bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-08. Epidemiology of childhood brain tumors in Morocco
Authors: Erefai Ouassima , Haimer Amal , Habib Faouzi , Soulaymani Abdelmajid , Mokhtari Abdelrhani , Hami Hinde 
Published: June 2022

Abstract
INTRODUCTION: Brain tumors are the most common solid tumors and cause of cancer-related death in children less than 15 years of age. However, little is known about these tumors in Morocco. The aim of this study is to describe the epidemiological features of pediatric brain tumors in Morocco. METHODS: This is a descriptive retrospective study of pediatric brain tumor cases, diagnosed and treated between 1994 and 2015 at Al Azhar Oncology Center in Rabat. Patient’s age and sex, habitat area, overall survival and tumor characteristics were evaluated. RESULTS: During the study period, 41 children under the age of 15 years were diagnosed with brain tumors at Al Azhar Oncology Center. Brain tumors were more common among boys than girls, with a male-female ratio of 1.9. The average age of diagnosis was 7.47 ± 3.06 years (range 2-14 years). More than half (51.22%) of the cases were diagnosed in children aged 5-9 years. Regarding the habitat area, nearly two-thirds (62.50%) of children live at least 30 kilometer (km) away from the cancer center. Medulloblastoma was the most common tumor type with 34.15% of cases. Overall, one patient develops a metastasis. Among the cases for whom the outcome was known, five children died during the study period, consisting of three girls and two boys. CONCLUSIONS: Children’s brain tumors remain a serious public health problem in Morocco, especially with the limited number of specialized pediatric cancer centers. The travel burden is a significant factor affecting access to appropriate diagnosis and treatment and can impede the provision of high-quality care for cancer patients.
ETMR-01. Management of CNS tumor with BCOR internal tandem duplication with multimodalities therapy: Surgery, Intensive Chemotherapy, and Radiation
Authors: Mobark Nahla Ali , Alharbi Musa , Ballourah Walid , Alsultan Abdulrahman , El Manjomi Fahad , AlNaqib Zaid , Al-Banyan Ayman , Balbaid Ali Abdullah O , Abedalthagafi, MD Malak 
Published: June 2022

Abstract
The 2021WHO CNS tumor classification includes CNS tumors with internal tandem duplications in the BCL6 corepressor (BCOR) gene as a new entity of CNS embryonal tumors labelled high-grade neuroepithelial tumors with BCOR alterations (HGNET-BCOR) are characterized by genetic aberrations in the BCOR gene located at Xp11.4, leading to increased expression of BCOR mRNA and distinct DNA methylation profiles. currently no agreement on the optimal strategy to manage these rare tumors, which mostly occur in young children These tumors are usually treated as high grade glioma HGG with upfront radiation therapy with poor outcome. We report 2.5 years old boy presenting with headache and vomiting. MRI showed a well-defined left cerebellar mass, hyperintense in T2 and hypointense in T1, with restricted diffusion and no spinal CSF seeding metastases. He underwent gross surgical resection of the tumor initial pathological diagnosis was epithelioid high grade malignant neoplasm. Brain tumor methylation classifier analysis of resected tumor tissue confirmed a CNS tumor with BCOR internal tandem duplication (WHO grade 4). The patient was treated per COG ACNS0334 (3 induction cycles of vincristine, cyclophosphamide, cisplatin, etoposide, HDMTX, followed by consolidation with 3 cycles of carboplatin and thiotepa with autologous hematopoietic stem cell rescue). MRI brain before the start of chemotherapy showed a small recurrent mass within the surgical cavity. post-induction MRI detected stable-sized residual lesion in the surgical cavity; however, post-consolidation MRI showed complete resolution of the residual mass. The patient subsequently received craniospinal irradiation (36 Gy [CSI]) with a boost to the tumor bed up to 54 GY. By the time of writing this report our patient is still in complete remission. Our case showed that this aggressive brain tumor may respond well to intensive multimodalities therapy Further case studies and international prospective trials are needed to optimize the clinical management of these rare tumors.
ETMR-11. Transcriptional changes upon knockdown of alteredBCOR/BCORL1 transcripts in preclinical models of CNS embryonal tumors with BCOR-related alterations
Authors: Piontek Martin , Kirchhofer Dominik , Gabler Lisa , Lötsch-Gojo Daniela , Pirker Christine , Schmitt-Hoffner Felix , Jaunecker Carola N , Kool Marcel , Berger Walter , Gojo Johannes 
Published: June 2022

Abstract
BCL-6 transcriptional corepressor (BCOR) is an epigenetic regulator that silences gene expression mainly via the polycomb repressive complex 1.1 (PRC1.1). BCOR genomic alterations are found in a variety of different tumors and recently central nervous system (CNS) tumors with BCOR internal tandem duplication (ITD) were classified as a distinct molecular subgroup. We established and characterized two cell models derived from BCOR altered CNS tumor patients. One model is characterized by a frameshift mutation in the BCOR gene resulting in the expression of a truncated protein lacking the C-terminal PUFD domain required for correct assembly of the PRC1.1. Additionally, this model harbors a translocation of the BCOR homologue BCORL1. The second model has a characteristic internal tandem duplication (ITD) within the BCOR gene. To study the effects of mutated BCOR/BCORL1 on gene expression, we performed siRNA mediated knockdown of altered BCOR/BCORL1 transcripts in both models and analyzed transcriptional changes by mRNA expression array. Differentially expressed genes in BCOR/BCORL1 knockdown versus wild type conditions were enriched for signaling pathways involved in cell cycle progression, cell growth, DNA replication and cancer. This suggests that the alterations in BCOR/BCORL1 might have pro-oncogenic effects and thereby contribute to the aggressive phenotype of this disease. Especially in the BCOR ITD model knockdown of BCOR led to transcriptional downregulation of genes associated with the development of brain tumors such as FGF18, PDGFA and PDGFRA. Our results indicate that specific BCOR/BCORL1 alterations might impair its endogenous function as transcriptional repressor and deregulate the expression of multiple PRC1.1 target genes. An in depth characterization of epigenetic and transcriptional changes in BCOR/BCORL1 altered CNS tumors could lead to the identification of critical downstream effectors and ultimately reveal new therapeutic vulnerabilities.
GCT-05. Multi-institutional analysis of treatment modalities in metastatic germinoma in children
Authors: Shatara Margaret , Abu-Arja Mohammad H , MacDonald Shannon , Reiners Stephanie , Gorsi Hamza , Govender Dinisha , Dholaria Hetal , Nagabushan Sumanth , Schwartz Jonathan , Foo Jen Chun , Rajagopal Revathi , Perkins Stephanie , Bartels Ute , Zaghloul Mohamed S , Abdelhaleem Nada A , El-ayadi Moatasem , Abdelbaki Mohamed S 
Published: June 2022

Abstract
BACKGROUND: Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors, with germinoma accounting for two-thirds of cases. Neoadjuvant chemotherapy with response-based reduced radiotherapy dose and field has become the standard management of localized CNS germinomas, however, treatment of primary metastatic disease has remained controversial. Furthermore, there is limited published research on the use of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS: We performed a retrospective multi-institutional data collection and analysis of patients diagnosed with metastatic germinoma since 2000 to assess the overall survival (OS) and event-free survival (EFS) of the different treatment modalities administered. RESULTS: We identified 78 patients with germinoma, in two tertiary care centers, of which nine patients (11.5%; eight males) had metastatic disease. The median age at presentation was 13.3 years. All patients had a biopsy at presentation confirming the diagnosis. Three patients had positive CSF cytology (M1). Six patients received craniospinal irradiation (CSI) with boost to primary and metastatic sites, of which five patients received total CSI dose of 24 Gy, while the dose was unknown for one patient. One patient required one cycle of chemotherapy prior to CSI due to worsening visual changes, which subsequently resolved. One patient received two cycles followed by whole ventricular irradiation (WVI) of 23.4 Gy with a boost to the primary bed. One patient received WVI without neoadjuvant chemotherapy. One patient developed anoxic brain injury and only received chemotherapy. He died of recurrent progressive disease 15 months post-diagnosis. The median follow-up time was 77.5 months (range 15-130.5 months), with an OS of 88.9%. Further multi-institutional data collection and analysis is underway and will be presented at the meeting. CONCLUSION: We anticipate our results may elucidate the role of neoadjuvant chemotherapy in the treatment of metastatic germinoma, and whether when combined with lower CSI doses did not compromise EFS/OS.
GCT-19. Toward understanding of the pathogenesis of central nervous system germ cell tumors
Authors: Ichimura Koichi , Takami Hirokazu , Satomi Kaishi , Matsushita Yuko , Terashima Keita , Nishikawa Ryo 
Published: June 2022

Abstract
Central nervous system germ cell tumors (CNSGCT) are the most enigmatic brain tumors that arise predominantly in children and young adults. CNSGCTs are rare in Europe and North America, while they are rather common in East Asia. The genetic basis of the distinct regional prevalence is yet to be elucidated. The WHO Classification of Central Nervous System Tumours recognizes 6 subtypes of CNSGCT, however multiple subtypes are often present as a mixed tumor, and the subtype may change at the recurrence. In 2012, we organized the Intracranial Germ Cell Tumor Genome Analysis Consortium of Japan (iGCT Consortium) and have collected nearly 300 frozen tumor specimen and patients’ information for CNSGCT cases since then to comprehensively investigate the genomic/epigenomic mechanism of CNSGCT development. We found that alterations of the MAPK and/or PI3K pathways were present in approximately 50% of all subtypes of CNSGCTs, KIT mutations being the most common. Germinomas are characterized by global hypomethylation, indicating that their cell of origin may be primordial germ cells. Transcriptomic profiling suggested that germinomas and non-germinomatous germ cell tumors (NGGCTs) developed from the common cell of origin and then diverted at some stage. We also showed that components of mixed CNSGCT shared the identical somatic mutation while having distinct methylation profiles, supporting the common cell-of-origin theory. In this paper, we will present an overview of our investigation in the iGCT Consortium as well as some of the ongoing projects, single cell RNA sequencing among others.
HGG-10. Efficacy of convection-enhanced delivery of GB-13 (IL13.E13K-PE4E) in an orthotopic xenograft model of high-grade glioma is predicated on IL-13Rα2 expression.
Authors: Rechberger Julian , Porath Kendra , Schrecengost Randy , Sarkaria Jann , Daniels David 
Published: June 2022

Abstract
High-grade gliomas (HGG) encompass a large proportion of malignant tumors within the central nervous system. Despite advances in our understanding of underlying disease mechanisms, the prognosis remains dismal and efficacious therapies are lacking. As such, there is a dire, unmet, gap in clinical practice for treating this devastating disease. Here, we performed convection-enhanced delivery (CED) of GB-13 (also known as IL13.E13K-PE4E), a tumor-specific immunotoxin, into the mouse brain in an effort to assess safety and efficacy. Fifty-five nude mice were inoculated with cells from 3 distinct patient-derived HGG cell lines (low, medium and high IL-13Rα2 expression). After tumor size reached a pre-determined threshold, mice underwent stereotactic cannula placement into the tumor followed by a single 40-min ramped infusion (rate 0.2-0.8 ul/min) of GB-13 (volume of infusion 20 ul) at concentrations ranging from 5 to 50 ug/ml. Tumor progression was monitored semiweekly and animals were euthanized at the indication of progressive neurologic deficit. All animals tolerated the infusions without exhibiting any neurological changes. GB-13 decreased tumor burden and prolonged survival in a manner strongly associated with IL-13Rα2 expression. While no survival benefit was observed in animals harboring IL-13Rα2-low expressing HGG, IL-13Rα2-medium and -high animals lived significantly longer after GB-13 infusion than vehicle-treated animals (median survival prolongation &gt;25 days). Postmortem examination of the brains revealed no morphological changes beyond the site of the cannula tract. While GB-13 decreased cell proliferation and increased the number of apoptotic cells, neuronal cell density in ipsilateral brain regions was retained and no monocyte infiltrate was evidenced following GB-13 exposure. These findings indicate that a single therapeutic infusion of GB-13 administered by CED is well tolerated and underscore the potential of IL-13Rα2-targeted therapies in a subset of HGG with increased IL-13Rα2 expression.
HGG-23. The presence ofROS1 fusions are not limited only to infantile hemispheric glioma.
Authors: Trubicka Joanna , Ciołkowski Maciej , Perek-Polnik Marta , Dembowska-Bagińska Bożenna 
Published: June 2022

Abstract
INTRODUCTION: Diffuse pediatric-type high-grade gliomas are diffuse gliomas with histological features of malignancy, typically occurring in children, and infants. For these tumors, precise classification, identification of prognostic and predictive factors requires molecular analysis. The ROS proto-oncogene 1 (ROS1) gene encodes a receptor tyrosine kinase that is involved in chromosomal rearrangements in numerous malignancies, and may be an attractive therapeutic target, since specific inhibitors have been approved for several neoplasms. Molecular evaluation including detection of ROS1 fusions in pediatric gliomas are not included in standard diagnostic tests so far, therefore data on its significance is still limited. We present two cases of pediatric ROS1 fusion-positive brain tumors. METHODS AND RESULTS: The patient no.1 was 1 year old boy with disseminated brain lesions. Histopathological examination displayed the presence of a neoplasm, which was composed of round and spindle-shaped cells with palisading necrosis, mitotic activity, and microvascular proliferation. The patient no.2 is 9 years old girl with tumor located in left frontal lobe. Microscopically, the neoplasm revealed the presence of oligodenroglial-like component with microvascular proliferation, and high mitotic activity. Targeted gene sequencing panel - Ampliseq Childhood Cancer Panel for Illumina was used to detect diagnostic and targetable gene fusions. In both of patients ROS1:GOPC gene fusions were detect. Identified fusions allowed to established diagnosis - infant-type hemispheric glioma with ROS1 fusion (patient no 1) and - diffuse pediatric-type high grade glioma with ROS1 fusion (patient no 2). CONCLUSIONS: Our results indicate, that the presence of ROS1 fusions are not limited to the infant-type hemispheric gliomas only and may play a role in other glioma entities. It may be worth to include this biomarker in the diagnostic panel of pediatric brain tumors to establish a more precise diagnosis and a potential therapeutic target. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064).
HGG-54. CLK1 aberrant splicing in pediatric high-grade gliomas disrupts key oncogenic transcriptional programs
Authors: Naqvi Ammar , Ennis Brian , Jin Run , Gaonkar Krutika , Foster Jessica , Conkrite Karina , Rathi Komal , Kraya Adam , Sonawane Poonam , Madsen Peter , Storm Phillip , Resnick Adam , Rokita Jo Lynne 
Published: June 2022

Abstract
While much of the somatic coding variation underlying the oncogenic transformation of pediatric high-grade gliomas (HGGs) has been profiled, transcriptional splicing programs of these tumors remain under-explored. Here, we characterize aberrant alternative splicing in pediatric midline HGGs (n = 84). We identified 19,275 recurrent and significant (20% change from control, P &lt; 0.05, FDR &lt; 0.05) aberrant splicing events in 8,587 genes compared to non-diseased brainstem controls. Of those, 27% (n = 5,157) resulted in either a gain or loss of a known protein functional site within 3,294 genes. We prioritized splice variants affecting targetable kinases and found that mRNAs encoding CDC-like kinase 1 (CLK1), a known modulator of master splicing regulators, exhibit significantly increased exon 4 inclusion in midline HGGs. This leads to a gain of two known phosphorylation sites in CLK1, increased CLK1 protein expression and hyper-phosphorylation of Serine-rich splicing factors. To assess the impact of this event, we performed differential splicing and expression analyses, comparing tumors with the highest (n= 5) and lowest (n = 5) exon 4 inclusion. We discovered 3,037 genes to be differentially up-regulated in high exon 4 inclusion tumors with an enrichment of cancer-related pathways, including DNA repair, mitotic spindle, myogenesis and EMT. We next integrated these gene signatures with protein-protein interaction networks of kinase and transcription factors and show that increased CLK1 exon 4 inclusion disrupts critical regulatory networks, such as those involving FOXM1, which is implicated in cell cycle and proliferation processes. In summary, we describe aberrant splicing in pediatric HGGs as an additional mechanism that could drive tumorigenesis. Future work will focus on molecular validation and therapeutic targeting of CLK1 in available HGG models. Characterizing tumor-specific splicing variation has the potential to open new therapeutic strategies and understand mechanisms of treatment resistance in children with central nervous system tumors.
HGG-61.Landscape of cancer predisposition in pediatric high-grade glioma
Authors: Blattner-Johnson Mirjam , Sturm Dominik , Sievers Philipp , Jones Barbara , Schramm Kathrin , Balasubramanian Gnana Prakash , Sill Martin , Jäger Natalie , van Tilburg Cornelis M , Milde Till , Pajtler Kristian W , Dikow Nicola , Hirsch Steffen , Sutter Christian , Sahm Felix , Witt Olaf , Pfister Stefan M , Jones David T W 
Published: June 2022

Abstract
Current estimates indicate that approximately 8–10% of cancer incidence in young patients can be attributed to constitutional alterations in genes linked to tumor initiation. The rarity and highly heterogeneous nature of high-grade glioma (HGG) in children and adolescents requires coordinated efforts to capture the diversity of subtypes in a normal-tumor matched sequencing cohort. Combining sequencing data of two registries based at the Hopp Children's Cancer Center (KiTZ) Heidelberg (INFORM and MNP2.0) allowed us to investigate the landscape of constitutional alterations across 350 children with high-grade gliomas. Both cohorts independently showed a surprisingly high proportion of patients (17%) with constitutional pathogenic alteration variants in cancer predisposition genes (n=40/233 and 23/128). Our results confirm a high frequency of alterations affecting genes of the DNA mismatch repair (MMR) pathway in 44% of IDH-mutant tumors (n=12/27). Additionally, we observed an almost exclusive correlation of MSH6 constitutional variation and somatic mutation in the IDH1 gene (n=7/8). A hypermutator phenotype defined by a tumor mutational burden &gt;10 mutations/mb) was linked in 14/17 patients to a constitutional alteration in one of the following MMR genes: MLH1, MSH2, MSH6 or PMS2, with IDH-wildtype cases mostly classified as ‘RTK1 subtype’ by DNA methylation analysis. Constitutional alterations in TP53 were found in 5% of the total cohort. Furthermore, these tumors occurred exclusively in the group of H3-/IDH-wildtype glioblastoma (12%), and 8/18 tumors belong to the pedHGG_MYCN subgroup (conversely, this represents 40% of all ‘MYCN subtype’ patients, a highly significant enrichment over other subtypes (p&lt;0.001). The overall high percentage of constitutional alterations in pediatric HGG warrants human genetics counselling for all affected patients and their families. Additionally, the strong correlation of MSH6 and IDH mutations as well as Li-Fraumeni-Syndrome and MYCN positive signature should be further explored as this might open the avenue for much needed new therapeutic approaches.
IMG-08. Response assessment for pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group
Authors: Hoffman Lindsey M , Jaimes Camilo , Mankad Kshitij , Mirsky David M , Tamrazi Benita , Tinkle Christopher L , Kline Cassie , Ramasubramanian Aparna , Malbari Fatema , Mangum Ross , Lindsay Holly , Horne Vincent , Daniels David J , Keole Sameer , Grosshans David R , Poussaint Tina Young , Packer Roger , Cavalheiro Sergio , Bison Brigitte , Hankinson Todd C , Müller Hermann L , Bartels Ute , Warren Katherine E , Chintagumpala Murali 
Published: June 2022

Abstract
INTRODUCTION: Craniopharyngioma (CP) is a histologically benign tumor of the pituitary stalk that accounts for 4% of pediatric central nervous system (CNS) tumors. Given its location, CP often causes neuro-endocrine, hypothalamic, and vision dysfunction. Standard therapy consists of maximally safe resection +/- radiation therapy (RT). Medical management, including intra-cystic therapy, may have utility in certain contexts. Survival after CP is excellent, but quality of life is often poor secondary to functional deficits from the tumor and/or treatment. Few prospective CP trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, formed of international experts in relevant subspecialties, devised consensus guidelines from published literature and/or expert opinion to assess CP response in prospective clinical trials. RESULTS: Magnetic resonance imaging (MRI) is the recommended radiological modality for baseline and follow-up CP assessment. Computed tomography can be useful for identification of calcification in the initial diagnostic work-up. The committee defined specific standard MRI-based sequences focused on comprehensive evaluation of the suprasellar space. Radiologic CP response is defined by two-dimensional measurements of both solid and cystic tumor components. Three-dimensional measurements are also encouraged in prospective trials. In certain clinical contexts, response of solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment (including transient cyst growth during or after RT). Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into CP response definitions. In most circumstances, cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSION: CP is a common pediatric CNS tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for baseline and longitudinal assessments of CP to uniformly define response in future prospective trials.