Faculty Bibliography

Early detection and serial therapeutic monitoring for pediatric brain tumors are essential for diagnosis and therapeutic intervention. Currently, neuropathological diagnosis relies on biopsy of tumor tissue and surgical intervention. There is a great clinical need for less invasive methods to molecularly characterize the tumor and allow for more reliable monitoring of patients during treatment and to identify patients that might potentially benefit from targeted therapies, particularly in the setting where diagnostic tissue cannot be safely obtained. In this literature review, we highlight recent studies that describe the use of circulating tumor DNA, circulating tumor cells, circulating RNA and microRNA, and extracellular vesicles as strategies to develop liquid biopsies in pediatric central nervous system tumors. Liquid biomarkers have been demonstrated using plasma, urine, and cerebrospinal fluid. The use of liquid biopsies to help guide diagnosis, determine treatment response, and analyze mechanisms of treatment resistance is foreseeable in the future. Continued efforts to improve signal detection and standardize liquid biopsy procedures are needed for clinical application.

The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. As a reference WTC unexposed group, we randomly selected 24 age-matched cancer-free women from an existing prospective cohort who donated blood samples before 11 September 2001. The global DNA methylation analyses were performed using Illumina Infinium MethylationEpic arrays. Statistical analyses were performed using R Bioconductor package. Functional genomic analyses were done by mapping the top 5000 differentially expressed CpG sites to the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database. Among cancer-free subjects, we observed substantial methylation differences between WTC-exposed and unexposed women. The top 15 differentially methylated gene probes included BCAS2, OSGIN1, BMI1, EEF1A2, SPTBN5, CHD8, CDCA7L, AIDA, DDN, SNORD45C, ZFAND6, ARHGEF7, UBXN8, USF1, and USP12. Several cancer-related pathways were enriched in the WTC-exposed subjects, including endocytosis, mitogen-activated protein kinase (MAPK), viral carcinogenesis, as well as Ras-associated protein-1 (Rap1) and mammalian target of rapamycin (mTOR) signaling. The study provides preliminary data on substantial differences in DNA methylation between WTC-exposed and unexposed populations that require validation in further studies.

The tumor microenvironment (TME) plays critical roles in tumor growth and progression, however key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated. Herein, we investigate the epigenetic regulation of promoters and gene bodies and their effect on the TME composition of C-MPNSTs and SCMs. A cohort of 30 patients was analyzed using differential gene expression (DGE) and gene set enrichment analysis (GSEA) using the Nanostring platform. Methylation analysis was carried out utilizing an Infinium Methylation EPIC array targeting 866,562 methylation site (CpG) islands. DGE revealed overexpression of genes related to mast cells in the TME of SCMs, and a predominance of exhausted CD8⁺ T cells and macrophages in the TME of C-MPNSTs. Interestingly, we further observed promoter hypermethylation in key overexpressed genes and corresponding gene body hypomethylation. Analysis using ENCODE ChIP-sequencing data identified CTCF as the common transcription factor at the site of the hypomethylated probe. These findings support that the TME composition of C-MPNSTs and SCMs is at least partially independent on promoter methylation status, suggesting a possible relationship between gene body enhancers and expression of key TME genes in both entities.

Myxopapillary ependymoma (MPE) is a relatively common neoplasm arising primarily in the filum terminale/lumbosacral region of the spinal cord. It is designated as a grade I tumor in the most recent WHO Classification of Tumours of the CNS, although aggressive clinical behavior can be observed, especially in cases arising in an extradural location. Anaplastic transformation in MPE is exceedingly rare with <20 examples reported in the English literature, and consensus on diagnostic features and definitive grading remain to be determined. Here, we present 2 cases of recurrent MPE with anaplastic features, both of which had histology consistent with conventional MPE as well as areas with significant atypia, frequent mitotic figures, elevated Ki-67 proliferation indices (>10%-50%), necrosis, and focal vascular proliferation. Targeted next-generation sequencing panels revealed no definitive pathogenic mutations or fusion proteins in either case. Copy number profiling, methylation profiling, and t-Distributed Stochastic Neighbor Embedding were performed to investigate the molecular characteristics of these tumors. To the best of our knowledge, these are the first reported cases of MPE with anaplastic features with methylation profiling data. In addition, we review the literature and discuss common histologic and molecular findings associated with anaplastic features in MPE.

Chordoid meningioma is a rare histological variant, which comprises <1% of all meningiomas. In the initially reported case series, these tumors were described to have a high recurrence rate, especially following subtotal resection, and are thus designated as WHO grade 2, according to current diagnostic criteria. However, more recent case series suggested that chordoid morphology itself, in the absence of other atypical features, did not predict more adverse outcomes, and survival paralleled that of all meningiomas. Among a cohort of 1897 meningiomas resected between 1995 and 2019, we identified 11 cases of meningioma with predominant chordoid morphology and sufficient follow up. Nine of those were otherwise WHO grade I, and only one of them recurred. The two remaining cases otherwise qualified for atypical meningioma, one of which recurred and the patient died of disease. Compared to a control cohort of 473 nonchordoid meningiomas with available follow up, chordoid meningiomas that were otherwise WHO grade 1 had progression-free and overall survival of 100%, which paralleled nonchordoid grade 1 meningiomas by Kaplan-Meier survival curve analysis. The follow up interval ranged between 31 and 219 months, with mean follow up of 108 months. Moreover, genome wide DNA methylation profiling of these 9 chordoid cases classified 8 into methylation class Ben-2 category and only 1 into methylation class Int-A category. In summary, our own institutional experience suggests that chordoid histology alone does not portend a worse prognosis. Based on the methylation and survival data, we suggest that chordoid meningiomas should be graded analogously to nonchordoid meningiomas

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.ajpath.2020.07.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

The dynamics of viral load (VL) of the 2019 novel coronavirus (severe acute respiratory syndrome coronavirus 2) and its association with different clinical parameters remain poorly characterized in the US patient population. Herein, we investigate associations between VL and parameters, such as severity of symptoms, disposition (admission versus direct discharge), length of hospitalization, admission to the intensive care unit, length of need for oxygen support, and overall survival in a cohort of 205 patients from a tertiary care center in New York City. VL was determined using quantitative PCR and log10 transformed for normalization. Univariate and multivariate regression models were used to test these associations. We found that diagnostic viral load is significantly lower in hospitalized patients than in patients not hospitalized (log10 VL = 3.3 versus 4.0; P = 0.018) after adjusting for age, sex, race, body mass index, and comorbidities. Higher VL was associated with shorter duration of the symptoms in all patients and hospitalized patients only and shorter hospital stay (coefficient = -2.02, -2.61, and -2.18; P < 0.001, P = 0.002, and P = 0.013, respectively). No significant association was noted between VL, admission to intensive care unit, length of oxygen support, and overall survival. Our findings suggest a higher shedding risk in less symptomatic patients, an important consideration for containment strategies in severe acute respiratory syndrome coronavirus 2. Furthermore, we identify a novel association between viral load and history of cancer. Larger studies are warranted to validate our findings.

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

IDH-wildtype glioblastoma is a relatively common malignant brain tumor in adults. These patients generally have dismal prognoses, although outliers with long survival have been noted in the literature. Recently, it has been reported that many histologically lower-grade IDH-wildtype astrocytomas have a similar clinical outcome to grade IV tumors, suggesting they may represent early or undersampled glioblastomas. cIMPACT-NOW 3 guidelines now recommend upgrading IDH-wildtype astrocytomas with certain molecular criteria (EGFR amplifications, chromosome 7 gain/10 loss, and/or TERT promoter mutations), establishing the concept of a "molecular grade IV" astrocytoma. In this report, we apply these cIMPACT-NOW 3 criteria to 2 independent glioblastoma cohorts, totaling 393 public database and institutional glioblastoma cases: 89 cases without any of the cIMPACT-NOW 3 criteria (GBM-C0) and 304 cases with one or more criteria (GBM-C1-3). In the GBM-C0 groups, there was a trend toward longer recurrence-free survival (median 12-17 vs 6-10 months), significantly longer overall survival (median 32-41 vs 15-18 months), younger age at initial diagnosis, and lower overall mutation burden compared to the GBM-C1-3 cohorts. These data suggest that while histologic features may not be ideal indicators of patient survival in IDH-wildtype astrocytomas, these 3 molecular features may also be important prognostic factors in IDH-wildtype glioblastoma.