bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTHR-46. Single institution experience using molecular analysis of pediatric CNS tumors
Authors: Bendel Anne , Skrypek Mary , Pond Dinel , Olson Damon , Schultz Kris Ann , Roiko Samuel 
Published: June 2022

Abstract
Molecular analysis of pediatric CNS tumors helps confirm the diagnosis, but can also guide treatment by identifying prognostic factors allowing for treatment stratification, and by unveiling active signaling pathways which can be targeted. This report is a retrospective review of the molecular analysis performed on all CNS tumors biopsied or resected at Children’s Minnesota over the last 3 years to evaluate our current practices. From 2019-2021, 118 patients with newly diagnosed CNS tumors underwent surgery followed by molecular assessment (14 IHC/FISH, 85 NGS, 7 methylation profiling) on 100% of medulloblastoma, other embryonal tumors, and schwannoma; 90% of ependymoma; 88% of HGG; 71% of LGG/glioneuronal/neuronal tumors; and 50% of meningioma and craniopharygioma. MAPK pathway alterations were seen in 84% of LGG/glioneuronal/neuronal tumors, with KIAA1540-BRAF fusion seen exclusively in pilocytic astrocytoma and BRAFV600E alterations seen in diffuse LGG (75%), PLNTY and PXA. Frequent alterations seen in HGG included H3F3A-K27M, H3F3A-G34, TP53, PDGFRA, ATRX, CDKN2A/B. Common gene alterations in medulloblastoma included monosomy 6 (100%) and alteration of CTNNB1 (50%) in WNT subgroup; PTCH1 (75%) in SHH subgroup; MYC/MYCN gain (60%) or amplification (60%) in Non-WNT/SHH subgroup. Alterations in FOXR2 in CNS neuroblastoma, SMARCB1 in ATRT and C19MC in ETMR confirmed these diagnoses. Supratentorial ependymoma showed ZFTQ-RELA fusion (100%) and infratentorial ependymoma showed chromosomal copy number changes including 1q gain (40%). Meningiomas showed deletion of NF2 and SMARCB1 and craniopharyngioma had alterations in CTNNB1. Molecular analysis confirmed the diagnosis in 23% of tumors, aided with targeted treatment in 20% of patients (82% of HGG, 9% of LGG, 13% of medulloblastomas) and allowed for risk-adapted treatment in 93% of medulloblastomas. These findings indicate that identification of pathogenic variants in CNS tumors aids in the diagnosis and treatment of pediatric CNS tumors and should be considered standard practice.
LINC-11. Intrathecal methotrexate in a young child with medulloblastoma with extensive nodularity. An alternative to intra-ventricular route in Low and Middle Income Countries?
Authors: Leal-Cavazos Carlos , Arenas-Ruiz Jose , Vidal-Gutierrez Oscar 
Published: June 2022

Abstract
BACKGROUND: In places where determination of molecular subgrouping of Medulloblastoma is not available, histology remains standard for risk stratification and treatment. Young children with medulloblastoma treated with craniospinal irradiation show a negative impact in neurocognitive functions, thus avoiding radiation in this specific population is encouraged. High dose chemotherapy and stem cell rescue have been internationally used as a strategy to spare radiation in infants and young children with Medulloblastoma. German HIT protocol (SKK) reported a PFS 85±8 % and good cognitive outcome in patients with Desmoplastic Medulloblastoma treated with intra-ventricular (i.vtr.) methotrexate (MTX). SKK protocol includes 36 i.vtr. administrations of MTX through a subcutaneous reservoir. Complications related to the use of this kind of reservoir could be due to the lack of experienced staff. METHODS: We report a patient with localized Medulloblastoma with extensive nodullarity (MBEN) treated as per SKK using intrathecal route instead of i.vtr MTX. A 2.5 year old boy was diagnosed with MBEN, surgery was complete and no shunt was required. Spinal MRI and CSF cytology were negative. Patient received 3 cycles of SKK protocol and 2 cycles of modified SKK. During the first 3 cycles he received one dose of intrathecal MTX 8mg on weeks 1, 3, 5 and 7 (12 doses in all). Patient remains free of disease 2 years after chemotherapy completion and without signs of leukoencephalopathy on T2 weighted cranial MRI. DISCUSSION: Intrathecal administration of MTX is commonly used for the treatment of Acute Lymphoblastic Leukemia, the most common childhood cancer. Staff in Low and Middle Income Countries (LMIC) may be better trained for such procedure than using a ventricular access device. This strategy could be considered when using SKK protocol in selected young children with Demoplastic Medulloblastoma and MBEN in LMIC where centers with enough experience with ventricular access device placement and handling are scarce.
MODL-03. Establishment of intraventricular Shh inhibition as a therapeutic option for young patients with medulloblastoma
Authors: Kresbach Catena , Schoof Melanie , Holst Lea , Leven Tara , Yorgan Timur , Wrzeszcz Antonina , Rutkowski Stefan , Schüller Ulrich 
Published: June 2022

Abstract
The prognosis of pediatric medulloblastoma is still dissatisfying today and tumor survivors often suffer from severe treatment-related morbidities. This poses an urgent need for more efficient therapies. Shh medulloblastoma is characterized by mutations in the Sonic Hedgehog (Shh) pathway, providing an elegant way of targeted therapy. The small molecule Vismodegib allosterically inhibits Smoothened (SMO), an upstream activator of Shh, and shows promising anti-tumor effects against Shh medulloblastoma. Unfortunately, Vismodegib caused severe bone deformities in preclinical studies and clinical trials, preventing its systemic application in children. In a mouse model, we established an intraventricular therapy with Vismodegib combining the benefits of targeted drug delivery and minimal systemic side effects. We compare intraventricular, oral, and placebo treatment regarding effects on survival, tumor biology, and bone morphology.Math1-cre::Ptch1Fl/Fl mice show a homozygous loss of Ptch1 in Math1-positive cells, resulting in Shh pathway overactivation and development of Shh medulloblastomas. At postnatal day 11-13, Math1-cre::Ptch1Fl/Fl mice were randomized in four treatment arms: Group A (n=14) received intraventricular placebo, B (n=12) received 200 mg/kd/d oral Vismodegib, C (n=16) received 0.2 mg/kg/d intraventricular Vismodegib, and D (n=9) received 1.6 mg/kg/d intraventricular Vismodegib. Kaplan-Meier survival curves show a significant survival benefit of 1.6 mg/kg/d intraventricular Vismodegib over placebo (p=0.003). While all intraventricular treated animals develop proliferative tumors at end of observation, investigations at an early time point after completed treatment show promising anti-tumor effects with reduced or absent proliferation in the cerebellum compared to placebo. Bone histology and X-ray analysis of intraventricular treated mice show intact femoral and tibial growth plates, in contrast to orally treated mice that develop severe skeletal malformations. Based on these preliminary experimental results, we conclude that intraventricular application of a SMO-inhibitor might evolve as a promising new way of targeted treatment of Shh medulloblastoma in children.
MODL-14 Inhibition of cell cycle mechanisms to combat high-risk medulloblastoma
Authors: Bruckner Katharina , Mayr Lisa , Sickha Romana , Frederico Aniello , Madlener Sibylle , Gabler Lisa , Kirchhofer Dominik , Roessler Karl , Jäger Natalie , Berger Walter , Kool Marcel , Pfister Stefan M , Schueler Julia , Gojo Johannes , Lötsch-Gojo Daniela 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common embryonal brain tumor in children, characterized by a high level of heterogeneity within this entity. Four major molecular groups have been defined - WNT, Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4) - differing widely in genetic alterations and patient outcomes. Targeted treatment approaches are limited for high-risk MB including MYC-amplified G3, G4, or MYCN/GLI2-amplified SHH. Based on earlier studies describing the inhibition of cell cycle regulation as a therapeutic vulnerability in high-risk MB, we aimed to explore the efficacy and mode of action of approved CDK4/6 inhibitors in aggressive MB. First the in vitro sensitivity of pediatric G3 (n=5) MB cell models against palbociclib, ribociclib and abemaciclib was evaluated and compared to adult SHH (n=2) cells serving as MYC-negative controls. Abemaciclib most effectively reduced cell viability, exhibiting a mean IC50 value of 0.9 M in G3 compared to 2.1 M in SHH cells (p=0.007). Upon long-term exposure (7-10 days), again abemaciclib most potently decreased clonogenic survival already at 250nM in G3 MB cells. We observed a G1/S phase cell cycle arrest upon abemaciclib treatment and confirmed this by Western blot analyses, showing decreased Rb phosphorylation accompanied by reduced MAPK signaling. Interestingly, abemaciclib treatment distinctly reduced MYC protein and gene expression levels in MYC-amplified G3 cell models. In addition, exposure to abemaciclib decreased GLI2 and TERT mRNA levels, which was accompanied by induction of cellular senescence. Within the ITCC-P4 project, single mouse trials are currently being performed including abemaciclib treatment in orthotopic MB models. The detailed investigation of the precise mode of action in vitro and in vivo is ongoing. Summarizing, the CDK4/6 clinically approved inhibitor abemaciclib shows promising efficacy against high-risk MB in vitro.
MODL-30. Children’s Brain Tumor Network preclinical tumor models development and sharing platform: collaborative model empowering pediatric brain tumor discovery and global research.
Authors: Koptyra Mateusz , Baubet Valerie , Beale David , Patterson Luke , Biluck Ian , Hollawell Madison , Beck Christopher M , Sonawane Poonam , Griffin Crystal , Stern Allison , Madsen Peter , Foster Jessica , Lilly Jena , Mason Jennifer , Trooskin Gerri , Sullivan Catherine , Morgan Allison , Frenkel Beth , Lehmann Kaitlin , Lopez Lina , Nguyen Thinh , Agbodza Ena , Lopez-Gil Valeria , Helili Zeinab , Plisiewicz Alexa , Coleman Noel , Patton Tatiana , Stefankiewicz Stephanie , Arya Kamnaa , Velasco Ryan , Santi Mariarita , Viaene Angela , Storm Phillip B , Resnick Adam 
Published: June 2022

Abstract
Pediatric brain tumor preclinical field suffered for years from the lack of in vitro and in vivo models. With the explosion of novel therapy approaches for solid and brain tumors, including the immunotherapies it is essential to maximize the access to preclinical models for preclinical specificity, efficacy as well and safety. One of the many ways the Children’s Brain Tumor Network (CBTN) accelerates the pediatric brain tumor research and discovery is through support of the tumor model development program. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide provided free of charge. Here we present the resource platform with over 150 cell lines, organoids and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the tumor tissue use to generate a combination of cell line, organoids and/or xenograft models grown in animals. In recent years, consortium supported over 40 requests for cells lines used in basic biology and translational studies internationally. Current efforts focusing also on supporting large-scale data generation and testing through its collaborative model (Childhood Cancer Model Atlas, Procan, National Center for Advancing Translational Sciences) to maximize the molecular information available for each tumor model essential in preclinical screenings. The generated and returned to consortia data are bound with the deidentified patient clinical information and genomic data and freely available through Kid’s First Data, Cavatica and PedcBio portals. These efforts have already attracted interest from pharma stakeholders previously not observed in pediatric brain environment. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission to bring fast change to kids suffering from brain tumors.
RONC-10. Radiation-induced hypothyroidism in pediatric brain tumour survivors: radiation dose-volume predictors of its onset
Authors: Satragno Camilla , Verrico Antonio , Giannelli Flavio , Campora Sucheeta , Turazzi Marianna , Carmisciano Luca , Cavagnetto Francesca , Iorgi Natascia Di , Crocco Marco , Piccolo Gianluca , Casalini Emilio , Milanaccio Claudia , Garrè Maria Luisa , Belgioia Liliana , Barra Salvina 
Published: June 2022

Abstract
BACKGROUND: Central hypothyroidism is a well-known late effect of radiotherapy in children treated for brain tumours. AIM: To determine the risk of central hypothyroidism (CH) and the radiation dose-volume predictors of its onset. METHODS: We retrospectively analyzed 64 patients who received radiotherapy for brain tumours, with at least a 2-year-long serological follow-up, determined CH incidence and radiation predictive factors of its onset. To estimate the risk of CH according to the site of the tumour inside the central nervous system (CNS) we considered the sellar-suprasellar region, anterior cranial region, and others. For the same purpose, a further analysis was conducted comparing craniospinal radiotherapy (CSI) versus involved-field radiotherapy (IF-RT). Dose constraints for CH were determined using the Receiver Operating Characteristic to identify the pituitary mean dose cut-off and the probability of CH over time was assessed with the Cox model. RESULTS: 18 cases were excluded due to the presence of CH before RT; 17 of remaining 46 (37%) patients presented CH during follow-up: 14 of 17 (82%) patients received CSI, 3 (18%) IF-RT sellar-suprasellar region and anterior cranial region. A median dose higher than 30.5 Gy to the pituitary gland results in a 4-fold increased risk of central hypothyroidism (HR=3.9; 95% CI 1.1, 13.4; p=0.03). Almost 90% of events occurred within 5 years after treatment ended. 29 of 46 (63%) patients did not manifest CH and were in the "other regions”. However, 14 of these (48%) underwent CSI. CONCLUSIONS: Our data confirm the relationship between central hypothyroidism and mean pituitary radiation dose, and suggest a minimum of 5 years follow up in children brain tumor survivors. Tumours outside the sellar-suprasellar region, treated with radiotherapy, are not associated with CH onset. A significant association between CSI and risk of CH, highlighted with our analysis, warrants further investigations and a longer follow up
TBIO-08. The molecular basis for rational targeting of FGFR-driven growth and invasiveness in pediatric brain tumors
Authors: Migliavacca Jessica , Kumar Karthiga Santhana , Kopp Levi , Gries Alexandre , Yan Shen , Brunner Cyrill , Schuster Matthias , Jurt Simon , Moehle Kerstin , Zerbe Oliver , Schneider Gisbert , Grotzer Michael , Baumgartner Martin 
Published: June 2022

Abstract
The oncogenic activation of receptor tyrosine kinases (RTK) promotes growth, survival and dissemination in pediatric tumors including glioma, ependymoma and medulloblastoma (MB). Direct targeting of either the RTK or of downstream kinases can effectively block tumor promoting pathway functions. However, emergence of resistance is common. We hypothesized that alternative interference strategies that target protein-protein interactions (PPIs) instead of enzymatic activities could overcome the emergence of resistance. We characterized the molecular interactions downstream of the FGFR that regulate relevant growth and invasion-promoting mechanisms in MB cells, to identify potentially druggable PPIs. We found that the FRS2 protein is an essential up-stream effector of FGFR signaling towards invasiveness. Using a proteomics approach, we furthermore identified the Striatin 3 protein as a novel oncogenic effector of the FGFR pathway downstream of FRS2, as it integrates antagonistic growth and invasion signals downstream of FGFR. Mechanistically, Striatin 3 interacts with the Ser/Thr kinase MAP4K4, couples it to the protein phosphatase 2A, and thereby inactivates growth repressing activities of MAP4K4. In parallel, Striatin 3 enables MAP4K4-mediated phosphorylation of PKC-theta and VASP, which combined are necessary to promote tissue invasion. To selectively repress pro-invasive FGFR functions, we identified and functionally validated small molecule ligands of FRS2, that prevent FRS2 activation and downstream signaling. We demonstrate efficacy of these compounds in inhibiting invasion and growth promoting activities in vitro and in vivo, and identified potential off-target activities of the ligand using a proteome-wide interaction analysis. We propose inhibition of FRS2 by a small molecular PTB domain ligand as a strategy to repress FGF signaling in FGFR-driven tumors. The development of this ligand, and the de novo design of functional analogs thereof bear promise for further pre-clinical evaluation of these structures as anti-growth promoting and anti-metastatic therapeutics applicable to FGFR-driven tumors.
TBIO-11. The glutamine transporter and candidate diagnostic and therapeutic target SLC1A5 is associated with subtype-specific metabolic phenotypes and tumor prognosis in pediatric brain cancers
Authors: Kraya Adam , Jin Run , Zhao Chao , Familiar Ariana , Wellen Kathryn , Resnick Adam , Nabavizadeh Ali 
Published: June 2022

Abstract
Glutamine transporters play an important role in supporting increased tumor nutritional demands relative to non-cancerous cells, often through overexpression of the solute carrier (SLC) family of membrane transporters. Preclinical studies in adult cancers demonstrate that targeting glutamine addiction via SLC1A5 inhibition results in growth-inhibitory and tumoricidal effects. Given their relatively higher expression in cancer versus normal brain tissue, SLC transporters represent compelling targets for molecularly-targeted radiation and application of available prognostic amino-acid PET imaging probes. However, the role of SLC transporters in pediatric brain cancers has yet to be investigated. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes in ensemble survival models (Reactome: R-HSA-352230), we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Through transcriptome-based consensus clustering, we found that supratentorial, RELA fusion-positive ependymomas and sonic hedgehog-activated medulloblastomas were over-represented among clusters expressing higher levels of SLC1A5 (p = 3.38e-7 and p = 2.18-26, respectively). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 9.8e-4 and p = 0.032) and shorter PFS in LGG (p = 0.022). Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. Our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain cancers that warrant further investigation for molecularly-targeted treatment and amino-acid PET imaging.
INSP-05. Development of fast cortical rhythms in health and mental disease
Authors: Hanganu-Opatz Ileana 
Published: June 2022

Abstract
Synchronization of neuronal activity in fast oscillatory rhythms is a commonly observed feature in the adult cerebral cortex. While its exact functions are still a matter of debate, oscillatory activity in gamma frequency range (20-100 Hz) has been proposed to organize neuronal ensembles and to shape information processing in cortical networks. Gamma activity emerges from reciprocal interactions between excitatory and inhibitory neurons. A fine-tuned balance between excitatory drive and inhibitory feedback is mandatory for circuit function underlying cognitive performance, whereas imbalance between excitation and inhibition and resulting gamma disruption have been proposed to cause cognitive disabilities in psychiatric disorders. Despite extensive investigation of gamma activity in adult brain, its development and function early in life are still poorly understood. The talk will highlight recent experimental findings that uncover the mechanisms and role of fast oscillatory activity throughout development. We will uncover how different neuronal populations interact to generate gamma oscillations. Moreover, we will show that these early oscillations are necessary for the adult cognitive abilities. On the flip side, poorer mnemonic and social abilities that have been characterized in several psychiatric disorders, such as schizophrenia and autism, might result from developmental miswiring of the brain. Our data support this hypothesis by demonstrating that weaker fast oscillatory rhythms, sparser connectivity and lower communication are present in the core circuit of cognitive processing, including the prefrontal cortex, hippocampus and entorhinal cortex, in mouse models of these disorders. Together, these findings highlight the relevance of fast cortical rhythms early in life for the adult brain function.
INSP-09. Using genetically engineered mouse models and patient-derived orthotopic xenografts to develop new therapies for pediatric brain tumors.
Authors: Jonchere Barbara , Pribnow Allison , Morfouace Marie , Shelat Anang , Yu Jiyang , Rankovic Zoran , Gajjar Amar , Northcott Paul A , Robinson Giles W , Roussel Martine F 
Published: June 2022

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor. Extensive molecular analysis by many groups around the world demonstrated four distinct subgroups, WNT, SHH, Group3 and Group4 that now all have been divided into 11 total subtypes, 8 for Grou3 and Group4 medulloblastoma. SHH with MYCN amplification and TP53 mutations and Group3 with MYC amplification are the most aggressive and the least curable with few to no therapeutic options for recurrent tumors. Over the last two decades, my group developed several murine models for Group3 with MYC and SHH with MYCN overexpression and p53 loss of function and patient-derived orthotopic xenografts that recapitulate the four tumor subgroups. In addition, several human Group3 medulloblastoma lines with MYC amplification have been established in 2D and 3D cultures. I will discuss how the development of these murine and human medulloblastoma models combined with high throughput drug screens and pre-clinical trials at St. Jude led to the identification of new therapies currently evaluated in clinical trials.