bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-06. REMARKABLE RESPONSE TO BRAF INHIBITOR IN AN INFANT WITH DISSEMINATED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT)
Authors: Aung Le Le 
Published: December 2020

Abstract

INTRODUCTION
Diffuse Leptomeningeal Glioneuronal Tumor (DLGNT) are rare CNS tumors and in infants, they can be lethal. There are several anecdotal reports in infants with low grade gliomas (LGG) with treated with BRAF inhibitors.

METHODS
A six-month old baby girl presented with a 2-week history of absent visual contact and vomiting. Imaging revealed a large 4.7 X 4.2 X 2.8 cm suprasellar charismatic region mass and multiple small extra-axial plaques in spinal canal. The child developed significant ascites post VP shunt requiring shunt externalization, extensive protein infusion support and hospitalization for six weeks. Immunohisto-chemical staining revealed Olig-2 and S-100, GFAP and synaptophysin positive. EMA showed patchy cytroplasmic reactivity in stromal cells and CD99 showed diffuse reactivity in stromal and lesional cells. INI-1, IDH-1, and CD117 were negative. Ki-67 proliferation index was 8–10%. PCR for BRAF V600E/E2/D was detected and KIAA1549-BRAF fusion as negative. This was confirmed by Genome Wide Next Generation Sequencing. While waiting for GNS testing results, the baby received one dose of Vinblastine. However, within seven days of initiating Debrafenib, significant clinical and radiological responses were observed.

CONCLUSION
The baby continues safely on Debrafenib with continued dramatic radiological response. This suggest that there may be a role in early initiation of targeted therapy such as BRAF inhibitors rather than giving standard chemotherapy such as Vinblastine or Carboplatin-Vincristine in extremely ill infants with low grade gliomas.
HGG-12. A CASE OF PEDIATRIC SPINAL HIGH-GRADE GLIOMA WITH NTRK1 GENE FUSION
Authors: Morisako Tamaki , Umebayashi Daisuke , Kamata Kazuaki , Yamamoto Hiroyuki , Yamanaka Takumi , Takeuchi Hayato , Takahashi Yoshinobu , Tatsuzawa Kazunori , Miyachi Mitsuru , Yagyu Shigeki , Iehara Tomoko , Hosoi Hajime , Hashimoto Naoya 
Published: December 2020

Abstract

INTRODUCTION
Tumors arising from the spinal cord are uncommon, especially high-grade tumors in pediatric patients. We report a case of high-grade glioma in the spinal cord harboring NTRK1 gene fusion, who received effective entrectinib therapy. CASE REPORT: A 5-year-old boy presented right hemiparesis and MR imaging revealed an intramedullary enhancing mass at the vertebral body level between C3 and Th1. He underwent microsurgical partial resection and the histological diagnosis was low-grade astrocytoma. After the first-line chemotherapy with vincristine and carboplatin, his right hemiparesis deteriorated and recurrent MR imaging showed growth of the tumor. He underwent microsurgical partial resection again and the histological examination was high-grade glioma with endothelial proliferation and necrosis. The chemoradiotherapy with temozolomide and focal irradiation of 50.4 Gy were given, and his neurological symptom slightly improved. One month later, he presented respiratory disturbance and required assisted ventilation with tracheostomy. MR imaging showed tumor progression invading upward to medulla oblongata. NTRK1 gene fusion was detected in the previous surgical specimen by a gene panel testing, and he received entrectinib, a potent inhibitor of tropomyosin receptor kinase (TRK). Since then, no tumor progression has been demonstrated for several months by MRI and he has been stable neurologically.

CONCLUSION
High-grade spinal cord tumors are rare and effective treatment strategies have not been addressed. Although the frequency of the gene fusion is very low in pediatric gliomas, identification of the driver gene aberration like in this case by a gene panel can provide potential targeted therapies for selected patients.
HGG-14. TREATMENT AND PROGNOSTIC FACTORS FOR PEDIATRIC GLIOBLASTOMAS--THE 10 YEARS EXPERIENCE FROM ONE SINGLE CENTER
Authors: Li Juan , Lai Mingyao , Hu Qingjun , Zhou Cheng , Zhou Zhaoming , Shan Changguo , Hong Weiping , Zhang Xing , Zhang Yangqiong , Luo Rishun , Wang Lichao , Lu Ming , Cai Linbo 
Published: December 2020

Abstract

OBJECTIVE
We retrospectively analyzed the clinical features of pediatric glioblastoma patients in our center in the past 10 years.

METHODS
From November 2009 to December 2018, patients with glioblastoma under 18 years were admitted to Guangdong Sanjiu Brain Hospital. Clinical and pathological features were summarized, and the curative effect was evaluated.

RESULTS
A total of 31 pediatric patients were enrolled. The median age is 13.8 years (range 0.8–18), including 19 males and 12 females. To Sep, 2019, the median follow-up time was 18 months(Range 4–80 months). Among them,2 were lost to follow-up,13 died, 16 still survived, and the longest survivor survived for 80 months. The median survival time was 16.4 months, the 2-year survival rate was 38%. In the prognostic factor analysis, the median survival time of patients with surgical resection ≥90% was 18 months (95% CI 15.9–20 months), and for children with resection 90% was 11 months (95% CI 9.9–12 months), P=0.027, with significantly statistically difference. Multivariate analysis showed that tumor resection rate was an independent prognostic factor for survival.

CONCLUSION
The prognosis of pediatric glioblastoma is still dismal. This study demonstrates that prognosis of such patients with GTR or near GTR is better.
HGG-16. EXOSOME-MEDIATED INTER-CLONAL INTERACTIONS IN PEDIATRIC GBM AND DIPG
Authors: Pericoli Giulia , Galardi Angela , Petrini Stefania , Giorda Ezio , Petrilli Lucia Lisa , Paolini Alessandro , Colletti Marta , De Billy Emmanuel , Pascucci Luisa , Peinado Hector , Court Will , Jones Chris , Carai Andrea , Mastronuzzi Angela , Masotti Andrea , Locatelli Franco , Giannatale Angela Di , Vinci Maria 
Published: December 2020

Abstract
Pediatric Glioblastoma (pGBM) and Diffuse Intrinsic Pontine Glioma (DIPG) are highly heterogeneous brain tumors which we demonstrated are comprised by distinct sub-clones interacting in a functional network. Exosomes are known to mediate the crosstalk between tumor and its microenvironment. Based on this, we aimed to investigate the role of exosomes in mediating pGBM and DIPG inter-clonal communication. By using optical barcoding for single cell-tracking, we generated two bulk multicolor patient derived-cell lines (one DIPG H3.3K27M and one pGBM histone WT) from which we obtained two and five single cell-derived clones respectively. The sub-clones demonstrated significantly phenotypic differences in terms of morphology, growth, adhesion, migration and invasion properties. In particular, co-culture experiments, with the two most different clones for both cell-lines, confirmed the cell-cell interaction key role in driving their more aggressive phenotype. Furthermore, we found that pGBM and DIPG sub-clones release exosomes which are actively and differentially up-taken by individual clones. Analysis of the exosomal microRNAs showed a different profile between the two selected clones in each cell-line. In particular, we found a pool of five upregulated microRNAs in 1C5 clone (DIPG cell-line) strongly associated to Wnt-signaling and PI3K-AKT pathway. Similarly, a pool of five upregulated microRNAs for 5E2 clone (pGBM cell-line) were found associated with focal adhesion and PI3K-AKT pathway. Our study may provide novel therapeutic strategies by interfering with the exosome-mediated inter-clonal communication in pGBM and DIPG.
HGG-26. H3G34V MUTATION AFFECTS GENOMIC H3K36 METHYLATION IN PEDIATRIC GLIOMA
Authors: Huang Tina , Piunti Andrea , Bartom Elizabeth , Qi Jin , Hashizume Rintaro , Shilatifard Ali , Saratsis Amanda 
Published: December 2020

Abstract

BACKGROUND
Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas. This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase), resulting in reduced H3K36me on H3G34V nucleosomes relative to wild-type. This contributes to genomic instability and drives distinct gene expressions associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3G34V on genomic H3K36me3 enrichment in vitro.

METHODS
Doxycycline-inducible short hairpin RNA (shRNA) against H3F3A was delivered via lentivirus to established H3G34V mutant pediatric glioma cell line KNS42, and H3G34V introduced into H3.3 wild type normal human astrocytes (NHA). Transfections were confirmed by western blot, fluorescent imaging, and flow cytometry, with resulting H3.3WT and H3K36me3 expression determined by western blot. H3.3WT, H3K36me3, and H3G34V ChIP-Seq was performed to evaluate genomic enrichment.

RESULTS
Complete knockdown of H3G34V was achieved with DOX-induced shRNA, with no change in total H3.3, suggesting disproportionate allelic frequency of genes encoding H3.3 (H3F3A and H3F3B). Modest increase in H3K36me3 occurred after H3F3A-knockdown from KNS42, suggesting H3G34V alone impacts observed H3K36me3 levels. Distinct H3K36me3 genomic enrichment was observed with H3G34V knock-in.

CONCLUSIONS
We demonstrate that DOX-inducible knockdown of H3F3A in an H3G34V mutant pediatric glioma cells and H3G34V mutation transduction in wild-type astrocytes affects H3K36me3 expression. Further evaluation by ChIP-Seq analysis for restoration of wild-type genomic H3K36me3 enrichment patterns with H3G34V knockdown, and mutant H3K36me3 patterns with H3G34V transduction, is currently underway.
HGG-35. PEDIATRIC PLEOMORPHIC XANTHOASTROCYTOMA WITH ANAPLASIA TREATED WITH SURGERY AND ADJUVANT CHEMOTHERAPY: A CASE SERIES OF 3 LONG-TERM SURVIVORS
Authors: Ronsley Rebecca , Dunham Christopher , Yip Stephen , Hukin Juliette , Cheng Sylvia 
Published: December 2020

Abstract

OBJECTIVE
Pleomorphic xanthoastrocytoma (PXA) with anaplasia is a rare histological subtype of central nervous system astrocytoma and generally treated as high grade gliomas. The optimal extent of therapy required is unknown. Here we report on 3 pediatric cases of PXA with anaplasia. We also describe molecular features and methylation profile of PXA with anaplasia compared to age-matched PXA without anaplasia.

METHODS
Our institutional database was queried for cases of PXA since 1998 and 3 cases with anaplasia were identified and records reviewed.

RESULTS
2/3 patients were male and all were aged 12 at diagnosis. All underwent a gross total resection (GTR), where the diagnosis of PXA with anaplasia was made. Immunohistochemistry demonstrated that two cases were BRAF V600E positive and two were CD34 positive. Methylation profiling revealed unique pattern of CpG methylation/unmethylation. All patients underwent 5400cGy radiation to the surgical bed. 2/3 patients received concurrent temozolamide with radiation followed by maintenance chemotherapy with temozolamide and lomustine for 6 cycles as per the Children’s Oncology Group Protocol ACNS0423. These two patients had a continued complete response. The third patient received temozolamide following radiation and subsequently had recurrent disease at the end of treatment and went on to have a re-resection GTR and achieved complete response after 6 cycles of lomustine, vincristine and procarbazine. All are alive with no evidence of disease at more than 2 years post treatment completion (OS=100%,EFS=67%).

CONCLUSIONS
This rare pediatric tumor is not well understood. The genetic landscape may be informative for optimizing treatment and prognosis.
HGG-37. PAEDIATRIC GLIOBLASTOMA CELLS SHOW CRITICAL DEPENDENCIES ON EPIGENOMIC AND EPITRANSCRIPTOMIC CONTROL OF GENE EXPRESSION BY H3.3G34R/V MUTATIONS
Authors: Bjerke Lynn , Mackay Alan , Rogers Rebecca , Grabovska Yura , Molinari Valeria , Temelso Sara , Cole Kristina , Waanders Angela , Carcaboso Angel Montero , Vinci Maria , Jones Chris 
Published: December 2020

Abstract
H3.3G34R/V mutations are restricted to glioblastomas of the cerebral hemispheres, and occur predominantly in adolescents and young adults. We had previously shown these mutations to result in a global re-organisation of the activating mark H3K36me3 to drive transcription of key developmental transcription factors and oncogenes such as MYCN, however the precise mechanism was unclear. Using multiple H3G34R/V samples and ChIP-seq with antibodies specific to both wild-type and mutant histone H3.3, we show a high degree of incorporation of mutant histone into nucleosomes, with only a minority (&lt;15%) remaining wild-type only. Heterogenous G34-mutant nucleosomes displayed significantly elevated H3K36me3 binding, the majority apparently in trans to the mutation on the wild-type H3.3, and expression signatures associated with chromatin modification, cell cycle progression, DNA repair and gene transcription. Super-enhancer analysis by H3K27ac ChIP-Seq highlighted lineage-dependent transcription factors and previously identified targets MYCN and NOTCH1 (both stabilised by FBXW7, down-regulated by loss of chromosome 4q), as well as specific H3K36 lysine demethylases and splicing factors. Whole-genome CRISPR-Cas9 screening of patient-derived H3.3G34R/V cells identified critical dependencies on these latter targets, in addition to a general essentiality for genes involved in RNA processing. Assessment of RNA methylation by MeRIP-seq revealed a strong concordance of m6A-modified RNA and H3K36me3 binding, with differentially modified transcripts in mutant cellsassociated with the 3’-UTR but also the promoter and gene bodies. These data highlight the critical nature of the epitranscriptome in H3.3G34R/V-mutant paediatric glioblastoma, and highlight novel targets for therapeutic intervention.
HGG-39. CLINICAL CHARACTERISTICS AND OUTCOME OF PATIENTS WITH RADIATION-INDUCED GLIOMA
Authors: Ohno Makoto , Miyakita Yasuji , Takahashi Masamichi , Ohmura Takaki , Satomi Natsuko , Tamura Yukie , Matsushita Yuko , Ichimura Koichi , Narita Yoshitaka 
Published: December 2020

Abstract
The development of gliomas subsequent to therapeutic cranial irradiation is a rare but serious complication. The purpose of this study is to understand the clinical characteristics and outcome of patients with radiation-induced glioma (RIG). Between 2001 and 2018, we identified 10 patients with RIG, which satisfied the Cahan’s criteria in our data base. There was no sex predominance (M: 5, F: 5), and the median age of the primary diseased was 13.5 years (range: 1–39). The primary diseases included 2 germinoma, 2 acute lymphoblastic lymphoma, 2 medulloblastoma, 1 diffuse astrocytoma, 1 pilocytic astrocytoma, 1 pituitary adenoma and 1 metastatic tumor from lung cancer. All the patients received cranial radiation (range: 12–60 Gy). The median latency time between primary disease and RIG was 16 years (range: 9–30 years), which was not correlated with age at the time of primary disease (r2= 0.014, p=0.74). Radiation-induced gliomas included 8 glioblastoma and 2 grade III glioma based on histological diagnosis. After surgical removal or biopsy of the RIG, 4 patients underwent chemotherapy alone (nimustine, temozolomide (TMZ), carboplatin and etoposide), and 6 received chemotherapy (nimustine, TMZ, bevacizumab) combined with radiotherapy (range: 40-66Gy). The median progression free survival and survival time from RIG were 10.1 and 27.5 months, respectively. In summary, RIG may occur many years after successful initial treatment using radiotherapy, and the outcome of our patients with RIG supports the use of radiotherapy and/or chemotherapy after surgical resection.
HGG-45. PROTEOMIC ANALYSIS OF PEDIATRIC DIFFUSE ASTROCYTOMAS YIELDS PATHWAYS ASSOCIATED WITH BOTH PROGRESSION-FREE AND OVERALL SURVIVAL
Authors: Sells Blake , Fleming Jessica , Graham Richard , McElroy Joseph , Haque Jahar , Boué Daniel , Becker Aline , Bell Erica , Finlay Jonathan , Chakravarti Arnab 
Published: December 2020

Abstract
Brain tumors are now responsible for more deaths each year than any other childhood cancer. Current studies aim to discover key molecular drivers that can explain prognosis and serve as targets for new therapeutic approaches, reducing morbidity. In this study, we performed LC-MS/MS proteomics on a cohort of 28 primary diffuse astrocytoma formalin-fixed paraffin embedded samples (WHO Grades II-IV) from patients at Nationwide Children’s Hospital with a median follow-up time of 2.3 (0.6–20.2) years. Ingenuity Pathway Analysis was used to analyze the proteomic data after using both age and grade as covariates and only including proteins with p-values less than 0.05. The upregulation of a well-known oncogenic pathway, the Protein Kinase A signaling pathway, was significantly associated with greater risk of progression and death (P=5.5E-07 and P=4.6E-04). Integrin signaling, a pathway commonly suppressed in cancer, was similarly downregulated in those with greater risk of progression and death (P=3.3E-04 and P=1.7E-07). A global upstream analysis of the proteomic data also predicted activation of the oncogene MYCN in those who performed poorly, supporting previous studies. When comparing grade II (n=10) to grade III (n=8) and IV (n=10) primary tumors, the pathway most upregulated in higher histopathological grades was EIF2 Signaling (P=4.9E-49). This pathway has previously been associated with resistance in adult glioblastoma. These pathways, and the proteins detected within, may provide novel means by which to better understand and treat pediatric diffuse gliomas. Ongoing studies are in progress to understand how these pathways drive aggressiveness and differ from adult astrocytomas.
HGG-49. A PEDIATRIC THALAMIC HIGH-GRADE GLIOMA WITH H3F3A K27M AND BRAF V600E DOUBLE MUTATIONS
Authors: Terashima Keita , Sugawa Masahiro , Sakamoto Kenichi , Kiyotani Chikako , Osumi Tomoo , Shioda Yoko , Deguchi Takao , Kato Motohiro , Tomizawa Daisuke , Usami Kenichi , Ogiwara Hideki , Tsutsumi Yoshiyuki , Fuji Hiroshi , Nakano Noriyuki , Yoshioka Takako , Nakano Yoshiko , Ichimura Koichi , Matsumoto Kimikazu 
Published: December 2020

Abstract

CASE
A 18-month-old boy presented with approximately 2 months history of progressive left hemiparesis and left exotropia. MRI study showed a 3–4 cm T1-iso, T2-high tumor at right thalamus to midbrain with little contrast enhancement. The patient underwent endoscopic biopsy of the tumor, which showed relatively dense proliferation of small cells with round nuclei, mitosis of the tumor cell, but no necrosis. Immunohistochemical showed positive stain of GFAP and Olig2. Ki-67 was 34%. The histopathological diagnosis was compatible with high grade glioma. Chemotherapy with vincristine, cyclophosphamide, cisplatin and etoposide was initiated. Molecular testing of the tumor revealed H3F3A K27M and BRAF V600E double mutations in DNA from frozen tumor tissue.

DISCUSSION
The concurrent mutation of H3F3A K27M and BRAF V600E in pediatric glioma is very rare, but there are several cases previously reported in literature. Interestingly those cases are heterogenous in age, location, histopathological subtypes and clinical outcome.
HGG-53. PROJECT HOPE: “PEDIATRIC AND AYA HIGH-GRADE GLIOMA OMICS PROJECT”- A LONGITUDINAL MOLECULAR LANDSCAPE OF HIGH-GRADE GLIOMAS RESOLVED AT SINGLE-CELL LEVEL
Authors: Hack Olivia A , Babikir Husam , Jiang Li , Shamardani Karin , Liu Ilon , Shaw McKenzie , Cunliffe-Koehler Kennedy , Resnick Adam , Prados Michael , Monje Michelle , Diaz Aaron , Filbin Mariella G 
Published: December 2020

Abstract
High-grade gliomas (HGG) are among the most prevalent and fatal cancers in pediatric, adolescent, and young adult (AYA) patients. Especially understudied are older children and young adults, aged 16–39 years. Previously, we profiled primary pediatric HGGs through single-cell transcriptomics and identified the genetic, epigenetic and developmental programs that drive their malignant progression. However, the questions of how these programs compare to those in older HGG patients, what the mechanisms are by which these tumors ultimately evolve to drive recurrence and treatment resistance, and how distinct tumor cell subpopulations bidirectionally communicate with their microenvironment remain to be elucidated. Here, we use single-nucleus RNA sequencing to compare 11 paired, matched high-grade gliomas at diagnosis and recurrence and 15 additional H3K27M primary and recurrent DMG samples in pediatric and AYA patients. In all tumors, we find both undifferentiated and differentiated tumor cells recapitulating distinct glial lineages, as well as diverse microenvironmental cell populations. When longitudinally comparing this tumor architecture within matched pairs, we find substantial differences in transcriptional program expressions. Diagnostic samples include more differentiated, astrocyte-like tumor cells, while cells from recurrent samples more highly express ribosomal and heat-shock protein genes, suggesting tumor progression- and treatment-related shifts. Ongoing sequencing and analysis will allow for unprecedented insight into the evolutionary dynamics of pediatric and AYA high-grade gliomas as well as delineate differences in the biology of DMGs occurring in different age groups. This multi-institutional project was funded by the National Institute of Health.
HGG-54. HISTOLOGICAL AND MOLECULAR CHARACTERIZATION OF HIGH-GRADE BRAIN TUMORS SECONDARY TO TOTAL BODY IRRADIATION FOR HEMATOLOGICAL MALIGNANCIES
Authors: Miele Evelina , Pagliara Daria , Pedace Lucia , Camassei Francesca Diomedi , Cacchione Antonella , Colafati Giovanna Stefania , Carai Andrea , Locatelli Franco , Mastronuzzi Angela 
Published: December 2020

Abstract

INTRODUCTION
Hematopoietic stem cell transplantation (HSCT) is increasingly used in the treatment of acute leukemias (AL), non-Hodgkin lymphomas and other primary malignancies. However, a growing number of neoplasms secondary to HSCT are reported. The combination of total body irradiation (TBI) and high dose chemotherapy (HD-CT) as conditioning regimen is considered a risk factor. We present four children who survived AL, treated with HSCT and conditioning regimens including TBI/HD-CT. These patients developed a high-grade-brain tumor. We analyzed histological and molecular characteristics of neoplasms.

METHODS
Histologically, tumors were assessed for: presence of mitosis, necrosis and vascular proliferation; expression of ki67; expression of neuronal and glial markers, p53 and therapeutic targets. We analyzed the DNA methylation profile (DMP) of all tumors using IlluminaEPICarrays and compared it to the brain tumor classifier which allowed to generate the CNVs.

RESULTS
Morphologically two cases were defined as anaplastic astrocytoma, two cases as glioblastoma. Based on the DMP, all cases were found to belong to the methylation class “glioblastoma, IDH wildtype, subclass midline”, hypermutants, with gain of chromosome 1q and loss of 1p. Two cases showed PDGFRA amplification. All patients were treated with Temozolomide combination therapy +/- Bevacizumab and radiation therapy. At progression three patients were treated with checkpoint inhibitors.

CONCLUSIONS
The improvement of the precision medicine is fundamental in the therapeutic decision of brain tumors and even more in neoplasms secondary to antiblastic treatments. DMP and CNV have proven to be useful tools to complement the histological characterization of the reported cases.