Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer (TC). We evaluated the efficacy of everolimus in aggressive, radioactive iodine refractory (RAIR) TC and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic TC cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009-2013 in patients with incurable RAIR TC who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated TC (DTC), 10 with medullary TC (MTC), and 7 with anaplastic TC (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months post study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt mutated ATC subgroups appeared to benefit from everolimus. Treatmentrelated adverse events were as anticipated. Conclusion:Everolimus has significant anti-tumor activity in TC. While genomic profiling does not currently guide therapeutic selection in TC patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine.

Objectives Pediatric eustachian tube dysfunction (ETD), otitis media with effusion (OME), and tympanic membrane retraction (TMR) have been well studied, but no large analyses have described the associated burden beyond childhood. The potential impact and feasibility of prospective trials designed to optimize management of affected adults are thus unclear. Our objectives were therefore (1) to determine the national visit burden associated with ETD/OME/TMR beyond childhood and (2) to examine risk factors specific to adults, highlighting differences in comparison with children. Study Design Cross-sectional analysis of a national database. Setting Ambulatory visits in the United States. Methods Epidemiologic analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (2005-2012) included data from 761,291 observations representing 9,369,388,092 visits. Chi-square test with Bonferroni adjustment for multiple comparisons was utilized for hypothesis testing. Results Visits related to ETD/OME/TMR exceeded 2 million per annum in patients 0 to 20 years of age (mean 2,625,965; range 2,239,288-3,329,858). Among those >20 years old, visits also exceeded 2 million (mean, 2,025,050; range, 1,550,669-2,353,799). Characteristics differed according to age: whereas ETD/OME/TMR affected more males <20 years, females were more frequently diagnosed in the older age group ( P < .0001). Patients >20 to 40 years of age were the most likely to visit the emergency department ( P = .0022). There were no statistically significant differences per season or region. The related diagnoses of cholesteatoma and chronic otitis media prompted additional visits. Conclusions ETD/OME/TMR is associated with a visit burden for adults that extends beyond childhood. Among adults, there may also be age-related differences in patient characteristics.

Purpose: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes.Experimental Design: Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes.Results: PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n ¼ 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P ¼ 0.0006). Oncogenic RAS mutations (n ¼ 13) were associated with significantly poorer progression-free survival (P ¼ 0.0001) and lower overall survival (P ¼ 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response.Conclusions: Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort.

BackgroundIdentification of a microRNA (miRNA) pattern to be used as a biomarker for HNSCC is challenging given the heterogeneity of the disease and different methodologies used. To better define the field, we performed a prospective analysis of blood, tumor, and paired benign tissues in tongue squamous cell carcinoma (SCC) patients.MethodsPlasma samples were collected prior to surgery, and paired tumor and benign tissue blocks were collected from tongue cancer resections. Circulating free and exosomal miRNA, and paired tumor and benign tissues miRNA were analyzed. TaqMan-based miRNA arrays were used to quantitate the expression of 747 human miRNAs. The comparative Ct method assessed the miRNA profile results, and Student’s t-test determined statistical significance between tumor and benign samples.ResultsSixteen of 359 miRNAs detected were differentially expressed between paired tumor and benign tissue. Nine were upregulated, and seven downregulated in tumor tissue. All nine upregulated and six of seven downregulated tumor miRNAs were expressed in circulating exosomes. In contrast, eight of nine upregulated and four of seven downregulated tumor miRNAs were circulating free in the plasma.ConclusionAn aberrantly expressed pattern of miRNA was identified in both tumor and plasma of patients with tongue SCC, suggesting this may be a biomarker for SCC of the oral tongue. Circulating exosomes appear to be a more reliable method for evaluation of circulating tumor-miRNA expression. Further studies with a larger cohort of patients and serial blood samples are needed to validate our findings.