bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCT-72. ANALYSIS OF microRNA EXPRESSION PROFILE OF INTRACRANIAL GERM CELL TUMORS: A PROMISING TOOL FOR DIFFERENTIAL DIAGNOSIS
Authors: Nakano Yoshiko , Satomi Kaishi , Takami Hirokazu , Nishikawa Ryo , Yamasaki Fumiyuki , Taketoshi Maehara , Saito Nobuhito , Kanemura Yonehiro , Sakamoto Hiroaki , Ochiya Takahiro , Ichimura Koichi 
Published: December 2020

Abstract

INTRODUCTION
One of the major limitations of pathological diagnosis for intracranial germ cell tumors (iGCTs) is tumor heterogeneity, which cannot be evaluated using limited amount of tumor tissues. In this study, we performed comprehensive analysis of microRNA (miRNA) of iGCTs to identify miRNAs profile to help determine tumor diagnosis.

METHODS
RNA was extracted from frozen samples of 16 germinoma and 14 NGGCTs. Five non-iGCT pediatric brain tumor tissues were used as control. miRNA expression analysis was performed using a 3D-Gene Human miRNA Oligo Chip ver.22 (Toray Industries, Inc) which was designed to detect 2565 miRNAs. The miRNA expression profile was analyzed using t-SNE dimensionality reduction and weighted average difference method (WAD).

RESULTS
Different histological subtypes of the iGCTs and control samples were clustered into distinct classes. Furthermore, we found that the germinoma, NGGCTs and control samples may be readily distinguished by expression patterns of miR-200 and miR-371a-3p: a high expression of miR-200 was observed in the NGGCTs, whereas a high expression of miR-371a-3p was observed in all cases of germinoma and some of NGGCTs. Neither of miR-200 nor miR371-3p was highly expressed in control samples.

CONCLUSION
Our data indicated that germ cell tumor and other pediatric brain tumors, and also germinoma and NGGCT can be distinguished by expression patterns of 2 micro RNA, miR-200 and miR-371a-3p. These 2 microRNA may serve as a useful tool for supporting the pathological diagnosis of iGCTs.
GCT-75. ISOLATED PITUITARY STALK THICKENING
Authors: Bennett Julie , Nobre Liana , Bouffet Eric , Abla Oussama , Wasserman Jonathan , Ertl-Wagner Birgit , Bartels Ute 
Published: December 2020

Abstract

OBJECTIVES
Only few studies have examined the predictive factors and outcome of isolated pituitary stalk thickening (PST) in children. We aim to describe our institutional cohort to determine predictors of future malignancy.

METHODS
A search of the radiology, endocrinology and neuro-oncology databases was performed to identify patients with isolated PST diagnosed between January 2000 and June 2019. Clinical data was collected. A detailed radiology review of baseline and follow up magnetic resonance imaging (MRI) was undertaken in a blinded fashion by two examiners.

RESULTS
Forty-four patients were identified, with 37 meeting criteria for isolated PST and adequate imaging. Median age of baseline MRI was 9.9 years (range 0.9–17.5). Twenty-three were female (62%). Median follow up time was 5 (0.31–18.6) years. Indication for MRI was symptoms of diabetes insipidus (DI) in 28 patients with the remainder having other concerns for endocrine disturbance (7), headache (1) or visual impairment (1). Thirty-five subjects had pituitary dysfunction (95%), including 30 with diabetes insipidus (81%). Nine patients developed a malignancy (24%), with germinoma (5), Langerhans cell histiocytosis (3) and lymphoma (1) at a median of 0.36 years, 0.63 years and 1.1 years respectively. Elevated white blood cell count (&gt;5 x 106/L) in initial cerebrospinal fluid analysis was predictive of future diagnosis of germinoma or lymphoma (p=0.027).

CONCLUSION
In this cohort 24% of children with PST were eventually diagnosed with a neoplasia after a median of 0.63 years. Pleocytosis in initial CSF samples was predictive for future development of germinoma or lymphoma.
HGG-04. ZINC ENHANCES TEMOZOLOMIDE CYTOTOXICITY IN PEDIATRIC GLIOBLASTOMA MULTIFORME MODEL SYSTEM
Authors: Toren Amos , Yalon Michal , Dafni Aner , Mehrian-Shai Ruty 
Published: December 2020

Abstract

BACKGROUND
Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients respond to it positively. We have shown that zinc metal reestablishes chemosensitivity in adult GBM in vitro and also in vivo but this effect has not been tested with pediatric GBM.

METHODS
Using Human pediatric glioblastoma cell lines- KNS42 (mutant p53/ MGMT [+]) and SF188 (mutant p53/ MGMT [-]), we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM.

RESULTS
In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and a decrease in growth fraction as manifested by low ki67. Beta gal analysis showed that most of the remaining cells after the combination therapy are in senescence state. In order to eliminate the senescent population created as a result of the combined treatment of TMZ and Zinc, we decided to use a senolytic agent Navitoclax (ABT-263) that was demonstrated to be effective in reducing senescent cells by specific inhibition of Bcl-2, Bcl-XL and Bcl-w. Following the addition of Navitoclax to the combined treatment, SF188 cells, but not KNS42, show a significance reduction in viability compare to the combination treatment.

CONCLUSIONS
Our results suggest that zinc may serve as a potentiator of TMZ therapy in pediatric GBM patients and using a second hit with senolytic drug in some cases may be even more beneficial.
HGG-07. CYCLIN-DEPENDENT KINASES AS TARGET STRUCTURES FOR CANCER THERAPY – A COMPARATIVE IN VITRO ANALYSIS ON PATIENT-DERIVED GLIOBLASTOMA CELL CULTURE MODELS
Authors: Riess Christin , Classen Carl Friedrich , Maletzki Claudia 
Published: December 2020

Abstract

INTRODUCTION
Current therapeutic approaches have limited clinical success for Glioblastoma patients, making novel strategies urgent. Cyclin-dependent kinases (CDK) are crucial in cell cycle, oncogenic transcription, DNA repair, and stem-cell renewal. Glioma cells frequently show genomic alterations in CDKs. Here, we evaluated the antitumoral activity of selective CDK inhibitors (CDKI) abemaciclib (CDK4/6), palbociclib (CDK4/6), and dinaciclib (CDK1/2/5/9) alone and in combination with chemo-/radiotherapy. MATERIALS/

METHODS
Low passage glioblastoma cell lines (N=5) with different molecular characteristics were cultured in 2D and 3D (neurospheroids (NSPs), glioma stem-cells (GSCs). The impact of CDKI alone or in combination with TMZ and radiation (2Gy) was examined. Viability was measured using Calcein-AM and 3D-Glo assays; DNA double-strand breaks by γ-H2AX immunofluorescence. Functional analyses were performed from a 2D culture (72h treatment).

RESULTS
Dinaciclib significantly affected viability of GBM cell lines even shortly after low-dose treatment. CDK 4/6 inhibitors were less effective. Abemaciclib and dinaciclib acted radio-sensitizing. Dinaciclib combined with different substances (72h, dose: IC20), synergistically potentiated antitumoral effects. In a scratch assay, abemaciclib decelerated wound healing; dinaciclib even induced cell death. Microarray analysis revealed altered gene expression: Genes mediating cell adhesion, division, DNA-binding, apoptosis (Casp3,Casp8), senescence (ASF1A,CENPA,FBXO31), and autophagy (ATG4D,ATG2A,SOGA1) were upregulated. Chemotaxis-mediating (CXCL8,CCL20) and proto-oncogenes like JUNB and FOS were strongly down-regulated. Long-term treatment induced dinaciclib resistance in 1/5 cases, and none abemaciclib-treated cells. This was reversed when dinaciclib was combined with TMZ.

CONCLUSION
Our results demonstrate strong anti-GBM activity of dinaciclib and abemaciclib, with additive effects of chemotherapy and radiosensitization, encouraging to move forward this strategy.
HGG-09. FIRST LINE THERAPY OF PEDIATRIC GLIOBLASTOMA WITH LAROTRECTINIB
Authors: Alharbi Musa , Mobark Nahla Ali , Balbaid Ali Abdullah O , Alanazi Fatmah A , Aljabarat Wael Abdel Rahman , Bakhsh Eman A K , Turkistani Murad , Abedalthagafi Malak 
Published: December 2020

Abstract

PURPOSE
In this case report, we document new recommendations for the treatment of pediatric glioblastoma based on a genetic understanding of the disease.

PATIENTS AND METHODS
A Saudi girl aged 18 months presented with a history of right sided weakness and partial seizures. MRI revealed the presence of large complex left frontal tumor. Craniotomy and gross total resection were performed. post-operatively The patient showed excellent recovery with no neurological deficits. Pathology reports confirmed glioblastoma (GBM). Due to the expected poor survival, the patient’s family declined standard therapy, including chemotherapy and/or radiation therapy.

RESULTS
Molecular analysis showed positive fusion mutations for ETV6-NTRK3 making the patient an ideal candidate for larotrectinib, an oral tyrosine kinase (TRK) inhibitor. Unfortunately, follow-up MRI showed local tumor recurrence at 3-months post-surgery. The family agreed to the initiation of oral larotrectinib as a less invasive therapy. The patient tolerated Larotrectinib very well with no reported side effects. Follow up MRI was performed 8-weeks post-larotrectinib treatment and showed significant tumor regression, indicating an excellent treatment response.

CONCLUSION
This case highlights how TRK-inhibitors can be integrated as a first-line therapy for pediatric high grade GBMs harboring TRK-fusions. We also highlight the need for the integration of genomic profiling and molecular analysis into the routine histopathologic analyses of pediatric patients with malignant primary intracranial tumors, to detect any genetic mutations that can be targeted with available therapies to avoid the morbidity associated with non-precision conventional therapies.
HGG-18. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA
Authors: Kawakibi Abed Rahman , Tarapore Rohinton S , Gardner Sharon , Chi Andrew , Kurz Sylvia , Wen Patrick Y , Arrillaga-Romany Isabel , Batchelor Tracy T , Butowski Nicholas A , Sumrall Ashley , Shonka Nicole , Harrison Rebecca , DeGroot John , Mehta Minesh , Odia Yazmin , Hall Matthew D , Daghistani Doured , Cloughesy Timothy F , Ellingson Benjamin M , Umemura Yoshie , Schwartz Jonathan , Yadav Vivekanand , Cartaxo Rodrigo , Siada Ruby , Miklja Zachary , Bruzek Amy , Cantor Evan , Wierzbicki Kyle , Paul Alyssa , Wolfe Ian , Leaoard Marcia , Garton Hugh , Mody Rajen , Robertson Patricia L , Lu Guangrong , Merdinger Krystal , Venneti Sriram , Oster Wolfgang , Allen Joshua E , Koschmann Carl 
Published: December 2020

Abstract
ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.
HGG-19. IDENTIFICATION OF NOVEL SUBGROUP-SPECIFIC miRNA EXOSOMAL BIOMARKERS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Petrilli Lucia Lisa , Paolini Alessandro , Galardi Angela , Pericoli Giulia , Colletti Marta , Ferretti Roberta , Paolo Virginia Di , Pascucci Luisa , Peinado Hector , Jones Chris , Cacchione Antonella , De Palma Luca , Alonso Marta , Moore Andrew , Carcaboso Angel Montero , Carai Andrea , Mastronuzzi Angela , Locatelli Franco , Masotti Andrea , Giannatale Angela Di , Vinci Maria 
Published: December 2020

Abstract
Pediatric high-grade gliomas (pHGG) are heterogeneous brain tumors for which new specific diagnostic/prognostic biomarkers are needed. In this study, we aimed to identify new pHGG subgroup specific biomarkers by exploiting exosomes, known vehicles of oncogenic signals. We used plasma from 23 patients (including 6 controls) and conditioned medium from 12 patient-derived cell-lines, representing all locational and molecular subgroups. Upon exosome isolation, total RNA was extracted and miRNAs were assessed using a PCR Panel. Analysis of plasma miRNome showed that tumor exosomal samples were largely clustered together, independently from their locational and/or molecular subgroup. We identified 20 significantly upregulated and 25 downregulated miRNAs compared to controls. Interestingly, 27 miRNAs were expressed only in tumors. Furthermore, the unsupervised clustering showed a clear separation based on locational (hemispheric vs pontine) and mutational (WT vs H3.3G34R or H3.3G34R vs H3K27M) subgroup comparisons, with the identification of distinct miRNomes underlying the key role of location and mutations in defining the pHGG exosomal miRNA profile. This was further confirmed analyzing the miRNOme from cell-line derived exosomes. Moreover, we identified a pool of significantly differentially regulated miRNAs in diagnose vs relapse and biopsy vs autopsy cell-lines. Most importantly, when comparing hemispheric vs pontine and H3.3G34R vs H3.3K27M, we identified respectively four and three miRNas equally dysregulated and in common between plasma and cell-lines. Those were strongly associated mainly to transcriptional regulation and targeting TTC9, linked to cancer invasion and metastasis. Based on this, we suggest exosomal miRNAs as a powerful new pHGG diagnostic/prognostic tool.
HGG-21. GERMLINE MUTATIONS IN MSH2 GENE IN PEDIATRIC PATIENTS WITH CONGENITAL AND SPORADIC GLIOBLASTOMA
Authors: Ejmont Maria , Rydzanicz Małgorzata , Grajkowska Wiesława , Perek-Polnik Marta , Sowińska Agnieszka , Kozłowska Magdalena , Łastowska Maria , Pronicki Maciej , Płoski Rafał , Dembowska-Bagińska Bożenna , Trubicka Joanna 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma (GBM) remains one of the biggest therapeutic challenges in neuro-oncology. In spite of multimodal treatment approaches the prognosis of GBM is extremely poor, median survival is estimated about 12–16 months. Although GBM is one of the most common and malignant primary brain tumors, pediatric glioblastoma, including congenital is a very rare tumor, with an incidence of about 1.1–3.4 per million live births. Moreover, the mode of presentation, behavior, response to therapy and molecular background of pediatric glioblastomas differs from adult type of GBM. Until now, about ten patients with congenital glioblastoma have been described and in none of them germline markers were examined. Here we report two patients with GBM, one with congenital tumor with germline mutations in MSH2 gene.

METHODS
Targeted Next-Generation Sequencing (NGS) of the probands DNA extracted from leucocytes was performed using the TruSight One sequencing panel on an Illumina HiSeq 1500. Applied gene panel investigated the coding sequence and splice sites of 4813 genes associated with known disease phenotypes. The NGS data were analyzed using an in-house procedure. Identified variants were validated by Sanger sequencing.

RESULTS
NGS analysis of patients constitutional DNA revealed know, pathogenic variants c.940C&gt;T and c.942 + 3A&gt;T in MSH2 gene (NM_000251.3) associated with MMR-dependent hereditary cancer syndromes.

CONCLUSION
Molecular analysis are heavily needed for better understanding of pediatric GBM etiology and new treatment modality implementation. Identification of this oncogenic driver may provide insight into the pathogenesis of GBM, including congenital cases. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064 and 2016/21/B/NZ2/01785).
HGG-24. HIGH-GRADE GLIOMA WITH A NOVEL FUSION GENE OF VCL-ALK
Authors: Yamamoto Shunsuke , Koga Yuhki , Ono Hiroaki , Asai Hiroshi , Ono Kyutaro , Hatae Ryusuke , Hata Nobuhiro , Mizoguchi Masahiro , Yamamoto Hidetaka , Suzuki Satoshi O , Iwaki Toru , Ohga Shouichi 
Published: December 2020

Abstract
A previously healthy 2-year-old boy presented with status epilepticus following intermittent vomiting. Computed tomography scan showed a 7cm mass on the left occipital lobe with midline shift, inferior cerebellar herniation, and diffuse cerebral edema. The extensive dissemination to bilateral cerebral hemispheres, brain stem, and optic nerve was also observed. He underwent brain biopsy from the lesion on his left occipital lobe. The histopathological diagnosis determined the diffuse or epithelial proliferation of astrocytic tumor cells with high mitotic rate, positive for p53 and glial fibrillary acidic protein positive staining consistent with high-grade glioma. The progressive tumor led to communicating hydrocephalus, that was favorably controlled by cerebrospinal fluid shunting. The data from the FoundationOne CDx cancer genome profile disclosed a novel VCL- anaplastic lymphoma kinase (ALK) fusion in the tumor cells of the patient. ALK rearrangement was determined to be positive for the tumor cells assessed by fluorescence in situ hybridization. Only 4 pediatric cases of glioma with ALK-rearrangement have ever been reported. All of them received subtotal or gross total resections and then survived with or without chemotherapy. This is the first case of glioma harboring VCL as a novel partner of ALK fusion gene. After the favorable response to the first-line chemotherapy, subsequent irradiation therapy has now been scheduled. The molecular classification of high-grade glioma may help to expand the targeted therapy for unresectable advanced brain tumor.
HGG-34. DETECTION OF ONCOGENIC FUSION EVENTS IN SUPRATENTORIAL GLIOBLASTOMAS OF YOUNG CHILDREN
Authors: Pietsch Torsten , Vokuhl Christian , Gielen Gerrit H , von Bueren Andre O , Dörner Everlyn , Kristiansen Glen , Waha Andreas , Kramm Christof 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma in infancy and early childhood is characterized by a more favorable outcome compared to older children, a stable genome, and the occurrence of tyrosine kinase gene fusions that may represent therapeutic targets.

METHODS
50 glioblastomas (GBM) with supratentorial location occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET, Molecular Inversion Probe (MIP) methodology, and targeted RNA sequencing.

RESULTS
37 supratentorial GBM occurred in the first year of life, 13 GBM between one and four years. 18 cases showed fusions of ALK to different fusion partners; all occurred in the first year of life (18/37 cases, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two novel fusions. The different methods led to comparable results; targeted RNA sequencing was not successful in a fraction of cases. Break-apart FISH led to reliable results on the next day, MIP technology represented the most sensitive method for analysis of FFPE samples.

CONCLUSIONS
Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of children younger than four years; the most frequent were ALK fusions occurring in infant GBM. DNA based MIP technology represented the most robust and sensitive assay.
HGG-47. DECREASED GROWTH VELOCITY WITH LONG TERM USE OF BRAFV600e AND MEK INHIBITION IN A PATIENT WITH ANAPLASTIC GANGLIOGLIOMA
Authors: Tran Hung , Cooper Robert 
Published: December 2020

Abstract

PURPOSE
To describe decreased growth velocity with long term use of BRAFV600e and MEK inhibition in a patient with anaplastic ganglioglioma.

RESULTS
4-year-old patient was found to have a 6 x 4.6 x 5 cm mass in the hypothalamus. Pathology consistent with anaplastic ganglioglioma and chromosomal microarray revealed a BRAFV600e mutation. Patient started on dabrafenib and trametinib and tumor decreased 85% after 3 months. She is stable without significant toxicities 39 months on therapy, and is now 8 years old. Patient had been growing at the 25% for weight and 12% for height but is now 65% for weight and 0.5% for height. It is difficult to tease out the relationship between the tumor, the location of the tumor, and the BRAF and MEK inhibitors and their effect on growth. Discussions with the family and endocrinology are ongoing but being &lt;1% for height will lead to decrease in quality of life.

CONCLUSIONS
Further follow-up study is needed to determine if this is truly a long-term toxicity, or if this may just be a direct result of the location of the tumor. Would supplementation with growth hormone in this patient lead to losing control of a high grade tumor, or would it simply replace a hormone that is not produced?
HGG-51. PAIRED EPITHELIOID GLIOBLASTOMA PATIENT DERIVED XENOGRAFT MODELS WITH/WITHOUT MOLECULAR TARGET THERAPY
Authors: Sasame Jo , Tateishi Kensuke , Ikegaya Naoki , Miyake Yohei , Miyake Shigeta , Nakamura Taishi , Yamamoto Tetsuya 
Published: December 2020

Abstract
Epithelioid glioblastoma (E-GBM) predominantly arises at younger age and promotes dismal prognosis. Because of its rare etiology, pathological and genetical characterization of E-GBM remains elusive. Herein, we report 2 patient-derived E-GBM xenograft (PDX) models from young adult patients (YMG62 and YMG89) with BRAFV600E and TERT promoter mutation. The YMG62 patient received dabrafenib with trametinib, while YMG89 patient received dabrafenib monotherapy after recurrence with Stupp regimen. These molecular target therapies were initially responded, but gradually became resistant (YMG62R and YMG89R) and resulted in lethal. Treatment resistant cells were collected from CSF. These primary cells were propagated at multiple passage in vitro. Paired PDX models were established from initial and recurrent cells. All PDX tumors were preferentially disseminated and negative expression of GFAP, which were recapitulated to the patient characteristics. BRAF and MEK inhibitor moderately suppressed cell viability of YMG62 and YMG89 in vitro. However, BRAF and MEK inhibitor became resistant at recurrence in vitro. Western blotting indicated retained phospho-MEK expression after BRAF/MEK inhibitor treatment in recurrent cells, which implies crucial role of MEK activation for tumor maintenance in BRAFV600E mutant E-GBM. Together, paired E-GBM PDX models with/without molecular target therapy recapitulate patient characteristics, which may contribute to elucidate tumor biology and establish novel therapeutic target in E-GBM.