bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-49. BRAINSTEM AND PONTINE VOLUMETRIC ANALYSIS AS A SURROGATE MEASURE OF LOCAL DISEASE CONTROL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Bander Evan D , Freret Morgan E , Wembacher-Schroeder Eva , Wolden Suzanne L , Souweidane Mark M 
Published: December 2020

Abstract

INTRODUCTION
Response-assessment in pediatric neuro-oncology (RAPNO) criteria designed to describe treatment outcomes are poorly implemented in diffuse intrinsic pontine glioma (DIPG), due to inter-observer variability in measurement of tumor volume, lack of tumor enhancement, and undefined relationships between radiographic parameters and survival. Given these issues, this study assessed whether anatomically defined brainstem and pontine volumes can serve as surrogate measures of local disease burden and response to therapy in DIPG.

METHODS
Thirty-two consecutive patients with newly diagnosed DIPG were treated with standard definitive radiation therapy (RT) between 2010 and 2016 at a single institution. MRI brain scans throughout treatment course were analyzed using iPlan® Flow software (Brainlab AG, Munich, Germany). Semi-automated 3D measurements of the brainstem and pons were calculated using a built-in knowledge-based segmentation approach and manually adjusted.

RESULTS
Mean age at diagnosis was 6.5+/-0.5 years (range 2–12 years). Median follow up time was 317 days. Average brainstem volume at diagnosis (Vdiag) was 52.7+/-2.1mL with subsequent decrease at first post-RT MRI to 41.4+/-2.0mL (p &lt; 0.0001). By time of last follow up, brainstem volume increased to 51.9+/-3.3, no longer significantly different as compared to Vdiag (p=0.61). The same relationships were found for pontine volume.

CONCLUSIONS
Volumetric changes in the brainstem and pons occur in response to treatment and correlate with local disease burden and response to therapy. This surrogate may be a useful standardized measure in ongoing and future trials involving localized delivery of therapeutics in DIPG that require evaluation of local-regional disease control in addition to survival.
DIPG-51. ACVR1 MUTATIONS PROMOTE TUMOR GROWTH IN MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Adorno Jennifer Ocasio , Hover Laura , He Chen , Zhu Xiaoyan , Goldhamer David , Carcaboso Angel , Yadavilli Sridevi , Nazarian Javad , Baker Suzanne 
Published: December 2020

Abstract
Mutations in the gene encoding activin A receptor type 1 (ACVR1) are found in approximately 25% of diffuse intrinsic pontine gliomas (DIPGs), a pediatric glioma with 2-year survival rate of less than 10%. ACVR1mutations frequently coincide with activating PIK3CA or PIK3R1 mutations, indicating a potential cooperative effect of BMP and PI3K signaling in gliomagenesis. We used genetically engineered mice with inducible knock-in of Acvr1R206H or Pik3caE545K alleles, such that cre-mediated recombination resulted in expression of the gain of function mutated genes from their endogenous promoters at physiological levels. Cre-mediated deletion in GFAP-CreER;Pik3caE545K/+;p53cKO mice (Pik3ca;p53) mediated Trp53 deletion and expression of Pik3caE545K in glial progenitors, and spontaneously induced high-grade glioma (HGG) in mice with complete penetrance. Heterozygous knock-in of the Acvr1R206H allele accelerated tumorigenesis and impaired survival in Pik3ca;p53 mice (Acvr1;Pik3ca;p53). Transcriptomic analysis of Acvr1;Pik3ca;p53 tumors compared to Pik3ca;p53 littermate controls, as in patient-derived tumors, revealed broad molecular signatures associated with cell fate commitment and chromosome maintenance. Pharmacologic inhibition of ACVR1 was sufficient to impair growth in human patient-derived DIPG cell lines. Together, our studies show that ACVR1 activation promotes tumor growth in spontaneous mouse HGG and patient-derived DIPG cells, suggesting that ACVR1 inhibition may produce a clinically significant therapeutic effect in DIPG.
DIPG-56. EXPLORATION OF TUMOR/STROMA INTERACTIONS IN DIPG XENOGRAFT BY SPECIES-SPECIFIC RNA-SEQ DECONVOLUTION INDICATES A ROLE OF MICROGLIA CELL IN DIPG DEVELOPMENT
Authors: Merlevede Jane , Plessier Alexandre , Felix Arthur , Philippe Cathy , Dret Ludivine Le , Hardy David , Beccaria Kevin , Grill Jacques , Castel David , Varlet Pascale , Debily Marie-Anne 
Published: December 2020

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) and more largely Diffuse Midline Gliomas H3 K27M-mutant (DMG) harbor a unique property of infiltration. Our objective is to elucidate/describe the cellular and molecular determinants of micro-environmental modifications resulting from the tumour/stroma dialogue as it might provide pro-invasive conditions that favour the development of the disease. To this end, we performed RNA-seq analyses to characterize exhaustively the bidirectional molecular modifications of the stroma/tumour in DIPG xenograft models. Gene expression changes in murine microenvironment compartment were investigated as continuous or semi-continuous traits of tumor load by measuring transcriptome in zone with high vs. low infiltration. We observed substantial modulations in gene expression in the microenvironment associated with increasing tumor cell content, pointing to a modification of the macrophage/microglial infiltrate. The expression or overexpression of several modulated genes was validated by IHC in the stroma of DMG primary tumors. Among them, overexpression of the cytokine CCL3 was confirmed, reflecting the activation status of microglial cells. Moreover, we observed in patients that the density of IBA-1 positive microglial cells increases according to the extent of tumor infiltration and that a significant part of them harbor a mitotic status, supporting their interaction with DMG cells. The involvement of this interaction in DMG development needs further evaluation and might represent opportunity to slow down DIPG extension.
DIPG-60. PILOT STUDY OF CIRCULATING TUMOR CELLS IN PEDIATRIC HIGH GRADE BRAIN TUMORS
Authors: Zaky Wafik , Dao Long , Ragoonanan Dristhi , Bath Izhar , Yi Sofia , Gill Jonathan , Khatua Soumen , Li Shulin 
Published: December 2020

Abstract

BACKGROUND
Despite its increasing use, circulating tumor cells (CTCs) have not been studied in pediatric brain tumors.

METHODS
Cell surface vimentin (CSV) is a marker for CTC detection. We developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova Cytoquest platform. PBMCs isolated from blood samples from 52 brain tumor patients were processed to isolate CSV+ CTCs. Captured cells were then stained for CSV and CD45 and scanned to determine the number of CTCs. DIPG samples were additionally examined for H3K27M expression on CSV+ cells. Long term cancer survivors were used as a control cohort.

RESULTS
86.4% of all the samples exhibited between 1–13 CSV+ CTCs, with a median of 2 CSV+ CTCs per sample. Using a value of ≥ 1 CTC as a positive result, the sensitivity and specificity of this test was 83.05% and 60.0% respectively. 19 DIPG samples were analyzed and 70% (13 samples) were positive for 1–5 CTCs. Five of these 7 positive CSV+ CTCs DIPG samples were also positive for H3K27M mutations by immunohistochemistry (71%). Mean survival in days for the CTC positive and negative DIPG samples were 114 and 211 days, respectively (p= 0.13).

CONCLUSION
This is the first study of CTCs in pediatric CNS tumors using an automated approach. Patients with brain tumors can exhibit CSV+ CTCs within peripheral blood. The use of specific molecular markers such as H3K27M can improve the diagnostic capability of liquid biopsies and may enable future disease assessment for personalized therapy.
DIPG-61. RESCUE REGIMENS AFTER BIOMEDE: POSSIBLE INFLUENCE ON OS ASSESSMENT
Authors: Carlo Daniela Di , Pommier Bertille , Teuff Gwenael Le , Abbou Samuel , Berlanga Pablo , Geoerger Birgit , Puget Stephanie , Beccaria Kevin , Blauwblomme Thomas , Debily Marie-Anne , Castel David , Lechapt Emmanuelle , Varlet Pascale , Dangouloff-Ros Volodia , Boddaert Nathalie , Vassal Gilles , Deley Marie-Cécile Le , Grill Jacques 
Published: December 2020

Abstract
BIOMEDE is a multicentric randomized phase II trial to evaluate in DIPG the OS of patients treated with dasatinib, erlotinib or everolimus. The OS is the result of the first line treatment but it could also be affected by re-irradiation and the second line treatment received after progression, especially in case of a possible crossover outside of the trial. This preliminary analysis focuses on the first patients enrolled at Gustave Roussy (n=37). The median age at diagnosis was 7 years, median interval from diagnosis to progression and median survival after progression were 7 (1–20) and 2 (0–13) months respectively. Initial treatment was everolimus for 13, dasatinib for 20, erlotinib for 4 patients. The most frequent targetable molecular alterations were mTOR pathway in 6, PDGRFA in 4, ACVR1 in 3 patients. Out of the 31 patients who relapsed and were evaluable, 18 and 13 had a median survival &lt; 3 and &gt; 3 months respectively. At relapse patients have received different types of therapies, in 6 cases matching the molecular profile of the tumour obtained by sequencing. At progression, seven patients switched from dasatinib to mTOR inhibitors and 2 patients switched from everolimus to dasatinib. Patients with OS after progression &gt; 3 months had higher rate of reirradiation (77% vs 5%), steroid weaning (69% vs 33%) and Lansky/Karnowsky &gt; 50% (85 vs 67%). Extended results on the entire cohort will be presented. It will be important to consider the distribution of reirradiation to interpret the results of the randomisation on OS.
DIPG-66. FEASIBILITY AND APPLICABILITY OF MOLECULAR GUIDED THERAPY IN HIGH GRADE GLIOMA/DIFFUSE MIDLINE GLIOMA: RESULTS FROM BEAT CHILDHOOD CANCER NMTRC-009 MOLECULAR GUIDED THERAPY STUDY
Authors: Harrod Virginia , Nagulapally Abhinav , Lewis Elizabeth , Sholler Giselle 
Published: December 2020

Abstract
High grade gliomas/diffuse midline gliomas (HGG/DMG) historically have a poor prognosis with an overall survival of less than 20% at 5 years. The pathophysiology is under close investigation across the world in efforts to understand this tumor type with aims of increasing effective treatment options. We present our results on the feasibility and outcomes of patients treated on our Molecular Guided Therapy study. Tumor samples were analyzed with whole exome (DNA) and RNA sequencing. Three drug matching algorithms were utilized to generate a report that was reviewed at a multi-institutional tumor board meeting, culminating in a proposed treatment protocol. Eleven patients enrolled, but one did not complete cycle 1 of therapy due to progression of disease, thus ten patients (6-HGG, 4-DMG) were evaluable and received at least 2 cycles of therapy. Time to reports generated and tumor board assembly was (median) 18 and 24 days, respectively. Secondary goals included evaluation of efficacy. Responses showed 50% of patients with stable disease or better at 2 cycles of therapy, but these were temporary with median time to progression of 81 days. In conclusion, we determined that it is feasible to collect individual biological DNA and RNA sequencing information to offer patients individualized treatment plans for this devastating group of diseases. Though data is not statistically significant, we show that there is a suggestion of efficacy in this approach to treatment for patients, indicating a need to expand on this treatment approach with individualized medicine.
DIPG-68. ALPHA-THALASSEMIA X-LINKED MENTAL RETARDATION PROTEIN (ATRX) LOSS-OF-FUNCTION IN A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Shen Chen , Picketts David , Becher Oren 
Published: December 2020

Abstract
Diffuse Intrinsic Potine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Previous discoveries have revealed that, DIPG harbors distinct genetic alterations, when compared with adult high-grade glioma (HGG) or even with non-DIPG pediatric HGGs. ATRX alteration is found in 9% of clinical cases of DIPG, and significantly overlaps with H3.3K27M mutation and p53 loss, the two most common genetic changes in DIPG, found in 80% and 77% clinical cases, respectively. Here we developed genetically engineered mouse model of brainstem glioma using the RCAS-Tv-a system by targeting PDGF-B overexpression, p53 loss, H3.3K27M mutation and ATRX loss-of function to Nestin-expression brainstem progenitor cells of the neonatal mouse. Specifically, we used Nestin-Tv-a; p53 floxed; ATRX heterozygous female and Nestin-Tv-a; p53 floxed; ATRX floxed male breeders, generated offsprings with ATRX loss of function (n=18), ATRX heterozygous females (n=6), and ATRX WT (n=10). Median survial of the three groups are 65 days, 88 days and 51 days, respectively. Also, ATRX null mice is lower in tumor incidence (44.4%), compared with ATRX WT (80%). We evaluated the pathological features of DIPG with or without ATRX alteration, RNA-seq is performed to identify differentially expressed genes between ATRX WT and loss-of-function. In conclution, this study generated the first genetically modified mouse model studying ATRX loss-of-function in DIPG, and suggested that ATRX loss-of-function in DIPG may slow down tumorigenesis and decrease tumor incidence.
DIPG-71. SELECTIVE HDAC INHIBITOR RG2833 INDUCES DIPG CELL DEATH VIA DOWNREGULATION OF THE NFĸB PATHWAY
Authors: Barnett Katherine , Novak Orlandi , Eberhart Charles , Raabe Eric 
Published: December 2020

Abstract
Histone deacetylase (HDAC) inhibitor panobinostat demonstrated activity against diffuse intrinsic pontine glioma (DIPG) in vitro, but its efficacy in vivo was limited by toxicity and poor blood brain barrier penetration. RG2833 (RGFP109) is a selective HDAC1/3 inhibitor that has established brain penetration. In clinical trials, the Cmax (plasma) of RG2833 was 32uM. RG2833 demonstrated cytotoxicity against temozolomide-resistant glioblastoma and downregulated the NFĸB pathway. Because this pathway is overexpressed in DIPG and may play a role in DIPG cell growth and survival, we hypothesized that RG2833 would kill DIPG cells. Treatment of DIPG cell lines with RG2833 as a single agent suppresses cell proliferation in the 5–10μM range (MTS assay for HSJD007 p=0.0004 10μM vs DMSO, JHH-DIPG1 p=0.001 10μM vs DMSO, SF-7761 p=0.04 10μM vs DMSO, SU-DIPG13 p=0.01 10μM vs DMSO by t-test). RG2833 induces apoptosis by 48 hours as measured by Western blot for cPARP and cleaved caspase 3 immunofluorescence (HSJD007 p&lt;0.003 8μM vs DMSO, JHH-DIPG1 p=0.0026 10μM vs DMSO by t-test). RG2833 also slows cell proliferation as measured by Western blot for pRb and immunofluorescence for BrdU (HSJD007 p=0.008 8μM vs DMSO, JHH-DIPG1 p=0.0002 10μM vs DMSO by t-test). Western blot confirmed a dose-dependent increase in histone 3 acetylation with RG2833 treatment at 5 hours. We detected increased acetylated p65 and decreased expression of the NFĸB regulated pro-survival genes BCL2, BCL-xL, and XIAP with RG2833 treatment. Together, this data shows that HDAC inhibitor RG2833 may be a promising therapeutic candidate for DIPG via downregulation of the NFĸB pathway.
EPCT-09. CLR 131 IN PATIENTS WITH RELAPSED OR REFRACTORY PEDIATRIC MALIGNANCIES
Authors: Puccetti Diane , Otto Mario , Morgenstern Daniel , DeSantes Kenneth , Cho Steven , Hall Lance , Oliver Kate , Longcor Jarrod 
Published: December 2020

Abstract

BACKGROUND
CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers by malignant cells. CLR 131 selectively delivers radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues.

OBJECTIVE
CLR 131 is being examined in a Phase 1 trial, CLOVER-2 (NCT03478462), to determine the safety, tolerability, and initial efficacy of CLR 131 in children and adolescents with relapsed/refractory malignancies.

METHODS
Eligibility criteria include children with relapsed or refractory solid tumors or malignant brain tumors for which there are no standard treatment options with curative potential. Subjects must be between ages 2 and 21 with no limit to the number of prior therapies. CLR 131 is administered as a single infusion in escalating doses beginning at 15 mCi/m2. Adverse events (AEs) are graded by NCI-CTCAE v5.

RESULTS
As of 10Jan2020, four subjects with brain tumors have received CLR 131; one at 15 mCi/m2 and three at 30 mCi/m2. Diagnoses included DIPG (2), glioblastoma (1), and medulloblastoma (1). Median age is 13 years (range 10–15) and patients received a median of two prior therapies (range 1 to 8). There were no treatment emergent AEs at the 15 mCi/m2 dose level attributed to CLR 131 by the investigator. Assessment of the 30 mCi/m2 dose level is ongoing.

CONCLUSIONS
CLR 131 is a unique, first in class targeted radiotherapeutic for pediatric malignancies. Preliminary data shows an acceptable and expected safety profile in this patient population. Dose escalation to determine the highest tolerated dose is ongoing.
EPCT-11. PHASE 1 STUDY OF FLUVASTATIN-CELECOXIB COMBINATION IN CHILDREN WITH RELAPSING/REFRACTORY OPTICO-CHIASMATIC LOW-GRADE GLIOMA OR HIGH-GRADE GLIOMAS (FLUVABREX): FINAL RESULTS
Authors: Andrew Nicolas , Sterin Arthur , Solas Caroline , Deley Marie-Cécile Le , Probst Alicia , Aerts Isabelle , Faure-Conter Cécile , Bertozzi Anne-Isabelle , Chastagner Pascal , Entz-Werle Natacha , De Carli Emilie , Dory-Lautrec Philippe , Bouche Gauthier , Leblond Pierre 
Published: December 2020

Abstract

BACKGROUND
Preclinical data support the activity of celecoxib and fluvastatin in high grade (HGG) and low grade gliomas (LGG). A Phase I study was designed to evaluate this combination in children with refractory/relapsed glioma. AIM: To assess the safety, pharmacokinetics (PK), maximum tolerated dose, Recommended Dose for Phase II (RDP2). METHOD: Multicenter phase I trial, including patients aged 6 to 21 year old. Fluvastatin starting dose was 2 mg/kg/day, 14/28 days, with fixed dose of celecoxib (200–800 mg /day). Four dose levels of fluvastatin (2, 4, 6, 8 mg/kg/day) were evaluated. A Continual Reassessment Method was used for dose escalation. Dose-limiting toxicities (DLT) were determined on the 1st cycle. PK samples were obtained at D1 and D14 of cycle 1, pre-dose of cycle 2.

RESULTS
20 patients were enrolled with a median age of 12 years (5.9–19). They previously received a median of 3 (1–7) lines of treatment. Ten patients were treated for LGG and 10 for HGG, receiving a median of 3.5 cycles (1–21). Patients with LGG received a median of 9 cycles (1–21). Among the 17 patients evaluable for DLT, 2 DLTs were reported: 1 grade 3 maculo-papular rash (4 mg/kg), and 1 grade 4 increase of CPK (6 mg/kg). The RP2D of fluvastatin is 6 mg/kg/day.

CONCLUSION
In children with refractory/relapsed glioma, the RDP2 of fluvastatin associated with celecoxib is 6 mg/kg/day. This combination is well tolerated encouraging a phase 2 study in LGG.
EPEN-03. LONG-TERM FOLLOW-UP OF AIEOP 2ND SERIES OF CHILDREN AND ADOLESCENT WITH PRIMARY INTRACRANIAL (ST:SUPRATENTORIAL; PF: POSTERIOR FOSSA) EPENDYMOMA AND METHYLATION GROUPS RE-ANALYSES
Authors: Massimino Maura , Buttarelli Francesca Romana , Witt Hendrik , Johann Pascal , Minasi Simone , Pfister Stefan M , Pajtler Kristian W , Antonelli Manila , Barretta Francesco , Modena Piergiorgio , Gandola Lorenza , Garrè Maria Luisa , Bertin Daniele , Mastronuzzi Angela , Mascarin Maurizio , Quaglietta Lucia , Viscardi Elisabetta , Sardi Iacopo , Ruggiero Antonio , Pollo Bianca , Buccoliero Annamaria , Boschetti Luna , Biassoni Veronica , Schiavello Elisabetta , Chiapparini Luisa , Erbetta Alessandra , Giangaspero Felice 
Published: December 2020

Abstract

BACKGROUND
This 2002–2014 Italian prospective study stratified 160 patients by surgical resection (complete=NED/incomplete=ED) and centrally-reviewed grade. Grade2/NED patients received focal radiotherapy (RT) up to 59.4Gy, Grade3/NED received 4 courses of VEC(vincristine,etoposide,cyclophosphamide) after RT.ED patients received 1–4 VEC courses, second-look surgery, 59.4 Gy+8Gy boost on measurable residue.

METHODS
We re-analyzed data at 115 months follow-up including methylation profile on available samples.

RESULTS
Global PFS/OS at 5/10 years were 66/59% and 80/74%, respectively. Of the 64 relapsers at median 20 months, 53 died at median 37/18 months after diagnosis/relapse, respectively.10/64 relapsed after 5 years (66–126 months); 4 died, relapse was local in 8/10, metastatic 1, combined 1;5/10 patients were below age 3, 5 females, 8 PF tumors. Their survival post-relapse was not longer than earlier relapsers’. At univariable analysis, age over 3 years, female sex, complete surgery, grade 2, no shunt confirmed better PFS/OS. 66/95 analyzed tumors received a score &gt;0.80 through the DNA methylation-based central nervous system tumor classifier: 41/8 as PFA/PFB, respectively,14/17 ST as RELA-positive (3 scored for other molecular entities i.e. anaplastic PXA, LGG MYB, HGNET). Prognostic factors were equally distributed among PFA/PFB groups,1 only group B patient relapsed locally at 96 months.

CONCLUSIONS
Already published prognostic factors remained at long-term follow-up;6.2% patients had late relapses. OS after relapse was not better in late relapsers. Group B confirmed better prognosis but all patients had received «at least» adjuvant RT. Modern ependymoma trials need long follow-up to draw firm conclusions.
EPEN-05. CLINICAL AND GENETIC EVOLUTION OF EPENDYMOMA EXPOSED FROM A MULTI-RECURRENCE GIRL CASE
Authors: Chen Zhong-ping , Wang Jing , Xi Shao-yan , Zhao Qi , Xia Yun-fei , Guo Cheng-cheng , Yang Qun-ying , Li Zhao-jie , Li Zhi , Han Fu , Wang Fang , Sai Ke , Cai Hai-ping , Zhang Xiang-heng , Ke Chao , Wang Jian 
Published: December 2020

Abstract
Ependymomas are glial brain tumors accounting for approximately 2~3% of all primary tumors of the central nervous system (CNS), and 12% of all pediatric intracranial tumors. To better understand the evolution process of ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. This girl was diagnosed as ependymoma at age of 9 years old, and experienced 7 times tumor relapse and received 9 times surgeries but finally ceased at 19 years old with multiregional recurrences. The pathological characteristics, radiographic images and therapeutic strategies of the patient were all retrieved. Molecular markers confirmed the diagnosis of anaplastic ependymoma based on the updated WHO guideline for CNS tumors. Whole-genome sequencing (WGS) was performed to elucidate the landscape of mutation signatures and to identify potential driver mutations along the tumor progression. The seven tumor specimens showed a highly branched evolutionary pattern. There were six gene mutations found in 5 of the 7 specimens (PCDHA4, PCDHA8, SEC14L6, SETD2, RIOK2, and SLCO2A1) and three in 6 of 7 the samples (RYR1, SNX25, DSC2). Strikingly, there was one gene, ADGRL3, which was found to be consistently mutated in the entire disease progression process. Our findings therefore suggest that ADGRL3 might play roles in the disease progression of ependymoma patient.