bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-53. "Profile of High Grade Gliomas and Diffuse Intrinsic Pontine Gliomas in Greek Pediatric Patients: an 8-year Single Institution's experience"
Authors: Roka Kleoniki , Filippidou Maria , Vlachou Antonia , Gavra Maria , Panagopoulos Dimitrios , Markogiannakis Georgios , Kokkinou Eleftheria , Alexopoulou Aikaterini , Chasiotou Maria , Sfakianos Georgios , Pons Roser , Stefanaki Kalliopi , Kattamis Antonis 
Published: June 2022

Abstract
BACKGROUND/OBJECTIVES: Aggressive clinical and biological behavior, high morbidity and mortality are the main characteristics of pediatric high-grade-gliomas (HGG). Our aim was to study patients (pts) with ΗGG or diffuse-intrinsic-pontine-glioma (DIPG), diagnosed in the largest pediatric neurooncology Center in Greece. DESIGN-METHODS: We performed a retrospective-review of newly-diagnosed pts with HGG or DIPG during 2014-2021. Gender, age, location, resectability, type of surgery, histological and molecular characteristics, management and outcome were analyzed. RESULTS: During the study-period, 38pts (18females), median age:9.35y(range:3days-16.9y), were diagnosed in our center. The most common tumor-location were pons (17/38 pts) and parietal lobe (11/38 pts). DIPG based on imaging-studies was diagnosed in 16pts.
Surgical approach was performed in 32pts (VP-shunt insertion:8, biopsy:12, partial resection:6, subtotal: 6). In 23pts(5 brainstem-tumors) a histological-diagnosis was feasible. Astrocytoma grIV was found in 60.8% and grΙΙΙ in 26.1%(14 and 6 respectively). Of notice, 3 additional pts with histological findings of low-grade(2grII and 1gr1), were upgraded in grIV after molecular-studies and DNA-methylation analysis. Furthermore, 17.3% of the pts (4/23, 3 located in the midline) carried a Η3Κ27Μ-mutation (diffuse midline glioma, DMG), 17.3% a Η3F3A-mutation and 8.6% showed ΕGFR-overexpression. All patients&gt;3years of age were treated upfront according to HIT-HGG2013 with radiotherapy-temozolomide (29/32pts). In 5DIPG pts, reirradiation after disease-progression resulted in temporary symptomatic improvement. HGG-pts upon progression were treated with bevacizumab-irinotecan. Of the 38pts, 6pts elected to receive treatment in other countries. Overall-survival was 75.1%,15.1% and 3.7% at 1,2 and 3 years post-diagnosis respectively. Patients with DIPG/ DMG and non-midline HGG had a median overall-survival of 1.10 years and1.34 years, respectively. CONCLUSIONS: The experience of our unit concurs with worldwide published series and shows that pediatric HGG and DIPG have a dismal prognosis. Re-irradiation may offer short survival prolongation. ASKNOWLEDGEMENTS: Authors asknowledge the contribution of KiTZ-Heidelberg in molecular diagnostics through collaboration with ACCC.
IMG-06. Comparing between MR spectroscopy done at 1.5T and 3T
Authors: Tang Phua Hwee , Nisa Sameema 
Published: June 2022

Abstract
INTRODUCTION: In hospitals with heavily utilised MRI scanners, it may not be possible to schedule the patient on 1 particular scanner for all scans and thus this project was carried out to determine if there is any significant difference in the spectroscopy profile between 1.5 T and 3T MRI scanners late year 2021. AIM: To describe the MR spectroscopy profile of normal brain tissue performed on 1.5T and 3T MRI scanners in KK Women’s and Children’s Hospital. METHODS: Three healthy adult volunteers with normal body mass index underwent MRI brain scans after informed consent in this Institute Review Board approved study. MRI brain scans were performed on 1.5T General Electric MRI scanner and 3T Siemens Skyra MRI scanner 1 week apart. NAA/Cr, Cho/Cr and Cho/ NAA values were obtained from the right and left cerebral hemispheres.
RESULTS: Average NAA/Cr in the right cerebral hemisphere is 2.06+/-0.10 at 1.5T. Average NAA/Cr in the left cerebral hemisphere is 2.01+/-0.23 at 1.5T. Average NAA/Cr in the right cerebral hemisphere is 1.56+/-0.09 at 3T. Average NAA/Cr in the left cerebral hemisphere is 1.81+/-0.29 at 3T. Average Cho/Cr in the right cerebral hemisphere 1.06+/-0.14 at 1.5T. Average Cho/Cr in the left cerebral hemisphere is 1.11+/-0.22 at 1.5T. Average Cho/Cr in the right cerebral hemisphere is 0.90+/-0.05 at 3T. Average Cho/Cr in the left cerebral hemisphere is 0.95+/-0.27 at 3T. Average Cho/NAA in the right cerebral hemisphere is 0.51+/-0.06 at 1.5T. Average Cho/NAA in the left cerebral hemisphere is 0.58+/-0.00 at 1.5T. Average Cho/NAA in the right cerebral hemisphere is 0.55+/-0.05 at 3T. Average Cho/NAA in the left cerebral hemisphere is 0.52+/-0.07 at 3T. CONCLUSION: MR spectroscopy values obtained from 1.5T and 3T MRI scanners show no significant difference(P&gt;0.05).
IMG-07. Contralateral transient contrast enhancement in a patient with IDH1wt MGMT promoter-methylated GBM responding to TMZ and individualized multimodal immunotherapy
Authors: Matiashchuk Andrii , Makalowski Jennifer , Bitar Michael , Van de Vliet Peter , Stuecker Wilfried , Van Gool Stefaan 
Published: June 2022

Abstract
Immunotherapy-induced MRI changes remain challenging when treating GBM patients with immunotherapy as part of a combined treatment. The iRANO criteria provide a decision-tree in order to avoid over- and under-treatment reactions when contrast-enhancing lesions become visible and should be interpreted. We report a 34-year female, 34 weeks pregnant, who presented with epilepsy, and was diagnosed with IDH1wt MGMT promoter-methylated GBM after biopsy. On MRI, the left occipital lesion was mostly cystic-necrotic with peripheral contrast enhancement, and crossed over the corpus callosum to the right. The volume was calculated as 64 cm³ (abc/2 formula). She was treated with radiochemotherapy and 12 TMZm cycles. Within each TMZ cycle 5 days of immunogenic cell death (ICD) therapy (5 injections with Newcastle Disease Virus and 5 sessions of modulated electrohyperthermia (Oncotherm 50 min 40-60 Watt) was added at days 8 to 12. After all chemo-/ICD-therapy we continued with active specific immunotherapy: two autologous mature monocyte-derived dendritic cell vaccines loaded with ICD therapy-induced serum-derived antigenic extracellular microvesicles and apoptotic bodies (IO-Vac®). One month after the second IO-Vac®, 17 months after diagnosis, a temporal right FLAIR-visible region showed expansion, and three months later also diffuse contrast enhancement, which was confirmed in a control scan one month later. The original tumor was meanwhile reduced to 16 cm³. However, in the last available scan, two months after the former, the contrast enhancement was disappeared, and the pathologic area on FLAIR was diminished. The original tumor size was reduced to 2 cm³, two year after first diagnosis. She showed allergic skin reactions to TMZ, which was covered with systemic histamine intake. There were no side effects related to multimodal immunotherapy. Transient MRI changes can be observed even in distance from the original tumor and can be interpreted as immune-mediated effects when the original tumor is responding.
IMG-10. Determining brain tumour grade non-invasively using a simplified MRI perfusion protocol: single-bolus, leakage-corrected dynamic susceptibility-contrast MRI
Authors: Withey Stephanie , MacPherson Lesley , Oates Adam , Powell Stephen , Novak Jan , Bailey Simon , Mitra Dipayan , Arvanitis Theodoros N , Khan Omar , Rose Heather E L , Worthinton Lara , Peet Andrew C 
Published: June 2022

Abstract
INTRODUCTION: Perfusion is associated with grade and survival in children’s brain tumours. Dynamic susceptibility-contrast (DSC-) MRI measures perfusion non-invasively, estimating relative cerebral blood volume (rCBV). We previously showed significant differences between pre-treatment rCBV in low- and high-grade tumours in a multicentre study. Contrast agent leakage from tumour vessels during acquisition affects rCBV accuracy. A contrast agent pre-bolus can be given but this can be challenging in a clinical environment, introducing variability. Alternatively, a single bolus can be administered with leakage correction applied when processing the data. We investigated pre-treatment rCBV values in a multicentre study without pre-bolus administration. METHODS: Thirty-six patients underwent pre-treatment DSC-MRI scans at 2 centres on 4 different scanners. Protocols were variable. Pixel-by-pixel contrast agent concentration time courses were analysed. Maps of uncorrected (rCBVuncorr) and leakage-corrected rCBV (rCBVcorr) were produced. Whole-tumour regions-of-interest were defined and median whole-tumour DSC-MRI parameters calculated. Patients subsequently underwent surgery / biopsy. Tumours were classified and graded. RESULTS: Twelve tumours were classified as low-grade; 24 as high-grade. Median whole-tumour rCBVuncorr was significantly higher in high-grade tumours than in low-grade tumours (1.628 vs -0.167, p&lt;0.001). Median rCBV significantly increased in low-grade tumours following leakage correction (-0.167 to 1.072, p=0.007); there was no significant change for high-grade tumours. Using the median rCBVuncorr of 1.19 to differentiate between low- and high-grade tumours resulted in sensitivity and specificity of 75% and 100%, respectively; median 1.45 for rCBVcorr resulted in sensitivity and specificity of 67% and 100%, respectively. DISCUSSION: DSC-MRI measures of perfusion can distinguish between low- and high-grade paediatric brain tumours. Contrast agent leakage correction is essential for accurate measurement of rCBV. This is robust across multiple centres despite using multiple protocols. CONCLUSION: Pre-treatment multicentre perfusion MRI acquired with a single-bolus and contrast agent leakage correction can aid with differentiating between high- and low-grade paediatric brain tumours.
IMG-14. Cognitive deficits and altered functional network organization in pediatric brain tumor patients
Authors: Seitzman Benjamin , Anandarajah Hari , McMichael Alana , Dworetsky Ally , Coalson Rebecca , Dowling Anna , Mitchell Timothy , Olufawo Michael , Agamah Alikem , Butler Rachel , Jiang Catherine , Gu Hongjie , Dierker Donna , Barbour Dennis , Schlaggar Bradley , Strahle Jennifer , Limbrick David , Rubin Joshua , Shimony Joshua , Perkins Stephanie 
Published: June 2022

Abstract
INTRODUCTION: Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. Mechanisms of cognitive injury are poorly understood, and predictors of long-term outcome are lacking. Large-scale, distributed brain systems provide a window into brain organization and function that may yield insight into these mechanisms and outcomes. Recent evidence suggests that systems-level changes are related to cognitive performance across the lifespan. Here, we evaluated brain network architecture, cognitive performance, and brain-behavior relationships in pediatric brain tumor patients.
METHODS: Forty-nine patients (ages 7-18y.o.) with any brain tumor diagnosis underwent resting state functional Magnetic Resonance Imaging (rsfMRI) during regularly scheduled clinical visits. All patients were tested with the NIH Toolbox Cognition Battery. One-hundred thirty-nine age- and sex-matched typically developing children were used as controls. All data were processed to minimize artifactual sources of variance. Functional brain networks were created for each patient via rsfMRI data from 300 regions of interest that sample the whole brain. Multilinear models were implemented to examine brain-behavior relationships, while accounting for demographic and clinical factors.
RESULTS: Functional network organization was significantly altered in patients compared to controls (p&lt;0.001). Network organization was more affected in patients who received whole-brain radiation therapy than those who did not (t=2.52, p&lt;0.015). Patients demonstrated significant impairments in multiple domains of cognitive performance, e.g. attention (p&lt;0.0001). Weak relationships were found between cognitive performance and network organization, none of which survived multiple comparison correction.
CONCLUSIONS: Brain network architecture is significantly altered in pediatric brain tumor patients. Whole-brain radiation was related to the largest changes. Most network and cognitive changes were significant with large effect sizes, yet brain-behavior relationships were weak. Our results suggest that systems-level changes in brain organization may provide insight into long-term changes in brain function in pediatric brain tumor patients.
IMMU-02. Targeted innovative antibody fragment-based immunotherapy for medulloblastoma
Authors: Niesen Judith , Krüger Christina , Kreuter Naomé , Haferkamp Undine , Pless Ole , Schüller Ulrich 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor accounting for ~20 % of childhood brain tumors. One third of all MB are characterized by constitutive activation of the Sonic Hedgehog (SHH)-signaling pathway. This tumor type shows overexpression of the epidermal growth-factor receptor (EGFR), which we detected in SHH-MB patient samples, transgenic SHH MB mouse models, and MB-cell lines. In contrast, non-neoplastic cells only express EGFR at low levels. Intensive radio-/chemotherapy often leaves the young patients with significant long-term burdens including problems in brain development and cognitive deficits. Thus, there is an urgent need to develop new targeted therapies that can prevent tumor recurrence without affecting healthy cells. We selected EGFR as a potential therapy target using EGFR-specific antibody fragments (scFvs) as part of immunoconjugates, namely bispecific T-cell engagers (BiTEs) and immunotoxins (ITs). Both, the EGFR-specific BiTEs and the ITs showed specific binding and cytotoxic activity in MB cells. Effector- and target-cell specificity was demonstrated via flow cytometry for the BiTEs. BiTEs and ITs selectively killed MB-tumor cells and showed pro-apoptotic effects without unspecific effects. Furthermore, preliminary results from an innovative hiPSC-based in vitro-BBB-model suggest, that the ITs are able to cross the BBB. Finally, by having a functional cloning- and expression system for the BiTEs and ITs available, target-scFvs can be easily exchanged by novel antigens or peptides to obtain additional targeted immunotherapies. Together, these results pave the way for preclinical in vivo experiments and future clinical trials in patients with SHH MB.
IMMU-10. TUMOR ASSOCIATED MYELOID CELLS DRIVE THE IMMUNOBIOLOGY OF HIGH RISK PEDIATRIC EPENDYMOMA
Authors: Griesinger Andrea , Riemondy Kent , Eswaran Nithyashri , Donson Andrew , Willard Nicholas , Paine Simon , Bowes Georgia , Rheaume John , Chapman Rebecca , Ramage Judith , Jackson Andrew , Grundy Richard , Foreman Nicholas , Ritzmann Timothy 
Published: June 2022

Abstract
Molecular profiling of pediatric ependymoma (EPN) has previously identified discrete neoplastic subpopulations, of which Mesenchymal EPN Cells (MEC) characterize Posterior Fossa A tumors (PFA). MECs are associated with tumor immunosuppression. Here we further characterize the EPN immune environment using single-cell sequencing, spatial phenotyping and cytokine analyses to better define infiltrating myeloid subpopulations. We hypothesize that neoplastic and myeloid cells interact to propagate an immune suppressive environment conferring resistance to traditional therapies. We delineated myeloid cell subpopulations from single-cell RNA-seq of 26 pediatric EPNs and validated them through deconvolution of bulk gene expression profiling (n=299). To define subpopulation spatial distribution, we interrogated a range of tumor and myeloid markers using multiplex immunofluorescence (mIF). Finally, using single-cell cytokine analyses, we gained further insight into myeloid subpopulation function. Eight distinct myeloid subpopulations were identified, relating to macrophages, microglia and monocytes. A subpopulation of cells with wound healing ontologies and characterized by TREM1 expression, demonstrated features of myeloid derived suppressor cells, including IL6/STAT3 pathway activation. We called these hypoxia-M. Like MEC neoplastic cells, hypoxia-M was associated specifically with PFA1 subgroup EPN in both single-cell and bulk tumor gene expression profiling (p&lt;0.001). Additionally, the presence of MEC and hypoxia-M correlated strongly in gene expression (r2=0.92, p&lt;0.001) and IHC analyses, where they co-located to borders between necrosis, blood vessels and viable tumor. Analysis using mIF (n=54) confirmed MEC/hypoxia-M co-location and highlighted that all types of immune cell corralled in significant numbers around areas of vasculature and necrosis. Single cell cytokine analyses demonstrated that hypoxia-M secrete IL-8 which, we hypothesize, amplify the pro-tumor phenotype in PFA1 tumor microenvironment. EPN is characterized by discrete myeloid cell subpopulations which contribute to the tumor microenvironment. Treatment strategies must focus on modifying this pro-tumor, immunosuppressive microenvironment to deliver more effective treatment for childhood ependymoma.
IMMU-16. Next-generation CAR T-cells targeting IL13RA2 and secreting IL-15 achieve durable tumour clearance in pre-clinical model of diffuse midline glioma
Authors: Hotblack Alastair , Wawrzyniecka Patrycja , Cheng Gordon Weng-Kit , Nannini Francesco , Pule Martin , Straathof Karin 
Published: June 2022

Abstract
T-cells engineered with a chimeric antigen receptor (CAR) to acquire tumour specificity provide a possible new treatment approach for childhood brain tumours. Durable clinical remissions have been achieved with CD19-directed CAR T-cells in refractory B-cell malignancies including control of leptomeningeal disease and parenchymal deposits. Early clinical data of CAR-T cells in adult glioblastoma and diffuse midline glioma (DMG) further support the rationale for development of CAR-T cell therapy for paediatric high-grade gliomas (pHGG) and other high-risk childhood brain tumours. IL13RA2 provides a suitable CAR target. It is expressed in the majority of pHGG including DMGs while expression is absent on normal (paediatric) brain tissue. Early results with CAR T-cell therapy for adult HGG has shown that IL13RA2 can be safely targeted, and potent anti-tumour activity is possible. However, responses are variable and ultimately transient. This is likely due to the immunosuppressive environment encountered by CAR T-cells at tumour sites which hampers persistent tumour-directed immunity. Here we develop a next generation CAR approach engineering T-cells with both a CAR and a cytokine signal which supports persistent anti-tumour immunity. We have generated novel IL13RA2-specific antibodies and used these to construct CARs. Using a functional screening approach assessing target-specific cytolytic function, T-cell proliferation and cytokine release, we selected the optimal IL13RA2-CAR design. Then, we generated a next generation CAR construct co-expressing inflammatory cytokine IL-15 with the IL13RA2-CAR. In a PDX model of DMG, T-cells transduced with IL13RA2-CARIL-15, in contrast to IL13RA2-CAR alone, induced long-term tumour clearance. Further in vitro testing of IL13RA2-CARIL-15 showed enhanced proliferation and resistance to immune-suppressive secreted factors such as TGF-β. In conclusion, co-expression of IL-15 with IL13RA2-CAR enhances CAR T-cell proliferation and in vivo persistence and achieves durable tumour clearance. IL13RA2-CARIL-15 is being translated into a phase I clinical trial for patients with DMG.
IMMU-17. Comprehensive immunological gene expression profiling of pediatric brain tumors
Authors: Levine Adrian , Nobre Liana , Milos Scott , Johnson Monique , Laxer Benjamin , Ryall Scott , Siddaway Robert , Tabori Uri , Hawkins Cynthia 
Published: June 2022

Abstract
Immunotherapy, predominantly through immune checkpoint inhibition (ICI), has had incredible success in treating some metastatic cancers, however, outside of rare cases of mismatch repair deficient (MMRD) gliomas, brain tumors have not had consistent responses to ICI. This can be attributed to a variety of factors including a low tumor mutation burden, lack of T cell infiltrates, and the CNS immune privilege. There are numerous strategies to target the tumor immune microenvironment (TIME) beyond ICI, include CAR-T cells, tumor vaccines, and myeloid cell modulation. The investigation of these depends critically on detailed characterization of the cell populations and interactions in the CNS TIME. We developed a 103 gene NanoString immune-oncology gene expression panel that includes markers reflecting selected cell types, therapeutic targets, and cellular pathways, as well as the 18-gene Tumor Inflammation Signature, a well validate biomarker for ICI response. We have used this to characterize over 500 brain tumors, including a diverse set of 227 pediatric low-grade gliomas (LGG), 86 MMRD gliomas, 47 diffuse intrinsic pontine gliomas (DIPG), 26 ependymomas, 36 medulloblastomas, 70 adult gliomas, and 35 non-tumor brain samples. Our results demonstrate a broad range of immunologic states, including within groups of tumors with the same genetic driver alteration. In pediatric LGG with BRAF V600E, there was clear histologic correlation with immune status, as glioneuronal tumors had substantial upregulation of T cell markers and regulatory genes, while diffuse astrocytomas had a near normal immune profile. In DIPG there was strong upregulation of macrophage markers, contradicting prior reports that have characterized these tumors as immunologically neutral. In a set of MMRD gliomas treated with ICI we identified several differentially expressed genes correlating with therapeutic response, including CCL4, CXCL9, and HGPD. In sum, this provides a characterization of diverse immune activation states across pediatric gliomas and other brain tumors.
IMMU-20. Effective CAR-T cell medulloblastoma therapy in an immunocompetent mouse model
Authors: Tsahouridis Rania , Lim Chaemin , Sokolsky Marina , Dotti Gianpietro , Gershon Timothy 
Published: June 2022

Abstract
Immunotherapy with chimeric antibody receptor (CAR) T cells is effective for previously incurable hematologic cancers and may transform treatment for refractory brain tumors. However, CAR-T cell therapy for solid tumors has not yet been as successful as for leukemias, and animal models are needed to improve implementation. At present, preclinical studies of CAR-T cell therapy for brain tumors have typically used exogenous tumors, xenografted into immunocompromised mice, because primary mouse brain tumors do not express antigens that match brain tumor-specific antigens in humans. To advance preclinical development of CAR-T brain tumor therapy, we engineered mice to develop medulloblastomas that express B7-H3, an antigen specifically expressed on human medulloblastomas and other pediatric brain tumors. We show that treating these tumors with B7-H3-directed CAR-T cells provokes anti-tumor responses both in vitro and in vivo. Administering B7-H3 CAR-T cells by intracranial injection increased the event-free survival time of mice with medulloblastoma, in a dose-dependent manner. CAR-T cell treatment was not curative as an isolated intervention, suggesting that cure will require pairing with surgical resection and additional adjuvant therapy. Our model presents new opportunities to study the mechanisms of CAR-T cell efficacy and recurrence in an immunocompetent host with intact vasculature and blood-brain barrier. Our ongoing studies using scRNA-seq will allow us to define therapy-induced changes in tumor cells, CAR-T cells and cells of the tumor microenvironment and to test new T-cell modifications and combinations of therapeutic modalities, toward a goal of optimizing CAR-T cell therapy for pediatric brain tumors.