bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPEN-04. SIOP EPENDYMOMA I: FINAL RESULTS, LONG TERM FOLLOW-UP AND MOLECULAR ANALYSIS OF THE TRIAL COHORT: A BIOMECA CONSORTIUM STUDY
Authors: A. Ritzmann Timothy , Chapman Rebecca J , Macarthur Donald , Mallucci Conor , Kilday John-Paul , Thorp Nicola , Modena Piergiorgio , Giagnacovo Marzia , Dineen Rob , Jaspan Timothy , Pajtler Kristian W , Jacques Thomas S , Paine Simon M L , Ellison David W , Bouffet Eric , Grundy Richard G 
Published: June 2021

Abstract

Introduction
Surgery and radiotherapy are established childhood ependymoma treatments. The efficacy of chemotherapy has been debated. We report final results of the SIOP Ependymoma I trial, with 12-year follow-up, in the context of a post-hoc analysis of more recently described biomarkers.

Aims and Methods
The trial assessed event free (EFS) and overall survival (OS) of patients aged three to 21 years with non-metastatic intracranial ependymoma, treated with a staged management strategy targeting maximum local control. The study also assessed: the response rate (RR) of subtotally resected (STR) disease to vincristine, etoposide and cyclophosphamide (VEC); and surgical operability. Children with gross total resection (GTR) received radiotherapy of 54 Gy in 30 daily fractions over six weeks, whilst those with STR received VEC before radiotherapy. We retrospectively assessed methylation and 1q status alongside hTERT, RELA, Tenascin C, H3K27me3 and pAKT expression.

Results
Between 1999 and 2007, 89 participants were enrolled, 15 were excluded with metastatic (n=4) or non-ependymoma tumours (n=11) leaving a final cohort of 74. Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. 1q gain was associated with poorer EFS (p=0.002, HR=3.00, 95%CI 1.49–6.10). hTERT expression was associated with worse five-year EFS (20.0% Vs 83.3%, p=0.014, HR=5.8). GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.006, HR=2.81, 95% confidence interval 1.35–5.84). There was an improvement in GTR rates in the latter half of the trial (1999-2002 32.4% versus 2003-2007 56.8%). Despite the protocol, 12 participants with STR did not receive chemotherapy. However, chemotherapy RR was 65.5% (19/29, 95%CI 45.7–82.1).

Conclusions
VEC exceeded the pre-specified RR of 45% in children over three years with STR intracranial ependymoma. However, cases of inaccurate stratification at treating centres highlights the need for rapid central review. We also confirmed associations between 1q gain, hTERT expression and outcome.
EPEN-11. TUMOR DIFFERENTIATION IMPACTS THE BIOLOGY OF RECURRENCE IN CHILDHOOD POSTERIOR FOSSA EPENDYMOMA
Authors: Donson Andrew , Ritzmann Timothy , Willard Nicholas , Griesinger Andrea , Amani Vladimir , Harris Faith , Grimaldo Enrique , Sanford Bridget , Riemondy Kent , Hankinson Todd , Grundy Richard , Foreman Nicholas 
Published: June 2021

Abstract
Ependymoma (EPN) of childhood is curable in only 50% of cases, with recurrences in the remainder that are refractory to treatment. In recent years significant advances have been made in understanding the molecular and cellular biology of EPN. Recent studies show that PFA subgroup EPN are comprised of multiple neoplastic subpopulations that show undifferentiated, differentiated and mesenchymal characteristics. These studies focused on tumor at presentation, with recurrent EPN being less well understood. In the present longitudinal study we examine changes in neoplastic cell heterogeneity in serial presentations of PFA EPN using deconvolution (Cibersort) of bulk RNAseq data. Analysis of a cohort of 48 PFA EPN presenting at Children’s Colorado showed survival and PFA1/PFA2 subtype assignment was associated with the proportion of individual neoplastic subpopulations as determined by deconvolution. Tumors that subsequently regrew had a significantly higher estimated proportion of undifferentiated EPN cells (UEC) at presentation, than those that were non-recurrent after 5 years follow-up. This outcome association potentially age related, as UEC proportions are significantly higher in PFA arising in children &lt; 1 year old who have a particularly poor prognosis. Changes in PFA neoplastic subpopulations at recurrence was performed in two cohorts of patients from Children’s Colorado (n=23) and Nottingham, UK (n=15). As a whole, no subpopulation proportion was significantly changed at recurrence. However, separation of PFA into subtypes PFA1 and PFA2 revealed an increase in the proportion of the cilia-differentiated EPN cell subpopulation is more frequent event in PFA1 (15/24), and rare in PFA2 (2/11). Changes in other neoplastic subpopulations at recurrence were smaller and only seen in PFA1, both UEC and mesenchymal subpopulations being lower at recurrence. In summary, only PFA1 showed dynamic changes in neoplastic subpopulation proportions at recurrence, with potential impacts on transcriptomic based-subgroup assignment, whereas PFA2 proportions remained largely stable.
HGG-03. THE GLYCOSPHINGOLIPIDS METABOLISM IS A NOVEL TARGET IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Paret Claudia , Sandhoff Roger , El Malki Khalifa , Frauenknecht Katrin B M , Wingerter Arthur , Lehmann Nadine , Vewinger Nadine , Faber Jörg 
Published: June 2021

Abstract
H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) is a rare malignant brain tumour entity in children and adults with a median overall survival of around 12 months. Genomic and proteomic analysis may help to identify new target structures, however not all relevant targets are covered by these analyses. Glycosphingolipids and particularly gangliosides play a major role in brain development and have been involved in the pathology of brain tumours. The conversion of ceramide to glucosylceramide via glucosylceramide synthase (GCS) is one of the first steps in the synthesis of glycosphingolipids. Therefore, targeting GCS will inhibit their synthesis. Here we analysed the glycosphingolipids composition and tested GCS inhibitors in an in vitro model of H3K27M-mutant DMG. Methods: H3K27M-mutant DMG primary cells were established from needle biopsies of two paediatric patients and characterised by immunohistochemistry. Glycosphingolipids were analysed by thin layer chromatography, liquid chromatography-coupled tandem mass spectrometry and flow cytometry. The effect of the GCS inhibitor eliglustat on the cell proliferation was examined. Results. The primary cells maintained the features of the tumour of origin, including the H3K27M mutation. Neutral glycosphingolipids with 1 to 4 monosaccharides and the ganglioside GD2 were expressed at high concentration. Eliglustat completely abrogated the proliferation of the H3K27M-mutant DMG primary cells. Conclusions. The glycosphingolipids oncometabolism represents a novel target in H3K27M-mutant DMG. The GCS inhibitors eliglusat and miglustat are already used to treat paediatric patients with the lysosomal storage disorders Niemann Pick’s and Gaucher′s disease and miglustat can cross the blood-brain barrier. Thus, our finding may accelerate the access of H3K27M-mutant DMG patients to novel innovative clinical studies based on the inhibition of the glycosphingolipids metabolism.
HGG-14. ACT001 – A PROMISING THERAPEUTIC FOR DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Upton Dannielle , George Sandra , Liu Jie , Cai Dongpo , Su Steven Yung-Chang , Manoharan Neevika , Foresto Steve , Hassall Tim , Tsoli Maria , Ziegler David 
Published: June 2021

Abstract
Diffuse Intrinsic Pontine Gliomas (DIPGs) are a subset of Diffuse Midline Gliomas (DMG) and are the most devastating of all brain tumors. There are no effective treatments and all children die of their tumor within 12-months. We performed a high-throughput drug screen with 3,570 biologically active, clinically approved compounds against a panel of DIPG cultures. Parthenolide, a compound derived from the herb T.parthenium, was found to be one of the most effective drugs tested, demonstrating significant anti-tumor activity. However, parthenolide also affected healthy cell viability and showed no in-vivo efficacy. ACT001 is a novel agent in clinical development that is a fumarate salt form of dimethylamino-micheliolide, which is semi-synthesized from parthenolide. ACT001 is blood-brain-barrier permeable and exerts an anti-tumor effect via inhibition of NF-κB and STAT3 pathways. ACT001 demonstrated potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells and inhibited colony formation in-vitro. To determine whether this activity could be replicated in-vivo, we tested ACT001 in a DIPG-orthotopic model. ACT001 was well tolerated and significantly improved survival of tumor-bearing animals, extending survival by 33% in ACT001 treated mice. We have initiated a Phase 1 paediatric trial of ACT001 for children with relapsed/refractory solid or CNS tumors, with an expansion cohort planned for patients with DIPG/DMG. Eleven patients have been enrolled, and the dose escalated from dose level-1 at 188mg/m2 bd to dose level-4 at 700mg/m2 bd. To date, no dose limiting or Grade 3/4 toxicities have been observed. At the highest dose level, clinical activity has been demonstrated in two patients, one with DIPG with a reduction in tumor burden, and another with DMG with H3K27M mutation with an objective radiographic and clinical response. These combined preclinical and clinical results suggest that ACT001 is an active novel therapy for patients with DIPG/DMG.
HGG-21. MALIGNANT SYNAPTIC PLASTICITY IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Taylor Kathryn , Barron Tara , Hartmann Griffin , Zhang Helena , Hui Alexa , Gillespie Shawn , Monje Michelle 
Published: June 2021

Abstract
Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicate the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.
HGG-30. BRAIN PENETRANT HDAC INHIBITOR RG2833 SYNERGIZES WITH LOMUSTINE AND RADIATION TO INDUCE DIPG CELL DEATH
Authors: Barnett Katherine , Novak Orlandi , Eberhart Charles , Raabe Eric 
Published: June 2021

Abstract
Diffuse intrinsic pontine glioma (DIPG) is driven by epigenetic dysregulation. The pan-HDAC inhibitor panobinostat showed pre-clinical efficacy against DIPG, but was limited by toxicity in clinical trials. RG2833 (RGFP109) is a selective HDAC1/3 inhibitor with established brain penetration. RG2833 reverses temozolomide-resistance in glioblastoma through downregulation of the NFĸB pathway. As this pathway is upregulated in DIPG and may contribute to tumorigenesis, we hypothesized that RG2833 would kill DIPG cells. We found that RG2833 treatment inhibits cell growth in the 4 to 9μM range in both autopsy and biopsy-derived DIPG cell lines (MTS assay for HSJD007 p=0.0004, JHH-DIPG1 p=0.001, SF-7761 p=0.04, SU-DIPG13 p=0.01 by t-test). Western blot confirmed on target activity by increased histone 3 acetylation at IC50 doses. RG2833 induces apoptosis (cPARP Western blot, cleaved caspase 3 immunofluorescence HSJD007 p&lt;0.003, JHH-DIPG1 p=0.0026 by t-test) and slows cell proliferation (phospho-Rb Western blot, BrdU immunofluorescence HSJD007 p=0.008, JHH-DIPG1 p=0.0002 by t-test) in multiple DIPG cell lines. RG2833 disrupts the NFĸB pathway through acetylation of p65, resulting in decreased expression of NFĸB regulated pro-survival genes (Western blot for BCL2, BCL-xL, and XIAP). In a DIPG flank tumor mouse model, treatment with RG2833 alone for 1 week suppresses flank tumor growth (p&lt; 0.005 by t-test) and induces apoptosis (Western blot for cPARP). We next assessed whether RG2833 combines synergistically with conventional therapies. We found that RG2833 has strong synergism with both lomustine and radiation to slow DIPG cell growth in vitro (ZIP synergy scores by SynergyFinder for RG2833+lomustine in JHH-DIPG1 17.8 and HSJD007 17.7, RG2833+radiation in JHH-DIPG1 9.7 and JHH-DIPG16A 10.9). Evaluation of combination treatment for apoptotic effects in vitro and in vivo are ongoing. This data identifies selective HDAC inhibitor RG2833 as a promising therapy for DIPG that combines synergistically with conventional therapies.
HGG-42. PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) SHOWS ROBUST RESPONSE TO IMIPRIDONE BASED COMBINATION THERAPY
Authors: Borsuk Robyn , Zhou Lanlan , Chang Wen-i , Zhang Yiqun , Prabhu Varun , Allen Joshua , Tapinos Nikos , Lulla Rishi , El-Deiry Wafik 
Published: June 2021

Abstract
ONC201 is a first-in-class small molecule imipridone therapy, which is known to selectively induce apoptosis of cancer cells independent of p53. This novel chemotherapeutic, as well as its analogs ONC206 and ONC212, has been shown to have potent preclinical efficacy against H3K27M mutant diffuse intrinsic pontine glioma (DIPG). We sought to identify synergy between imipridones and other FDA-approved chemotherapeutics. Seven patient-derived DIPG cell lines, six H3.3K27M mutant (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SUDIPG-27, SU-DIPG-29, SF8628), and one H3.1K27M mutant (SU-DIPG-36) were grown in culture and exposed to first and second generation imipridones, both as monotherapies and in combination with histone de-acetylase inhibitors [HDACi], Marizomib, Etoposide, and Temozolomide. A dose dependent response was demonstrated across all cell lines, with increased potency of ONC206 and ONC212 as compared to ONC201, with half maximal inhibitory concentration (IC50) of 0.11 µM, 0.03 µM, and 1.46 µM respectively. Strong synergy is demonstrated between ONC201 and Panobinostat with best combination index (CI) of 0.01. ONC201 similarly shows strong synergy with Romidepsin with best CI of 0.02, and Marizomib with best CI of 0.18. Combination of ONC201 and Etoposide or Entinostat shows some synergy, with best CI of 0.53 and 0.71 respectively. When combined with Temozolomide, some synergy is evident, however, there is overall poor efficacy, with lack of cell death even at the highest doses of Temozolomide. Second generation imipridones show a similar pattern of strong synergy with Panobinostat, Romidepsin, and Marizomib. Immunoblotting showed evidence of apoptosis, as measured by the induction of PARP cleavage, with a combination of imipridones and Panobinostat, as well as induction of integrated stress response with a combination of imipridones and Romidepsin. These results are indicative of promising synergy between imipridones and Panobinostat, Romidepsin, or Marizomib against H3K27M mutant DIPG, combinations which should be considered for future clinical trials.
IMMU-05. IMMUNOTHERAPY WITH RESIQUIMOD REPOLARIZES TUMOR-ASSOCIATED MYELOID CELLS AND IMPROVES EVENT-FREE SURVIVAL IN A TRANSGENIC MOUSE MODEL OF SONIC-HEDGEHOG (SHH) MEDULLOBLASTOMA
Authors: Park Christopher , Thang Morrent , Hwang Duhyeong , Lim Chaemin , Dismuke Taylor , Sokolsky Marina , Vibhakar Rajeev , Donson Andrew , Gershon Timothy 
Published: June 2021

Abstract
Resiquimod is a synthetic small molecule agonist of Toll-like receptors 7 and 8 (TLR-7/8) that modulates innate immune cells. We found TLR-7/8 are expressed in medulloblastoma exclusively by tumor-associated myeloid cells (TAMs). We tested whether systemically administered resiquimod modulated TAMs in a genetic Sonic hedgehog (SHH) medulloblastoma model, and whether this modulation would be therapeutically beneficial. We generated mice with medulloblastoma by crossing hGFAP-Cre and SmoM2 mouse lines. The resulting hGFAP-Cre/SmoM2 (G-Smo) mice developed medulloblastoma with 100% frequency and showed a median survival of 14.5 days (n=12). Treatment with 3 doses of resiquimod at postnatal days 10, 12 and 14 reduced tumor size and increased median survival to 37 days (n=10) (p=0.003508). Cellular studies showed that resiquimod altered TAM phenotype, rapidly inducing expression of the inflammatory marker VCAM1, and more slowly increasing TAM populations. Responses to the 3-dose regimen were ultimately limited by recurrence and all mice eventually died of tumor progression. Continued resiquimod therapy with every other day dosing was less effective than the 3-dose regimen, suggesting that TAM responses to resiquimod are dynamic and change with prolonged exposure. Our data show that innate immunity, mediated by TAMs and stimulated by TLR-7/8 agonist therapy, can produce a significant anti-tumor effect in medulloblastoma. The common expression of TLR-7/8 on TAMs in patient-derived medulloblastoma samples and in the mouse model suggests that resiquimod may produce similar anti-medulloblastoma effects in humans. Further studies are needed to define the mechanism of the anti-tumor effect in detail, to determine the optimal dose regimen, and to determine if resiquimod can combine effectively with additional adjuvant therapies to produce curative effects.
IMMU-11. CLINICAL UPDATES AND CORRELATIVE FINDINGS FROM THE FIRST PATIENT WITH DIPG TREATED WITH INTRACRANIAL CAR T CELLS
Authors: Vitanza Nicholas , Wilson Ashley , Gust Juliane , Huang Wenjun , Perez Francisco , Albert Catherine , Pinto Navin , Gardner Rebecca , Orentas Rimas , Berens Michael , Jensen Michael , Park Julie 
Published: June 2021

Abstract
We report preliminary data for the first subject with diffuse intrinsic pontine glioma (DIPG) treated with intracranial CAR T cells. BrainChild-03 (NCT04185038) is a phase 1 trial of repetitively-dosed locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or DIPG. DIPG patients enroll on Arm C, on which B7H3CARs are delivered into the ventricular system via a CNS reservoir catheter. This study does not use lymphodepletion. Primary endpoints are feasibility and safety, with second endpoints of disease response. This 18-year-old female (BrainChild-03 S005) with radiographically-classic DIPG and biopsy-confirmed H3 K27M mutation enrolled on Arm C after progression 552 days from diagnosis following focal radiation and temozolomide, irinotecan, and bevacizumab. Apheresis and manufacturing produced 4.2x109 second-generation B7H3CARs with a methotrexate-resistant human DHFR mutein (huDHFRFS; L22F,F31S) in a single transcript in combination with the B7-H3-specific CAR and EGFRt, each separated by a T2A linker, allowing methotrexate selection and enrichment. At time of submission, she has received 10 every-other-week outpatient infusions of 1x107 B7H3CARs (first dose on October 2, 2020). She has had no DLTs, but has experienced grade 2 fever and grade 2–3 headache peaking ~12–48 hours after each infusion. Following the 8th CAR T cell infusion, she experienced increased focal weakness and dysarthria at ~72 hours with resolution after 48 hours. She has not experienced cytokine release syndrome (CRS). She has stable disease 138 days post-initial CAR T cell infusion. Frequently collected correlative studies have detected viable B7H3CARs in the CSF post-infusion via flow cytometry. CSF cytokine analysis has revealed elevations of CXCL10, GM-CSF, and G-CSF following B7H3CAR infusions, without correlation in the serum. A second evaluable subject with DIPG has also received 4 locoregional doses of 1x107 B7H3CARs without a DLT. She also has stable disease and detectable viable B7H3CARs in the CSF.
IMMU-15. QUANTIFYING INTRATHECAL DRUG DELIVERY UTILIZING PROGRAMMABLE VENTRICULOPERITONEAL SHUNTS
Authors: McThenia Sheila , Pandit-Taskar Neeta , Grkovski Milan , Donzelli Maria , Diagana Safiatu , Greenfield Jeffrey , Souweidane Mark , Kramer Kim 
Published: June 2021

Abstract

Background
Programmable ventriculoperitoneal (pVP) shunts are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of thecal space drug concentrations with minimization in the peritoneum. Drug delivery quantification using several types of pVP shunts has not been reported.

Methods
We performed a retrospective analysis on patients with CNS tumors and pVP shunts at Memorial Sloan Kettering Cancer Center from 2003–2020, noting shunt model. CSF flow through the pVP shunt was evaluated using In-111-DTPA scintigraphy at approximately 4 hours and 24 hours after injection. pVP shunts were calibrated pre-injection to minimize peritoneal flow and re-calibrated to baseline setting 4–5 hours following injection. Scintigraphy studies quantified ventricular-thecal and peritoneal drug activity at these 2 time points.

Results
Twenty-one CSF flow studies were administered to 15 patients, ages 1–27 years. Diagnoses included medulloblastoma (N=10), metastatic neuroblastoma (N=3), pineoblastoma (N=1), and choroid plexus carcinoma (N=1). pVP shunt models included Aesculap Miethke proGAV (N=3), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 5), and Sophysa Polaris (N= 1). All 21 studies (100%) demonstrated ventriculo-thecal drug activity. 29% (6 of 21) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 21) of the studies had minimal peritoneal uptake (&lt;12%), and 24% (5 of 21) demonstrated moderate peritoneal uptake (12–37%). pVP shunt models measuring minimal to no peritoneal uptake included: Aesculap Miethke proGAV (N=2), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 3), and Sophysa Polaris (N= 1).

Conclusions
Successful drug delivery to the ventriculo-thecal space can be accomplished using pVP shunts: 80% of studies have minimal (&lt;12%) peritoneal drug activity. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies reliably assess drug distribution.