Supratentorial ependymoma in childhood: more than just RELA or YAP

AbstractTwo distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified—RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class “EP, RELA-fusion”; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.

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Glioma with Leptomeningeal Spread Mimics Chronic Meningoencephalitis in a Young Adult

Case Reports in Neurology ◽

10.1159/000513562 ◽

2021 ◽

pp. 179-183

Author(s):

Ann-Kristin Becker ◽

Marta Leonora Frank ◽

Michael Friese ◽

Joachim Röther

Keyword(s):

Brain Tumor ◽

Back Pain ◽

Young Adult ◽

Lower Back Pain ◽

Low Grade Glioma ◽

Low Grade ◽

Who Grade ◽

Leptomeningeal Spread ◽

Lower Back ◽

Uncommon Case

The most malignant type of intrinsic brain tumor is glioblastoma (WHO grade IV). Primary leptomeningeal spread is rare and leads to a variety of differential considerations, as there is no typical clinical or imaging pattern. Here we present a rare and uncommon case of a primary leptomeningeal glioblastoma in combination with a low-grade glioma in a 21-year-old male, initially presenting with only headache and lower back pain. The presented case illustrates the challenging differential considerations and the severe course of leptomeningeal glioblastomas.

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Effect of adjuvant radiotherapy after subtotal resection for WHO grade I meningioma: a propensity score matching analysis of the Brain Tumor Registry of Japan

Journal of Neuro-Oncology ◽

10.1007/s11060-021-03775-x ◽

2021 ◽

Author(s):

Soichi Oya ◽

Fusao Ikawa ◽

Nao Ichihara ◽

Masahiko Wanibuchi ◽

Yukinori Akiyama ◽

...

Keyword(s):

Brain Tumor ◽

Propensity Score ◽

Propensity Score Matching ◽

Adjuvant Radiotherapy ◽

Subtotal Resection ◽

Who Grade ◽

Tumor Registry ◽

Propensity Score Matching Analysis ◽

The Brain

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EPID-22. CHARACTERIZATION OF RADIATION-INDUCED MENINGIOMAS IN A BRAIN TUMOR DATABASE

Neuro-Oncology ◽

10.1093/neuonc/noaa215.340 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii83-ii83

Author(s):

Nilan Vaghjiani ◽

Andrew Schwieder ◽

Sravya Uppalapati ◽

Zachary Kons ◽

Elizabeth Kazarian ◽

...

Keyword(s):

African American ◽

Brain Tumor ◽

Radiation Treatment ◽

Latency Period ◽

Data Set ◽

Who Grade ◽

Significant Difference ◽

Radiation Induced ◽

Grade Ii ◽

The Mean

Abstract PURPOSE Radiation-induced meningiomas (RIMs) are associated with previous exposure to therapeutic irradiation. RIMs are rare and have not been well characterized relative to spontaneous meningiomas (SMs). METHODS 1003 patients with proven or presumed meningiomas were identified from the VCU brain tumor database. Chart review classified RIM patients and their characteristics. RESULTS Of the 1003 total patients, 76.47% were female with a mean ± SD age of 67.55 ± 15.50 years. 15 RIM patients were identified (66.67% female), with a mean ± SD age of 52.67 ± 15.46 years, 5 were African American and 10 were Caucasian. The incidence of RIMs was 1.49% in our data set. The mean age at diagnosis was 43.27 ± 15.06 years. The mean latency was 356.27 ± 116.96 months. The mean initiating dose was 44.28 ± 14.68 Gy. There was a significant difference between mean latency period and ethnicity, 258.3 months for African American population, and 405.2 months for Caucasian population (p = 0.003). There was a significant difference between the mean number of lesions in females (2.8) versus males (1.2; p = 0.046). Of the RIMs with characterized histology, 6 (55%) were WHO grade II and 5 (45%) were WHO grade I, demonstrating a prevalence of grade II tumors approximately double that found with SMs. RIMs were treated with combinations of observation, surgery, radiation, and medical therapy. Of the 8 patients treated with radiation, 4 demonstrated response. 8 of the 15 patients (53%) demonstrated recurrence/progression despite treatment. CONCLUSION RIMs are important because of the associated higher grade histology, gender, and ethnic incidences, and increased recurrence/progression compared to SMs. Despite the presumed contributory role of prior radiation, RIMs demonstrate a significant rate of responsiveness to radiation treatment.

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PATH-13. PLEOMORPHIC XANTHOASTROCYTOMA INTEGRATED GENOMIC CHARACTERIZATION - WHAT HAVE WE LEARNED?

Neuro-Oncology ◽

10.1093/neuonc/noaa222.648 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii426-iii427

Author(s):

Rachael Vaubel ◽

Valentina Zschernack ◽

Alissa Caron ◽

Dragana Milosevic ◽

Robert Jenkins ◽

...

Keyword(s):

Overall Survival ◽

Strong Predictor ◽

Progression Free Survival ◽

Genetic Alterations ◽

Pleomorphic Xanthoastrocytoma ◽

Who Grade ◽

Targeted Next Generation Sequencing ◽

Genomic Characterization ◽

Promoter Mutations ◽

Methylation Profiling

Abstract Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma occurring predominantly in children and young adults. It is characterized histologically by large pleomorphic, spindled and lipidized cells with frequent eosinophilic granular bodies and pericellular reticulin deposition. BRAF p.V600E mutation and CKDN2A/B deletion are the most common genetic alterations. We report the integrated genomic characterization of a cohort of 67 patients (37 F, 30 M; median age 20.3 years (interquartile 13.4–32.9) with histologically defined PXA (52, 78%) or anaplastic PXA (A-PXA) (15, 22%), using genome-wide cytogenetic (ThermoFisher Oncoscan, n=67), methylation profiling (Illumina EPIC array, n=43), and targeted next generation sequencing (n=32). BRAF p.V600E mutation (n=51, 76.1%) and CDKN2A/B deletion (n=63; 94%) were the most frequent alterations. Of 16 BRAF p.V600E negative cases, 7 showed an alternative BRAF activating mutation (n=2), NF1 (n=3) mutation or ATG7-RAF1 fusion (n=2). Targeted TERT analysis found promoter mutations in 3 (of 58) cases, but TERT amplification was absent. Supervised and unsupervised methylation profiling against a comprehensive reference cohort demonstrated consensus grouping with the PXA class in 36 of 43 cases; while the minority grouped with a ganglioglioma class (n=3), with reactive brain or had no resolvable subgroup (n=4). Follow-up was available in 61 patients (91.0%) (median 63 months). Overall survival was significantly different between PXA and A-PXA (5-year:80.4% vs. 55.1%; p=0.001), but not progression-free survival (5-year:61.7% vs. 39.8%; p=0.128). Our data confirm the high frequency of MAP-K abnormalities and CDKN2A/B deletion in PXA. WHO grade remains a strong predictor of patient overall survival.

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Anatomical phenotyping and staging of brain tumors

10.1101/2021.03.14.21253533 ◽

2021 ◽

Author(s):

Kevin Akeret ◽

Flavio Vasella ◽

Victor E. Staartjes ◽

Julia Velz ◽

Timothy Müller ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Tumor Progression ◽

Survival Probability ◽

Central Nervous System Lymphoma ◽

Staging System ◽

Growth Behavior ◽

Who Grade ◽

Staging Systems ◽

Grade Ii

AbstractIn contrast to most other tumors, the anatomical extent of brain tumors is not objectified and quantified through staging. Staging systems are built on the understanding of the anatomical sequence of tumor progression and its relation to histopathological dedifferentiation and survival. While major advances in the understanding of primary brain tumors at a histological, cellular and molecular level have been achieved in recent decades, our understanding at a macroscopic anatomical level is limited. The aim of this study was to describe the anatomical phenotype of the most frequent brain tumor entities based on topographic probability and growth behavior analysis. The association of anatomical tumor features with survival probability was assessed and a prototypical staging system for WHO grade II-IV glioma was proposed based on the hypothesized anatomical sequence of tumor progression. The analysis is based on data from a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumor. On preoperative MRI, the relative tumor density (RTD) of different topographic, phylogenetic and ontogenetic parcellation units was derived through normalization of the relative tumor prevalence to the relative volume of the respective structure. While primary central nervous system lymphoma (PCNSL) showed a high RTD along white matter tracts, the RTD in metastases was highest along terminal arterial flow areas. Neuroepithelial tumors (NT) demonstrated a high and homogeneous RTD along all sectors of the ventriculo-cortical axis, avoiding adjacent units, consistent with a transpallial behavior within phylo-ontogenetic radial units. Additionally, the topographic probability in NT correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. The anatomical tumor growth behavior was analyzed by comparing pre- and postoperative MRI, showing that a ventriculofugal growth dominates in NT. With progressive histopathological dedifferentiation of NT, a gradual deviation from this neuroepithelial anatomical behavior was found. By comparing survival probability, we identified prognostically critical steps in the anatomical behavior of NT. Based on a hypothesized sequence of anatomical tumor progression, we developed a three-level prototypical staging system for WHO grade II-IV glioma. This staging system proved to be accurate across histological, molecular, radiomorphological and clinical strata based on Kaplan Meier curves and multivariable survival analysis. Similar to staging systems for other tumors, a staging system such as this one may have the potential to inform stage-adapted treatment decisions.

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A 14q+ Marker and a Late Replicating Chromosome #22 in a Brain Tumor: Brief Communication

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/59.4.1193 ◽

1977 ◽

Vol 59 (4) ◽

pp. 1193-1195 ◽

Cited By ~ 21

Author(s):

Kiyomi Yamada ◽

Masumi Yoshioka ◽

Hiroshi Oami

Keyword(s):

Brain Tumor ◽

Chromosome 22

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A Liquid Biopsy to Assess Brain Tumor Recurrence: Presence of Circulating Mo-MDSC and CD14+ VNN2+ Myeloid Cells as Biomarkers That Distinguish Brain Metastasis From Radiation Necrosis Following Stereotactic Radiosurgery

Neurosurgery ◽

10.1093/neuros/nyaa334 ◽

2020 ◽

Vol 88 (1) ◽

pp. E67-E72

Author(s):

David C Soler ◽

Amber Kerstetter-Fogle ◽

Theresa Elder ◽

Alankrita Raghavan ◽

Jill S Barnholtz-Sloan ◽

...

Keyword(s):

Brain Tumor ◽

Brain Metastasis ◽

Stereotactic Radiosurgery ◽

Peripheral Blood ◽

Radiation Necrosis ◽

Surrogate Marker ◽

Suppressor Cells ◽

Surgical Biopsy ◽

Hla Dr ◽

The Us

Abstract BACKGROUND Brain metastases (BM) are the most common type of brain tumor malignancy in the US. They are also the most common indication for stereotactic radiosurgery (SRS). However, the incidence of both local recurrence and radiation necrosis (RN) is increasing as treatments improve. MRI imagery often fails to differentiate BM from RN; thus, patients must often undergo surgical biopsy or resection to obtain a definitive diagnosis. OBJECTIVE To hypothesize that a marker of immunosuppression might serve as a surrogate marker to differentiate patients with active vs inactive cancer—including RN. METHODS We thus purified and quantified Monocytic Myeloid-Derived Suppressor Cells (Mo-MDSC) by flow cytometry in patients proven by biopsy to represent BM or RN. RESULTS We report the utility of the previously reported HLA-Dr-Vnn2 Index or DVI to discriminate recurrent BM from RN using peripheral blood. The presence of CD14+ HLA-DRneg/low Mo-MDSC is significantly increased in the peripheral blood of patients with brain metastasis recurrence compared to RN (Average 61.5% vs 7%, n = 10 and n = 12, respectively, P < .0001). In contrast, expression of VNN2 on circulating CD14+ monocytes is decreased in BM patients compared to patients with RN (5.5% vs 26.5%, n = 10 and n = 12, respectively, P = .0008). In patients with biopsy confirmed recurrence of brain metastasis, the average DVI was 11.65, whereas the average DVI for RN patients was consistently <1 (Avg. of 0.17). CONCLUSION These results suggest that DVI could be a useful diagnostic tool to differentiate recurrent BM from RN using a minimally invasive blood sample.

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Variant Philadelphia Translocation with BCR/ABL Fusion Gene Site In 10q24 In a Case of Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v116.21.4839.4839 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4839-4839

Author(s):

Rossana Bonomi ◽

Pablo Lopez ◽

Daniela Infante ◽

Isabel Moro ◽

Victoria Elizondo ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Chromosome 9 ◽

Chromosome 22 ◽

Fish Analysis ◽

Signal Pattern ◽

Ph Chromosome ◽

Fusion Signal

Abstract Abstract 4839 Introduction. Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome (Ph) observed in more than 90% of patients with CML as a result of t(9;22)(q34;q11), leading to the formation of chimeric gene BCR/ABL encoding for proteins with abnormal tyrosine kinase activity. Cytogenetic variants of Ph chromosome can be identifed in 5 to 10% of CML patients, involving additional chromosomes other than 9 and 22. To explain the formation of variant translocations one-step, two-step and multi-step mechanisms have been proposed. Rarely, the variant Ph chromosome results from a BCR insertion on the ABL region and form a BCR/ABL fusion gene, generally mapping to 9q34, instead of the usual location at 22q11. In very few variant Ph cases, the insertion of the BCR/ABL product in a third chromosome was demonstrated. Case Report 28 year-old man, with bilateral central scotoma and gingivorragia. Physical examination: Grade 4 splenomegaly. Peripheral blood count showed hemoglobin concentration 11.5 g/dl, platelet count: 300.000/mm3, and white blood cell count 590.000/mm3. Blood smear: myelemia exhibiting 30% of myeloid blasts. Bone marrow biopsy: panmyelosis showing 20% of myeloid blasts. Cytogenetic analysis by G-banding performed in peripheral blood verified the following karyotype: 46, XY, t(9;22;10)(q34;q11;q24)[20] The analysis of the BCR-ABL fusion gene according to standard protocols detected the presence of the b3a2 isoform. Fluorescence in situ hybridization (FISH) studies using dual color dual fusion probes in metaphases showed a signal pattern 1F2G1R. The fusion signal mapped to 10q24, the red signal to 9q34, and the normal green signal to chromosome 22, while a second low intensity green signal mapped to the Ph chromosome. No signal was observed in der(9). Interphase FISH analysis in nuclei (n=200) presented the same signal pattern. Instead of using whole chromosome probes for 9 and 22, we hybridised probes used to detect DiGiorge syndrome. These probes detect gene control ARSA (spectrum green) localized at 22q13 and Tuple1 at 22q11 (spectrum orange). Two signals, green and orange were identified in normal chromosome 22. Ph chromosome showed the orange signal, whereas the green signal mapped to der(10). Discussion. The localization of the hybrid BCR/ABL gene on chromosomes other than 22q is a rare event wich can only be detected by FISH techniques. When these unusual translocation occurs, the hypothesis most often put forward is that several consecutive chromosome rearrangements have taken place. In the present case the interpretation of karyotypes, FISH data and molecular evidence lead to the following hypothesis: Insertion of the BCR sequence from chromosome 22 to chromosome 9 may have ocurred, producing a BCR/ABL fusion in der(9). The Ph chromosome detected by G-banding showed a different green fluorescence intensity in the metaphase FISH signal pattern with BCR/ABL dual color dual fusion probes, as a result of an insertion on chromosome 9. This first event was followed by the translocation between the derivative 9 and chromosome 10, being the final localization of the BCR/ABL gene in 10q24. FISH analysis using a DiGeorge syndrome probe, supports the hypothesis of a multistep mechanism underlying insertion and translocations events in the present case. The relocation of BCR/ABL fusion sequence on sites other than chromosme 22q11 represent a rare type of variant Ph translocation. At least 21 cases described in the literature, showed fusion gene BCR/ABL located at 9q24. Only 12 patients with variant Ph were reported bearing BCR/ABL on a third chromosome. All of them involved a masked Ph chromosome. To our best knowledge this is the first report showing a variant Ph chromosome detected by G-banding in a CML patient due to a BCR insertion on ABL sequences and exhibiting the fusion signal in a third chromosome. Disclosures: No relevant conflicts of interest to declare.

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