Faculty Bibliography

BACKGROUND:Human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPV-negative head and neck cancers (HNCs). METHODS:We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs. RESULTS:KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations. CONCLUSION:Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments. FUNDING:This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.

Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.

Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted hepatocyte growth factor (HGF) facilitates HNSCC progression, however very little is known about the role of CAFs in HNSCC metabolism. Here we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic fibroblast growth factor (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation (OXPHOS) and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (p<0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR.

Purpose:This experiment sought to determine whether children's increased susceptibility to nonsimultaneous masking, particularly backward masking, is evident for speech stimuli. Method:Five- to 9-year-olds and adults with normal hearing heard nonsense consonant-vowel-consonant targets. In Experiments 1 and 2, those targets were presented between two 250-ms segments of 70-dB-SPL speech-shaped noise, at either -30 dB signal-to-noise ratio (Experiment 1) or at the listener's word recognition threshold (Experiment 2). In Experiment 3, the target was presented in steady speech-shaped noise at listener threshold. For all experiments, percent correct was estimated for initial and final consonants. Results:In the nonsimultaneous noise conditions, child-adult differences were larger for the final consonant than the initial consonant whether listeners were tested at -30 dB signal-to-noise ratio (Experiment 1) or at their individual word recognition threshold (Experiment 2). Children were not particularly susceptible to backward masking relative to adults when tested in a steady masker (Experiment 3). Conclusions:Child-adult differences were greater for backward than forward masking for speech in a nonsimultaneous noise masker, as observed in previous psychophysical studies using tonal stimuli. Children's greater susceptibility to nonsimultaneous masking, and backward masking in particular, could play a role in their limited ability to benefit from masker envelope modulation when recognizing masked speech.

Purpose/UNASSIGNED:It has been widely reported that a proportion of healthy, community-dwelling seniors will develop dysphagia in the absence of a known neurological, neuromuscular, or structural cause. Our objective was to test whether various feasible, noninvasive measures of swallowing could differentiate safe versus unsafe and efficient versus inefficient swallowing on videofluoroscopy (VF) in a sample of healthy seniors. Method/UNASSIGNED:VFs from 44 (21 male, 23 female) healthy community-dwelling seniors (> 65 years old) were compared with a series of feasible, noninvasive swallowing metrics: maximal tongue strength (anterior and posterior), hand grip strength, pharyngeal volume, age, body mass index, 3-oz water swallow challenge, the 10-item Eating Assessment Tool questionnaire, and the Frailty Index. The VF protocol included 9 liquid barium boluses (3 × 5 ml thin, 3 × 20 ml thin, and 3 × 5 ml nectar). Each swallow was rated (randomized and blind) for safety using the Penetration-Aspiration Scale score and for efficiency using the Normalized Residue Ratio Scale (NRRS). Participants were deemed "unsafe" if they had any single Penetration-Aspiration Scale scores ≥ 3 and "inefficient" if they had any NRRS valleculae score > 0.082 or NRRS pyriform sinus score > 0.067. Univariate analyses of variance were run for each continuous swallowing measure by swallowing safety and swallowing efficiency status. Pearson's chi-square analyses were used to compare binary outcomes by swallow safety and efficiency status. Bonferroni corrections were applied to control for multiple comparisons. Results/UNASSIGNED:None of the swallowing measures significantly differentiated safe from unsafe swallows. Although several variables trended to distinguishing efficient from inefficient swallows (age, 10-item Eating Assessment Tool, 3-oz water swallow challenge), only one variable, pharyngeal volume, was significantly different between efficient and inefficient swallows (p = .002). Conclusion/UNASSIGNED:Our findings support the notion that larger pharyngeal volumes (measured using acoustic pharyngometry) are associated with worse swallowing efficiency, a finding we attribute to atrophy of the pharyngeal musculature in healthy aging.

OBJECTIVE:To assess changes in the practice patterns of urologists performing male infertility procedures (vasal reconstruction, sperm retrieval, varicocelectomy) from 2004 to 2015 in the United States. DESIGN/METHODS:Examination of self-reported procedural volumes from urologists undergoing certification and recertification using case log data provided by the American Board of Urology. The study period was stratified into early (2004-2007) and recent (2012-2015) time periods. SETTING/METHODS:Not applicable. PATIENT(S)/METHODS:None. INTERVENTION(S)/METHODS:None. MAIN OUTCOMES MEASURE(S)/METHODS:Temporal variations in male infertility practice patterns among different urologic subspecialties between the early and recent time periods. RESULT(S)/RESULTS:The overall proportion of total male infertility procedures performed by andrologists significantly increased between the early and recent groups (23% to 26%). This growth was driven by a significant increase in the proportion of varicocele repairs being performed by andrologists between the early and recent periods (19% to 25%). Most notably, an assessment of total number of male infertility procedures performed by newly certifying urologists showed that there was a significant increase in the overall proportion of all male infertility procedures being performed by recently trained andrologists (24% to 35%). This significant increase was seen individually among all three types of male infertility procedures. CONCLUSION(S)/CONCLUSIONS:With the increased trend in urologists obtaining fellowship training, male infertility surgical volume is beginning to shift from general urologists to subspecialized andrologists.

Singing behavior in the adult male zebra finch is dependent upon the activity of a cortical region known as HVC (proper name). The vast majority of HVC projection neurons send primary axons to either the downstream premotor nucleus RA (primary motor cortex) or Area X (basal ganglia), which play important roles in song production or song learning, respectively. In addition to these long-range outputs, HVC neurons also send local axon collaterals throughout that nucleus. Despite their implications for a range of circuit models, these local processes have never been completely reconstructed. Here we use in vivo single-neuron Neurobiotin fills to examine 40 projection neurons across 31 birds with somatic positions distributed across HVC. We show that HVC_(RA)and HVC_(X)neurons have categorically distinct dendritic fields. Additionally, these cell classes send axon collaterals that are either restricted to a small portion of HVC ("local neurons") or broadly distributed throughout the entire nucleus ("broadcast neurons"). Overall, these processes within HVC offer a structural basis for significant local processing underlying behaviorally-relevant population activity.

The overall goal of this study was to identify an objective physiological correlate of electric-acoustic pitch matching in unilaterally implanted cochlear implant (CI) participants with residual hearing in the non-implanted ear. Electrical and acoustic stimuli were presented in a continuously alternating fashion across ears. The acoustic stimulus and the electrical stimulus were either matched or mismatched in pitch. Auditory evoked potentials were obtained from nine CI users. Results indicated that N1 latency was stimulus-dependent, decreasing when the acoustic frequency of the tone presented to the non-implanted ear was increased. More importantly, there was an additional decrease in N1 latency in the pitch-matched condition. These results indicate the potential utility of N1 latency as an index of pitch matching in CI users.

A population of appropriately selected patients does not respond, or does not achieve cure, with hypoglossal nerve stimulation (HGNS). We describe the case of nonresponder whose obstructive sleep apnea (OSA) resolved with the addition of chin strap. After initial placement and titration of HGNS implant, follow-up sleep study demonstrated persistent moderate OSA. Drug-induced sleep endoscopy demonstrated supraglottic collapse with activate neurostimulation. With mouth closure and change of stimulation settings to unipolar from bipolar, the airway collapse and desaturations improved. The follow-up polysomnogram with (HGNS) therapy and chin strap demonstrated resolution of sleep apnea. Laryngoscope, 2017.