bluuebunny/crossref_metadata_2025_split huggingface dataset:
SL1 GENETICS OF PEDIATRIC BRAIN TUMORS: RECENT ADVANCES AND FUTURE PERSPECTIVES
Authors: Jones David T W 
Published: December 2019

Abstract
The last decade has seen a true revolution in our understanding of the oncogenic mechanisms underlying human tumors, brought about by transformative advances in the technologies available to interrogate the (epi)genetic composition of cancer cells. The dynamic pediatric neuro-oncology community has proven to be very agile in adapting to these changes, and has arguably been at the forefront of some of the most exciting new discoveries in tumor biology in recent years. For example, high-throughput genomic sequencing has revealed highly frequent mutations in histone genes in pediatric glioblastoma; highlighted an ever-expanding role for oncogenic gene fusions in multiple pediatric brain tumor types, and also shed light on novel phenotypic patterns such as chromothripsis (dramatic chromosomal shattering) and somatic hypermutation - the latter being a possible marker for response to novel immunotherapeutic approaches. Epigenetic profiling has also identified a role for ‘enhancer hijacking’ (whereby genomic rearrangement brings an active enhancer element in close proximity to a proto-oncogene) in multiple pediatric brain tumors, and is even pointing towards a fundamentally new way in which tumors may be molecularly classified.
In coming years, the major challenge will be to harness the power of these discoveries to more accurately diagnose patients and to identify potential therapeutic targets in a more personalized way, so that these major biological advances can also be translated into substantial clinical benefit. Examples such as the dramatic responses observed in childhood brain tumor sufferers to BRAF V600E and NTRK inhibitors demonstrate the promise that such an approach can hold, but it will require a fundamental shift in the way that clinical trials are planned and conducted in order to optimize patient care.
This talk will highlight some of the most striking developments in the field, and look at the challenges that remain before these can lead to improved patient outcomes.
AS1-KL-1 DEVELOPMENT OF HIGH-DOSE CHEMOTHERAPY INCLUDING THIOTEPA COMBINED WITH AUTOLOGOUS PERIPHERAL BLOOD STEM CELL RESCUE
Authors: Hara Junichi 
Published: December 2019

Abstract
Thiotepa is a classic alkylating agent that was launched in 1958 in Japan. We have consistently developed thiotepa-containing HDC since 1992, inspired by the fact that thiotepa was used as an alternative to melphalan as a high-dose chemotherapy (HDC) drug for neuroblastoma in the United States. Thiotepa is considered to be a drug suitable for brain tumor treatment because of its good BBB permeability, equal concentration in cerebrospinal fluid and blood, and the characteristics of alkylating agents that enhance the effect by log ratio of dose. Melphalan, which is also an alkylating agent as a central agent of HDC, has a strong antitumor effect, so we planned to use both at the maximum tolerated dose for each. Therefore, in order to reduce toxicity, it was decided to divide it into two doses at weekly intervals and to administer thiotepa for 24 hours in order to prevent hepatic sinus obstruction syndrome (SOS). Since 1993, a dose determination study was conducted, and the doses of thiotepa and melphalan were determined to be 800 mg/m2 and 280 mg/m2, respectively. Autologous peripheral blood stem cell transplantation using this regimen was performed as a consolidation therapy for metastatic pediatric medulloblastoma in 28 and 15 patients, respectively, in 2 series. Five-year progression-free survival rates of 82.1 ± 7.2% and 92.9 ± 6.9% were obtained. After that, the supply was stopped in 2009. This time, a domestic study was conducted with the dose of melphalan reduced to 210 mg/m2, and this year, a new indication (pretreatment for autologous hematopoietic stem cell transplantation in childhood malignant solid tumors) was acquired and launched. By this dose reduction, reduced gastrointestinal toxicity such as mucosal damage is expected. The JCCG clinical trials incorporating HDC will be conducted in medulloblastoma, ATRT, and refractory germ cell tumors.
MS1 TOWARD ESTABLISHMENT OF ROUTINE MOLECULAR DIAGNOSTICS FOR ADULT GLIOMAS UNDER THE NATIONAL HEALTH INSURANCE
Authors: Ichimura Koichi 
Published: December 2019

Abstract
Molecular diagnosis is now an official part of the diagnosis of brain tumors. Since WHO2016 incorporated the status of IDH mutation and 1p/19q codeletion as a part of the definition for oligodendrogliomas, astrocytomas and glioblastomas, molecular tests have become an essential part of the clinical management of adult gliomas. However, these tests are not covered by the National Health Insurance in Japan, and the cost and the limited availability of tests are prohibitive to perform molecular tests in most hospitals where brain tumor patients are treated. In 2015, the Committee for Molecular Diagnosis of Brain Tumor was established within the Japan Society for Neuro-Oncology in order to develop a standardized molecular tests for adult gliomas under the National Health Insurance. For the detection of 1p/19q codeletion, FISH is the most commonly used method. However, the widely available commercial FISH probe is located within 1p36, the regions where partial deletion often occurs in glioblastoma. This could lead to miss-judgement of 1p/19q codeletion which may result in miss-diagnosis. We have designed a novel FISH probes located in the region of 1p and 19q where partial deletions are rarely found, and are developing them as an in vitro diagnostic tests. Our ultimate aim is to establish a standardized molecular tests for adult gliomas under the National Health Insurance.
SDS2 CHALLENGES IN TREATMENT OF GLIOBLASTOMA: CURRENT CONCEPTS AND THERAPEUTIC PERSPECTIVES
Authors: Wick Wolfgang 
Published: December 2019

Abstract
The natural disease course in glioblastoma is grim, in adults as well as in children. To date, there are no options for primary, secondary or tertiary prevention. However, unlike the fatalistic approach generally taken, there are subgroups of patients or individuals clearly benefitting over a variable time from current treatments, radiation and alkylating chemotherapy, as well as experimental precision or immune interventions. This heterogeneity in treatment response reflects the biological heterogeneity of the disease, which needs to be addressed in current preclinical and clinical investigations as well as this identifies primary and acquired treatment resistance as the key challenge in the field of glioblastoma. Importantly, even for most conventional treatments the basic molecular mechanisms for primary or secondary resistance are unknown or incompletely understood.
The present view is that progress will be made with a more precise classification and grouping of glioblastoma. The methylation subgroups clearly provide a first step, but further tumor bulk but potentially also subclonal or single-cell analyses might provide further insights and will be a prerequisite to meaningfully interpretable trials.
Novel preclinical and translational concepts of glioblastoma in adults reflecting the proposed network architecture of the glioma, but also the glioma-brain interface may for the first time separate options for trial interventions in glioblastoma form the usual mainstream in oncology.
Clinical trials of the past years have revealed the potential for further developing a lomustine/temozolomide combination in O6-methylguanine DNA-methyltransferase (MGMT) promoter hypermethylated glioblastoma and allow leaving out temozolomide for glioblastoma harboring an unmethylated MGMT promoter. The latter is not clinical standard, however we should at some point make sure we still understand, why temozolomide is provided in this biological situation and how we make a next step.
The field of immunoneurooncology is rapidly growing with preclinical work and trial concepts, but whereas patients with brain metastases seem to benefit from this development, success in glioblastoma is restricted to uncontrolled earl-phase developments.
EL1 BUILDING A CAREER IN NEURO-ONCOLOGY RESEARCH
Authors: Cavenee Webster K 
Published: December 2019

Abstract
A young neurosurgeon has several interesting and important possible career paths: clinical care, clinical/translational research and more fundamental research. Each of these has its own requirements for training, talent and commitment. A closer inspection of each of these, however, reveals that they are basically quite similar. From this, several general conclusions can be gleaned and recommendations for optimizing the chances of long-term career success. In this short talk, I will review the aspects of our training program that has allowed each of our Japanese trainees to have remarkable success both while with us in the US and upon their return to Japan. My goal is to explicitly describe and state these as a roadmap for success, particularly in the rapidly developing field involving the application of molecular and genetic technologies to translational and basic neuro-oncology research—but also as more generally applicable principles.
S5-KL-1 CANCER GENOMIC MEDICINE: FROM BENCH TO CLINIC
Authors: Aburatani Hiroyuki 
Published: December 2019

Abstract
Over the last two decades, genomic technology such as microarray and next generation sequencing (NGS) enabled comprehensive analysis of cancer genome. International cancer genome consortium, established in 2007, completed the analysis of 25,000 cases and has brought discovery of novel cancer driver genes and improved our understanding cancer biology. For example, discovery of IDH1/2 mutation in various cancers created a new concept, 2-hydroxyglutarate as Oncometabolite. The mutational signature patterns allow us to predict how the individual cancer was developed. Anti-cancer drugs, such as alkylating agents, occasionally modify the bases and introduce mutations through mispairing in replication.
Currently we are aware that cancer is a genetic disease, where accumulation of genetic and epigenetic alterations in the genome leads to cellular transformation, and that mutation in each patient is unique. To realize the personalized oncology, clinical sequencing test was developed. This year a couple of NGS-based cancer panel tests have been approved for reimbursement by nation-wide healthcare system in Japan.
In this seminar I will discuss the future improvement in genomic oncology.
ANGI-01 ALTERATION IN IMMUNE REGULATORY CELLS BEFORE AND AFTER TREATMENT BY STUPP REGIMEN WITH OR WITHOUT BEVACIZUMAB FOR GLIOBLASTOMA
Authors: Tanaka Toshihide , Tamura Ryota , Yamamoto Yohei , Morimoto Yukina , Teshigawara Akihiko , Tochigi Satoru , Hasegawa Yuzuru , Takei Jun , Akasaki Yasuharu , Sasaki Hikaru , Murayama Yuichi 
Published: December 2019

Abstract

BACKGROUND
In our previous study, bevacizumab (Bev), a humanized anti- vascular endothelial growth factor monoclonal antibody, downregulated the expression of programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immune checkpoint molecules, suppressed the infiltration of immunosuppressing cells such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and induces cytotoxic T lymphocytes (CTL) infiltration. To explore the possibility that inhibition of immunosuppressive cell infiltration and induction of CTL were attributed to not only Bev alone but also radiation (RT) or temozolomide (TMZ), we re-evaluated those alterations in the tumor tissue obtained from patients before and after the treatment using Stupp regimen (RT concomitant with TMZ) without Bev therapy.

MATERIALS & METHODS
We analyzed 10 tumor tissues from 5 patients with GBMs, which were paired samples of pre- and post- standard chemoradiotherapy (Stupp regimen: RT plus concomitant and adjuvant TMZ). Immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissue of 10 tumors. The sections were stained with anti-Ki-67, anti-VEGF-A, anti-VEGFR1, anti-VEGFR2, anti-CD34, anti-HIF1 alpha, anti-CA9, anti-nestin, anti-PD-1, anti-PD-L1, anti-CD4, anti-CD8, anti-Foxp3, and anti-CD163 antibodies. All expressions were assessed by authors with blinded clinical information.

RESULTS
Immunohistochemical analyses demonstrated that the expression levels of immune regulatory molecules such as Foxp3, CD163, PD-1, PD-L1, CD4, and CD8 were not significantly changed after the treatment using the Stupp regimen, compared with combinational usage of Bev. In addition, expressions of VEGF/VEGFR, hypoxic markers, and stem cell marker were not altered before and after Stupp regimen, either. Bev persistently inhibited immune suppressive cells and immune checkpoint molecules via down-regulation of VEGF pathway. In contrast, Stupp regimen did not affect immune regulations and tumor microenvironment.

CONCLUSION
These results suggested that immunosupportive effect was caused by Bev administration, leading to the novel combinational treatment strategies, in addition to Stupp regimen.
CBMS-05 COMPREHENSIVE METABOLOMIC ANALYSIS OF IDH1R132H CLINICAL GLIOMA SAMPLES REVEALS SUPPRESSION OF Β-OXIDATION DUE TO CARNITINE DEFICIENCY
Authors: Miyata Satsuki , Tominaga Kaoru , Sakashita Eiji , Urabe Masashi , Onuki Yoshiyuki , Gomi Akira , Yamaguchi Takashi , Mieno Makiko , Mizukami Hiroaki , Kume Akihiro , Ozawa Keiya , Watanabe Eijyu , Kawai Kensuke , Endou Hitoshi 
Published: December 2019

Abstract

BACKGROUND
Gliomas with isocitrate dehydrogenase 1 (IDH1) mutation have alterations in several enzyme activities, resulting in various metabolic changes. The aim of this study was to investigate the mechanism for the better prognosis of gliomas with IDH mutation by performing metabolomic analysis.

METHODS
To comprehensively understand the metabolic state of human gliomas, we analyzed clinical samples obtained from surgical resection of glioma patients (grades II-IV) with or without the IDH1 mutation, and compared them with U87 glioblastoma cells overexpressing IDH1 or IDH1R132H cDNA. We used capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry for these analyses.

RESULTS
In clinical samples of gliomas with IDH1 mutation, levels of 2-hydroxyglutarate (2HG) were significantly increased compared with gliomas without IDH mutation. Gliomas with IDH mutation also showed decreased 2-oxoglutarate and downstream intermediates in the tricarboxylic acid cycle and pathways involved in production of energy, amino acids, and nucleic acids. The marked difference in the metabolic profile in IDH mutant clinical glioma samples compared with that of mutant IDH expressing cells includes a decrease in β-oxidation due to acyl-carnitine and carnitine deficiencies.

CONCLUSIONS
These metabolic changes may explain the lower cell division observed in IDH mutant gliomas and may be one mechanism of the better prognosis in IDH mutant gliomas.
ET-05 PRECLINICAL STUDY OF AN ANTI-HUMAN TISSUE FACTOR ANTIBODY-DRUG CONJUGATE IN A MALIGNANT GLIOMA XENOGRAFT MODEL
Authors: Takashima Hiroki , Manabe Shino , Tsuji Atsushi , Saga Tsuneo , Tsumura Ryo , Anzai Takahiro , Koga Yoshikatsu , Yasunaga Masahiro , Kuroda Jun-Ichiro , Mukasa Akitake , Matsumura Yasuhiro 
Published: December 2019

Abstract
Whereas macromolecules such as antibody hardly extravasate from normal blood vessels compared with low molecular agents, macromolecules leak from tumor vasculature because of the enhanced permeability. As a result, macromolecules selectively accumulate at tumor sites. We apply this phenomenon, known as the enhanced permeability and retention effect (EPR effect), to drug delivery for cancer therapy. Drug delivery system (DDS) based on the EPR effect is called the passive targeting. On the other hand, DDS based on antigen-antibody or ligand-receptor interaction is the active targeting. Antibody-drug conjugate (ADC), antibody conjugated with antitumor agents, retains both of the passive and active targeting functions. Tissue factor (TF), an initiator in the extrinsic pathway of blood coagulation, is overexpressed in various cancers including malignant glioma. To target the molecule in tumor sites, we have produced several anti-TF monoclonal antibodies. Previously, we evaluated tumor accumulation of an indium-111-labeled anti-TF antibody in an orthotopic glioma xenograft model with high expression of TF by single photon emission computed tomography/computed tomography (SPECT/CT). The imaging study showed that anti-TF antibody significantly accumulated in the tumor compared with control antibody (P &lt; 0.01). The finding suggests that blood-brain barrier in brain tumors is broken and antibodies accumulate in tumors by utilizing both of the passive and active targeting. In this study, to prepare anti-TF ADC, we conjugated monomethyl auristatin E (MMAE), a microtubule inhibitor, to humanized anti-TF antibody. The anti-TF ADC recognized TF expressed in glioma cells and showed potent cytocidal activity against human glioma cell lines depending on TF expression. In addition, we evaluated in vivo antitumor effect of the ADC in a mouse model subcutaneously inoculated with TF-overexpressing glioma cells. Anti-TF ADC showed a significant higher antitumor effect compared with control ADC (P = 0.015).
ET-13 CONTROL OF ACTIVATED MICROGLIA THROUGH P2X4 RECEPTOR IN RADIATION BRAIN NECROSIS
Authors: Natsuko Kondo , Yoshinori Sakurai , Kajihara Takayuki , Takada Takushi , Takai Nobuhiko , Kume Kyo , Miyatake Shinichi , Oda Shoji , Suzuki Minoru 
Published: December 2019

Abstract

INTRODUCTION
Brain radiation necrosis (RN) is severe adverse event after radiation therapy for brain tumor patients, especially in case of re-irradiation. Although corticosteroids or vitamin E, etc. are clinically used for RN, the effect is limited and underlying mechanism is to be cleared. Therefore, we established RN mouse model with irradiating right hemisphere of mouse brain using proton beam at dose of 60 Gy [Kondo et al., 2015]. In this study, we investigated change of phospholipids and lipid mediators after irradiation using this RN model in correlation with microglia activation.

METHODS
After irradiation, change of phospholipids and lipid mediators in mouse brain was investigated using imaging mass spectrometry and LC-MS. Immunohistochemistry on microglia and P2X4 receptor, a receptor for lysophosphatidylcholine (LPC) was performed.

RESULTS
In imaging mass spectrometry, 1 and 4 months after irradiation, phosphatidylcholine (PC): (16:0/20:4), (18:0/20:4) decreased in irradiated area compared non-irradiated area. On the other hand, LPC: (16:0) increased in irradiated area compared to non-irradiated area after 1 month and 4 months irradiation. PC (16:0/20:4) is a precursor of LPC (16:0) and arachidonic acid (20:4). By LC-MS, LPC was twice higher in irradiated area compared to non-irradiated, 6 months after irradiation. Microglia was highly activated in irradiated area compared to non-irradiated from 3 months after irradiation to 8 months and strongly co-expressed P2X4 receptor was confirmed in irradiated area after 6 months. Preliminary P2X4 receptor agonist administration test prolonged the RN to 12 months after irradiation.

CONCLUSION
In RN, LPC may continuously activated microglia through P2X4 receptor and cause chronic inflammation after irradiation. P2X4 agonist administration test including action resolution and immunohistochemistry is ongoing.
TB-02 NF-KB CANONICAL PATHWAY ACTIVATION DRIVES GLYCOLYSIS AND TUMOR PROGRESSION IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Tateishi Kensuke , Sasaki Nobuyoshi , Kawazu Masahito , Miyake Yohei , Nakamura Taishi , Yoshii Yukie , Matsushita Yuko , Miyake Shigeta , Sasame Jo , Yamanaka Shoji , Yamamoto Tetsuya , Wakimoto Hiroaki , Nagane Motoo , Ichimura Koichi 
Published: December 2019

Abstract
Recent genomic analyses have identified highly recurrent genetic alterations in PCNSL. However, due to the lack of clinically representative PCNSL preclinical models, the pathogenic mechanisms of these alterations remains largely unknown. Here, we established the largest panel of 12 clinically relevant PCNSL patient-derived orthotopic xenografts retained the histopathologic phenotype, lymphoma expression subtype, copy number alterations and 90% of the non-synonymous mutations of primary tumors, with 100% concordance of MYD88 and CD79B mutations, which are highly recurrent in PCNSL. Patient tumor regression with high-dose methotrexate correlated with in vitro sensitivity to methotrexate in corresponding PCNSL models. By knocking down canonical NF-kB pathway genes, we found that successful orthotopic xenograft formation was dependent on NF-kB canonical pathway activation induced by MYD88 mutation or overexpression of EBV-related LMP1. Metabolically, PCNSL xenografts phenocopied the high 18F-fluorodeoxyglucose uptake observed in patients and demonstrated glycolytic dependence, revealing new potential therapeutic strategies in PCNSL. Collectively, we found NF-kB canonical pathway activation as a crucial driver of PCNSL xenograft progression and found that NF-kB canonical pathway induced an addiction to glycolysis, revealing a novel potential therapeutic strategy. Our PCNSL xenograft panel represents a valuable and reproducible preclinical tool that has the potential to help decipher how genetic and/or epigenetic alterations contributes to lymphomagenesis and tumor maintenance and enhance the development of novel therapeutic strategies in PCNSL.
TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES
Authors: Kawauchi Daisuke , Pajtler Kristian , Wei Yiju , Okonechnikov Konstantin , Silva Patricia , Jones David , Hoshino Mikio , Pfister Stefan , Kool Marcel , Li Wei 
Published: December 2019

Abstract
YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.