graft uptake rate compared with the 5-day bolster duration group (77.5% vs 59.9%), with an effect size of -0.632 (95% CI, -1.260 to -0.004). Patients with Adult Comorbidity Evalution-27 scores of 3 had poorer rates of STSG uptake compared with patients with Adult Comorbidity Evalution-27 scores of 0 to 2 (65.9% vs 82.9%), with an effect size of 0.599 (95% CI, -0.191 to 1.389). No donor site infections were noted in either group. Conclusions and Relevance/UNASSIGNED:Fourteen-day bolster application to the fibula free flap donor site was associated with better STSG uptake rates than 5-day bolster application.