bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCT-04. Stereotactic biopsy split-course radiation therapy for diffuse midline glioma of the pons (SPORT-DMG): Early phase II enrolling clinical trial
Authors: Cunningham Danielle , Schwartz Jonathan , Guerin Julie , Johnson Derek , Khatua Soumen , Laack Nadia , Ahmed Safia , Silvera Victoria Michelle , Brinkmann Debra , Pafundi Deanna , Keating Gesina , Raghunathan Aditya , Giannini Caterina , Daniels David , Mahajan Anita 
Published: June 2022

Abstract
Diffuse midline glioma (DMG) of the pons remains the leading cause of death among pediatric patients with brain tumors, despite numerous attempts to intensify treatment. While standard treatment includes 54Gy in 30 fractions of radiation over six weeks of time, nearly all patients progress within the treatment field, and many experience symptomatic radionecrosis with steroid dependence. Symptom improvement typically begins after 20Gy to the tumor. Both hypofractionation and reirradiation after recurrence have been found to be safe for patients with DMG. Our study aims to enroll patients with newly diagnosed pontine DMG aged &gt;1 year (no maximum age), and collect molecular information about DMG via stereotactic biopsy, followed by a short 2 week course of 25Gy in 10 fractions of radiation, with volumes guided by MRI with tractography reconstruction and FDOPA PET radiotracer uptake. Patients are followed closely and can complete the 25Gy in 10 fraction radiation course up to 3 times total for meeting radiographic and clinical progression criteria. Our primary endpoint is to estimate the time to progression from diagnosis to after receiving the second 25Gy course, and to compare this to the historical 7 month standard from diagnosis to progression after one 54Gy course. We aim to improve the time interval where patients are asymptomatic at home while minimizing time receiving daily treatments. Other endpoints will include the patient quality of life, caregiver quality of life, PFS intervals after each course, overall survival, and toxicity.
EPCT-08. Disease-specific working groups within the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and Children’s Brain Tumor Network (CBTN) facilitate multi-disciplinary collaboration and translation of innovative strategies in pediatric neuro-oncology
Authors: Kline Cassie , Resnick Adam , Prados Michael , Mueller Sabine 
Published: June 2022

Abstract
BACKGROUND: In Summer 2019, PNOC leadership developed working groups to align basic scientists, clinical researchers, and foundations for rapid translation of novel therapies for children and young adults with central nervous system tumors. Soon after, PNOC partnered with the Children’s Brain Tumor Network (CBTN) to grow collaborations and augment preclinical resources. Since their inception, working groups have advanced translation of new therapies and biomarkers, developed pipelines for preclinical and clinical research, and expanded global collaborations. DESIGN: Each working group is led by 2 to 3 experts in a disease, such as medulloblastoma, diffuse midline glioma, or craniopharyngioma, or subject matter, like imaging, nursing, or diversity, equity, and inclusion. A project manager coordinates regular multidisciplinary meetings to share new findings from research laboratories, provide updates on clinical trial development (with real-time feedback and incorporation of trial endpoints and biomarkers), and invite speakers to share advancements in the disease or subject of interest. RESULTS: Eleven working groups have been created with over 200 members across the United States, Europe, Australia. More than 20 foundations, led predominantly by families, provide support and insight to guide working group efforts. Working groups have developed 4 clinical trials (n=2, diffuse midline glioma; n=1, craniopharyngioma; n=1, medulloblastoma) and completed 3 international surveys, investigating experiences of patients/families affected by craniopharyngioma, evaluating diversity and inclusion throughout the consortia, and assessing nursing and advanced practice provider needs. Additional accomplishments include a registry for atypical teratoid rhabdoid tumors, a population dataset evaluating diversity in clinical research participation across consortia, incorporation of nursing members for review and refinement of clinical trial protocols, and updated imaging case report forms for application across clinical trials. CONCLUSION: Multidisciplinary working groups within international consortia facilitate efficient translation of multi-pronged strategies to improve the care of children and young adults with central nervous system tumors.
EPEN-04. Refinement of molecular and clinical characteristics in a cohort of 1,801 ependymomas
Authors: Pohl Lara , Obrecht Denise , Schweizer Leonille , Wefers Annika , Rutkowski Stefan , Bockmayr Michael , Schüller Ulrich 
Published: June 2022

Abstract
DNA methylation profiling led to the definition of ten molecular types of ependymomas with distinct biological and clinical features. The largest published reference cohort consists of 500 ependymomas encompassing nine molecular types that were known at this point. Our study aimed to confirm and refine molecular and clinical characteristics of ependymoma types and subtypes based on a considerably larger, well-annotated cohort of ependymal tumors. Here, we analyzed previously published and newly generated DNA methylation profiles, generated on the Illumina 450k and EPIC arrays, from a total of n=1,801 ependymomas. We looked at both global DNA methylation as well as inferred copy number profiles and correlated these data with clinical parameters. Patients with EPN-PFA, EPN-RELA, and EPN-MYCN tumors showed the worst outcome with 10 year-overall survival rates of 56%, 64%, and a 5 year-overall survival rate of 73%, respectively. EPN-PFA, the most frequent tumor type in our series, occurred in children in &gt;98% of cases, epigenetically split into two major subtypes, and harbored chromosome 1q gains and 6q losses as markers for worse survival (p&lt;0.0001 and p=0.042, respectively). In supratentorial EPN-RELA, a combined loss of CDKN2A/B indicated a worse survival compared to the wildtype (p=0.0004), but the loss of only CDKN2A or CDKN2B did not. Ten out of 169 EPN-RELA were located in the posterior fossa, and Kaplan Meier estimators showed that these tumors relapsed or progressed even earlier than supratentorial cases with a combined loss of CDKN2A/B (p=0.0062). SP-MPE and PF-SE, which are generally regarded as non-aggressive tumors, only had a 10-year progression-free survival of 60% and 63%, respectively, in our series. In ongoing analyses, we are training machine learning algorithms to more accurately predict survival and response to treatments. These methods shall help clinicians make informed decisions regarding treatment options on new patients.
EPEN-20. PDL1 expression and tumor-infiltrating immune cell subpopulations: The role of immune-checkpoint molecules in the prognosis of patients with supratentorial ependymoma and its correlation to survival
Authors: Malik Rafat , Sharma Agrima , Kumar Amandeep , Singh Manmohan , Suri Vaishali , Sharma Mehar Chand 
Published: June 2022

Abstract
Immune checkpoint blockade of the programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) axis has shifted the way advanced cancers are treated. The 'ST-RELA fusion positive' and 'PF-A' molecular subgroups of ependymomas (EPN) have a dismal prognosis. AIMS: This study is undertaken to look for immunological microenvironment in ependymomas. Based on L1CAM protein expression and/or the presence of RELA/YAP1 fusion transcripts by RT-PCR, all supratentorial (ST) Grade-II/III EPNs were classified as ST-RELA, ST-YAP, and ST-not otherwise specified (NOS). Based on H3K27me3 protein expression and chromosome 1q gain, all posterior fossa (PF) EPNs were classified as PF-A or PF-B. PD-L1 (SP263, Ventana) and CD8 immunohistochemistry was performed. The enrichment of RelA protein at the PDL1 promoter site was investigated using chromatin immunoprecipitation-qPCR (ChIP-qPCR) in three ST-RELA samples. A total of 83 intracranial EPNs were included in our preliminary data, and we discovered that PD-L1 expression correlates with increasing cytotoxic T-lymphocyte infiltrates in intracranial ependymomas using PD-L1 and CD8 IHC. The majority of PD-L1-positive intracranial EPNs are members of the ST-RELA subset, which also has the highest CTL density. Our findings suggest that ST-RELA EPNs could be used in immunotherapy to target immune checkpoint modulators. To further this research, we are looking into the presence of tumour infiltrating cells such as CD3, CD8, CD163, FOXP3, and others, which can aid in characterising the tumour microenvironment in cell types expressing PD-L1.This study will also be used to predict the prognostic significance of PD-L1/PD1 and other tumour cell infiltrating biomarkers in ependymomas and correlate it with survival outcomes.
EPEN-26. Chemokine receptor blockade reverses CCL2 mediated immunosuppression and restores CAR-T cell function in posterior fossa ependymoma
Authors: Cole Allison P , Donson Andrew M , Pierce Angela M , Grimaldo Enrique , Calhoun Jacob D , Griesinger Andrea M , Sublett Caroline , Kaplan Rosandra N , Fry Terry J , Foreman Nicholas K , Nellan Anandani 
Published: June 2022

Abstract
Trastuzumab-based HER2 CAR-T constructs have demonstrated preclinical efficacy in medulloblastoma and are being evaluated for use in children and young adults with recurrent or refractory CNS tumors. Preliminary results demonstrate immune activation but no objective tumor response in three patients, including two patients with posterior fossa (PF)-EPN. A key finding in the serum and CSF of all three patients was very high levels of the inflammatory chemokine CCL2 following treatment with CAR-T cells. Preclinical studies suggest that high levels of CCL2 may impede T cell mediated anti-tumor activity in CNS tumors. The role of CCL2 to enhance or diminish CAR-T cell efficacy for CNS tumors is unknown. We evaluated a second generation trastuzumab-based HER2 CAR construct with a 4-1BB co-stimulatory domain in two ultra-high-risk patient-derived xenograft (PDX) models that faithfully recapitulate PFA-EPN. In contrast to preclinical studies in other cancers, treatment with trastuzumab-based HER2 CAR-T cell alone causes only partial regression of tumors and robust infiltration of immunosuppressive monocytes in PFA-EPN PDX mouse models. We studied constitutive NF-kB activation because it is a hallmark of PFA-EPN that drives dysregulation of inflammatory genes and forms an immunosuppressive tumor microenvironment. Upon tumor recognition, CAR-T cells produce high amounts of the cytokine tumor necrosis factor-alpha, which is an extracellular stimulus that propagates NF-kB activation in PFA-EPN. We show that HER2 CAR-T cell treatment causes increased nuclear translocation of the RELA NF-kB subunit, which induces CCL2 gene transcription and chemokine release. This results in CCL2-CCR2 ligand/receptor mediated influx of inflammatory monocytes and regulatory T cells, impairing CAR-T cell effector function. Inhibition of CCR2 restores anti-tumor CAR-T cytotoxicity against bulky orthotopic tumors by decreasing the infiltration of inflammatory monocytes and regulatory T cells. Combinatorial strategies addressing tumor mediated immunosuppression should be evaluated in upcoming CAR-T cell trials for patients with high-risk CNS tumors.
EPID-04. PREDCAP, the French registry of predisposition to pediatric cancers
Authors: Guerrini-Rousseau Lea , Hoarau Pauline , Bougeard Gaelle , Golmard Lisa , Colas Chrystelle , Gauthier-Villars Marion , Houdayer Claude , Frebourg Thierry , Bourdeaut Franck , Brugieres Laurence 
Published: June 2022

Abstract
A pathogenic or likely pathogenic variant (PV) in a major cancer predisposition gene is identified in almost 10% of children or young adults who developed a cancer, regardless of their family history. This incidence may increase by the development of wide tumor sequencing programs leading to identify germline PVs in cancer patients and new cancer predisposition syndromes (CPS) associated with childhood cancers. Due to the rarity of each CPS, we still lack information about phenotype associated with most CPS especially cancer risks according to age as well as tumor characteristics and response to treatment. Within the French genetic multidisciplinary network involving pediatric oncologists, oncogeneticists and researchers, we have created a clinico-molecular registry for pediatric-CPS according to data protection regulation. The PREDCAP database collects clinical, genetic and molecular data from patients who developed pediatric tumors associated with a CPS, both retrospectively and prospectively. It includes a mandatory set of data on clinical phenotype, tumor characteristics (including treatment and outcome), family data and results of genetic analyses, with annual data updates. Interoperability with existing databases is planned, allowing for pooling of data collection and management. Aims of PREDCAP registry are to obtain reliable clinical and molecular data on pediatric CPS with a simplified and effective access. By collecting all available data on a large number of patients thanks to international collaborations, we hope to improve the knowledge on rare CPS, in particular, to better define the tumor spectrum and the penetrance of PVs, to analyze the specificity of tumors associated with these germline PVs. With this tool, we wish to facilitate future projects using structured and centralized data, associated with a virtual bank of available tumor and constitutional DNA, to evaluate and improve the relevance of management recommendations established for each syndrome.
EPID-10. Creation, use, and effectiveness of a primary provider education tool for timely pediatric CNS tumor diagnosis based on HeadSmart
Authors: Pacheco Daniel , Fraley Claire , Walker David , Green Adam 
Published: June 2022

Abstract
BACKGROUND: Patients of minority race and ethnicity and lower socioeconomic status experience poorer survival of pediatric CNS tumors in the US. These disparities arise in part from differences in stage of disease at diagnosis, suggesting they could be mitigated by earlier diagnosis. HeadSmart is a campaign in the UK to increase awareness of pediatric CNS tumor symptoms among primary care practitioners and the public that has led to a significant decrease in time to diagnosis. METHODS: We created a 30-minute workshop, based on HeadSmart, to educate primary care providers on the presentation, common symptoms, work-up, and diagnosis of pediatric CNS tumors. We publicized the workshop throughout Colorado and delivered it via live webinar or online video recording. We collected demographic, specialty, and practice setting data from participants via optional survey. Participants could also take a 10-question, multiple-choice assessment of their knowledge on pediatric CNS tumor symptoms, work-up, and diagnosis before and after the workshop. RESULTS: We have now delivered the workshop to more than 400 providers in Colorado and the US. 39 providers participated in the survey; 19 completed both the pre- and post-workshop assessments. The mean pre-workshop score was 4.5 correct out of 10 (range 0-7); the mean post-workshop score was 5.4 (range 3-7) (unpaired t-test p=0.04). The mean improvement was 1.1 (paired t-test p=0.007). The majority of participants who completed the survey were pediatricians (n=30). Family practice (FP) physicians and pediatric/FP advance practice practitioners also participated. There was no significant difference in improvement for pediatricians vs. other providers. CONCLUSIONS: An educational tool based on the HeadSmart campaign was widely disseminated and is effective at increasing understanding of the timely diagnosis of pediatric CNS tumors among primary providers in Colorado. Further study, refinement, and dissemination have the potential to help mitigate disparities in pediatric CNS tumor outcomes.
ETMR-04. Embryonal tumor with multi-layered rosettes (ETMR) located in the brainstem: a case report on clinical decision-making and a multimodal, interdisciplinary treatment approach including interstitial brachytherapy
Authors: Jünger Stephanie T , Rueß Daniel , Goldbrunner Roland , Gielen Gerrit H , Peitsch Torsten , Johann Pascal , Landgraf Pablo , Simon Thorsten , Ruge Maximilian I 
Published: June 2022

Abstract
OBJECTIVE: Embryonal tumors with multi-layered rosettes (ETMR) (CNS WHO grade 4) comprise a rare and malignant tumor type affecting predominantly infants below 3 years of age. The treatment consists of maximal safe surgical resection, irradiation, and intensive medulloblastoma type chemotherapy. Despite aggressive treatment, the prognosis of these patients remains poor, especially for brainstem tumors. We present the case of a male infant diagnosed with a brainstem ETMR, successfully treated with an interdisciplinary multimodal approach, including stereotactic interstitial brachytherapy. RESULTS: A 19 month old boy first presented with hemiparesis, intermittent bradycardia and reduced consciousness. Initial imaging showed a brainstem lesion with characteristic features of a diffuse intrinsic pontine glioma (DIPG). We performed stereotactic biopsy to confirm the diagnosis and initiated temozolomide treatment. While the pathology result was still pending, the boy’s clinical condition deteriorated to a soporic state with stretch synergisms. By emergency open surgery, partial resection was achieved. Eventually, the patient recovered rapidly. After the diagnosis of ETMR was established, medulloblastoma type chemotherapy (systemic carboplatin/etoposide; intrathecal methotrexate) was administered. After two cycles, the patient showed only residual right-sided hemiparesis. However, imaging demonstrated only a minimal reduction of the tumor size. Therefore, stereotactic interstitial brachytherapy using 125iodine seeds and subsequent high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) was performed and overall tolerated well. After two months of brachytherapy and two additional cycles of chemotherapy, the MRI showed ≥ 50% reduction in tumor volume and no neurological deficit can be clinically detected. CONCLUSION: This case indicates that stereotactic interstitial brachytherapy during intensive systemic chemotherapy is feasible. It may provide a suitable treatment for malignant infant brain tumors. Furthermore, it shows that paediatric patients are capable of recovery even after devastating neurological symptoms. Lastly, it emphasizes the importance of multidisciplinary and multimodal treatment for rare diseases.
ETMR-05. Single-cell transcriptomics of ETMR reveals developmental cellular programs and tumor-pericyte communications in the microenvironment
Authors: de Faria Flavia W , Walter Carolin , Interlandi Marta , Melcher Viktoria , Riedel Nicole , Graf Monika , Moreno Natalia , Schoof Melanie , Holdhof Dörthe , Thomas Christian , Frühwald Michael C , Maerkl Bruno , Ho Ben , Sandmann Sarah , Varghese Julian , Ebinger Martin , Schuhmann Martin , Canak Aysegül , Huang Annie , Schüller Ulrich , Albert Thomas K , Kerl Kornelius 
Published: June 2022

Abstract
BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are pediatric brain tumors bearing a grim prognosis, despite intensive multimodal therapeutic approaches. Insights into cellular heterogeneity and cellular communication of tumor cells with cells of the tumor microenvironment (TME), by applying single-cell (sc) techniques, potentially identify mechanisms of therapy resistance and target-directed treatment approaches. MATERIAL AND METHODS: To explore ETMR cell diversity, we used single-cell RNA sequencing (scRNA-seq) in human (n=2) and murine ETMR (transgenic mode; n=4) samples, spatial transcriptomics, 2D and 3D cultures (including co-cultures with TME cells), multiplex immunohistochemistry and drug screens. RESULTS: ETMR microenvironment is composed of tumor and non-tumor cell types. The ETMR malignant compartment harbour cells representing distinct transcriptional metaprograms, (NSC-like, NProg-like and Neuroblast-like), mirroring embryonic neurogenic cell states and fuelled by neurogenic pathways (WNT, SHH, Hippo). The ETMR TME is composed of oligodendrocyte and neuronal progenitor cells, neuroblasts, microglia, and pericytes. Tumor-specific ligand-receptor interaction analysis showed enrichment of intercellular communication between NProg-like ETMR cells and pericytes (PC). Functional network analyses reveal ETMR-PC interactions related to stem-cell signalling and extracellular matrix (ECM) organization, involving factors of the WNT, BMP, and CxCl12 networks. Results from ETMR-PC co-culture and spatial transcriptomics pointed to a pivotal role of pericytes in keeping ETMR in a germinal neurogenic state, enriched in stem-cell signalling. Drug screening considering cellular heterogeneity and cellular communication suggested novel therapeutic approaches. CONCLUSION: ETMR demonstrated diversity in the microenvironment, with enrichment of cell-cell communications with pericytes, supporting stem-cell signalling and interfering in the organization of the tumor extracellular matrix. Targeting ETMR-PC interactions might bring new opportunities for target-directed therapy.
ETMR-06. Molecular and clinical characteristics of CNS tumors withBCOR(L1) fusion/internal tandem duplication
Authors: Gojo Johannes , Schmitt-Hoffner Felix , Mauermann Monika , von Hoff Katja , Sill Martin , Korshunov Andrey , Stichel Damian , Capper David , Tauziede-Espariat Arnault , Varlet Pascale , Aldape Kenneth , Abdullaev Zied , Donson Andrew , Pahnke Jens , Schüller Ulrich , Tran Ivy , Galbraith Kristyn , Snuderl Matija , Alexandrescu Sanda , Brandner Sebastian , Łastowska Maria , Miele Evelina , Lugt Jasper v , Meijer Lisethe , Bunt Jens , Kramm Christof , Hansford Jordan R , Krskova Lenka , Zapotocky Michal , Nobusawa Sumihito , Solomon David , Haberler Christine , Jones Barbara , Sturm Dominik , Sahm Felix , Jäger Natalie , Pfister Stefan M , Kool Marcel 
Published: June 2022

Abstract
Central nervous system (CNS) tumor with BCOR internal tandem duplication (BCOR-ITD) have recently been introduced in the 5th edition of the WHO classification of CNS tumors, however, their molecular makeup and clinical characteristics remain widely enigmatic. This is further complicated by the recent discovery of tumors characterized by gene fusions involving BCOR or its homologue BCORL1. We identified a cohort of 206 BCOR altered CNS tumors via DNA methylation profiling and conducted in-depth molecular and clinical characterization in an international effort. By performing t-SNE clustering analysis we found that BCOR-fusion tumors form a distinct cluster (n=61), adjacent to BCOR-ITD cases (n=145). The identified fusion partners of BCOR(L1) included EP300 (n=20), CREBBP (n=5), and NUTM2HP (n=1). Notably, three cases within the BCOR-ITD cluster harbored a c-terminal intragenic deletion within BCOR. With respect to clinical characteristics gender ratio was balanced in BCOR-fusion cases (m/f, 1.1), whereas predominance of male patients was observed in the BCOR-ITD group (m/f, 1.5). Moreover, age at diagnosis of BCOR-fusion patients was higher as compared to BCOR-ITD cases (15 vs 4.5 years). Interestingly, BCOR-fusion tumors were exclusively found in the supratentorial region being originally diagnosed as ependymomas or gliomas whereas BCOR-ITD emerged across the entire CNS with diverse original diagnoses. 8% of BCOR-ITD and none of BCOR-fusion cases were disseminated at diagnosis. In line with this observation, 40% of first relapses within the BCOR-ITD group were metastatic which was less frequent in BCOR-fusion tumors. Survival estimates demonstrated no differences, generally showing short median PFS (BCOR-fusion, 2 years, n=15; BCOR-ITD, 1.8 years, n=55) and intermediate OS rates (BCOR-fusion, 6.8 years, n=18; BCOR-ITD 6.3 years, n=60). Further molecular and clinical characterization is ongoing potentially revealing first therapeutic leads for these highly aggressive CNS tumor types.