bluuebunny/crossref_metadata_2025 huggingface dataset:
DIPG-38. ADDITION OF MULTIMODAL IMMUNOTHERAPY TO COMBINATION TREATMENT STRATEGIES FOR CHILDREN WITH DIPG: FINAL RESULTS OF A COHORT OF CHILDREN
Authors: Van Gool Stefaan , Makalowski Jennifer , Bonner Erin R , Feyen Oliver , Domogalla Matthias , Prix Lothar , Schirrmacher Volker , Nazarian Javad , Stücker Wilfried
Published: December 2020

The prognosis of children with Diffuse Intrinsic Pontine Glioma (DIPG) remains dismal in spite of radio- and chemotherapy or therapies based on molecular biology diagnostics. Immunotherapy is a powerful and promising approach for improving the overall survival (OS). A retrospective analysis for feasibility, immune responsiveness and OS was performed on 41 children treated in compassionate use with Newcastle Disease Virus, hyperthermia and autologous dendritic cell vaccines as part of an individualized combined treatment approach for DIPG patients at diagnosis (n=28), or at time of progression (n=13). All except one patient had reduced values of at least one immune test before starting immunotherapy. In all patients at least one PanTum Detect test was outside the normal range. Ten patients had PDL1 mRNA expression in circulating tumor cells at diagnosis. Multimodal immunotherapy was feasible as scheduled, until progression, in all patients without major toxicity. When immunotherapy was part of primary treatment, median PFS and OS were 8.4m and 14.4m respectively with a 2-year OS of 10.7%. When immunotherapy was given at the time of progression, median PFS and OS calculated from diagnosis were 6.5m and 9.1m respectively. Th1 shift and rise in PanTum Detect test scores were linked with longer OS. Multimodal immunotherapy is feasible without major toxicity, and its value as part of a combination treatment for primary diagnosed DIPG should be elaborated in clinical trials.
DIPG-42. TOWARD MULTIMODALITY THERAPY FOR DIPG/DMG: DEVELOPMENT AND INVESTIGATION OF CRANIOSPINAL IRRADIATION AND CONVECTION-ENHANCED DELIVERY PDX MODELS
Authors: Knox Aaron J , Gilani Ahmed , van Court Benjamin , Oweida Ayman , Flannery Patrick , DeSisto John , Lemma Rakeb , Chatwin Hannah , Gamboni Fabia , Brown Benjamin , Serkova Natalie , Vibhakar Rajeev , Dorris Kathleen , Wempe Michael , Reisz Julie A , Karam Sana D , Green Adam L
Published: December 2020

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are metastatic diseases, as demonstrated by early convection-enhanced delivery (CED) clinical trials in which prolonged local tumor control can sometimes be achieved, but fatal disseminated disease then develops. We hypothesize that improvements in treatment of both focal disease and the entire neuraxis are necessary for long-term survival, and patient-derived xenograft (PDX) models can help advance these efforts.

METHODS

We used a BT245 murine orthotopic DIPG PDX model for this work. We developed a protocol and specialized platform to deliver craniospinal irradiation (CSI) with a pontine boost. We separately compared intratumoral drug concentration by CED and intraperitoneal delivery. In our CED model, mice receive gemcitabine 60 ug x1 in 15 ul at 0.5 ul/minute through a stepped catheter design with silica tubing extending 2mm beyond a 27G needle.

RESULTS

Mice receiving CSI (4 Gy x2d) plus boost (4 Gy x2d) showed minimal spinal and brain leptomeningeal metastatic disease by bioluminescence, MRI, and pathology compared to mice receiving radiation to the pons only (4 Gy x4d) or no radiation. CED achieved an intratumoral gemcitabine concentration 50-fold greater than intraperitoneal dosing when controlled for dose.

CONCLUSIONS

In a DIPG PDX model, CSI+boost minimizes tumor dissemination compared to focal radiation, and CED achieves clinically significant improvements in intratumoral chemotherapy concentration compared to systemic delivery. Adding these modalities to current treatment could improve both focal and metastatic tumor control, leading to meaningful improvements in survival.
DIPG-43. CAN WE REPROGRAM DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)? EXPLORING THE ROLE OF DISTALLESS/DLX HOMEOBOX GENE REGULATION OF OLIGODENDROGLIAL PROGENITOR CELLS (OPC) IN THE DEVELOPING VERTEBRATE NERVOUS SYSTEM
Authors: Nevin Mikaela , Gallego Janine , Song Xiaohua , Jiang Qiang , Underhill Alan , Godbout Roseline , Becher Oren , Eisenstat David
Published: December 2020

BACKGROUND

The identification of H3.3/H3.1K27M in most DIPG has changed our understanding of this disease. H3K27M mutations usually demonstrate global loss of H3K27 trimethylation (me3) with gain of H3K27 acetylation (ac). Single cell RNAseq has identified the putative cell of origin as oligodendroglial progenitor cells (OPC). The distalless gene family is necessary for the differentiation and tangential migration of committed neural progenitors to become GABAergic interneurons. Dlx1/Dlx2 double knockout (DKO) cells from the ganglionic eminences (GE) transplanted into a wild-type environment become oligodendrocytes.

RESULTS

We identified DLX2 occupancy of early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required for OPC differentiation in vivo and confirmed direct DLX2 protein-promoter DNA binding in vitro. Co-expression of Dlx2 with target sequences reduced reporter gene expression in vitro. There was increased expression of OLIG2, NKX2.2 and PLP-1 expression in vivo, consistent with de-repression in the absence of Dlx1/Dlx2 function. Transient over-expression of a Dlx2-GFP construct into murine DIPG cells from a GEMM that develops DIPG resulted in significant increases in expression of Gad isoforms with concomitant decreases in Olig2 and Nkx2.2. Dlx2-transfected mDIPG cells also demonstrated reduced migration, invasion and colony formation in vitro. Of significance, there was global restoration of H3K27me3 with corresponding loss of H3K27ac expression in transfected cells compared to controls.

CONCLUSIONS

DLX2 promotes GABAergic differentiation and migration while concomitantly repressing OPC differentiation in vivo. Developmental reprogramming of mDIPG cells by DLX2 demonstrates the potential role for directed differentiation strategies towards improving patient outcomes for this devastating pediatric cancer.
DIPG-47. HISTONE MUTATIONS ENHANCE RAS MEDIATED ERK5 GROWTH SIGNALING IN DIFFUSE MIDLINE GLIOMAS
Authors: Stanton Ann-Catherine , Koncar Robert , Golbourn Brian , Dey Brittany , Agrawal Nishant , Mack Stephen , Pollack Ian , Agnihotri Sameer
Published: December 2020

Diffuse midline gliomas (DMGs) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DMG, who have a median survival time of less than one year. Most DMG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DMG growth. Suppression of ERK5 decreased DMG cell proliferation and induced apoptosis in vitro and in vivo. In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DMG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Additionally, persistent ERK5 depletion does not result in complete growth inhibition and therefore we set out to determine potential adaptation or resistance mechanisms in response to ERK5 loss. Using RNA-sequencing and Immunoprecipitation (IP) mass spectrometry (IP-MS), we have identified several positive and negative feedbacks involved in ERK5 that are also targetable. These findings identify the H3K27M mutation as an enhancer of RAS activation in DMG with ERK5 and ERK5 regulated networks immediately actionable pathways.
DIPG-50. A NOVEL ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODEL OF RADIATION-INDUCED GLIOMA
Authors: Whitehouse Jacqueline , Howlett Meegan , Stanley Jason , Hii Hilary , Valvi Santosh , White Christine , Mayoh Chelsea , Wong Marie , Strowger Brooke , Dyke Jason , Cowley Mark , Gottardo Nicholas , Endersby Raelene
Published: December 2020

Diffuse midline glioma (DMG) can arise as a primary tumour but also as a consequence of radiation therapy (RT) in survivors of other paediatric brain tumours. Radiation-associated gliomas are molecularly distinct from primary gliomas and have poorer overall survival. We report a case of radiation-associated DMG following treatment for medulloblastoma, and the development of a matched patient-derived xenograft (PDX) model. A four-year-old boy diagnosed with medulloblastoma was treated with surgical resection, RT and chemotherapy (COG:CCG-99701-Arm B). Eleven years post-diagnosis, the patient relapsed with radiation-associated DMG, participated in a Phase I clinical trial (COG:ACNS0927), and passed away eight months later. Tumour tissue collected at autopsy was intracranially implanted into immunodeficient mice and serially transplanted in vivo. Immunohistochemistry demonstrated both the primary DMG and PDXs expressed PDGFR-alpha and PTEN, were H3K27me3-positive, and had undetectable levels of p53. Sequencing revealed an activating mutation in PI3-kinase (H1047L) and variants of unknown significance in GRK4, FLG, BAZ2A, and CRTC3. DNA methylation array of the PDX demonstrated 1p loss, which is not typically associated with primary DMG, and broad deletion within 9p including CDKN2A/B, MTAP and multiple interferon genes. The methylation profile did not significantly classify with other tumours in the Molecular Neuropathology database (molecularneuropathology.org/mnp). We describe the first reported PDX model of radiation-associated DMG following medulloblastoma, which recapitulates the patient disease and is molecularly distinct from primary DMG. Interrogation of this model through RNA and whole genome sequencing presents a valuable opportunity to better understand and identify novel therapeutic vulnerabilities against this currently incurable disease.
DIPG-54. A NON-INVASIVE PROGNOSTIC CIRCULATING miRNAs SIGNATURE IN DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Iannò Maria Federica , Schiavello Elisabetta , Carenzo Andrea , Anichini Andrea , Biassoni Veronica , Gandola Lorenza , De Cecco Loris , Massimino Maura
Published: December 2020

Diffuse intrinsic pontine gliomas (DIPG) are the most common brainstem tumors of childhood and represent one of the most challenging paediatric tumours to treat. A non-randomized, open label phase II pilot study was conducted at Fondazione IRCCS Istituto Nazionale Tumori (Milan) to assess the efficacy in terms of objective response rate according to the RECIST criteria of combining nimotuzumab and vinorelbine with radiation in newly-diagnosed DIPG. Serum specimens were collected at baseline. microRNA expression profiling was performed using Agilent platform and Human miRNA SureSelect 8x60K containing 2006 miRNAs annotated on miRBase19.0. Primary data analysis yielded a matrix containing 330 detectable miRNA. Association with PFS allowed us to disclose a signature of 10 miRNAs able to stratify high and low risk patients (HR=4.33, 95%CI 1.49–12.54; p=4.27E-05). To test the 10 ct-miRNA model performance, we collected an independent cohort of the same sample size (n=24) and we derived the index values and risk stratification. The distribution of index values covers a range similar to the discovery cohort. Imposing the signature threshold patients were divided in high/low risk and Kaplan-Meier curves confirmed the different PFS time for the two groups with HR=3.5 (95%CI: 1.8–8.01, p-value=0.0002) for the high-risk patients, reaching AUC=0.833. Our signature is a biomarker based on non-invasive procedures for prognosis able to enter into clinical practice. Further validation on multicenter case series is warranted.
DIPG-59. UPREGULATION OF PRENATAL PONTINE ID1 SIGNALING IN DIPG
Authors: Harris Micah K , Yadav Viveka Nand , Stallard Stefanie , Woo Rinette , Siddaway Robert , Qin Tingting , Mullan Brendan , Miklja Zachary , Siada Ruby , Ravindran Ramya , Cao Xuhong , Pasternak Amy , Castro Maria G , Lowenstein Pedro R , Mody Rajen , Chinnaiyan Arul , Hawkins Cynthia , Desprez Pierre , McAllister Sean , Venneti Sriram , Koschmann Carl
Published: December 2020

BACKGROUND

Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with no curative therapies. Inhibitor of DNA binding (ID) proteins are key regulators of gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this has not been validated in human DIPG, nor has the regulation and targetability of ID1 been explored in DIPG.

RESULTS

Analysis of post-mortem tissue and multiple human datasets showed ID1 to be elevated in DIPG, and to correlate with reduced survival. In a multi-focal autopsy of a DIPG case, we also found ID1 expression to be heterogeneous and to correlate with tumor invasion. Chromatin immunoprecipitation qPCR (ChIP-qPCR) revealed elevated H3K27ac and low H3K27me3 at ID1 regulatory regions (enhancers/promoters) in DIPG tissue compared to normal brain, regardless of H3 or ACVR1 mutation status. Analysis of publicly-available ISH and ChIP-sequencing data of developing murine brains revealed H3K27ac at ID1 enhancers to be elevated in the prenatal hindbrain compared to prenatal forebrain and midbrain, and all postnatal brain regions. ID1 shRNA-mediated knockdown of primary human H3K27M DIPG cells (DIPG007) significantly reduced invasion and migration. We also treated DIPG007 cells with cannabidiol (CBD) and found reduced viability at clinically relevant dosing (IC50=2.4 uM) with dose-dependent reduction in ID1 protein.

CONCLUSIONS

These findings indicate that a multifactorial (genetic and regionally-based) epigenetic upregulation of ID1 drives DIPG invasiveness and is targetable with CBD. ID1 knockdown and CBD treatment experiments in murine models of DIPG are ongoing.
DIPG-73. SENESCENCE ASSOCIATED SECRETORY PHENOTYPE AS A MECHANISM OF RESISTANCE AND THERAPEUTIC VULNERABILITY IN BMI1 INHIBITOR TREATED DIPG
Authors: Balakrishnan Ilango , Danis Etienne , Pierce Angela , Madhavan Krishna , Wang Dong , Dahl Nathan , Bridget Sanford , Birks Diane K , Davidson Nate , Metselaar Dennis S , Neel Hans , Donson Andrew , Griesinger Andrea , Katagi Hiroaki , Vijmasi Trinka , Sola Ismail , Alimova Irina , Fosmire Susan , Hulleman Esther , Serkova Natalie J , Hashizume Rintaro , Hawkins Cynthia , Carcaboso Angel Montero , Gupta Nalin , Jones Ken , Foreman Nicholas , Green Adam , Vibhakar Rajeev , Venkataraman Sujatha
Published: December 2020

BACKGROUND

Diffuse intrinsic pontine gliomas (DIPGs) driven by mutations in the histone 3 (H3) gene (H3K27M) are aggressive pediatric brain tumors for which there is no curative therapy.

METHODS

To identify novel therapeutic targets we performed a high throughput drug screen combined with an epigenetically targeted RNAi screen using H3K27M and H3.3 WT DIPG cells.

RESULTS

Chemical and genetic depletion of BMI1 in vitro resulted in inhibition of clonogenicity and cell self-renewal consistent with previous studies. We show for the first time that clinically relevant BMI1 inhibitors attenuates growth of orthotopic DIPG xenografts as measured by MRI and prolong survival in vivo. We found that BMI1 inhibition drives phenotypic cellular senescence and that the senescent cells were able reactivate to form new neurospheres in vitro and tumor growth in vivo. RNA-seq, ChIP-Seq and immuno-proteomic analysis revealed that the senescent cells induced the expression of the Senescence Associated Secretory Phenotype (SASP) cytokines by increasing occupancy of activated histone marks at SASP factor promoters. The SASP results in increased expression of anti-apoptotic BH3 proteins including BCLxl, and BCL2. Treatment of the PTC028 treated senescent DIPG cells with BH3 mimetics induces apoptosis and clears the senescent cells. Combining BH3 mimetics with BMI1 inhibition attenuates tumor growth in vivo synergistically and significantly prolongs survival of DIPG bearing mice compared to BMI1 inhibition alone.

CONCLUSION

These data inform the current trial of BMI1 inhibition as a monotherapy and predict the need for adding BH3 mimetics to achieve efficacy.
DIPG-74. RE-IRRADIATION OF DIPG: DATA FROM THE INTERNATIONAL DIPG REGISTRY
Authors: Lafay-Cousin Lucie , Lane Adam , Schafer Austin , Saab Raya , Cheng Sylvia , Bandopadhayay Pratiti , Zaghloul Mohamed , El-Ayadi Motasem , Dorris Kathleen , Packer Roger , Kilburn Lindsey , Minturn Jane , Dodgshun Andrew , Parkin Sara , Lombardi Mercedes Garcia , Cohen Kenneth , Gass David , Goldman Stewart , Sandler Eric , Warren Katherine , Greiner Robert , Gottardo Nicholas , Dholaria Hetal , Hassall Tim , Coven Scott , Hansford Jordan , Samson Yvan , Leary Sarah , Bartels Ute , Bouffet Eric , Ma Jie , Tinkle Christopher , Monje-Deisseroth Michelle , Fisher Paul , Tsui Karen , Ziegler David , Chintagumpala Murali , Gururangan Sridharan , Wagner Lars , Koschmann Carl , DeWire-Schottmiller Mariko , Leach James , Jones Blaise , Fuller Christine , Drissi Rachid , Chaney Brooklyn , Black Katie , Fouladi Maryam , Strother Douglas
Published: December 2020

PURPOSE

To review data from DIPG Registry patients recorded to have received a second course of radiation therapy (rRT).

METHODS

The International DIPG Registry was searched for patients with DIPG who were treated with a known dose of rRT. Doses of rRT, timing from initial diagnosis and primary radiation therapy (pRT), radiographic response to rRT and survival from diagnosis (OS) were evaluated.

RESULTS

Sixty (11.2%) of 535 Registry patients underwent rRT; dose was provided for 44 patients. Median (range) data from those 44 revealed that rRT was given at 12 (2–65) months from initial diagnosis of DIPG and at 9.6 (1–61) months from completion of pRT at a dose of 26.7 (1.8–74) Gy. After completion of rRT, MRI showed response, progression, stable disease or was not available in 19, 8, 3 and 14 patients, respectively. Median PFS and OS were 11 and 18.1 months, respectively. 475 Registry patients did not undergo rRT; their ages, duration of symptoms, and primary treatment with or without chemotherapy were not significantly different from the rRT cohort. Median PFS and OS for the non-rRT patients were 6.9 and 10 months, respectively. rRT patients were more likely to have had radiographic evidence of tumor necrosis at diagnosis than non-rRT patients.

CONCLUSIONS

Administration of rRT to patients with DIPG has been inconsistent with respect to timing and dose. Toxicity, response and quality of life data are incomplete, but survival appears to be lengthened with rRT. Prospective clinical trials will elucidate benefits and risks of rRT.
DIPG-75. PRECISION MEDICINE FOR PAEDIATRIC HIGH-GRADE DIFFUSE MIDLINE GLIOMAS - RESULTS FROM THE ZERO CHILDHOOD CANCER COMPREHENSIVE PRECISION MEDICINE PROGRAM
Authors: Khuong-Quang Dong-Anh , Nagabushan Sumanth , Manoharan Neevika , Arndt Greg , Barahona Paulette , Cowley Mark J , Ekert Paul G , Failes Tim , Bolanos Noemi Fuentes , Gauthier Maely , Gifford Andrew J , Haber Michelle , Kumar Amit , Lock Richard B , Marshall Glenn M , Mayoh Chelsea , Mould Emily , Norris Murray D , Gopalakrishnan Anjana , Omer Natacha , Trebilcock Peter , Trahair Toby N , Tsoli Maria , Tucker Katherine , Wong Marie , Tyrrell Vanessa , Lau Loretta , S, Ziegler David
Published: December 2020

The Australian Zero Childhood Cancer (ZERO) program aims to assess the feasibility of a comprehensive precision medicine approach to improve outcomes for patients with an expected survival <30%. ZERO combines molecular profiling (whole genome sequencing, whole transcriptome sequencing, DNA methylation profiling) with in vitro high-throughput drug screening (HTS) and patient-derived xenograft drug efficacy testing. We report on the cohort of patients with midline high-grade glioma (HGG), including H3-K27M DMG, enrolled on the pilot study (TARGET) and on the ongoing ZERO clinical trial (PRISM). We identified 48 patients with midline HGG. Fresh or cryopreserved samples were submitted in 37 cases and cell culture was attempted in 30/37 cases with 45% success rate. The most commonly mutated genes/pathways identified by molecular profiling include H3-K27M mutations, DNA repair pathway, and PI3K/mTOR pathway. Two targetable fusions (NTRK and FGFR1) were reported. Five patients with germline alterations were identified. Thirty-five (72%) patients received a therapeutic recommendation from the ZERO molecular tumour board and the main recommended therapies were mTOR inhibitors, PARP inhibitors or tyrosine kinase inhibitors. HTS added evidence for the recommended therapy (n=3) or identified novel potential therapy (n=1). Out of the 35 patients, 16 received a recommended drug. Response to treatment was complete response for five months (n=1), partial response for nine months (n=1), stable disease (n=4), and progressive disease (n=10). These results highlight the feasibility of the ZERO platform and the value of fresh biopsy, necessary for pre-clinical drug testing. Targetable alterations were identified leading to clinical benefit in six patients.
DIPG-76. HISTONE H3 PHOSPHORYLATION IN H3K27M MIDLINE GLIOMAS
Authors: Zhang Liang , Day Charles , Hinchcliffe Edward , Daniels David
Published: December 2020

Diffuse midline gliomas (DMG) patients have a dire prognosis despite radiation therapy and there is an urgent need to develop more effective treatments. DMG are characterized by heterozygous mutations in select H3 genes resulting in the replacement of lysine 27 by methionine (K27M) that leads to global epigenetic reprogramming and drives tumorigenesis. We previously reported that pharmacological inhibition of aurora kinase (AKI) may represent a targeted approach for treating tumors with this mutation. Our analysis with both published dataset and patient samples showed that patients with higher aurora kinase A (AKA) expression were associated with worse survival. AKA phosphorylates H3S10 and H3S28 during mitosis. Intriguingly, phosphorylation of the H3S28 (H3S28ph) by AKA blocks PRC2 methyltransferase activity and decreases global H3K27me3 in certain stem cells. We propose that a similar mechanism occurs in H3K27M DMG tumors, where there is a reciprocal relationship between H3S28ph and H3K27me3. We found that AKI significantly decreases H3S28ph while increasing H3K27me3 specifically in H3K27M tumors. To further evaluate the link between the H3K27M mutation and H3 serine phosphorylation, we used CRISPR/Cas9-directed gene editing to silence H3S28ph by replacing serine with alanine (H3S28A) in DIPG cell lines. Ectopic expression of histone H3S28A leads to a prominent epigenetic changes in H3K27M tumors and is similar to AKA inhibition. Overall, this study highlights H3S28ph, one of the targets of AK, is a key driver of epigenetic changes in H3K27M tumors through both direct and indirect changes to H3K27me3 and H3K27ac across the genome.
DIPG-77. TREATMENT EXTENT AND THE EFFECT ON SURVIVAL IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Baugh Joshua , Colditz Niclas , Janssens Geert , Dietzsch Stefan , Hargrave Darren , von Bueren André , Kortmann Rolf-Dieter , Bison Brigitte , van Vuurden Dannis , van Zanten Sophie Veldhuijzen , Kramm Christof
Published: December 2020

BACKGROUND

Front line radiotherapy for diffuse intrinsic pontine glioma (DIPG) remains the only standard of care. Is this still appropriate?

PATIENTS AND METHODS

We examined survival outcomes across six treatment modalities including I) no treatment (n=19), II) radiotherapy alone (n=38), III) radio-chemotherapy (n=101), IV) radiotherapy and relapse chemotherapy (n=35), V) radio-chemotherapy and relapse chemotherapy (n=163), and VI) radio-chemotherapy and relapse chemotherapy, plus reirradiation (n=54). Data were collected retrospectively using the Society of Pediatric Oncology and Hematology (GPOH) and the SIOPE DIPG Registry. 410 patients were included with radiologically centrally reviewed DIPG, mostly unbiopsied. Of note, the untreated patients and radiotherapy only cohorts chose limited treatment voluntarily.

RESULTS

Median overall survival (MOS) of the whole cohort was 11 months and progression free survival (PFS) 7 months. PFS was not significantly different between the treatment groups. OS and post-progression survival (PPS) were significantly different between cohorts. For the respective treatment groups, median OS was 3 months (I), 7 months (II), 8 months (III), 13 months (IV), 13 months (V), and 15 months (VI). For only front line vs at least one second line therapy, MOS was 8 months vs 14 months and PPS 2 months vs 5 months.

CONCLUSIONS

Although subject to biases to some extent, it seems that additional therapies beyond radiation therapy are of benefit to extending survival in DIPG patients. This is at least partially caused by the introduction of reirradiation regimens. To what extent other therapies contribute to survival and quality of life is subject to further investigation.
DIPG-80. CLINICAL AND RADIOGRAPHIC RESPONSE TO ONC201 IN A PEDIATRIC PATIENT WITH A THALAMIC H3K27M AND BRAFV600E MUTANT DIFFUSE MIDLINE HIGH GRADE GLIOMA
Authors: Duke Elizabeth , Murnick Jonathan , Tarapore Rohinton , Allen Joshua , Kilburn Lindsay
Published: December 2020

Recent improved understanding of the molecular markers of high grade glioma has shifted the approach to these aggressive CNS tumors to increasingly use molecularly guided targeted therapies. Treatment of patients with BRAFV600E mutant high grade gliomas with BRAF inhibitors has shown efficacy, however the impact of concomitant H3K27M mutation is unknown. ONC201 targets dopamine receptor D2 (DRD2), which is shown to be broadly overexpressed in the thalamus as well as multiple tumor types; its antagonism has demonstrated anti-tumor efficacy and immunomodulatory properties in preclinical studies. ONC201 has also demonstrated clinical efficacy in patients with H3K27M mutant gliomas. We present the case of a 9-year-old male with a right thalamic H3.3K27M mutant diffuse midline glioma with a concomitant BRAFV600E mutation with an ongoing partial response to ONC201 treatment. The patient was diagnosed in May 2018. He underwent biopsy, followed by standard focal proton radiation therapy (54Gy) and subsequent treatment with dasatinib, bevacizumab and everolimus over the course of five months. After continued radiographic progression on serial imaging, in April 2019 he started ONC201 375mg orally once per week through an expanded access trial. He has tolerated the medication well with grade 1 nausea and fatigue. Over the next nine months, he demonstrated clinical and radiographic improvement with modest increased use of his left side and MRIs showing progressive decrease in size of the thalamic lesion with a 70 % decrease in the target lesion (measuring 53x62mm prior to treatment, decreased to 38x26mm in January 2020).
DIPG-82. CLINICAL EXPERIENCE OF CONVECTION ENHANCED DELIVERY (CED) OF CARBOPLATIN AND SODIUM VALPROATE INTO THE PONS FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) IN CHILDREN AND YOUNG ADULTS AFTER RADIOTHERAPY
Authors: Szychot Elwira , Walker David , Collins Peter , Hyare Harpreet , Shankar Ananth , Bienemann Alison , Hollingworth Milo , Gill Steven
Published: December 2020

PURPOSE

Effective treatment of diffuse intrinsic pontine glioma (DIPG) remains a formidable challenge due to inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies. The BBB can be overcome by directly infusing drugs into pons using method of convection-enhanced delivery (CED). We describe our clinical experience and what we have learned about the safety and feasibility of treating DIPG with intermittent CED of carboplatin and sodium valproate to the pons through the Renishaw Drug Delivery System (RDDS).

METHODS

Retrospective review (2017–2020) of children with DIPG, who following radiotherapy, received compassionate treatment commencing 3.3–10 months post diagnosis (median 4.9 months). They received up to 7 cycles of 3–6 weekly pontine infusions of carboplatin (0.12-0.18mg/ml) and sodium valproate (14.4- 28.8mg/ml).

RESULTS

13 children 3–19 years (mean 6.9 years) were treated. There were no surgical complications. With the exception of infusion channels blocking in one device there were no adverse device effects. Two patients developed persistent 6th nerve palsies, which led to drug concentration reduction in the combination therapy. Subsequently infusion/ drug related toxicities were transient. Tumour was controlled in pons in 11/13 patients. Median progression free survival (PFS) was 13.0 months, while median overall survival (OS) was 15.3 months.

CONCLUSIONS

Use of the RDDS was safe and well tolerated in all 13 patients. Treatment improved control of pontine disease resulting in longer PFS and OS than reported for conventional therapy and merits further evaluation in a clinical trial.
DIPG-84. COMPLEMENTARY AND ALTERNATIVE MEDICINE IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: El-Khouly Fatma , Adil Syed , Hendrikse Harry , Kaspers Gertjan , Kramm Christof , van Zanten Sophie Veldhuijzen , van Vuurden Dannis
Published: December 2020

INTRODUCTION

Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive childhood brainstem malignancy with a two-year survival rate of ≤10%. In this international survey study we aim to evaluate the use of complementary and alternative medicine (CAM) in this patient population.

METHODS

Parents of-, and physicians treating DIPG patients were asked to participate in a retrospective online survey with questions regarding CAM use during time of illness.

RESULTS

120 parents and 75 physicians contributed to the online survey between January and May 2020. Physicians estimated that <50% of their patients used CAM, whereas 69% of the parents reported to have used CAM to treat their child during time of illness. Cannabis was the most widely used form of CAM, followed by vitamins and minerals, melatonin, curcumin and boswellic acid. CAM was mainly used to actively treat the tumor. Other motivations were to treat side effects of chemotherapy, or to comfort the child. Children diagnosed ≥2016 were more likely to use CAM (χ2=6.08, p=0.014). No significant difference was found between CAM users and non-users based on ethnicity (χ2=4.18, p=0.382) and country of residence (χ2=9.37, p=0.154). Almost 50% of the physicians do not frequently ask their patients about possible CAM use.

CONCLUSION

This survey demonstrates that worldwide a considerable number of DIPG patients use CAM. Physicians should be more aware of potential CAM use and more actively discuss the topic. More research is needed to gain knowledge about possible anticancer effects of CAM and their interactions with conventional therapies.
EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPY IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Baig Muhammad , Johnson Jason , Gupta Sumit , Sadighi Zsila , Zaky Wafik , Khatua Soumen
Published: December 2020

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG.

METHODS

After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible.

RESULTS

Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease.

CONCLUSION

Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.
EPCT-15. THE REMIND TRIAL: MULTI-ANTIGEN TARGETED T CELLS FOR PEDIATRIC CNS TUMORS
Authors: Grant Melanie , Fortiz Maria Fernanda , Wang Lu , Lang Haili , Datar Anushree , Reynolds Emily , Terpilowski Madeline , Lazarski Chris , Tanna Jay , Pitino Adriana , Zhang Nan , Hoq Fahmida , Hanley Patrick , Kilburn Lindsay , Packer Roger , Rood Brian , Bollard Catherine , Hwang Eugene
Published: December 2020

BACKGROUND

Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity.

METHODS

Patients (n=9) have received autologous tumor antigen-associated T cells (TAAT) (up to 4x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response. RESULTS/

DISCUSSION

9/9 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) of the CD3+ cells, respectively. TAAT with specificity for 1–3 TAAs, at varying frequencies, was demonstrated in 8/9 TAAT by anti-IFN-γ ELISPOT. Plasma cytokine profiles demonstrated infusion-related immune cytokine responses. In summary, TAAT are safe and may elicit anti-tumor responses in vivo. To confirm TAAT-driven effects, we are evaluating plasma proteomic profiles for immune-response signatures and assessing unique T cell receptor rearrangements of infused TAAT. Response assessment and dose escalation are ongoing.
EPCT-16. A PHASE IB STUDY OF PTC596 IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA AND HIGH GRADE GLIOMA
Authors: Smiley Natasha Pillay , Baxter Patricia , Kumar Shiva , Hwang Eugene , Breneman John , Lane Adam , Doughman Renee , Deutsch Michelle , Stevenson Charles , Stewart Clinton , Leach Jim , Li Xiao-Nan , Romero Sonia , Maliakal Pius , Gao Lan , Fouladi Maryam , Drissi Rachid
Published: December 2020

BACKGROUND

BMI-1 is highly expressed in DIPG. Downregulation leads to inhibition of cell proliferation, cell cycle signaling, self-renewal, telomerase expression, activity, and suppression of DIPG cell migration. Targeted inhibition of BMI-1 sensitizes DIPG cells to radiation and drug-induced DNA damage. PTC596 (formulated by PTC Therapeutics, Inc.) is a novel, orally available drug that inhibits microtubule polymerization, resulting in G2/M cell cycle arrest and post-translational modification of BMI-1 protein and reduced BMI-1 protein levels. OBJECTIVES: To estimate the maximum tolerated dose and describe dose limiting toxicities, pharmacokinetics and pharmacodynamics of PTC596 in children 3–21 years of age with newly diagnosed diffuse intrinsic pontine glioma and high-grade gliomas.

METHODS

PTC596 is administered twice per week orally during radiotherapy and as maintenance for up to two years. The starting dose of PTC596 was 200 mg/m2, with a subsequent dose level of 260mg/m2/dose. Pharmacokinetics are performed in Cycles 1 and 2.

RESULTS

This study is currently ongoing. Nine patients (7 with DIPG, 2 with HGG), 8 evaluable, have been enrolled. At dose level 1, 200 mg/m2, three evaluable patients were enrolled and experienced no DLTs. At dose level 2, among 5 evaluable patients, 2 experienced dose-limiting grade 4 neutropenia. PTC596 has been otherwise well tolerated. Five patients remain in Cycles 2–11.

CONCLUSION

This phase I trial is ongoing. PTC596 is tolerable at dose level 1. We are amending the protocol to introduce tablets that can be dissolved in liquid to allow enrollment of younger patients and those unable to swallow whole tablets.
EPEN-02. EVALUATION OF TREATMENT OUTCOMES AND EXPRESSION OF EMT-RELATED TRANSCRIPTION FACTORS AS NOVEL THERAPEUTIC TARGETS IN PEDIATRIC EPENDYMOMA
Authors: Makino Keishi , Kuroda Jun-ichiro , Shinojima Naoki , Fujimoto Kenji , Takada Akira , Mukasa Akitake
Published: December 2020

OBJECTIVE

Intracranial ependymomas are common brain tumors in children. However, prognosis, especially in young children, remains poor because of the chemo- and radioresistant properties of intracranial ependymomas. Furthermore, effective treatments for intracranial ependymomas remain a challenge. The epithelial-to-mesenchymal transition (EMT) is important for invasion and metastasis in many cancers. This study aimed to evaluate and compare treatment outcomes with the expression of EMT-related transcription factors in pediatric ependymomas.

MATERIAL AND METHODS

Medical and radio-imaging data of 22 (11 boys, 11 girls) patients aged <15 years with intracranial ependymomas were reviewed from January 1983 to December 2018. Six cases were subdivided into clinicopathological-molecular subgroups and immunohistochemically analyzed for Slug and ZEB.

RESULTS

The median age at the start of treatment was 5 years (range 8 months–15 years) (9 cases were aged <3 years). The median progression-free survival (PFS) was 25.6 (range, 0.8–383.5) months; the median overall survival (OS) was 81.9 (range, 2.9–383.5) months. Extent of resection and malignant histology were significant prognostic factors for OS and PFS in multivariate analysis. There were 6 cases (2 cases of PFA, 2 of PFB, 1 of ST and 1 case of ST-RELA). Nuclear expression of ZEB1 was found in all tumors; however, that of Slug increased only in PFA and PFB tumors, which were associated with a poor prognosis.

CONCLUSION

Expression of EMT-related transcription factors was increased in pediatric ependymomas. These data suggest that EMT is a novel therapeutic target for treating pediatric intracranial ependymomas.
EPEN-06. CHEMOTHERAPY OF RECURRENT EPENDYMOMA: LONG-TERM RESPONSE ONLY IN FEW CASES
Authors: Adolph Jonas , Tippelt Stephan , Mikasch Ruth , Pfister Stefan , Pajtler Kristian , Witt Hendrik , Witt Olaf , Bison Brigitte , Warmuth-Metz Monika , Kortmann Rolf-Dieter , Dietzsch Stefan , Pietsch Torsten , Timmermann Beate , Fleischhack Gudrun
Published: December 2020

INTRODUCTION

The efficacy of chemotherapy in recurrent ependymoma is unclear. We present results from the German HIT-REZ-studies.

METHODS

137 patients were analyzed regarding the treatment with chemotherapy at first recurrence, the time from first relapse to progression (PFS) and to either time-point of death or last follow-up (OS). Tumor response evaluation was based on MRI and clinically; molecular data was available in 80.

RESULTS

In our cohort, 96 patients (20 supratentorial, 73 infratentorial, 3 spinal) received chemotherapy during first recurrence: 49 (51.0%) temozolomide (TMZ) monotherapy, 12 (12.5%) HIT-SKK regime, 9 (9.4%) carboplatin/etoposide (CE) and 26 (27.1%) other combinations. In 19.8% (26.5% in TMZ), chemotherapy was administered prior to surgery (neoadjuvant), which resulted in tumor progression in 78% (85% in TMZ). Gross-total resection was achieved in 86% without neoadjuvant chemotherapy and in 74% (69% in TMZ) with neoadjuvant treatment. Switching to trofosfamide/etoposide (TE) after surgery and unresponsiveness to TMZ showed further progression in all cases of tumor-residuum after surgery. Regarding 1-year-PFS, treatment with HIT-SKK (50.0%±14.4%) or CE (55.6%±16.6%) was advantageous over TMZ (30.2%±6.7%). However, 5-y-OS was lower in CE (19.0% ±16.8%) than in TMZ (39.8%±7.7%) and HIT-SKK (42.9%±8.7%). Long-term control was seen in individual cases of TMZ, HIT-SKK and CE, with TMZ providing longest response of 72 months.

CONCLUSION

Neoadjuvant TMZ has no significant advantage regarding PFS. However, in few cases chemotherapy prevented progression after incomplete resection. Difficulties in response evaluation and variability in therapies hinder conclusions. Supported by the German Children’s Cancer Foundation
EPEN-10. SPINAL MYXOPAPILLARY EPENDYMOMA AND METHYLATION-PROFILING: THE MD ANDERSON CANCER CENTER (MDACC) EXPERIENCE
Authors: Gupta Sumit , Tian Xiangjun , Wang Jing , Huse Jason , Rhines Laurence , Zaky Wafik , Tatsui Claudio , Khatua Soumen
Published: December 2020

INTRODUCTION

Spinal myxopapillary ependymoma (MPE) is a rare histological variant of ependymoma, classified as WHO grade I tumor. Further interrogation of the molecular and clinical profile is warranted, to better understand the biology and clinical phenotype. We summarize our institutional experience with spinal MPE including methylation-profiling.

METHODS

A retrospective analysis of charts during the period of 2001 to 2019 of histologically proven MPE was done. We performed methylation profiling for 12 patients by Infinium MethylationEPIC Kit.

RESULTS

26 patients with spinal MPE were identified, median age of diagnosis was 34.2 years with a range of 11 to 59.9 years. Ten patients were below 30 years of age, lumbar spine location was commonest and 6 had leptomeningeal spread at diagnosis. All the patients underwent surgery and 11 received radiation following surgery. Eight patients below the age of 30 received radiation due to residual disease or metastases. Methylation profiling revealed 11,752 CpGs differentially methylated between the younger and older patients (p < 0.05), however only one CpG cg22496254 associated with gene NCAPG/DCAF16 (role in promoting mitosis) was detectable with FDR < 0.25 that overly methylated in the younger age group. This is a new finding in MPE.

CONCLUSIONS

Spinal MPE is a rare spinal tumor. Our study though limited by numbers, showed younger patients had aggressive phenotype, most requiring radiation. Methylation profiling reaffirmed this finding and trend in the younger patients. Prospective studies in a larger cohort of patients with methylation profiling are needed to identify prognostic variables and new targets for treatment.
EPEN-13. PRIMARY EXTRADURAL SACROCOCCYGEAL SUBCUTANEOUS MYXOPAPILAR EPENDYMOMA MISDIAGNOSED AS PILONIDAL CYST IN A 7 YEAR-OLD BOY: A CASE REPORT
Authors: del Campo Regina M Navarro-Martin , Tavares-Macias Geronimo M , Pozos-Ochoa Luis Ivan , Orozco-Alvarado Ana L , Sanchez-Zubieta Fernando , Arredondo-Navarro Luis Angel
Published: December 2020

BACKGROUND

Ependymomas occur in the brain or spinal cord and rarely as an extraspinal variety at the sacrococcygeal region, separated from the spinal cord. This rare presentation is thought to originate from a group of heterotopic ependymal cells called the coccygeal medullary vestige. There are few reports of this occurrence in children. CLINICAL CASE: A 7-year-old male presented with a history of a soft mass arising in the sacrococcygeal area 3 years earlier, diagnosed as pilonidal cyst at primary level and treated with surgery twice, as this mass recurred the boy was sent to our hospital, a 3rd surgery was performed, all tumoral tissue was removed, no attachment with dural space was founded, pathology revealed myxopapilar ependymoma with positivity for PS100, EMA and Vimentin. After surgery a Follow up MRI of cranium and spine showed absence of disease, no radiotherapy neither chemotherapy was implemented. He has been on surveillance from 3 years now without recurrence.

CONCLUSION

This report highlights the fact that pediatric ependymoma can have an extradural presentation and can be confounded with pilonidal cyst, total resection is needed to control the disease. Potential for recurrence or metastatic disease can continue 20 years from the time of primary tumor, so prolonged surveillance is important.
EPEN-20. EZHIP/CATACOMB COOPERATES WITH PDGF-A AND p53 LOSS TO GENERATE A GENETICALLY ENGINEERED MOUSE MODEL FOR POSTERIOR FOSSA A EPENDYMOMA
Authors: Kagan Emily , Brat Daniel , Shilatifard Ali , Piunti Andrea , Becher Oren
Published: December 2020

BACKGROUND

PFA ependymoma is a pediatric brain tumor with only 30% long-term survival. Recently a gene called CXORF67/EZHIP/CATACOMB (henceforward: CATACOMB) was found to be overexpressed in PFA ependymoma. CATACOMB’s mechanism of action has been found to be analogous to that of the H3K27M mutation as its expression reduces H3K27me3 via inhibition of PRC2 catalytic activity.

METHODS

We infected NESTIN- or GFAP-expressing neonatal hindbrain progenitors with wild-type CATACOMB or a loss of function (LOF) point mutant (M406K), alone, with PDGFA, and with and without p53 deletion.

RESULTS

CATACOMB overexpression alone or with p53 loss was insufficient to induce tumorigenesis. CATACOMB overexpression with PDGFA and p53 loss was sufficient to induce tumorigenesis using either the LOF mutant (M406K) or the wild-type CATACOMB in both cells-of-origin. The histology appeared more ependymoma-like when CATACOMB was expressed in GFAP-expressing progenitors. Median survival for the model initiated in NESTIN progenitors was 99.5 days for the CATACOMB mutant (n=26) group and 61 days for the CATACOMB wild-type (n=28; log-rank test p=0.0033). Median survival for the model initiated in GFAP progenitors were 144 days for the CATACOMB mutant (n=19) group and 65 days for the CATACOMB wild-type (n=21; log-rank test is P<0.0013). Immunohistochemistry for H3K27me3 demonstrated that CATACOMB wild-type tumors had reduced H3K27me3 compared to CATACOMB mutant tumors.

CONCLUSIONS

Disrupting CATACOMB inhibitory activity toward PRC2 significantly increases survival in mice in both models, suggesting this activity plays a critical role in accelerating tumorigenesis. Ependymoma-like histology was more commonly observed in the model initiated in the GFAP-expressing progenitors.