Faculty Bibliography

In contrast to adulthood, meningiomas are rare among children and adolescents. Although recent papers have characterized the genomics of adult meningiomas, the molecular profiles of childhood meningiomas have not been elucidated in detail. We analyzed 41 tumor samples from 37 pediatric meningioma patients (female: 17, male: 20; age range: 1-21 years). Atypical meningioma WHO grade II was the most frequent histological subtype (N=14, 38%). Most tumors were located at the convexity (N=18) or the skull base (N=15). Lack of SMO, AKT, KLF4/TRAF7 mutations by Sanger sequencing (n=22) prompted whole genome sequencing of a subset (n=7). All seven cases exhibited bi-allelic inactivation of NF2 (combined large deletion and germline (5/7) or somatic (2/7) base exchanges/frameshifts). Subsequently, tumor samples from all 37 patients were subjected to 450K DNA methylation profiling and targeted DNA sequencing using brain tumor specific gene panel. Loss of chromosome 22 was frequent (N=28, 76%), followed by loss of chromosome 1 (N=12, 32%) and chromosome 18 (N=7, 19%). Moreover, separation into three groups was evident: One encompassing all clear-cell meningiomas with enrichment for SMARCE1 mutations, a second dominated by atypical meningiomas, and a third group composed of benign meningiomas, as well as rare subtypes such as rhabdoid meningiomas. When analyzed with 105 adult tumors, most of pediatric meningiomas (28/37) clustered into a separate methylation group both by unsupervised hierarchical clustering and t-stochastic nearest neighbor embedding (t-SNE). Four recurrences were similar to the primary tumor. These data suggest that pediatric meningiomas are genetically distinct from adult counterparts

OBJECTIVE:Technological change is leading to an evolution in medical education. The objective of our study was to assess the impact of a medical knowledge app, called PulseQD, on resident education within our otolaryngology-head and neck surgery department at Montefiore Medical Center, Albert Einstein College of Medicine (Bronx, NY). METHODS:A prospective cohort study was conducted within the Department of Otolaryngology-Head and Neck Surgery from July 2016 to June 2017. All faculty attendings and residents were asked to participate in the study and were included. A Web and mobile-based app, PulseQD, that allowed for collaborative learning was implemented. Questionnaires were given at the beginning and end of the academic year. Otolaryngology Training Exam (OTE) scores were collected RESULTS: A total of 20 residents and 13 faculty members participated in the study. Residents used online sources of medical information significantly more often than faculty (90% and 54%, respectively, P = 0.0179). Residents and faculty felt that PulseQD offered a valuable perspective on clinically relevant medical information (P = 0.0003), was a great way to test clinical and medical knowledge (P = 0.0001), and improved the sharing and discussing of medical knowledge (P < 0.0001). There was a statistically significant 5.8% improvement in OTE scores (P = 0.0008) at the end of the academic year. CONCLUSION/CONCLUSIONS:The implementation of a novel mobile app, PulseQD, was well received by residents and faculty in the Department of Otolaryngology-Head and Neck Surgery. Preliminary data suggest that app-based learning may lead to improved performance on knowledge-based assessments. LEVEL OF EVIDENCE/METHODS:NA. Laryngoscope, 2017.

BACKGROUND: 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. METHODS: We analyzed pediatric and adult pineoblastoma samples (n=23) using integrated genomic studies, including genome-wide DNA methylation profiling, whole-exome or whole-genome sequencing, and whole-transcriptome analysis. RESULTS: Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower grade pineal tumors and normal pineal gland. Recurrent somatic mutations were found in genes involved in PKA-and NF-kappaB 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. Expression of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain. Whole-transcriptome analysis showed that homozygous loss of DROSHA led to distinct changes in RNA expression profile. Disruption of the DROSHA locus in human neural stem cells using the CRISPR/Cas9 system, led to decrease of the DROSHA protein, and massive loss of miRNAs. CONCLUSION: We identified recurrent homozygous deletions of DROSHA in pineoblastoma, suggesting that different mechanisms disrupting miRNA processing are involved in the pathogenesis of familial versus sporadic pineoblastoma. Furthermore, a novel microduplication of PDE4DIP leading to upregulation of DUF1220 protein suggests DUF1220 as a novel oncogenic driver in pineoblastoma

We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted.

BACKGROUND:RAS mutations are common in the available mutational analysis of cytologically indeterminate (Cyto-I) thyroid nodules. However, their reported positive predictive value (PPV) for cancer is widely variable. The reason for this variability is unknown, and it causes clinical management uncertainty. A systematic review was performed, evaluating the PPV for cancer in RAS mutation positive Cyto-I nodules, and variables that might affect residual heterogeneity across the different studies were considered. METHODS:PubMed was searched through February 22, 2017, including studies that evaluated at least one type of RAS mutation in Cyto-I nodules, including any (or all) of the Bethesda III/IV/V categories or their equivalents and where the histological diagnosis was available. The PPV residual heterogeneity was investigated after accounting for Bethesda classification, blindedness of the histopathologist to the RAS mutational status, Bethesda category-specific cancer prevalence for each study, and which RAS genes and codons were tested. This was studied using five meta-regression models fit to different sets of Bethesda classification categories: Bethesda III, IV, or V (III/IV/V); Bethesda III or IV (III/IV); Bethesda III only; Bethesda IV only; and Bethesda V only. RESULTS: = 34.4%), with significant Cochran's Q-test for Bethesda III (p < 0.001) and IV (p = 0.04). CONCLUSION/CONCLUSIONS:The PPV of RAS mutations in Bethesda III and IV categories is quite heterogeneous across different studies, creating low confidence in the accuracy of a single estimate of PPV. Clinicians must appreciate this wide variability when managing a RAS-mutated Cyto-I nodule. Future studies should seek to resolve this unexplained variability.

Several different entities with distinct clinical and histopathological features are described within in the group of pineal tumors. Whereas pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID) and papillary tumors of the pineal region (PTPR) predominantly affect adults and are associated with a relatively favorable prognosis, pineoblastoma (PB) occurs at young age and constitutes a highly aggressive tumor. Despite multimodal treatment, prognosis is poor (especially for infants and patients with metastatic disease), and therapeutically actionable molecular targets are lacking to date. Most PB arise sporadically, however, DICER1 or RB1 germline mutations are known to predispose to the development of PB, the latter in the context of trilateral retinoblastoma. Genome-wide DNA methylation profiling and copy-number analysis were used to investigate the biological features of 230 pineal tumors of different histologies. Known histopathological entities (PC, PTPR, PPTID) could be clearly separated by unsupervised clustering, as well as further distinct subgroups, including the previously hypothesized PTPR-A and PTPR-B groups. Notably, several biologically discrete subgroups were formed by the tumors initially diagnosed as PB or pineal primitive embryonal tumors/PNETs, which showed distinct clinical associations (e.g. age distribution). Somatic deletions of DROSHA, an endoribonuclease involved in miRNA processing upstream of DICER1, seem to be a recurrent feature of the largest subgroup. Rarer DICER1 and DGCR8 alterations in this group confirm a central role of altered miRNA biogenesis in the development of this subset of PB. Further molecular and functional characterization of novel sub-clusters, including ongoing miRNAseq, will provide insights into the oncogenesis of PB

STUDY OBJECTIVES/OBJECTIVE:Hospital readmissions are an important metric of quality and safety. This study seeks to characterize the relationship between readmissions and obstructive sleep apnea (OSA). A better understanding of this relationship could be utilized to develop preventative measures and reduce readmission rates. METHODS:A retrospective review of patients discharged over a 24-month period to a Department of Defense hospital was conducted. Medical records review provided demographic data, presence of OSA and comorbid diseases, and whether readmission occurred within 30 days of discharge. Statistical analysis assessed risk factors for readmission, and multivariate analysis was performed. Next, 125 readmitted patients with OSA were randomly selected for detailed chart review and compared to a matched cohort that was not readmitted. RESULTS:= .48) was similar between the groups. Also, inpatient (27.2% versus 26.4%) and outpatient (38.4% versus 37.6%) positive airway pressure (PAP) treatment rates were not different. CONCLUSIONS:This study found OSA to be an independent risk factor for readmission within 30 days of discharge. PAP therapy appears to be underutilized in patients with known OSA. Additional studies are needed to define the relationship between OSA, PAP adherence, and hospital readmission.

Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. Cancer Res; 78(9); 2383-95. ©2018 AACR.

OBJECTIVES/HYPOTHESIS: Although the primary goal of medialization laryngoplasty is to improve glottic closure, implant placement is also likely to alter the biomechanical properties of the vocal fold (VF). We sought to employ novel, nanoscale technology to quantify these properties following medialization based on the hypothesis that different medialization materials will likely yield differential biomechanical effects. STUDY DESIGN: Ex vivo. METHODS: Nine pig larynges were divided into three groups: control, Silastic (Dow Corning, Midland, Michigan, U.S.A.) block medialization, or Gore-Tex (W.L. Gore & Associates, Newark, Delaware) medialization. Laryngoplasty was performed on excised, intact larynges. The larynges were then bisected in the sagittal plane and each subjected to dynamic nanomechanical analysis (nano-DMA) at nine locations using a 250-mum flat-tip punch and frequency sweep-load profile across the free edge of the VF and inferiorly along the conus elasticus. RESULTS: Silastic block and Gore-Tex implant introduced increased storage and loss moduli. Overall, storage moduli mean (maximum) increased from 38 kilopascals (kPa) (119) to 72 kPa (422) and 129 kPa (978) in control, Gore-Tex, and Silastic implants, respectively. Similarly, loss moduli increased from 13 kPa (43) to 22 kPa (201) and 31 kPa (165), respectively. Moduli values varied widely by location in the Silastic block and Gore-Tex groups. At the free VF edge, mean (maximum) storage moduli were lowest in the Gore-Tex group, 20 kPa (44); compared to control, 34.5 kPa (86); and Silastic, 157.9 kPa (978), with similar loss and complex moduli trends. CONCLUSION: Medialization laryngoplasty altered VF structure biomechanical properties; Silastic and Gore-Tex implants differentially impact these properties. LEVEL OF EVIDENCE: NA. Laryngoscope, 2017.