Faculty Bibliography

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

A significant proportion of healthy seniors report difficulty swallowing, thought to result from age-related decline in muscle bulk/function. Effortful Swallowing (ES) is used both as a compensatory maneuver to improve pharyngeal propulsion/clearance and has been proposed as an exercise to improve pharyngeal strength. This study sought to quantify the immediate kinematic, temporal, and functional changes during an ES maneuver to quantify its exercise potential to combat age-related changes in swallowing. Videofluoroscopy data were collected from 44 healthy seniors (21 male) over 65 years old (mean = 76.9, SD = 7.1). Each participant swallowed six 5 ml boluses of Varibar nectar-thick liquids: three with regular effort and three using ES. Individual swallows (n = 260) were measured on pharyngeal constriction, pharyngeal shortening, laryngeal closure duration, hyoid movement duration, UES opening duration, stage transition duration, pharyngeal transit time, pharyngeal response duration, Normalized Residue Ratio Scale (NRRS), and the Penetration-Aspiration Scale (PAS). Non-parametric Wilcoxon Rank Sum for repeated measures tested the effect of ES on each outcome. Exact p-values were calculated based on permutation methods, individual p values < 0.008 was deemed to be significant. The ES maneuver significantly prolonged all temporal variables. While we found no significant differences for pharyngeal constriction, significantly less (i.e., worse) pharyngeal shortening was observed in ES condition compared with regular effort swallows. Further, significantly worse pyriform sinus residue (NRRSv) was observed in the ES condition. No differences between ES and regular effort swallows were noted for pharyngeal constriction, NRRSv or PAS. We speculate that these negative manifestations of worse kinematics (less pharyngeal shortening) and function (increase in NRRSp) may be the result of forced volitional manipulation of swallowing in the ES condition in an otherwise normal elderly swallow.

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.

Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.

OBJECTIVE Temporal lobe encephaloceles and cerebrospinal fluid otorrhea from temporal bone defects that involve the tegmen tympani and mastoideum are generally repaired using middle fossa craniotomy, mastoidectomy, or combined approaches. Standard middle fossa craniotomy exposes patients to dural retraction, which can lead to postoperative neurological complications. Endoscopic and minimally invasive techniques have been used in other surgeries to minimize brain retraction, and so these methods were applied to repair the lateral skull base. The goal of this study was to determine if the use of endoscopic visualization through a middle fossa keyhole craniotomy could effectively repair tegmen defects. METHODS The authors conducted a retrospective review of 6 cases of endoscope-assisted middle fossa repairs of tegmen dehiscences at a tertiary care medical center within an 18-month period. RESULTS All cases were successfully treated using a keyhole craniotomy with endoscopic visualization and minimal retraction. Surgical times did not increase. There were no major postoperative complications, recurrences of encephaloceles, or cerebrospinal fluid otorrhea in these patients. CONCLUSIONS Endoscopic visualization allows for smaller incisions and craniotomies and less risk of brain retraction injury without compromising repair integrity during temporal encephalocele and tegmen repairs.

Activation of the MAPK pathway represents a hallmark of pediatric low-grade glioma (pLGG) and is frequently caused by BRAF alterations. BRAF-V600E represent an aggressive type of pLGG with less than optimal response to conventional chemo-radiation approaches. While clinical trials using BRAF-V600E inhibitors are ongoing, these data are not yet available. We have assembled an international cohort of BRAF-V600E glioma patients treated off-label with BRAF inhibitors as a monotherapy. Complete molecular, clinical and imaging data is being collected and compared to previous chemo-radiation therapies. Ongoing data form the taskforce on 40 BRAF-V600E gliomas from 25 international institutions is summarized below. The most prevalent histologies were ganglioglioma, pilocytic astrocytoma and pleomorphic xanthoastrocytoma, located mainly in the chiasm, brainstem and temporal lobes. Strikingly, 66% of BRAF V600E pLGG patients achieved partial response (PR) to targeted inhibitors versus only 6.6% response to conventional chemotherapy (p<0.001). Five patients progressed during treatment 0.5 to 2.1 years after the start of BRAF inhibitor therapy. Additionally, 3 pLGG progressed after discontinuation of therapy. Two-year progression-free survival was 84.2% (95%CI,69.3-100) versus 50% (95%CI,32.2-77.5) with targeted agents and chemotherapy, respectively (p=0.021). Interestingly, 6 patients with BRAF V600E positive high-grade glioma did not exhibit objective responses to BRAF inhibitor therapy and the majority suffered from early progression. Our data suggest BRAF inhibitors to be potent therapeutic agents in BRAF-V600E pLGG but not HGG. Future studies aimed at mechanism of resistance and differential response to targeted agents are required

Objectives To investigate the clinical predictors and survival implications of perineural invasion (PNI) in parotid gland malignancies. Study Design Case series with chart review. Setting Tertiary care medical center. Subjects and Methods Patients with parotid gland malignancies treated surgically from 2000 to 2015 were retrospectively identified in the Head and Neck Cancer Registry at a single institution. Data points were extracted from the medical record and original pathology reports. Results In total, 186 patients with parotid gland malignancies were identified with a mean follow-up of 5.2 years. Salivary duct carcinoma (45), mucoepidermoid carcinoma (44), and acinic cell carcinoma (26) were the most common histologic types. A total of 46.2% of tumors were found to have PNI. At the time of presentation, facial nerve paresis (odds ratio [OR], 64.7; P < .001) and facial pain (OR, 3.7; P = .002) but not facial paresthesia or anesthesia (OR, 2.8, P = .085) were predictive of PNI. Malignancies with PNI were significantly more likely to be of advanced T and N classification, be high-risk pathologic types, and have positive margins and angiolymphatic invasion. PNI positivity was associated with worse overall (hazard ratio, 2.62; P = .001) and disease-free survival (4.18; P < .001) on univariate Cox regression analysis. However, when controlling for other negative prognosticators, age, and adjuvant therapy, PNI did not have a statistically significant effect on disease-free or overall survival. Conclusions PNI is strongly correlated with more aggressive parotid gland malignancies but is not an independent predictor of worse survival. Facial paresis and pain were predictive of PNI positivity, and facial paresis correlated with worse overall and disease-free survival.

Program cell death ligand-1 (PD-L1) membranous expression on >5% tumor cells (PD-L1 positive tumors) is an unfavorable prognostic marker in many solid tumors. We previously showed that approximately 40% of neurofibromatosis type 2 (NF2) meningiomas are PD-L1 positive tumors. However, due to the invasive nature of biopsies, collection of tumor tissue is not always feasible. Thus, a non-invasive alternative is needed to evaluate the status of tumor growth and confirm PD-L1 positive tumors before the consideration of immunotherapy. It has recently been revealed that expression of PD-L1 on tumor associated macrophages is also a strong prognostic indicator. We retrieved formalin-fixed paraffin-embedded (FFPE) tissue from 10 NF2 meningioma cases to identify PD-L1 expression on macrophages and/or monocytes. We found that 3 out of 4 PD-L1 positive tumors were associated with expression of PDL-1 on CD68 (-) monocyte-like cells located in the peri-and intravascular lumens. These cells were only observed in 1 out of 6 PD-L1 negative tumors. Compared to others, tumors with PD-L1 expression on monocyte-like cells presented a higher Ki-67 proliferative index that was above 10%. Our results suggest that PD-L1 positive circulating CD68 (-) monocyte-like cells are correlated with tumor cell PD-L1 expression and progression in NF2 meningiomas

OBJECTIVE:Bibliometric analysis is a commonly used analytic tool for objective determination of the most influential and peer-recognized articles within a given field. This study is the first bibliometric analysis of the literature in the field of invasive neuromodulation, excluding deep brain stimulation. The objectives of this study are to identify the 50 most cited articles in invasive neuromodulation, provide an overview of the literature to assist in clinical education, and evaluate the effect of impact factor on manuscript recognition. METHODS:Bibliometric analysis was performed using the Science Citation Index from the Institute for Scientific Information, accessed through the Web of Science. Search terms relevant to the field of invasive neuromodulation were used to identify the 50 most cited journal articles between 1900 and 2016. RESULTS:The median number of citations was 236 (range, 173-578). The most common topics among the articles were vagus nerve stimulation (n = 24), spinal cord stimulation (n = 9), and motor cortex stimulation (n = 6). Median journal impact factor was 5.57. Most of these articles (n = 19) contained level I, II, or III evidence. CONCLUSIONS:This analysis provides a brief look into the most cited articles within the field, many of which evaluated innovated procedures and therapies that helped to drive surgical neuromodulation forward. These landmark articles contain vital clinical and educational information that remains relevant to clinicians and students within the field and provide insight into areas of expanding research. Journal impact factor may play a significant role in determining the literary relevance and general awareness of invasive neuromodulation studies.

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.