Faculty Bibliography

OBJECTIVE: To determine (1) whether academic otolaryngologists who have received an American Academy of Otolaryngology- Head and Neck Surgery Foundation (AAO-HNSF) Centralized Otolaryngology Research Efforts (CORE) grant are more likely to procure future National Institutes of Health (NIH) funding; (2) whether CORE grants or NIH Career Development (K) awards have a stronger association with scholarly impact. STUDY DESIGN AND SETTING: Historical cohort. METHODS: Scholarly impact, as measured by the h-index, publication experience, and prior grant history, were determined for CORE-funded and non-CORE-funded academic otolaryngologists. All individuals were assessed for NIH funding history. RESULTS: Of 192 academic otolaryngologists with a CORE funding history, 39.6% had active or prior NIH awards versus 15.1% of 1002 non-CORE-funded faculty (P < .0001). Higher proportions of CORE-funded otolaryngologists have received K-series and R-series grants from the NIH (P-values < .05). K-grant recipients had higher h-indices than CORE recipients (12.6 vs 7.1, P < .01). Upon controlling for rank and experience, this difference remained significant among junior faculty. CONCLUSIONS: A higher proportion of academic otolaryngologists with prior AAO-HNSF CORE funding have received NIH funding relative to their non-CORE-funded peers, suggesting that the CORE program may be successful in its stated goals of preparing individuals for the NIH peer review process, although further prospective study is needed to evaluate a "cause and effect" relationship. Individuals with current or prior NIH K-grants had greater research productivity than those with CORE funding history. Both cohorts had higher scholarly impact values than previously published figures among academic otolaryngologists, highlighting that both CORE grants and NIH K-grants awards are effective career development resources.

The present study aimed to characterize the mechanical response of beagle sartorius muscle fibers under strain rates that increase logarithmically (0.1mm/min, 1mm/min and 10mm/min), and provide an analysis of the fracture patterns of these tissues via scanning electron microscopy (SEM). Muscle tissue from dogs' sartorius was excised and test specimens were sectioned with a lancet into sections with nominal length, width, and thickness of 7, 2.5 and 0.6mm, respectively. Trimming of the tissue was done so that the loading would be parallel to the direction of the muscle fiber. Samples were immediately tested following excision and failures were observed under the SEM. No statistically significant difference was observed in strength between the 0.1mm/min (2.560+/-0.37MPa) and the 1mm/min (2.702+/-0.55MPa) groups. However, the 10mm/min group (1.545+/-0.50MPa) had a statistically significant lower strength than both the 1mm/min group and the 0.1mm/min group with p<0.01 in both cases. At the 0.1mm/min rate the primary fracture mechanism was that of a shear mode failure of the endomysium with a significant relative motion between fibers. At 1mm/min this continues to be the predominant failure mode. At the 10mm/min strain rate there is a significant change in the fracture pattern relative to other strain rates, where little to no evidence of endomysial shear failure nor of significant motion between fibers was detected.

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

AIM: Metastasis of unknown primary (MUP) is commonly treated with radiation therapy (RT) to the entire mucosal surfaces and bilateral neck nodes (LN). We report outcomes of oropharynx-targeted RT, retropharyngeal nodes (RPN) and bilateral LN in this context. PATIENTS AND METHODS: Single-Institution retrospective study of 68 patients. Forty percent were treated with intensity-modulated radiation therapy (IMRT). Fifty-six percent received concurrent chemoradiotherapy (CCRT). The median age was 58 years, 82% were Caucasian, and 75% males. Stage III disease was present in 9%, stage IVA in 75% and IVB in 16%. RESULTS: At a median follow-up of 3.5 years, the actuarial locoregional control was 95.5%. The emergence of primary developed in 1patient (1.5%) and 2patients (3%) failed in the neck. The median time-to-locoregional failure (LRF) was 18 months. Actuarial long-term RT toxicity was grade 1 xerostomia (68%), dysphagia (35%), neck stiffness (15%) and trismus (6%). CONCLUSION: RT to the oropharynx, RPN, and bilateral neck provides excellent oncological and functional outcomes in MUP in non-Asian patients. Sparing the mucosal surfaces of the nasopharynx, hypopharynx, and larynx seems reasonable without impacting on survival and locoregional control.

BACKGROUND: Activation of the RAS-RAF-MEK-ERK signaling pathway is thought to be the key driver of pediatric low-grade astrocytoma (PLGA) growth. Sorafenib is a multikinase inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This multicenter phase II study was conducted to determine the response rate to sorafenib in patients with recurrent or progressive PLGA. METHODS: Key eligibility criteria included age >/=2 years, progressive PLGA evaluable on MRI, and at least one prior chemotherapy treatment. Sorafenib was administered twice daily at 200 mg/m2/dose (maximum of 400 mg/dose) in continuous 28-day cycles. MRI, including 3-dimensional volumetric tumor analysis, was performed every 12 weeks. BRAF molecular testing was performed on tumor tissue when available. RESULTS: Eleven patients, including 3 with neurofibromatosis type 1 (NF1), were evaluable for response; 5 tested positive for BRAF duplication. Nine patients (82%) came off trial due to radiological tumor progression after 2 or 3 cycles, including 3 patients with confirmed BRAF duplication. Median time to progression was 2.8 months (95% CI, 2.1-31.0 months). Enrollment was terminated early due to this rapid and unexpectedly high progression rate. Tumor tissue obtained from 4 patients after termination of the study showed viable pilocytic or pilomyxoid astrocytoma. CONCLUSIONS: Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to paradoxical ERK activation. Close monitoring for early tumor progression should be included in trials of novel agents that modulate signal transduction.

PURPOSE: Resection of the posterior mandible for tumor or osteonecrosis may include the mandibular condyle, an integral part of the temporomandibular joint (TMJ). Condylar reconstruction, including use of prostheses, the native condylar head, or part of the fibula, all have associated drawbacks including skull base erosion and the potential for ankylosis and TMJ dysfunction as well as the increased difficulty associated with trying to recapitulate the TMJ with high fidelity. We report our experience leaving a single side of the reconstructed mandible unsecured to the glenoid fossa, allowing the mandible to "hang." We hypothesized that a good functional recovery may be achieved with this simple approach while avoiding the potential for ankylosis and TMJ dysfunction. METHODS: A retrospective chart review of all patients undergoing free fibula reconstruction of the mandible with condylar removal was performed. Outcomes were determined by maximum interincisal opening, occlusion, and diet after full recovery. RESULTS: Six patients were studied. Two had condylar reconstruction with a contoured fibular head secured to the glenoid fossa. One of them had progressive postoperative trismus and ankylosis. One patient was reconstructed with the native condyle rigidly fixed to the fibula flap, complicated by avascular necrosis requiring condylar resection, with good function afterward. Three patients were left to "hang." All 3 had either normal or improved function after surgery. Two had slight ipsilateral deviation on mouth opening. CONCLUSIONS: Function can reliably be reestablished after segmental mandibulectomy and condylectomy with a vascularized fibula flap whose distal end is not precisely contoured or actively seated in the glenoid fossa, as a valid alternative to condylar reconstruction.

OBJECTIVE: To quantify the incidence of postoperative voice, swallowing, and other problems, including time to resolution following anterior transcervical approaches to the cervical spine, and to assess surgical factors associated with outcomes. STUDY DESIGN: Historical cohort study. SETTING: Academic medical center. SUBJECTS AND METHODS: One hundred eighty-eight consecutive patients with cervical spine disease who underwent an anterior transcervical approach to the spine by a single head and neck surgeon over a 4-year time period. Rather than primary, single-level approaches, all patients in this study had multilevel, high-cervical (above C4), low-cervical (below C6), and/or revision approaches. Postoperative voice, swallowing, and other complaints were measured as well as time to resolution using Kaplan-Meier method. Surgical factors related to outcomes were analyzed using regression analysis. RESULTS: Follow-up was available for 129 patients, with average and median time of 35 months. Seventy-seven patients (60%) had a postoperative issue, including 35 patients (27%) with postoperative voice complaint, 62 patients (48%) with postoperative swallowing complaint, and 16 patients (12%) with other problems. Swallowing and voice complaints persisted beyond 1 year in 28% and 9% of patients, respectively. Approaching spinal levels above C4 and exposing more than 3 spinal levels were 2 factors significantly related to voice and swallowing problems. CONCLUSION: There is a high incidence of subjective voice and swallowing complaints following transcervical anterior approaches to the spine, and such complaints can persist beyond 1 year in many patients. Exposure of more than 3 spinal levels or above level C4 are 2 factors significantly associated with outcome.

BACKGROUND: A large amount of interindividual variability exists in the occurrence of symptoms in patients receiving chemotherapy (CTX). The purposes of the current study, which was performed in a sample of 582 oncology outpatients who were receiving CTX, were to identify subgroups of patients based on their distinct experiences with 25 commonly occurring symptoms and to identify demographic and clinical characteristics associated with subgroup membership. In addition, differences in quality of life outcomes were evaluated. METHODS: Oncology outpatients with breast, gastrointestinal, gynecological, or lung cancer completed the Memorial Symptom Assessment Scale before their next cycle of CTX. Latent class analysis was used to identify subgroups of patients with distinct symptom experiences. RESULTS: Three distinct subgroups of patients were identified (ie, 36.1% in Low class; 50.0% in Moderate class, and 13.9% in All High class). Patients in the All High class were significantly younger and more likely to be female and nonwhite, and had lower levels of social support, lower socioeconomic status, poorer functional status, and a higher level of comorbidity. CONCLUSIONS: Findings from the current study support the clinical observation that some oncology patients experience a differentially higher symptom burden during CTX. These high-risk patients experience significant decrements in quality of life. Cancer 2014. (c) 2014 American Cancer Society.

Sensory experience during early development can shape the central nervous system and this is thought to influence adult perceptual skills. In the auditory system, early induction of conductive hearing loss (CHL) leads to deficits in central auditory coding properties in adult animals, and this is accompanied by diminished perceptual thresholds. In contrast, a brief regimen of auditory training during development can enhance the perceptual skills of animals when tested in adulthood. Here, we asked whether a brief period of training during development could compensate for the perceptual deficits displayed by adult animals reared with CHL. Juvenile gerbils with CHL, and age-matched controls, were trained on a frequency modulation (FM) detection task for 4 or 10 days. The performance of each group was subsequently assessed in adulthood, and compared to adults with normal hearing (NH) or adults raised with CHL that did not receive juvenile training. We show that as juveniles, both CHL and NH animals display similar FM detection thresholds that are not immediately impacted by the perceptual training. However, as adults, detection thresholds and psychometric function slopes of these animals were significantly improved. Importantly, CHL adults with juvenile training displayed thresholds that approached NH adults. Additionally, we found that hearing impaired animals trained for 10 days displayed adult thresholds closer to untrained adults than those trained for 4 days. Thus, a relatively brief period of auditory training may compensate for the deleterious impact of hearing deprivation on auditory perception on the trained task.