bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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 (>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

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

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

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

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

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

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>T and c.942 + 3A>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

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

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

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 <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

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.
IMG-01. DWI RATIO OF HISTOLOGICAL MOLECULAR SUBTYPES OF PAEDIATRIC MEDULLOBLASTOMAS
Authors: Tang Phua Hwee , Low Sharon , Tan Enrica , Chang Kenneth
Published: December 2020

AIM

To evaluate if diffusion weighted imaging (DWI) ratio on MRI is able to distinguish between the histological molecular subtypes of paediatric medulloblastomas.

MATERIALS AND METHODS

From 2002 to 2017, 38 cases of medulloblastoma with preoperative MRI available had histological subtyping performed with NanoString nCounter technology. The medulloblastomas were classified into 4 subtypes. There were 3 Sonic Hedgehog (SHH), 9 Wingless (WNT), 12 Group 3 and 14 Group 4 subtypes. Single operator manually outlined solid non-haemorrhagic component of the tumour on DWI images with largest axial tumour cross sectional diameter, correlating with the other MRI images (T1 pre and post contrast, SWI/GRE, FLAIR) to identify areas of haemorrhage. The same operator also drew region of interest to identify normal cerebellar tissue on the same axial images on which the tumour was outlined. All MRI images were obtained from the department’s Radiological Information System Picture Archiving and Communicating System (RIS PACS). DWI ratio for each case was obtained by dividing the values obtained from tumour by normal cerebellar tissue seen on the same axial image.

RESULTS

DWI ratio of all medullloblastomas is 1.34 +/- 0.18. DWI ratio of SHH subtype is 1.43 +/- 0.07. DWI ratio of WNT subtype is 1.40 +/- 0.07. DWI ratio of Group 3 subtype is 1.31 +/- 0.25. DWI ratio of Group 4 subtype is 1.30 +/- 0.17. There is no significant statistical differences in the DWI ratio between the various subtypes.

CONCLUSION

DWI ratio of medulloblastoma is unable to distinguish between the 4 medulloblastoma subtypes.
IMG-02. USEFUL DIAGNOSIS OF PEDIATRIC CYSTIC BRAIN TUMORS USING MULTIPLE POSITRON EMISSION TOMOGRAPHY STUDIES
Authors: Miyake Keisuke , Fujimori Takeshi , Toyota Yasunori , Ogawa Daisuke , Hatakeyama Tetsuhiro , Okauchi Masanobu , Kawanishi Masahiko , Tamiya Takashi
Published: December 2020

OBJECTIVE

Pediatric brain tumors are primarily diagnosed using MRI or CT examination; however, determining the correct diagnosis using only morphological MRI can sometimes be challenging. Positron emission tomography (PET) uses radiotracers for metabolic and molecular imaging. We examined the accumulation of multiple PET (FDG, MET, FLT, and FMISO) studies for diagnosing pediatric cystic brain tumors.

METHODS

We performed PET scans for eight pediatric patients (five pilocytic astrocytoma, one pleomorphic xanthoastrocytoma, one diffuse astrocytoma with IDH1 mutation, one ganglioglioma) from April 2010 to December 2019. The resulting studies were compared by measuring the tumor-to-normal lesion (T/N) ratio of FDG, MET, and FLT and the tumor-to-blood value (T/B) ratio of FMISO between each pediatric cystic brain tumor.

RESULTS

All pediatric brain tumors showed tumor uptake of FDG, MET, and FLT. We could not examine FMISO PET for one diffuse astrocytoma with IDH1 mutation. The T/N ratios of FDG, MET, and FLT and the T/B ratio of FMISO were 1.07, 2.76, 4.6, and 1.12 for pilocytic astrocytoma; 0.65, 4.6, 7.67, and 1.38 for pleomorphic xanthoastrocytoma; 0.61, 2.14, and 3.82 for diffuse astrocytoma with IDH1 mutation; and 0.79, 1.78, 5, and 1.49 for ganglioglioma, respectively. The T/N ratios of MET and FLT for pleomorphic xanthoastrocytoma were high, but the Ki-67 labeling index was 1%. In the ganglioglioma, the T/N ratio of FLT was high, but the T/N ratio of MET was low.

CONCLUSION

Specialized multiple PET accumulation patterns for tumors are useful for discriminating each tumor.
IMG-09. RESPONSE ASSESSMENT IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY COMMITTEE
Authors: Cooney Tabitha , Cohen Kenneth J , Guimaraes Carolina V , Dhall Girish , Leach James , Massimino Maura , Erbetta Alessandra , Chiapparini Luisa , Malbari Fatema , Kramer Kim , Pollack Ian F , Baxter Patricia , Laughlin Suzanne , Patay Zoltan , Poussaint Tina Young , Warren Katherine E
Published: December 2020

Optimizing the conduct of clinical trials for diffuse intrinsic pontine glioma (DIPG) involves use of consistent, objective disease assessments and standardized response criteria. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, an international panel of pediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response in children with CNS tumors. A subcommittee of RAPNO was formed to specifically address response assessment in children and young adults with DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its definition and recent molecular classifications, dearth of imaging response data, the phenomena of pseudoprogression, and measuring response in the era of focal drug delivery. The committee has recommended response be assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and anti-angiogenic agents. Clinical imaging standards and imaging quality control are defined. Unique recommendations for DIPG response include an eight-week response duration, a twenty-five percent decrease for partial response, and the distinction of pontine and extra-pontine response for trials that use focal drug delivery. The recommendations presented here represent an initial effort to uniformly collect and evaluate response assessment criteria; these recommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.
IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
Authors: Boult Jessica , Bjerke Lynn , Fofana Mariama , Vinci Maria , Molinari Valeria , Mackay Alan , Temelso Sara , Box Gary , Eccles Suzanne , Carcaboso Angel , Castro Maria , Waanders Angela , Cole Kristina , Jones Chris , Robinson Simon
Published: December 2020

Approximately 15% of paediatric/young adult cerebral hemispheric glioblastomas (pGBM) harbour G34R/V mutations in H3F3A, encoding the histone H3.3 variant. Development of novel therapeutic interventions demands models that accurately recapitulate this subset of disease and sensitive imaging methods with which to study tumours in situ. Three H3F3A_G34R primary-patient-derived cultures, alongside established cell-line KNS42 (H3F3A_G34V), were implanted orthotopically in immunocompromised mice. KNS42 (TP53_R342*) tumours were clearly detectable using T2-weighted (T2w)-MRI, enhanced following contrast agent administration, indicating impaired blood-brain barrier (BBB) integrity, and demonstrated minimal invasion. OPBG_GBM_001 cells (TP53_89-90X,ATRX_II2133-2144X) formed infiltrative tumours that were hyperintense on T2w-MRI and demonstrated contrast-enhancement suggestive of heterogeneous BBB integrity. HSJD_GBM_002 cells (TP53_P278T,ATRX_R666*) spread diffusely throughout the brain with their full extent typically not discernible by T2w-MRI, the BBB also remaining intact. No evidence of CHOP_GBM_001 tumour was detected by MRI 11months post-implantation. Immunocompetent syngeneic models using tumour cells induced by mutations modelling hemispheric pGBM (NRAS/shP53/shATRX±H3.3G34R) are being explored. Fast growing heterogeneous lesions with variable contrast-enhancement were identified; the H3.3G34R mutation conferred longer median survival (2 clones:25/28days, control:14days). These models have the advantage of an intact immune system and short latency for initial efficacy studies. Primary pGBM cells yield tumours that are more representative of the spectrum of clinical disease; variable hyperintensity on T2w-MRI corresponding to cellular density, with diffusely infiltrative disease less clearly definable, a paucity of oedema and a range of contrast-enhancement. Pathological features including giant multinucleated cells, and mitotic figures were also evident.
IMG-21. PROSPECTIVE PREOPERATIVE DETERMINATION OF ISOCITRATE DEHYDROGENASE MUTATION IN GLIOMAS USING SPECTRAL EDITING MAGNETIC RESONANCE SPECTROSCOPY
Authors: Nguyen Thanh , Melkus Gerd , Taccone Michael , Ghinda Diana , Torres Carlos , Zakhari Nader , Woulfe John , Jansen Gerrard , Cameron Ian , Moldovan Ioana , Alkherayf Fahad
Published: December 2020

BACKGROUND

Gliomas are the most common malignant brain tumors in children and adults. A subset of these tumors harbour mutations in the enzyme isocitrate dehydrogenase (IDH) which produces the novel oncometabolite 2-hydroxyglutarate (2HG). In general, patients with an IDH mutant glioma have a longer survival—often necessitating more re-treatment sessions over the span of a patient’s life and surveillance monitoring for tumor recurrence. The need to non-invasively detect early evidence of tumor recurrence is therefore heightened in this unique subset of patients with extended survival. As magnetic resonance spectroscopy (MRS) has been demonstrated to measure biochemical components of intracranial tumors using MRI, we conducted a study in 58 pre-operative adult patients to determine if a diagnosis of IDH mutant glioma could be made confidently using imaging data.

METHODS

Patients underwent neuroimaging for diagnosis or preoperative planning on a 3 tesla MR scanner. A MEGA-PRESS spectral editing technique was employed. Imaging findings were directly compared to post-operative histopathologic diagnosis. RESUTLS: For all patients with gliomas from grade II to IV, detection of 2-HG with MEGA-PRESS sequence had a sensitivity between 48% and 81%, specificity between 60% and 100%, PPV between 53% and 100% and NPV between 77% and 85% depending on the CRLB threshold. Among the different metabolite ratios, a 2-HG/NAA ratio >0.034 had the highest sensitivity and specificity, 86% and 73% respectively.

DISCUSSION

Magnetic resonance spectroscopy (MRS) is an underused advanced MR technique that deserves consideration in pediatric neuro-oncology given its utility in non-invasively detecting malignant gliomas.
IMMU-03. UPDATES ON BRAINCHILD-01, -02, AND -03: PHASE 1 LOCOREGIONAL CAR T CELL TRIALS TARGETING HER2, EGFR, AND B7-H3 FOR CHILDREN WITH RECURRENT CNS TUMORS AND DIPG
Authors: Vitanza Nicholas , Gust Juliane , Wilson Ashley , Huang Wenjun , Perez Francisco , Wright Jason , Leary Sarah , Cole Bonnie , Albert Catherine , Pinto Navin , Orentas Rimas , Jensen Michael , Park Julie
Published: December 2020

We report preliminary results of three Phase 1 trials of repetitively dosed locoregional CAR T cells for children with recurrent/refractory CNS tumors, targeting HER2 (BrainChild-01), EGFR (BrainChild-02), and B7-H3 (BrainChild-03). Cells are delivered into the tumor cavity (Arm A) or ventricular system (Arm B and BrainChild-03’s DIPG-specific Arm C). Primary endpoints are feasibility and safety. Successful CAR T cell manufacture occurred in 2/2 subjects (BrainChild-01) and 2/3 (BrainChild-02). All subjects tolerated intra-patient dose escalation from 1x107 to 2.5x107 cells/dose without DLTs. Two subjects were evaluable on BrainChild-01 (S-001: glioblastoma, Arm A, survival 173 days post-first infusion, received 6 infusions; S-002: ependymoma, Arm B, survival 111 days, 9 infusions). One subject was evaluable on BrainChild-02 (glioblastoma, Arm A, withdrew from trial at 49 days, 5 infusions). One enrolled patient on BrainChild-03 has not begun treatment. None of the subjects developed new neurologic toxicities, although transient worsening of baseline tumor-related signs and symptoms were seen. Secondary endpoints are efficacy and disease response. No objective radiographic responses have been observed. Both BrainChild-01 subjects had transient systemic CRP elevations following infusions (S-001: peak of 3.9 post Course 1 Week 1; S-002: peak of 2.3 post Course 2 Week 1), possibly indicating an inflammatory response. Both subjects had post-infusion CSF cytokine elevations (CXCL10, GCSF, GM-CSF, IFNa2, IFNg, IL-10, IL12-p40, IL12-p70, IL-15, IL-1a, IL-3, IL-6, IL-7, TNFa, VEGF) without concurrent systemic changes. In summary, we provide preliminary evidence of safety and feasibility of intracranial delivery of CAR T cells for pediatric CNS tumors.
IMMU-17. CAR T CELLS TARGETING THE INTEGRIN ALPHAVBETA3 EXHIBIT ROBUST ANTI-TUMOR RESPONSES AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND GLIOBLASTOMA (GBM)
Authors: Cobb Dustin , de Rossi Jacopo , Liu Lixia , An Erin , Lee Daniel
Published: December 2020

Effective therapies for DIPG and GBM are lacking. CD19 chimeric antigen receptor (CAR) T cells are highly effective in patients with refractory B-cell malignancies. We aim to develop novel CARs for high-grade gliomas. The integrin complex alphavbeta3 was selected as a CAR-T cell target due to its expression on gliomas and their vasculature, yet with minimal expression throughout normal tissues, vessels and organs. Indeed, a majority of DIPG and GBM cell lines express surface α vβ 3. Second-generation CAR-T cells expressing an anti-α vβ 3 scFv and either a CD28 or 4-1BB co-stimulatory domain and CD3zeta were constructed. Transduced healthy, donor-derived T cells exhibited high level CAR expression, efficient expansion, and representative populations of memory subsets including central, effector, and stem cell-like memory CAR-T cells. α vβ 3.28z and α vβ 3.BBz CAR-T cells exhibited antigen-specific in vitro cytotoxicity and cytokine production against DIPG and GBM cell lines. Both CARs mediated rapid and robust anti-tumor responses in NSG mice bearing orthotopic DIPG or GBM tumors. 5/13 α vβ 3.28z and 0/14 α vβ 3.BBz treated animals died without detectable disease within 2 weeks of infusion suggesting different toxicity profiles and is consistent with faster CAR-T cell expansion in CD28-versus 4-1BB-containing CD19 CAR-T cells seen clinically. Our results demonstrate that α vβ 3.BBz CAR-T cell therapy may be both highly effective and safe in DIPG and GBM patients. Due to the restricted nature of α vβ 3 expression in normal tissues, the robust responses seen in tumor-bearing mice, and the slower kinetics of α vβ 3.BBz CAR-T cell expansion, a first-in-human clinical trial is being planned.
LGG-04. A PHASE II RE-TREATMENT STUDY OF SELUMETINIB FOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA (pLGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY
Authors: Fangusaro Jason , Onar-Thomas Arzu , Wu Shengjie , Poussaint Tina Young , Packer Roger , Kilburn Lindsay , Qaddoumi Ibrahim , Dhall Girish , Pollack Ian F , Lenzen Alicia , Partap Sonia , Fouladi Maryam , Dunkel Ira
Published: December 2020

The PBTC conducted a re-treatment study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive pLGG. Eligible patients must have previously enrolled on PBTC-029 or PBTC-029B and progressed after coming off treatment with selumetinib. Patients must have maintained stable disease (SD) for ≥12 courses or had a sustained radiographic response (partial or complete) during their first exposure to selumetinib. Thirty-five eligible patients (median age: 13.11 years [range 7.96–25.33]) were enrolled, 57% of whom had optic pathway or hypothalamic target lesions. At the time of submission, median duration of treatment was 18 courses (range 2–48) and 21 subjects remained on therapy. Best responses reported to date are 6/35 (17%) partial response, 22/35 (63%) SD and 7/35 (20%) progressive disease with a 2-year progression-free survival of 75.7 + 8.3%, which met the design parameters for success. The most common attributable toxicities were grade 1 diarrhea, elevated AST, hypoalbuminemia, elevated CPK, maculo-papular rash, fatigue, paronychia, ALT elevation, acneiform rash and grade 2 CPK elevation. Rare grade 3 toxicities included CPK elevation (3), lymphopenia (2), paronychia (2) and ALT elevation (2). There was only one grade 4 CPK elevation. Five patients (14%) required dose reductions due to toxicity. There does not appear to be a notable difference in toxicities observed during initial selumetinib therapy versus re-treatment. In pLGG that has recurred/progressed following treatment with selumetinib, re-treatment with selumetinib appears to be effective with 80% of patients again achieving response or prolonged stable disease. Long-term follow-up is ongoing.
LGG-11. INSTITUTIONAL EXPERIENCE OF BRAF TARGETING THERAPY
Authors: Lola Gino Bardi , Sato Mariko
Published: December 2020

BACKGROUND

The use of BRAF inhibitors is widely accepted in adult oncology as treatment for BRAF mutated cancers. BRAF alterations are frequently found in both pediatric low grade and high-grade gliomas, which has opened a new door to targeted therapies for pediatric gliomas. Targeted therapy drugs are associated with predictable patterns of adverse events. However treating in children may potentiate unique challenges. We present our institutional experience of targeted therapy with a focus on adverse events.

METHODS

We conducted a retrospective chart review of patients treated with BRAF and/or MEK inhibitors between 2015–2019.

RESULTS

There are nine patients treated with either MEK inhibitor(n=) or the combination therapy(n=). The most common diagnosis was Pilocytic astrocytoma. Targeted therapy was chosen as salvage therapy in all patients. The most common side effect was a pruritic erythematous rash, observed in 8 out of 9 patients. Cardiac toxicity (Grade 2, n=1) and GI toxicity (Grade 3, n=1) were found in patients treated with MEK inhibitor. Both cases resulted in cessation of therapy or significant decreased dose respectively. While two patients died due to progression of disease and two other continued to progress, 5 patients have demonstrated stable disease while on therapy.

CONCLUSIONS

Our study revealed the incidence of severe adverse events in two patients with BRAF targeted therapy. Due to the potential life-long use of targeted therapy, it is important to follow guidelines of adverse event monitoring and to develop a prevention and management strategy for severe adverse events.
LGG-24. CARBOPLATIN-INDUCED HEMATURIA IN A PEDIATRIC PATIENT WITH LOW-GRADE GLIOMA AND REVIEW OF LITERATURE
Authors: Hoover Alex , Sato Mariko
Published: December 2020

OBJECTIVE

In this case report, we present a pediatric patient with gross hematuria and hydroureteronephrosis associated with high dose carboplatin. Given the paucity of literature on the subject, we also conduct and present a review of cases. CASE PRESENTATION: A 6-year-old Caucasian female with history of Type 1 neurofibromatosis was undergoing treatment for a low-grade glioma with monthly high dose carboplatin (560 mg/m2). After 8th dose out of 13, the patient developed severe nausea and vomiting and was admitted for dehydration. She was noted to have microscopic hematuria. After 9th dose, the patient again developed severe nausea, vomiting and gross hematuria with clots. She was admitted and treated with IV hydration. Renal ultrasound showed newly developed bilateral hydroureteronephrosis. Coagulation studies were normal. Multiple cultures and viral studies were negative. Hematuria cleared spontaneously after 4 days of aggressive hydration.

RESULTS

Subsequent carboplatin was given with aggressive hydration and minimized nausea/vomiting and no hematuria was observed. Literature review revealed only 4 reported cases of carboplatin-induced hematuria, including only one pediatric case that occurred in a patient with concurrent thrombocytopenia. Carboplatin may exhibit toxicity to the transitional epithelial cells of the urogenital tract causing hemorrhage from the renal pelvis and ureters. If untreated, this may lead to urinary outflow obstruction and subsequent obstructive nephropathy.

CONCLUSION

We present a rare toxicity, gross hematuria caused by high-dose carboplatin treatment. Providers should be aware of this rare toxicity and provide timely hydration and supportive care to prevent development of obstructive kidney injury and/or renal failure.
LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES
Authors: Valiakhmetova Andge , Papusha Ludmila , Yasko Ludmila , Druy Alexander , Karachunsky Alexander , Novichkova Galina , Hwang Eugene I , Packer Roger J
Published: December 2020

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare disease, newly recognized in the 2016 WHO classification of tumors of the CNS. Most DLGNTs are low-grade neuroepithelial tumors with variable elements of neuronal/neurocytic and glial differentiation, have diffuse leptomeningeal enhancement on MRI, and typically harbor KIAA1549-BRAF fusions. Other alterations, such as the BRAF V600E substitution, are less common. Here, we present three cases of DLGNT with different presentations and outcomes. The first patient is a 2yr-old male with KIAA1549-BRAF fusion, and was treated with Carbo/VCR chemotherapy after a biopsy, with resultant ongoing stable disease for 3.5 years. The second patient, an 8yr-old male had the BRAF V600E point mutation and was treated with conventional chemotherapy (VCR/carboplatin). On progression, he received the BRAF inhibitor vemurafenib, achieving a complete response which last 14 month. The third patient, a 27 month old male, harbored a KIAA1549-BRAF fusion and was treated at diagnosis with the MEK inhibitor trametinib. The tumor has been radiographically stable in the context of clinical improvement for 21 months since the treatment initiation, ongoing 24 month. In summary, we present further evidence of MAPK pathway alterations in children with DLGNT. We describe a range of molecular presentations and clinical outcomes, including one patient treated with conventional chemotherapy with further stabilization of disease during 3.5 years and two patients who were successfully treated with targeted therapy.
LGG-28. NOVEL BRAF INTRAGENIC DELETION IN A GLIOMA: A CASE REPORT OF A PEDIATRIC PATIENT
Authors: Flores Valerie Cruz , Sutcliffe Maxine , Geller Thomas , Gomez Ignacio Gonzalez , Smith Stephanie , Stapleton Stacie
Published: December 2020

BACKGROUND

Numerous variant BRAF genetic alterations have been associated with malignancies. BRAF activating fusions/mutations are frequently present in low grade gliomas. BRAF intragenic deletions have been reported in melanoma, but have not previously been reported in gliomas.

OBJECTIVE

To report a BRAF intragenic deletion in a pediatric patient with recurrent low-grade glioma.

RESULTS

A 3-year-old female underwent a complete resection of a posterior fossa pilocytic astrocytoma. She had recurrences at age 4, and then at age 9; pathology was consistent with pilocytic astrocytoma. Microarray analysis on sample from the first recurrence showed one region of loss encompassing 86 Kbp within the BRAF gene. The deletion breakpoints are within intron 1 and 9, resulting in loss of exons 2 through 9, inclusive. This has been previously described melanoma, but appears to be a novel finding in glioma. It is hypothesized that, since the loss retains the kinase and ATP binding pocket domains but deletes the N-terminal conserved region 1 and 2 (CR1, CR2) of the BRAF gene, it is likely functionally similar to the loss and activation resulting from the more usually described KIAA1549 and BRAF gene fusion.

CONCLUSION

This is the first BRAF intragenic deletion involving exons 2–9 reported in a glioma. Although 86kbp is small using whole genome microarray technology, it is large using sequencing strategies, and a targeted sequencing approach to investigate the BRAF gene would not readily identify this deletion. It is speculated that the deletion may be under ascertained in the pediatric population.
LGG-31. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW GRADE GLIOMAS: ANALYSIS OF AN EXPANDED MULTI-INSTITUTIONAL COHORT WITH 101 PAIRED TUMOR SAMPLES
Authors: Lazow Margot A , Schafer Austin , DeWire-Schottmiller Mariko D , Lane Adam , Boué Daniel R , Osorio Diana S , Finlay Jonathan L , Wright Erin , Rush Sarah , Hoffman Lindsey M , Reuss Jamie , Hummel Trent R , Salloum Ralph , de Blank Peter M , Smiley Natasha Pillay , Sutton Mary E , Asher Anthony , Stevenson Charles B , Drissi Rachid , Fouladi Maryam , Fuller Christine
Published: December 2020

INTRODUCTION

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence.

METHODS

Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries.

RESULTS

101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]).

CONCLUSIONS

Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.