Faculty Bibliography

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.

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.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To assess patterns of care and outcomes with the use of neoadjuvant chemotherapy followed by definitive radiation in local-regionally advanced nasopharyngeal carcinoma. STUDY DESIGN/METHODS:Retrospective database analysis. METHODS:We queried the National Cancer Database for patients with T3-4N2 or T1-4N3 nasopharyngeal carcinoma who received concurrent chemoradiotherapy or neoadjuvant chemotherapy followed by radiation. Overall survival (OS) was analyzed using the Kaplan-Meier method, propensity-score matching, and a Cox proportional hazards model adjusting for demographic and disease-specific prognostic factors. RESULTS:P = .001). At a median follow-up of 36.6 months, patients had 3-year OS of 66% in the neoadjuvant group compared with 70% in those who received concurrent chemoradiotherapy (log rank P = .29). On subgroup analysis by histology, T stage, and N stage, there remained no differences in OS between the two groups. On multivariable analysis, there was no significant survival difference associated with neoadjuvant chemotherapy (adjusted hazard ratio [HR]: 1.05, 95% confidence interval [CI]: 0.89-1.25, P = .54). In a propensity score-matched population of 1,008 patients (504 with neoadjuvant therapy and 504 without), there was no significant survival difference associated with neoadjuvant chemotherapy (H: 1.13, 95% CI: 0.93-1.38, P = .22). CONCLUSIONS:Neoadjuvant chemotherapy was used in over 25% of patients, and its use is increasing. However, neoadjuvant chemotherapy was not associated with any differences in survival compared to concurrent chemoradiotherapy. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2018.

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.

IMPORTANCE/OBJECTIVE:The American Joint Committee on Cancer, 8th edition (AJCC-8) contains a new staging system for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). Our study aim was to evaluate the effectiveness of the AJCC-8 relative to the AJCC 7th edition (AJCC-7). MATERIALS AND METHODS/METHODS:A retrospective chart review was performed on a multi-institutional, prospectively collected dataset from two tertiary referral centers. All patients had HPV+ OPSCC treated primarily with surgery. The prognostic value of AJCC-7 and AJCC-8 were compared for 5-year overall survival (OS) and disease-specific survival (DFS). RESULTS:AJCC-8 pathological staging effectively risk stratified patients, creating a Cox model with a better fit (lower Akaike's Information Criterion, p < 0.0001) when compared to AJCC-7 pathological stages for both OS and DFS. The AJCC-8 pathologic staging did not produce a better fit than the AJCC-8 clinical staging (p = 0.15) for OS, however, AJCC-8 pathologic was more effective than AJCC-8 clinical for DFS (p < 0.0001). 76% of patients did not change their stage between clinical and pathologic AJCC-8 staging; 14% were upstaged by 1, <1% were upstaged by 2, 7% were downstaged by 1, and 3% downstaged by 2. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:The new AJCC-8 staging system represents a significant improvement over AJCC-7 for risk stratification into groups that predict overall survival and disease-specific survival of surgically treated HPV+ OPSCC patients. The AJCC- 8 pathologic staging system was not significantly better than the AJCC-8 clinical staging system for overall survival, however, the pathologic staging system was better than the clinical for disease free survival.

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.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

Objective/UNASSIGNED:To access the long-term outcomes of children implanted during most sensitive period for language development. Study design/UNASSIGNED:Literature review. Method/UNASSIGNED:An initial PubMed search was carried out using the search terms language development and cochlear implant resulted in 1149 citations. A second search was carried out on the initial citations using the criterion of implantation in the period of birth to 24 months, which identified 386 articles. These were analyzed to determine those studies in which linguistic outcome was measured at least three or more years following implantation. Results/UNASSIGNED:Twenty-one reports published from 2004 to 2017 that met the criteria. The range of follow-up was from 3 years to an excess of 10 years. Four => 10-year follow-up reports were consistent in showing that the earlier the subject is implanted the better the outcome. Many, but not all, of these children did obtain age-appropriate language. There were 17 reports with follow-up from 3 to less than 10 years. In 7 of the 11 studies, the children's expressive language was reported to have reached an age level of less than 80%. The results for receptive language showed that 4 of the 11 studies found that the children achieved a receptive language age level of less than 80%. There were 8 studies which documented the effect of implantation before 12 months of age and between 12 and 24 months of age and they all found that the earlier the implantation, the better the outcome for language. Conclusion/UNASSIGNED:The cochlear implant is efficacious in the amelioration of receptive and expressive language deficits in most congenitally deafened children implanted before the age of one. The language outcomes for those implanted after the age of one decline as the age of implantation increases. Level of Evidence/UNASSIGNED:N/A.