Faculty Bibliography

OBJECTIVES:Adjuvant radiation therapy (RT) is indicated for patients with salivary gland malignancies with risk factors for recurrence following resection. We analyzed patients treated with adjuvant RT with or without concurrent chemotherapy to determine the impact of prognostic and treatment factors. MATERIALS AND METHODS:Retrospective analysis was performed of 128 patients treated with surgical resection followed by intensity-modulated radiotherapy. In total, 31 (24.2%) patients were treated with concurrent chemoradiotherapy. The Kaplan-Meier method was used to estimate rates of progression-free survival (PFS), local-regional control, distant control, overall survival. Multivariable Cox regression was performed to evaluate factors significant on univariate analysis. RESULTS:The 5-year rates of PFS, local-regional control, freedom-from distant metastasis, and overall survival were 61.2%, 85.8%, 76.5%, and 73.7%, respectively. Predictors of decreased PFS on univariate analyses were age, tumor stage, nodal stage, positive surgical margins, histology, high grade, perineural invasion, lymphovascular space invasion, extranodal extension, and use of chemoradiotherapy. On multivariable analysis, elevated T-stage, positive surgical margins, and presence of extranodal extension were predictive of decreased PFS. The acute toxicity rates were 30.3% grade 1, 51.5% grade 2, 11.4% grade 3, and 0.8% grade 4. There was no difference in rates of grade 3 or higher acute toxicity with use of RT alone versus chemoradiotherapy (P=0.183). CONCLUSIONS:Use of chemoradiotherapy for adjuvant treatment of salivary gland malignancies was well-tolerated, but no improvement in survival was seen with the use of chemoradiotherapy in both the overall study population and a subset with high-risk features. Caution should be used when using this modality until randomized evidence becomes available.

Context modulates the brain's response to sensory input. Recent work has identified the neurons that implement contextual gating of a startle behavior in zebrafish and suggests a synaptic mechanism for this modulation.

Head and neck squamous cell carcinoma (HNSCC) is associated with low survival, and the current aggressive therapies result in high morbidity. Nutraceuticals are dietary compounds with few side effects. However, limited antitumor efficacy has restricted their application for cancer therapy. Here, we examine combining nutraceuticals, establishing a combination therapy that is more potent than any singular component, and delineate the mechanism of action. Three formulations were tested: GZ17-S (combined plant extracts from Arum palaestinum, Peganum harmala and Curcuma longa); GZ17-05.00 (16 synthetic components of GZ17-S); and GZ17-6.02 (3 synthetic components of GZ17S; curcumin, harmine and isovanillin). We tested the formulations on HNSCC proliferation, migration, invasion, angiogenesis, macrophage viability and infiltration into the tumor and tumor apoptosis. GZ17-6.02, the most effective formulation, significantly reduced in vitro assessments of HNSCC progression. When combined with cisplatin, GZ17-6.02 enhanced anti-proliferative effects. Molecular signaling cascades inhibited by GZ17-6.02 include EGFR, ERK1/2, and AKT, and molecular docking analyses demonstrate GZ17-6.02 components bind at distinct binding sites. GZ17-6.02 significantly inhibited growth of HNSCC cell line, patient-derived xenografts, and murine syngeneic tumors in vivo (P < 0.001). We demonstrate GZ17-6.02 as a highly effective plant extract combination and pave the way for future clinical application in HNSCC.

The molecular foundations of Hürthle cell carcinoma (HCC) are poorly understood. Here we describe a comprehensive genomic characterization of 56 primary HCC tumors that span the spectrum of tumor behavior. We elucidate the mutational profile and driver mutations and show that these tumors exhibit a wide range of recurrent mutations. Notably, we report a high number of disruptive mutations to both protein-coding and tRNA-encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole-chromosomal duplications of chromosomes 5 and 7 and widespread loss of heterozygosity arising from haploidization and copy-number-neutral uniparental disomy. We also identify fusion genes and disrupted signaling pathways that may drive disease pathogenesis.

OBJECTIVE:To demonstrate the long-term benefits of implantation in patients with high-frequency sensorineural hearing loss, this report provides 5-year follow-up on a group of implant recipients who were subjects of the Cochlear™ Nucleus® Hybrid™ L24 Implant System pivotal clinical study. METHODS:The results of three related clinical studies were compiled to provide outcome data after 1, 3, and 5 years of implant use in a group of subjects who presented with preoperative high-frequency hearing loss and were implanted with a Nucleus Hybrid L24 (Cochlear Ltd., Sydney, Australia) cochlear implant. A subset of the 50 adult subjects (N = 32) who participated in the Hybrid L24 pivotal Investigational Device Exemption (IDE) completed comprehensive evaluations at 12 months postactivation, 3 years postactivation, and then as part of a postapproval study at 5 years postactivation. Testing included audiometric, speech perception, and subjective satisfaction measures. RESULTS:Mean unilateral speech perception performance was significantly improved at all postoperative intervals compared to preoperative best-aided results and has remained stable to 5 years postactivation. Ninety-four percent of subjects had measurable hearing, and 72% continued to use electric-acoustic stimulation in the implanted ear after 5 years of implant use. Subjective satisfaction results support objective performance improvements. CONCLUSION/CONCLUSIONS:Results demonstrate long-term success of patients with high-frequency hearing loss following Hybrid L24 (Cochlear) cochlear implantation. Benefits include speech perception abilities significantly better than those in the preoperative best-aided condition, with additional benefit in those using electric-acoustic stimulation in the implanted ear. LEVEL OF EVIDENCE/METHODS:2b. Laryngoscope, 2018.

BACKGROUND:Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS:We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS:Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS:Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

We conducted a retrospective chart review of 27 patients-7 men and 20 women, aged 47 to 94 years (mean: 71.3)-with symptomatic epiphora secondary to dacryostenosis who had undergone thulium: YAG (Tm:YAG) laser dacryocystorhinostomy (DCR). Among them, dacryostenosis had been documented in 35 eyes by dacryocystography. The Tm:YAG procedure involved the administration of local anesthesia, after which a 600-μm laser fiber was inserted into the lacrimal canaliculi and then into the nasolacrimal duct. Under endoscopic visualization, the DCR was performed anterior and inferior to the middle turbinate, which created an opening. Silicone stents were then inserted and tied intranasally. In the immediate postoperative period, all 27 patients noted initial improvement. During a follow-up of 22 days to 25 months (mean: 11.3 mo), 24 of the 27 patients (89%) remained symptom-free, while the remaining 3 patients (11%) experienced a treatment failure and required revision surgery. To the best of our knowledge, only two articles on thulium laser therapy for DCR have been previously published, both approximately 25 years ago; both involved the use of a thulium along with holmium and chromium in cadavers. As far as we know, our case series is the largest in the English-language literature that has documented the use of the thulium in laser therapy for DCR, and it is the only in vivo study. We found that DCR with the Tm:YAG laser was an effective and affordable option for patients with symptomatic epiphora secondary to lacrimal obstruction.

PURPOSE/OBJECTIVE:Recent advances in sodium brain MRI have allowed for increased signal-to-noise ratio, faster imaging, and the ability of differentiating intracellular from extracellular sodium concentration, opening a new window of opportunity for clinical application. In gliomas, there are significant alterations in sodium metabolism, including increase in the total sodium concentration and extracellular volume fraction. The purpose of this study is to assess the feasibility of using sodium MRI quantitative measurements to evaluate gliomas. METHODS:), apparent intracellular sodium concentration (aISC), and apparent total sodium concentration (aTSC). Measurements were made within the contralateral normal-appearing putamen, contralateral normal-appearing white matter (NAWM), and solid tumor regions (area of T2-FLAIR abnormality, excluding highly likely areas of edema, cysts, or necrosis). Paired samples t test were performed comparing NAWM and putamen and between NAWM and solid tumor. RESULTS:(p = 0.19). CONCLUSION/CONCLUSIONS:Quantitative sodium measurements can be done in glioma patients and also has provided further evidence that total sodium and extracellular volume fraction are increased in gliomas.