Faculty Bibliography

Physicians should be aware of both websites and videos available online regarding the otoplasty procedure to provide quality care. This study systematically analyzes the authorships, reliability, quality, and readability of the websites, as well as the authorships and primary objectives of the videos regarding otoplasty. Validated instruments were used to analyze the reliability, quality, and readability of websites, and videos were systematically categorized and analyzed. A Google search was conducted, and the first five pages of results were included in this study. After excluding unrelated websites, the remaining 44 websites were categorized by authorship (physician, patient, academic, or unaffiliated) and were analyzed using the validated DISCERN instrument for reliability and quality, as well as various other validated instruments to measure readability. A YouTube search was also conducted, and the first 50 relevant videos were included in the study. These videos were categorized by authorship and their primary objective. Website authorships were physician-dominated. Reliability, quality, and overall DISCERN score differ between the four authorship groups by a statistically significant margin (Kruskall-Wallis test, p < 0.05). Unaffiliated websites were the most reliable, and physician websites were the least reliable. Academic websites were of the highest quality, and patient websites were of the lowest quality. Readability did not differ significantly between the groups, though the readability measurements made showed a general lack of material easily readable by the general public. YouTube was likewise dominated by physician-authored videos. While the physician-authored videos sought mainly to inform and to advertise, patient-authored videos sought mainly to provide the patient's perspective. Academic organizations showed very little representation on YouTube, and the YouTube views on otoplasty videos were dominated by the top 20 videos, which represented over 93% of the total views of videos included in this study.

Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. However, the optimal treatment dose and schedule are unknown. This multicenter, phase II, openlabel study evaluated subjects (>=6 years old) with NF2 and progressive VS. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as >=20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. We enrolled 22 subjects (median age=23 years). The overall hearing and radiographic response rates were 41% (9/22) and 23% (5/22), respectively. In an unplanned post-hoc analysis, the hearing and radiographic response rates were 14% (1/7) and 0% in pediatric subjects <=21 years, as compared with 53% (8/15) and 33% (5/15) in adult subjects. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 women with elevated FSH underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates comparable to previous studies using lower doses. Pediatric subjects appear to benefit less than adults during bevacizumab treatment

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

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

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

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

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

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.