Faculty Bibliography

Importance/UNASSIGNED:Human papillomavirus (HPV) vaccination is recommended for children and younger adults but not older adults or those with prior HPV exposure, leaving a large portion of the population at risk for HPV-mediated disease. Emerging data suggest a possible role for vaccination as an adjuvant treatment for individuals with HPV-related clinical disease. Objective/UNASSIGNED:To systematically review the literature regarding HPV vaccination for secondary disease prevention after treatment of active clinical disease across disease sites to serve as a platform for the management of HPV-related disease of the head and neck. Evidence Review/UNASSIGNED:A systematic search from August 3 to 21, 2015, of the PubMed, MEDLINE, EMBASE, CINAHL, Cochrane Library, Web of Science, Biosis Citation Index, Current Contents Connect, Scientific Library Online, and Global Health databases used PRISMA guidelines to identify 326 relevant articles related to adjuvant use of HPV vaccination. Primary search terms were (HPV vaccine OR human papillomavirus vaccine OR papillomarvirus vaccines OR alphapapillomavirus vaccine) AND (HPV OR human papillomavirus OR alphapapillomavirus OR papillomaviridae OR virus warts OR wart virus) AND (recurrence OR relapse OR reoccurrence OR recurrences OR relapses OR relapsing). Forty-five full texts in English were reviewed, with 19 articles included in the final review. In some studies, subpopulations of individuals with HPV DNA positivity and/or seropositivity were extracted for inclusion. Included studies were assessed for bias and separated based on the presence of active clinical disease or HPV DNA positivity or seropositivity. Findings/UNASSIGNED:Nineteen studies with 22 474 unique patients were included in the review. When HPV vaccination was used as an adjuvant treatment for active clinical disease, 9 of 12 studies reported decreased disease recurrence, decreased disease burden, or increased intersurgical interval. In contrast, none of the 7 studies of vaccination in individuals with HPV DNA positivity and/or seropositivity without clinical disease reported improved outcomes. Conclusions and Relevance/UNASSIGNED:Differences between adjuvant vaccination in HPV-mediated clinical disease and vaccination in HPV DNA-positive and/or HPV-seropositive populations posit underlying differences in disease and immune processes. These data suggest that additional evaluation of adjuvant HPV vaccination in individuals with active clinical disease is warranted.

Importance/UNASSIGNED:Free flap reconstruction of the head and neck is routinely performed with success rates around 94% to 99% at most institutions. Despite experience and meticulous technique, there is a small but recognized risk of partial or total flap loss in the postoperative setting. Historically, most microvascular surgeons involve resident house staff in flap monitoring protocols, and programs relied heavily on in-house resident physicians to assure timely intervention for compromised flaps. In 2003, the Accreditation Council for Graduate Medical Education mandated the reduction in the hours a resident could work within a given week. At many institutions this new era of restricted resident duty hours reshaped the protocols used for flap monitoring to adapt to a system with reduced resident labor. Objectives/UNASSIGNED:To characterize various techniques and frequencies of free flap monitoring by nurses and resident physicians; and to determine if adapted resident monitoring frequency is associated with flap compromise and outcome. Design, Setting, and Participants/UNASSIGNED:This multi-institutional retrospective review included patients undergoing free flap reconstruction to the head and/or neck between January 2005 and January 2015. Consecutive patients were included from different academic institutions or tertiary referral centers to reflect evolving practices. Main Outcomes and Measures/UNASSIGNED:Technique, frequency, and personnel for flap monitoring; flap complications; and flap success. Results/UNASSIGNED:Overall, 1085 patients (343 women [32%] and 742 men [78%]) from 9 institutions were included. Most patients were placed in the intensive care unit postoperatively (n = 790 [73%]), while the remaining were placed in intermediate care (n = 201 [19%]) or in the surgical ward (n = 94 [7%]). Nurses monitored flaps every hour (q1h) for all patients. Frequency of resident monitoring varied, with 635 patients monitored every 4 hours (q4h), 146 monitored every 8 hours (q8h), and 304 monitored every 12 hours (q12h). Monitoring techniques included physical examination (n = 949 [87%]), handheld external Doppler sonography (n = 739 [68%]), implanted Doppler sonography (n = 333 [31%]), and needle stick (n = 349 [32%]); 105 patients (10%) demonstrated flap compromise, prompting return to the operating room in 96 patients. Of these 96 patients, 46 had complete flap salvage, 22 had partial loss, and 37 had complete loss. The frequency of resident flap checks did not affect the total flap loss rate (q4h, 25 patients [4%]; q8h, 8 patients [6%]; and q12h, 8 patients [3%]). Flap salvage rates for compromised flaps were not statistically different. Conclusions and Relevance/UNASSIGNED:Academic centers rely primarily on q1h flap checks by intensive care unit nurses using physical examination and Doppler sonography. Reduced resident monitoring frequency did not alter flap salvage nor flap outcome. These findings suggest that institutions may successfully monitor free flaps with decreased resident burden.

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.

Objective/UNASSIGNED:Determine if anatomic dimensions of airway structures are associated with airway obstruction in obstructive sleep apnea (OSA) patients. Methods/UNASSIGNED: = 14) OSA as determined by clinical symptoms and sleep studies; volunteer sample. Skeletal and soft tissue dimensions were measured from radiocephalometry and magnetic resonance imaging. The soft palate thickness, mandibular plane-hyoid (MP-H) distance, posterior airway space (PAS) diameters and area, and tongue volume were calculated. Results/UNASSIGNED: = 0.004). The MP-H distance, PAS measurements, and tongue volume are of clinical relevance in OSA patients. Conclusions/UNASSIGNED:A long MP-H distance, and small PAS diameters and area are significant anatomic measures in OSA; however the most substantial parameter found was a large tongue volume.

Objective/UNASSIGNED:The study evaluated the addition of surgery (S) to radiation (RT) on survival of squamous cell carcinomas (SCC) of tonsillar-fossa (TF) in a modern cohort with similar epidemiology and treatment as current patients. Study Design/UNASSIGNED:Retrospective analysis utilizing Surveillance, Epidemiology, and End Results (SEER) Program data. Results/UNASSIGNED:< 0.001). Materials and Methods/UNASSIGNED:= 6,476). Primary outcome measures included overall survival (OS) and disease specific survival (DSS). Cox proportional hazard ratios (HR) were estimated for patients treated with S+RT compared to RT alone. Conclusions/UNASSIGNED:OS and DSS were superior for all stages combined and for stages 2, 3, and 4 in TF patients who received S+RT compared to RT alone.

OBJECTIVE:To investigate the way in which otology was practiced at the Academy of Gondishapur in ancient Persia from 200 to 600 CE. METHOD/METHODS:The pertinent literature, using German and English translations of Latin, Greek, Arabic, and Sanskrit documents, was identified and reviewed through the indices of available books and through a PDF search for the following topics: auricle, deaf, deafness, dizziness, ear, hearing, medicine, otitis, pinna, punishment-ear, speech, surgery, vertigo, and voice. RESULTS:The medical school at the Academy of Gondishapur followed the medical and surgical practices of Greece and Rome and, in the 6th century, incorporated those from India as detailed in the Shutra Samhita. This shutra, which originated during the first millennium BCE, detailed many interventions, among which one of the most unusual was the use of a pedicle cheek flap to restore the pinnae. The use of the pedicle flap for pinna restoration appears not have been reported in literature again until 1931, by Jacque Joseph. CONCLUSION/CONCLUSIONS:During the period of late antiquity, medical knowledge of both the east and west was preserved and taught in Persia. Among surgical interventions used during the first millennium BCE in India, knowledge of which passed, through the shutra, to the Sasanian Empire in the 6th century CE, was use of the pedicle cheek flap for pinna reconstruction. Even as late as the Renaissance, the pedicle flap was not known to surgeons in the West, and a pedicle flap, though not a cheek flap, was first incorporated into Western medical practice during the 1930s.

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679-91. ©2017 AACR.

The sequential activation of neurons has been observed in various areas of the brain, but in no case is the underlying network structure well understood. Here we examined the circuit anatomy of zebra finch HVC, a cortical region that generates sequences underlying the temporal progression of the song. We combined serial block-face electron microscopy with light microscopy to determine the cell types targeted by HVC_(RA)neurons, which control song timing. Close to their soma, axons almost exclusively targeted inhibitory interneurons, consistent with what had been found with electrical recordings from pairs of cells. Conversely, far from the soma the targets were mostly other excitatory neurons, about half of these being other HVC_(RA)cells. Both observations are consistent with the notion that the neural sequences that pace the song are generated by global synaptic chains in HVC embedded within local inhibitory networks.

Purpose/UNASSIGNED:Pediatric sarcomas provide a unique diagnostic challenge. There is considerable morphologic overlap between entities, increasing the importance of molecular studies in the diagnosis, treatment, and identification of therapeutic targets. We developed and validated a genome-wide DNA methylation based classifier to differentiate between osteosarcoma, Ewing's sarcoma, and synovial sarcoma. Materials and Methods/UNASSIGNED:DNA methylation status of 482,421 CpG sites in 10 Ewing's sarcoma, 11 synovial sarcoma, and 15 osteosarcoma samples were determined using the Illumina Infinium HumanMethylation450 array. We developed a random forest classifier trained from the 400 most differentially methylated CpG sites within the training set of 36 sarcoma samples. This classifier was validated on data drawn from The Cancer Genome Atlas (TCGA) synovial sarcoma, TARGET Osteosarcoma, and a recently published series of Ewing's sarcoma. Results/UNASSIGNED:Methylation profiling revealed three distinct patterns, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from TCGA were accurately classified as synovial sarcoma (10/10, sensitivity and specificity 100%), all but one sample from TARGET-OS were classified as osteosarcoma (85/86, sensitivity 98%, specificity 100%) and 14/15 Ewing's sarcoma samples classified correctly (sensitivity 93%, specificity 100%). The single misclassified osteosarcoma sample demonstrated high EWSR1 and ETV1 expression on RNA-seq although no fusion was found on manual curation of the transcript sequence. Two additional clinical samples, that were difficult to classify by morphology and molecular methods, were classified as osteosarcoma when previously suspected to be a synovial sarcoma and Ewing's sarcoma on initial diagnosis, respectively. Conclusion/UNASSIGNED:Osteosarcoma, synovial sarcoma, and Ewing's sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide diagnostic assistance when histological and standard techniques are inconclusive.