bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-22. Uptake of investigational therapy in children with High Grade Glioma
Authors: Toledano Helen , Abu-Quider Abed , Kaddan Walid , Fichman-Horn Suzanna , Kershenovich Amir , Michaeli Orli 
Published: June 2022

Abstract
High grade gliomas (HGG) in children carry a dismal prognosis. Standard therapy includes resection when possible, radiotherapy and sometimes the addition of temozolomide. There is no standard treatment for progression or relapse. Since November 2018 we have offered upfront molecular testing to all children with HGG who had biopsy/ resection. Testing was mainly done by next generation sequencing panel, and some had research based methylation profiling and RNA seq. We aimed to see whether families chose to receive additional investigational treatment as a result of the molecular testing results and whether the treatment involved participation in a clinical study, or whether treatment was compassionate. A total of 22 patients aged 2.8-16.8 years with HGG had a biopsy/resection over this three year period. Thirteen had diffuse midline glioma (DMG) of which 11 had the H3K27 mutation, and 9 were cortical. Six children had underlying predisposition syndromes: mismatch repair deficiency (n=3 proven + 1 highly suspected), neurofibromatosis1 (n=1), Li-Fraumeni (n=1). All the cortical gliomas had potential treatment options based on their molecular testing. 10/22 (45%) children received investigational therapy of which only three participated in a clinical study while the rest received compassionate therapy. Compassionate treatments included BRAF/MEK inhibitors (n=4), Larotrectinib (n=1), and immune checkpoint inhibitors (n=2). Of the 12 who did not receive investigational therapy, four, all cortical, have potential therapy options but are currently in remission. Of the remaining eight, two had very rapid clinical deterioration and died, and six (all DMG) did not wish/ were unable to travel abroad and no relevant clinical study was available locally. We conclude that the families of children with HGG are highly motivated to receive investigational therapy. Upfront molecular testing of these tumors, especially for cortical HGG, is imperative and there is a growing need for accessible clinical studies.
HGG-26. Comprehensive Genomic Profiling of Pediatric and AYA High-Grade Gliomas Reveals a High Prevalence of ATRX and Homologous Recombination Repair (HRR) Mutations
Authors: Kuang Zheng , Hiemenz Matthew , Huang Michael Angelo 
Published: June 2022

Abstract
BACKGROUND: Pediatric high-grade glioma (HGG) is a devastating heterogenous disease with a clear need for more effective treatment options. Advances in high-throughput molecular sequencing have advanced our understanding of these tumors and yet outcomes remain poor as only a very small subset of patients have demonstrated benefit from targeted therapy approaches. METHODS: We compiled genomic data from 980 pediatric (N=400) and AYA (18 to 30 yrs, N=580) HGG cases that underwent targeted, panel-based comprehensive genomic profiling (FoundationOne® CDx). RESULTS: Among pediatric patients, mutations in ATRX or HRR-related genes were among the most prevalent at 24.25% and 19.5%, respectively. Other commonly occurring mutations were seen in TP53 (58.25%), H3F3A (43%), and PIK3CA/PIK3R1 (22%). Among AYA patients, mutations in ATRX and HRR-related genes were seen in 51.72% and 17.24% of cases, respectively. The most common mutations seen in this older population were in TP53 (76.38%), IDH1/2 (50.86%), PI3KCA/PIK3R1 (20.52%), and H3F3A (18.28%). Among patients with diffuse midline glioma (harboring H3K27M mutations), ATRX and HRR mutations were reported in 21.27% and 13.57% of cases, respectively. Among pediatric patients with histone wild type HGG, mutations in ATRX and HRR-related genes occurred in 20.61% and 21.05% of cases, respectively. CONCLUSION: Alterations in ATRX and HRR-related genes are among the most prevalent mutations in pediatric and AYA HGG. Consideration should be made towards the development of subtype-specific treatment protocols using PARP and/or ATR inhibitors aimed at this subgroup of patients.
HGG-27. Understanding the role of PLAG family transcription factors in cortex development and tumorigenesis
Authors: Vaillant Jan , Hofmann Nina , Keck Michaela-Kristina , Jones David T W , Kutscher Lena M , Pfister Stefan M 
Published: June 2022

Abstract
Gliomas are the most common type of central nervous system (CNS) tumors in children. Therapy and outcome often reflect the grade of the tumor, with high grade glioma (HGG) leading to a significantly worse survival prognosis than low grade glioma. However, HGG are highly diverse regarding their molecular entities and clinical associations. In some pediatric-type histone 3 K27M mutated HGG, the zinc-finger transcription factor PLAG1 was previously found to be overexpressed, which is also confirmed by patient data from the INFORM program. Further, in a novel type of embryonic CNS tumors without histone mutations, the PLAG1-related genes PLAGL1/PLAGL2 are amplified. However, the consequences of aberrant PLAG gene expression on CNS tumor formation during development are unknown. Especially the understanding of downstream signaling pathways that are commonly altered by this transcription factor family could provide necessary starting points for more specific therapy. We use transgenic mouse models with targeted PLAG1 overexpression in neural stem and progenitor cells to investigate the function of PLAG1 in cerebral cortex development and tumorigenesis. We found that PLAG1 overexpression together with heterozygous loss of p53 activity causes neurological defects and impaired cortex development. Next, to understand how PLAG gene overexpression affects neural specification, we will overexpress the PLAG genes in embryonic neural stem and progenitor cells using in utero electroporation. After FACS isolation of electroporated cells and single nucleus RNA sequencing, we will assess how the overexpression changes the transcriptional trajectories of neural development in mouse cortex stem and progenitor cells. We hypothesize that an early event leads to the constitutive upregulation of PLAG genes, which are usually tightly regulated during development, in patients with pediatric brain tumors harboring aberrant PLAG gene expression. Deciphering the transcriptional downstream pathways of this aberrant expression in neural stem and progenitor cells seems promising to find new potential therapeutic targets.
HGG-28. CLIC1 and CLIC4 ion channel deficiency confers increased sensitivity to tumour treating fields and improved survival in paediatric glioblastoma
Authors: Griffin Michaela , Smith Stuart , Basu Surajit , Khan Raheela 
Published: June 2022

Abstract
Paediatric Glioblastoma Multiforme (pGBM) is a lethal brain cancer with an average survival of 14 months. Due to the scarcity of effective treatment, pGBM forms the leading cause of CNS cancer death in children. Optune™ is a non-invasive therapy that uses alternating electric fields – coined TT fields - to disrupt cancer cell division, however it is not currently approved in children. Evidence shows that ion channels not only regulate electrical signalling of excitable cells, but also play a crucial role in the development and progression of brain tumours, essential in cell cycle control and therefore presenting as valuable therapeutic targets. Candidate ion channel genes (ICG) associated with the malignant status of high-grade glioma (HGG) were identified via multivariate analysis of in-house and publicly available data sets. RNA sequencing of in-house patient tissues revealed an increased expression of CLIC1 and CLIC4, with pHGG exhibiting increased expression at protein and RNA levels in both the Paugh data set and in-house primary cell lines and TMAs. Clinical correlation determined that CLIC4 and CLIC1 deficiency was associated with increased overall survival (p=&lt;0.03). siRNA depletion of CLIC1 and CLIC4 propagated a reduction in the proliferation, migration and invasion of pHGG cell lines and resulted in cell cycle arrest. Furthermore, CLIC1 and CLIC4 deficiency exacerbated the killing capacity of TT fields. Whole transcriptome gene expression analysis (Human Clairom™ Array) of paediatric GBM cell lines treated with tumour treating fields and found that cells treated with TTfields exhibited a down-regulation in CLIC1 and CLIC4 compared to untreated cells. These data provide rationale that genetic, electrical, and pharmacological manipulation of ion channels will reduce the capacity of childhood brain tumours to proliferate and invade. Therefore, may be a suitable target for combination therapy to enhance the treatment efficacy of TTfields and help bring this non-invasive therapy to paediatric patients.
HGG-31. Unique case of a bithalamic H3K27-wildtype diffuse midline glioma, EGFR-altered with methylated MGMT
Authors: Reinecke James , Cottrell Catherine , Rush Sarah , Judd Alexis , Palmer Joshua , Pierson Christopher , Lazow Margot , Wilson Yelena 
Published: June 2022

Abstract
BACKGROUND: Diffuse midline gliomas are aggressive pediatric brain tumors frequently associated with somatic mutations in histone genes H3F3A (H3.3) and HIST1H3B (H3.1), which promote gliomagenesis through reprograming of the epigenetic landscape by inhibiting the tri-methylation of H3K27 (H3K27-me3). H3K27M-mutant gliomas comprise over 80% of diffuse midline gliomas, and are characterized by dismal outcomes as well as near-ubiquitous absence of MGMT promoter methylation. The subset of H3K27-wildtype diffuse midline gliomas remains incompletely understood with regards to underlying pathogenesis, therapeutic targets, and prognosis. We present the clinical, imaging, histopathologic, and molecular characteristics of a pediatric patient with a bithalamic H3K27-wildtype diffuse midline glioma, EGFR-altered with methylated MGMT. CASE: A 10-year-old female presented with an infiltrative bithalamic T2-hyperintense mass lacking diffusion restriction or contrast enhancement on MRI. Initial pathological inspection from biopsy was consistent with high-grade neuroepithelial tumor favoring high-grade glioma, however, immunohistochemistry was negative for H3K27M and demonstrated reduced H3K27-me3. DNA sequencing uncovered mutations in EGFR (exon 20 insertion) and TP53 (R175H), with overexpression of EGFR and CDK6 (but not EZHIP) identified by RNA-sequencing. Methylation profiling was consistent with high-grade glioma, matching closest with glioblastoma, IDH-wildtype, with positive MGMT promoter methylation. Treatment was initiated with focal chemoradiotherapy with concurrent temozolomide, with plans for adjuvant temozolomide/ lomustine.DISCUSSION: Our case adds to growing evidence suggesting bithalamic tumors represent a distinct genetic and epigenetic subset of diffuse midline gliomas often defined by H3K27-wildtype status, loss of H3K27-me3, and EGFR receptor alterations. Our patient’s H3K27-wildtype, EGFR-altered tumor had reduced H3K27-me3 as well as positive MGMT promoter methylation, a molecular characteristic that has not been well-studied in H3K27-wildtype bithalamic gliomas, but is suspected to confer sensitivity to alkylating chemotherapy. The prevalence, prognostic impact, and therapeutic implications of MGMT promoter methylation in bithalamic H3K27-wildtype diffuse midline gliomas, including potential association with EGFR aberrations, requires further exploration.
HGG-34. Upfront Molecular Targeted Therapy for the Treatment of BRAF-mutant Pediatric High-Grade Glioma
Authors: Rosenberg Tom , Yeo Kee Kiat , Mauguen Audrey , Alexandrescu Sanda , Prabhu Sanjay P , Tsai Jessica W , Malinowski Seth , Joshirao Mrinal , Parikh Karishma , Sait Sameer Farouk , Rosenblum Marc K , Benhamida Jamal K , Michaiel George , Tran Hung N , Dahiya Sonika , Kachurak Kara , Friedman Gregory K , Krystal JulieI , Huang Michael A , Margol Ashley S , Wright Karen D , Aguilera Dolly , MacDonald Tobey J , Chi Susan N , Karajannis Matthias A 
Published: June 2022

Abstract
BACKGROUND: The prognosis for pediatric high-grade glioma (pHGG) is poor despite aggressive multi-modal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 10.7 years (range: 1.8–20.3). Histologic diagnoses included HGG (n=6), glioblastoma (n=3), anaplastic ganglioglioma (n=4), diffuse midline glioma (n=3), high-grade neuroepithelial tumor (n=1), anaplastic astrocytoma (n=1), and anaplastic astroblastoma (n=1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range,0.3–6.5), three-year progression-free (PFS) and overall survival (OS) for the cohort were 65% and 82%, respectively, and superior to a historical control cohort treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes observed compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.
HGG-37. A case ofETV6-NTRK3 fusion driven infantile hemispheric glioma (IHG) with acquired drug resistance against first- and second-generation NTRK-inhibitors
Authors: Ku Dennis T L , Liu Anthony P Y , Kan Amanda N C , Yuen Liz Y P , Shing M K , Yan Carol Y L , Fu Eric , Yau Jeffrey P W , Luk C W , Ng H K , Chan Godfrey C F 
Published: June 2022

Abstract
A 3-month-old girl had left cerebral infantile hemispheric glioma (IHG), H3 wild type (wt), Grade IV (WHO2020) with diffuse leptomeningeal and spinal metastasis. Craniotomies were performed twice which achieved partial resection. Histopathology revealed high grade glioma, Ki67 30-40%, mitosis and widespread necrosis. IHC showed H3wt, IDH-, and retained INI-1. RNAseq found ETV6-NTRK3 fusion. She was treated per Baby POG-9233, however after 3 cycles, there was mixed response (static for primary, partial response for metastasis). She had severe developmental delay, right hemiparesis and dysphagia. Aiming for better disease control and potential resectability, we switched to first-generation NTRK-inhibitor, Larotrectinib. MRI at 3 months showed significant interval reduction in tumour size, then became static at 6 months. She was stable with gradual neurological improvement until 10 months after Larotrectinib, there was worsening neurology and imaging confirmed tumour progression with haemorrhage. Craniotomy was performed for haemostasis and tumour debulking. Histopathology showed same IHG with ETV6-NTRK3 fusion. Targeted panel sequencing found NTRK3 p.Gly623Arg mutation, a solvent-front substitution responsible for acquired resistance to first-generation TRK-inhibitors. BRAFV600E and MET amplification were not detected. Larotrectinib was switched to second-generation NTRK-inhibitor, Selitrectinib. MRI at 1 month showed post-operative changes, but disease progressed at 3 months and in an accelerated manner over the course of 10 days while on therapy. Choice of conventional chemotherapy and radiotherapy were discussed, but the girl deteriorated rapidly and deceased (3 months from start of Selitrectinib, 19 months from diagnosis). CONCLUSION: IHG is aggressive with challenging surgery and medical treatment. The use of small molecular inhibitor requires careful consideration, i.e. treatment effect, toxicity and potential acquired drug resistance as showed in this case. For unresectable tumour, it may be inevitable as we also reported a similar case with ROS1 fusion. Access to newer novel agents is difficult while therapeutic effect is uncertain.
HGG-38. Gliomatosis cerebri/Glioblastoma with discordant histological and molecular profiles - treatment and outcome of a pediatric patient
Authors: Harrod Virginia , Morris Jason , Ho Winson 
Published: June 2022

Abstract
Gliomatosis cerebri is no longer recognized as a distinctive pathological diagnosis, but a manifestation of diffuse glioma involving at least three cerebral lobes. Lack of understanding in this manifestation of CNS neoplasms limits treatment for this aggressive disease. Here we present a case of stabilization of disease in a pediatric patient with unusual molecular profiles normally associated with aggressive tumor behavior. A nine-year-old male presented with acute onset of right-sided vision changes, headache and numbness of the left arm and leg for one day. He also had a three-month history of an asymptomatic bump on the right temporal skull bone. MRI of the brain was significant for diffuse thickening of the cortex of the entire right hemisphere (temporal&gt;frontal&gt;parietal lobes). No specific enhancing lesion or restricted diffusion was noted. Histologically, the tissue had findings of diffuse low-grade astrocytoma. Molecular genetic testing was notable for TERT and EGFR mutations which are more consistent with adult type high-grade astrocytic tumors. MGMT promoter methylation array was negative. Final diagnosis was glioblastoma, IDH and H3 wildtype. All the molecular features of this tumor were high-grade with an average progression free survival of less than 12 months. Despite the lack of methylation, we opted to include alkylating agents in a maintenance chemotherapy treatment plan following radiation therapy with concurrent temozolomide. Despite poor prognostic factors, the patient is alive without signs of progression 2.5 years post-diagnosis. Targeted agents were not used in upfront treatment for this patient. This is a rare case of stabilization of disease with conventional treatment in a very aggressive tumor. This case is a rare constellation of an ‘adult-type’ molecular profile in a pediatric patient with a low grade, less aggressive behavior profile, and highlights the need to better understand this rare subtype of tumors in children.
HGG-39. Integrative analyses of BRAFp.v600e mutated gliomas: from epigenetic to metabolic characteristics
Authors: Lhermitte Benoit , Wolf Thibault , Namer Izzie Jacques , Bund Caroline , Fuchs Quentin , Dontenwill Monique , Entz-Werlé Natacha 
Published: June 2022

Abstract
BRAF p.v600e mutation is encountered in brain tumors, mostly low grade pediatric diffuse gliomas (LGG) and epileptogenic glioneuronal tumors such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. We studied retrospectively a monocentric cohort of 17 LGGs (14 GG and 3 pilocytic astrocytomas) and 7 BRAF pv600e HGG. The patients were aged below 20 years. We focused on extended tumors’ biology assessment (MethylEpic 850K, Next-Generation sequencing, RNA sequencing and metabolomics), as well as tumor immune microenvironment by immunohistochemistry. Among the LGGs, only one had a CDKN2A deletion and one a gain on chromosome 5. All except two LGGs had a complete surgical resection. Four of them were treated by chemotherapies but underwent relapses. All HGGs had a surgical resection followed by a first line chemotherapy (mainly Stupp protocol) and radiotherapy. Five patients relapsed rapidly, benefiting from targeted therapy with vemurafenib and/or biotherapy associating dabrafenib plus trametinib. Among those HGGs, we had both subgroups: “de novo” tumors and patients with a history of LGG tumors. Both were responding well to targeted treatments. The biology uncovers in all HGGs a loss of CDKN2A gene and/or protein. Additionally to this gene abnormality, specific transcriptomic expressions were associated to therapeutic response and immune microenvironment. Epigenetic modulation was linked to specific metabolic switches when BRAF p.v600e gliomas were getting higher grade features (e.g., glutaminolysis, serinolysis and phospholipidic metabolism). Those characteristics seem to be able to predict in LGG p.v600e potential evolution.
HGG-41. Glioma oncogenesis in the constitutional mismatch repair deficiency (CMMRD) syndrome
Authors: Guerrini-Rousseau Lea , Merlevede Jane , Denizeau Philippe , Andrejuolo Felipe , Varlet Pascale , Puget Stephanie , Beccaria Kevin , Blauwblomme Thomas , Cabaret Odile , Hamzaoui Nadim , Bourdeaut Franck , Faure-Conter Cecile , Muleris Martine , Colas Chrystelle , de Beaumais Tiphaine Adam , Castel David , Rouleau Etienne , Brugieres Laurence , Grill Jacques , Debily Marie-Anne 
Published: June 2022

Abstract
PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.