bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCMP-15. BEVACIZUMAB FOR THE TREATMENT OF CEREBRAL RADIATION NECROSIS: A RETROSPECTIVE COHORT STUDY
Authors: Luitse A , Dankbaar Jan , De Vos Filip , Fonville Susanne , Robe Pierre , Seute Tatjana , Verhoeff Joost , Snijders Tom 
Published: November 2019

Abstract

BACKGROUND
Cerebral radiation necrosis (RN) is a critical complication of radiotherapy for brain tumors. Treatment with corticosteroids provides suboptimal symptom relief, and may have considerable side effects. Small-scale studies support the use of bevacizumab, but systematic data from clinical practice on its efficacy and toxicity remain scarce.

METHODS
In this retrospective cohort study, we included consecutive patients with symptomatic RN that underwent treatment with bevacizumab in our academic neuro-oncology clinic. RN was diagnosed based on imaging, histology or both. The primary outcomes were reported neurological improvement during follow-up, the duration of response, the reported improvement on MRI, and radiological outcome according to RANO criteria. Other outcomes included reduction of dexamethasone dose and the occurrence of adverse events.

RESULTS
Of the 37 included patients (39 RN-episodes), the majority had a glioblastoma (n = 22) or other diffuse glioma (8), followed by brain metastases (4) or other (3). Clinical response was reported in 17 RN-episodes (43.6%) and lasted for a median of 13 weeks (IQR 6–32 weeks). Radiological improvement during follow-up was reported in 29 RN-episodes (80.6%). RANO-defined radiological responses included 1 complete response (3.4%), 7 partial responses (24.1%), 1 minor response (3.4%) and 17 stable disease (58.6%). In total, 36 adverse events occurred, most commonly venous thrombo-embolism, hypertension and dyspnea, with 8 grade III-IV complications and 2 deaths (grade V) which were possibly related to bevacizumab. Of 32 patients on dexamethasone, 9 (28.1%) had completely stopped its use at treatment cessation.

CONCLUSION
This observational study confirms that patients with cerebral RN can benefit both clinically and radiologically from bevacizumab treatment in a real-life clinical setting, although our results are more modest than previous literature suggests. The high prevalence of – sometimes severe – adverse events should be weighed against the possible clinical benefit when counselling patients about this treatment option.
PDCT-01. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSIC PONTINE GLIOMAS ERADICATION (BIOMEDE): RESULTS OF THE THREE-ARM BIOMARKER-DRIVEN RANDOMIZED TRIAL IN THE FIRST 230 PATIENTS FROM EUROPE AND AUSTRALIA
Authors: Grill Jacques , Le Teuff Gwenael , Nysom Karsten , Blomgren Klas , Hargrave Darren , McCowage Geoff , Bautista Francisco , van Vuurden Dannis , Dangouloff-Ros Volodia , Puget Stephanie , Varlet Pascale , Debily Marie-Anne , Vassal Gilles , Le Deley Marie-Cécile 
Published: November 2019

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating brain neoplasms. Despite 50 years of clinical trials, no improvement of survival has been observed and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. METHODS/AIMS: BIOMEDE was conceived as a randomized multi-arm multi-stage program (drop-the-loser adaptive design). It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets) with a planned sample size of 250 patients. A stereotactic biopsy was performed at diagnosis to centrally confirm the diagnosis of DIPG (presence of histone H3K27M mutation or loss of K27 trimethylation) and assess biomarkers/targets (PTEN-loss, EGFR-overexpression). Targeted therapies were started concomitantly with radiotherapy and were continued until disease progression. The main objective of the study was to compare the efficacy of randomized groups in terms of overall survival (OS).

RESULTS
At the 3rd interim analysis, based on 193 randomized patients among the 230 study patients, the IDMC concluded that the study was unlikely to meet its primary objective even if 250 patients were randomized. The median OS from the time of randomization was 10.9, 9.5 and 9 months for everolimus, dasatinib and erlotinib, respectively, which is comparable to historical controls. The median number of courses administered was 7, 5.5 and 6 respectively. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies.

CONCLUSION
BIOMEDE shows the feasibility of biologically-driven treatment in DIPG on a large international scale. Based on the better toxicity profile and the slightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the next step, BIOMEDE 2.0.
PDCT-07. EARLY RESULTS OF THE EMULATE THERAPEUTICS HÆLO™ SYSTEM IN PEDIATRIC BRAIN TUMORS
Authors: Chang Andrew , Gardner Sharon , Jaboin Jerry , Leary Sarah , Loret De Mola Rebecca , McClay Edward , Morgan Murray Donna , Nazemi Kellie , Pai Panandiker Atmaram , Salacz Michael , Stapleton Stacie , Kesari Santosh , Prados Michael 
Published: November 2019

Abstract

BACKGROUND
The EMulate Therapeutics Hælo system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE®) cognate for the treatment of pediatric brain tumors.

METHODS
Sixteen patients with brain tumors consisting of diffuse midline glioma/diffuse intrinsic pontine glioma (DMG/DIPG, n=14), recurrent medulloblastoma (n=1), or anaplastic astrocytoma (n=1) – were treated with the Hælo under FDA’s single-patient compassionate use pathway, as protocol deviations in a glioblastoma trial, or under TGA’s Special Access Scheme. Baseline information and on-treatment safety and exposure data were collected.

RESULTS
Patients ranged in age from 4 to 28 years (median = 8 years) and were diagnosed 91 – 1399 days (median = 397 days) prior to treatment with the Hælo system. Patients were treated for 2 – 52 weeks (median = 15 weeks), with 4 patients still alive (all with a diagnosis of DMG/DIPG), and 3 still on treatment (ranging 18 – 52 weeks). Two out of the 16 patients reported mild-moderate adverse events - one patient reported nausea, fatigue, and excessive sleepiness, and one patient reported vomiting. No device-related serious adverse events were reported. Other adverse events reported were generally associated with progressive disease. Unsolicited, anecdotal reports from some parents/caregivers noted improvements in mobility, speech, and visual acuity while on treatment.

CONCLUSIONS
The Hælo system appears to be safe and feasible for the treatment of pediatric brain tumors. Given that therapy is delivered non-invasively and no device-related serious adverse events were reported, further prospective study of the investigational device is warranted.
PDTM-02. TARGETING THE RB PATHWAY IN MEDULLOBLASTOMA
Authors: Jonchere Barbara , Stripay Jennifer , Pribnow Allison , Zindy Frederique , Min Jaeki , Freeman Burgess , Shelat Anang , Rankovic Zoran , Roussel Martine 
Published: November 2019

Abstract
Medulloblastoma (MB), the most common malignant pediatric brain tumor, is classified into four major molecularly and histopathologically distinct subgroups, among which MYC-driven Group 3 MBs confer a poor prognosis. The Cyclin D/CDK4/CDK6/RB pathway is frequently deregulated in MB leading to uncontrolled cell proliferation, but tumors express an intact RB protein (Northcott et al., Nature, 2017). Therefore, CDK4/6 inhibitor drugs offer a possible therapeutic approach to treat MBs. Because single agent therapy ultimately leads to drug resistance, we initiated in vitro combination drug screens to identify drug classes potentiating CDK4/6 inhibitors. We used Group 3 MB patient-derived orthotopic xenografts (PDOXs), a human cell line (HDMB03), and freshly dissociated tumor cells propagated only in the mouse brain. The drug screen included 90 compounds comprising targeted and cytotoxic drugs that are FDA approved or under active clinical investigation. Using a bioluminescence-based assay that measures ATP consumption (CellTiter-Glo) to evaluate the number of viable cells, these 90 compounds were screened in combination with a fixed concentration of ribociclib, one of the three FDA approved CDK4/6 inhibitors. The primary screen, carried out in HDMB03 cells, revealed several drugs with additive or synergistic potential when combined with ribociclib, including BET inhibitors, MEK inhibitors, PI3K/mTOR inhibitors and gemcitabine. We are currently evaluating the combination of brain penetrant compounds in Group 3 MB PDOXs. The identification of potent drug combinations should provide new therapeutic options for the treatment of Group 3 MB, one of the most difficult to treat.
PDTM-03. CHICKEN EMBRYO CHORIOALLANTOIC MEMBRANE (CAM) ASSAY AS A XENOGRAFT MODEL FOR TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Power Erica , Zhang Liang , Lucien-Matteoni Fabrice , Daniels David 
Published: November 2019

Abstract

BACKGROUND
Diffuse intrinsic pontine gliomas (DIPG), known today as diffuse midline gliomas with the H3K27M mutation, are inoperable and aggressive brain tumors found predominantly in children. Despite extensive research no treatment or cure has been elucidated. Studies in 2012 showed that the majority of DIPG tumors have the H3K27M mutation, but the development of novel therapeutics has been hindered by lack of good laboratory models. Although patient derived cell lines with the H3K27M mutation have increased, the development of good murine xenografts are lagging, requiring extensive time and money. Previous studies have shown that the chicken embryo Chorioallantoic Membrane (CAM) model is an affordable and time-efficient method of studying tumor biology and response to treatment. We sought to develop this in H3K27M tumors to bridge the gap between in vitro—in vivo studies.

METHODS
Three patient-derived H3K27M cell lines were cultured and implanted on the chick embryo CAM on day 9 post-fertilization. Tumors underwent multiple drug treatment with 0.5uM or 2.0uM Alisertib (days 11, 13, 15) or a single targeted radiation treatment at 2 Grey (day 13). Tumor volume was assessed via ultrasound on day 16. The tumor specimens were harvested and analyzed by immunohistochemistry.

RESULTS
Patient-derived DIPG cells implanted on the CAM maintain their molecular characteristics and form tumors on the surface of the CAM as evidenced by H&E and H3K27M status. Statistically significant differences in volume were found in three H3K27M DIPG lines in Alisertib treated tumors compared to the control (p< 0.001, p< 0.001, p= 0.005). Statistically significant differences in tumor volume were found when treating two DIPG lines with targeted radiation therapy compared to controls (p= 0.01, p= 0.02).

CONCLUSIONS
These results validated the CAM assay as a reliable xenograft model for studying DIPG tumor biology and determining efficacy of drug and radiation treatment.
PDTM-09. Yap1 FUNCTION IN SEX-BIASED MEDULLOBLASTOMA FORMATION AND ANTI-TUMOR IMMUNITY
Authors: Abdelfattah Nourhan , Natarajan Sivaraman , Chen Yaohui , Chow Kin-Hoe , Chen Shu-hsia , Olson James , Baskin David , Yun Kyuson 
Published: November 2019

Abstract
Immunotherapies offer remarkable potential to provide robust therapeutic benefit. Patients suffering from medulloblastoma (MB), the most frequent pediatric brain malignancy, can especially benefit from this approach, minimizing the devastating side effects of aggressive radiation and chemotherapies that disrupt normal brain development. However, regulators of the immune landscape remain poorly understood and no effective immunotherapies exist yet for MB. Here, we describe a sex-dependent Yap1 function in fSmoM2;GFAPcre SHH-MB (SG) mouse model. We show that Yap1 is both a cell-autonomous regulator of MB stem-cells and a non-cell-autonomous regulator of immune infiltrates in SHH-MB. Yap1 deletion in SG mice results in increased neuronal differentiation, significantly extended survival, and enhanced infiltration of peripheral blood immune cells (including cytotoxic T-cells, neutrophils, and macrophages). Additionally, this rescue phenotype is observed in a sex-biased manner: 65% of Yap1f/f;fSmoM2;GFAPcre males are rescued in contrast to 35% of females. These observations implicate Yap1 as a mediator of sex-biased brain-tumor formation, either through direct modulation of MB cells and/or through indirectly mediating the MB immune landscape. We are currently testing the role of sex-specific differences in the developing mouse brain to elucidate context-dependent function of Yap1 in MB genesis and maintenance.
PDTM-21. MULTI-MODAL PROFILING OF PEDIATRIC HIGH-GRADE GLIOMA SINGLE CELLS USING PATCH-SEQ
Authors: Gillespie Shawn , Arzt Marlene , Woo Pamelyn , Monje Michelle 
Published: November 2019

Abstract

Pediatric and adult high-grade gliomas are characterized by extensive intra-tumoral transcriptional heterogeneity. When measured by single cell RNA sequencing, gliomas reveal themselves as continuums of stemness and differentiation programs with important implications for therapy, but to date this transcriptional information has not been directly linked to physiological behaviors of cells. Recent work from our group establishes the electrical integration of glioma cells into neural circuitry. One subpopulation of glioma cells participates in glutamatergic synaptic communication with neurons, and a distinct subpopulation of cells sense and respond to extracellular potassium flux of neuronal networks by an entirely distinct mechanism. Our data support a model in which both modes of electrical communication are critical to glioma growth, but current associations between the electrophysiological properties of a cell, its transcriptional profile and developmental state are correlational in nature. Patch-seq is needed to clarify the relationship between transcriptional profiles of quiescent/cycling stem-like cells and the observed electrophysiological behaviors. Put more simply, patch-seq will clarify where the synaptically-connected glioma cells exist along a developmental hierarchy.

METHODS
Here, we adapt a recently described technique called patch-seq to record the electrophysiological profiles of individual pediatric high-grade glioma cells by whole cell patch-clamp and subsequently isolate their mRNA for single cell sequencing by smart-seq2 and analysis using Seurat. In this way, we couple electrophysiological and transcriptomic profiles to unambiguously assign functional identities to cells with transcriptional profiles along a developmental hierarchy.

RESULTS
We report the successful adaptation of patch-seq for use with patient-derived diffuse intrinsic pontine glioma (DIPG) xenografts in acute brain slice preparations, enabling evaluation of single glioma cells integrated in intact neural circuitry.

CONCLUSIONS
Data synthesizing the electrophysiological and transcriptomic profiles of single glioma cells in the context of the developmental hierarchy will be presented.
PDTM-27. THE CRISPR-Cas9 SYSTEM-MEDIATED ENDOGENOUS GENE-REARRANGEMENT INDUCED C11orf95-RELA FUSION IN VITRO AND IN VIVO THAT LED TO DEVELOPMENT OF BRAIN TUMORS
Authors: Takadera Mutsumi , Ozawa Tatsuya , Yamamoto Tetsuya , Ichimura Koichi 
Published: November 2019

Abstract
Recent large-scale genomic studies of ependymal tumors have identified recurrent RELA and YAP1 fusion genes in supratentorial ependymomas. We have so far shown that C11orf95-RELA fusion was a potent oncogene capable of inducing human ependymoma-like tumors in the RCAS/tv-a retroviral gene transfer system. However, molecular mechanism underlying the tumor formation has not been fully investigated. Given that C11orf95-RELA fusion genes are caused by gene rearrangement between C11orf95 and RELA gene due to chromothripsis involving 11q, it has been suggested that expression of these fusion genes is regulated under the C11orf95 promoter. In this study, we developed a system to reproduce the oncogenic gene rearrangement using the CRISPR-Cas9 system and examined if consequent endogenous ependymoma fusion genes are competent to form brain tumor in mice. Initially, we designed guide RNAs on the human and mouse genomic loci corresponding to breakpoints observed in human RELA fusion positive ependymomas and introduced them into HEK293T or NIH3T3 cells. RT-PCR and immunoblot analyses revealed that a combination of multiple guide RNAs efficiently induced gene rearrangement between C11orf95 and RELA gene, resulting in C11orf95-RELA fusion protein. Subsequently, we introduced the same guide RNAs using a lentiviral gene transfer system into mouse brain. Brain tumor formation was observed around 2 months after the guide RNA delivery, indicating successful gene rearrangement followed by C11orf95-RELA fusion expression in vivo. These results thus firmly establish that a gene rearrangement is the mechanism to form the C11orf95-RELA fusion which is the direct driver of tumorigenesis. Furthermore, we found that endogenous YAP1-FAM118B fusion gene can be also induced with a similar experimental strategy to that of C11orf95-RELA fusion. Our system to simulate genomic event will provide insights into the tumorigenic mechanism of ependymomas that harbor various fusion genes.
PDTM-31. INVESTIGATING THE EFFECT OF H3G34V MUTATION ON DISTINCT GENOMIC H3K36 METHYLATION PATTERNS IN PEDIATRIC GLIOMA
Authors: Huang Tina , Piunti Andrea , Ozark Patrick , Barton Elizabeth , Qi Jin , Hashizume Rintaro , Shilatifard Ali , Saratsis Amanda 
Published: November 2019

Abstract

BACKGROUND
Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas (pHGGs). This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase). Consequently, reduced H3K36me is observed on H3G34V nucleosomes relative to wild-type, contributing to genomic instability and driving a distinct gene expression signature associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3G34V mutation in pediatric glioma on genomic H3K36me3 enrichment in vitro.

METHODS
Doxycycline-inducible short hairpin RNA (shRNA) against H3F3A was delivered via lentivirus to established H3G34V mutant pediatric glioma cell line KNS42, and H3G34V introduced into H3.3 wild type normal human astrocytes (NHA). Transfections were confirmed by western blot, fluorescent imaging, and flow cytometry, with resulting H3.3WT and H3K36me3 expression determined by western blot. H3.3WT, H3K36me3, and H3G34V ChIP-Seq was performed to evaluate effects of H3G34V mutation on genomic enrichment patterns.

RESULTS
Complete knockdown of H3G34V was achieved with DOX-induced shRNA, with no change in total H3.3, suggesting disproportionate allelic frequency of genes encoding H3.3 (H3F3A and H3F3B). Modest increase in H3K36me3 expression occurred after H3F3A-knockdown from KNS42, suggesting H3G34V alone impacts observed H3K36me3 levels. H3G34V knock-in to NHAs was verified via western blot. Distinct H3K36me3 genomic enrichment was observed with H3G34V on ChIP-Seq.

CONCLUSIONS
We demonstrate that DOX-inducible knockdown of H3F3A in an H3G34V mutant pediatric glioma cell line, and H3G34V mutation transduction in wild-type NHAs, directly impacts H3K36me3 expression level. Further evaluation by ChIP-Seq analysis for restoration of wild-type genomic H3K36me3 enrichment patterns with H3G34V knockdown, and mutant H3K36me3 patterns with H3G34V transduction, is currently underway.
PDTM-33. EUROPEAN GENETIC ANCESTRY ASSOCIATED WITH RISK OF CHILDHOOD EPENDYMOMA
Authors: Zhang Chenan , Ostrom Quinn , Hansen Helen , de Smith Adam , Kline Cassie , Kruchko Carol , Vaksman Zalman , Diskin Sharon , Barnholtz-Sloan Jill , Ramaswamy Vijay , Taylor Michael , Bondy Melissa , Metayer Catherine , Wiemels Joseph , Walsh Kyle 
Published: November 2019

Abstract

BACKGROUND
Ependymoma is a histologically-defined central nervous system tumor most commonly occurring in children. Incidence differs by race/ethnicity, with individuals of European ancestry at highest risk. No large-scale genomic analyses of ependymoma predisposition have been conducted to date. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk.

METHODS
In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among admixed Hispanic and African-American subjects and estimated European substructure among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local European ancestry. We also re-analyzed CBTRUS data to examine subtype-specific differences in ependymoma incidence across racial/ethnic groups.

RESULTS
Each 20% increase in European ancestry was associated with 1.31-fold greater odds of ependymoma among Hispanic and African-American subjects (95% CI: 1.08–1.59, Pmeta=6.7×10–3). Among non-Hispanic whites, European ancestral substructure was also significantly associated with ependymoma risk. Local admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and genotype association analysis in the region identified an association upstream of R-spondin 4 that survived Bonferroni correction (P=2.2x10-5) but was not validated in an independent set of posterior fossa type A (PF-EPN-A) patients. In complementary CBTRUS analyses, American Indian/Alaskan Natives were at reduced risk relative to non-Hispanic whites (RR=0.64, 95% CI:0.46–0.87), as were African-Americans (RR=0.67, 95% CI:0.60–0.74) and Asian/Pacific Islanders (RR=0.86, 95% CI:0.73–1.00). Although overall ependymoma rates were similar in U.S. Hispanics (RR=0.96, 95% CI:0.88–1.05), lower rates were observed for myxopapillary ependymoma and other spinal ependymoma.

CONCLUSION
Inter-ethnic differences in ependymoma risk vary by histopathologic and potentially molecular subgroup, and are recapitulated in the genomic ancestry of ependymoma patients.