Faculty Bibliography

Chronic pain involves sensitization of nociceptors and synaptic transmission of painful signals in nociceptive circuits in the dorsal horn of the spinal cord. We investigated the contribution of clathrin-dependent endocytosis to sensitization of nociceptors by G protein-coupled receptors (GPCRs) and to synaptic transmission in spinal nociceptive circuits. We determined whether therapeutic targeting of endocytosis could ameliorate pain. mRNA encoding dynamin (Dnm) 1-3 and adaptor-associated protein kinase 1 (AAK1), which mediate clathrin-dependent endocytosis, were localized to primary sensory neurons of dorsal root ganglia of mouse and human and to spinal neurons in the dorsal horn of the mouse spinal cord by RNAScope®. When injected intrathecally to mice, Dnm and AAK1 siRNA or shRNA knocked-down Dnm and AAK1 mRNA in dorsal root ganglia neurons, reversed mechanical and thermal allodynia and hyperalgesia, and normalized non-evoked behavior in preclinical models of inflammatory and neuropathic pain. Intrathecally administered inhibiters of clathrin, Dnm and AAK1 also reversed allodynia and hyperalgesia. Disruption of clathrin, Dnm and AAK1 did not affect normal motor functions of behaviors. Patch clamp recordings of dorsal horn neurons revealed that Dnm1 and AAK1 disruption inhibited synaptic transmission between primary sensory neurons and neurons in lamina I/II of the spinal cord dorsal horn by suppressing release of synaptic vesicles from presynaptic primary afferent neurons. Patch clamp recordings from dorsal root ganglion nociceptors indicated that Dnm siRNA prevented sustained GPCR-mediated sensitization of nociceptors. By disrupting synaptic transmission in the spinal cord and blunting sensitization of nociceptors, endocytosis inhibitors offer a therapeutic approach for pain treatment.

IMPORTANCE:The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). OBJECTIVE:To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC. DESIGN, SETTING, AND PARTICIPANTS:This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement. INTERVENTIONS:Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m2) and RT (69.96 Gy) followed by 3 cycles of adjuvant bevacizumab (15 mg/kg) given concurrently with cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/d). MAIN OUTCOMES AND MEASURES:The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression-free (LRPF) interval, distant metastasis-free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation. RESULTS:Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%). CONCLUSIONS AND RELEVANCE:In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00408694.

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.

Balance and movement are impaired in many neurological disorders. Recent advances in behavioral monitoring provide unprecedented access to posture and locomotor kinematics but without the throughput and scalability necessary to screen candidate genes/potential therapeutics. Here, we present a scalable apparatus to measure posture and locomotion (SAMPL). SAMPL includes extensible hardware and open-source software with real-time processing and can acquire data from D. melanogaster, C. elegans, and D. rerio as they move vertically. Using SAMPL, we define how zebrafish balance as they navigate vertically and discover small but systematic variations among kinematic parameters between genetic backgrounds. We demonstrate SAMPL's ability to resolve differences in posture and navigation as a function of effect size and data gathered, providing key data for screens. SAMPL is therefore both a tool to model balance and locomotor disorders and an exemplar of how to scale apparatus to support screens.

BACKGROUND/OBJECTIVES/OBJECTIVE:Base of tongue (BOT) dysfunction is common following oropharyngeal concurrent chemoradiation therapy (CCRT). We present a clinically relevant animal model quantifying the effects of CCRT on tongue strength and elasticity over time. METHODS:Fifty-three male and 53 female Sprague-Dawley rats were randomized to control or experimental groups. Experimental animals received cisplatin, 5-fluorouracil, and 5 fractions of 7 Gy directed to the BOT. Controls received no intervention. At 2 weeks, 5 months, or 10 months after CCRT, animals underwent non-survival surgery to measure twitch and tetanic tongue strength, which were analyzed using multivariate linear mixed effects models. Tongue displacement, a surrogate for tongue elasticity, was also determined via stress-strain testing and analyzed via a multivariate linear mixed effects model. RESULTS:Reporting the combined results of both sexes, the estimated experimental group mean peak twitch forces became more divergent over time compared to controls, being 8.3% lower than controls at 2 weeks post-CCRT, 15.7% lower at 5 months, and 31.6% lower at 10 months. Estimated experimental group mean peak tetanic forces followed a similar course and were 2.9% lower than controls at 2 weeks post CCRT, 20.7% lower at 5 months, and 27.0% lower at 10 months. Stress-strain testing did not find CCRT to have a significant effect on tongue displacement across experimental timepoints. CONCLUSIONS:This study demonstrates an increasing difference in tongue strength over time between controls and animals exposed to CCRT. Tongue elasticity was not significantly affected by CCRT, suggesting that changes in strength may not be caused by fibrosis. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2022.

Systemic symptoms resulting from exposure to members of the Lepidoptera order, such as moths, butterflies, and caterpillars, are known as lepidopterism. Most cases of lepidopterism are mild and result from dermal exposure to urticating hairs; ingestion is less common and generally more medically significant because the hairs may get embedded in the patient's mouth, hypopharynx, or esophagus, leading to dysphagia, drooling, edema, and possible airway obstruction. In previous cases of symptomatic caterpillar ingestion reported in the literature, extensive efforts, including direct laryngoscopy, esophagoscopy, and bronchoscopy, were undertaken to remove these hairs. We review the case of a 19-mo-old previously healthy male infant who presented to the emergency department with vomiting and inconsolability after ingesting half of a woolly bear caterpillar (Pyrrharctia isabella). His initial examination was notable for embedded hairs in his lips, oral mucosa, and right tonsillar pillar. The patient underwent a bedside flexible laryngoscopy, which revealed a single hair embedded in the epiglottis, without significant edema. He was stable from a respiratory standpoint and, thus, was admitted for observation and IV dexamethasone without any attempt to remove the hairs. He was discharged in good condition after 48 h; at a follow-up visit 1 wk later, no remaining hairs were visible. This case demonstrates that lepidopterism secondary to caterpillar ingestion is amenable to conservative management and does not require routine removal of urticating hairs in patients who do not show signs of airway distress.

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.