bluuebunny/crossref_metadata_2025 huggingface dataset:
Perspective from South Africa and sub-Saharan Africa
Authors: Benn Carol
Published: December 2019

Abstract: A continent-wide review of surgical management of breast care in Africa described a disproportionate number of black African patients presenting with locally advanced and metastatic disease (stage 3 or 4). Only 25% presented with early-stage disease (stage 1 or 2). Investment in breast cancer research and treatment in low- and middle-income countries (LMICs) should be a global health priority. In South Africa and other LMICs the first screening goal is to reduce late presentation and late-stage disease through community-based population-level screening combined with open access to health care services for any women with breast symptoms. The aim is to decrease current provider-dependent delays. Increased availability of multidisciplinary teams functioning in specialist centres should improve access and thus decrease the numbers of locally advanced breast cancers presenting, with a knockdown effect on decreasing low survival rates.
Deep residual detection of radio frequency interference for FAST
Authors: Yang Zhicheng , Yu Ce , Xiao Jian , Zhang Bo
Published: December 2019

Radio frequency interference (RFI) detection and excision are key steps in the data-processing pipeline of the Five-hundred-meter Aperture Spherical radio Telescope (FAST). Because of its high sensitivity and large data rate, FAST requires more accurate and efficient RFI flagging methods than its counterparts. In the last decades, approaches based upon artificial intelligence (AI), such as codes using convolutional neural networks (CNNs), have been proposed to identify RFI more reliably and efficiently. However, RFI flagging of FAST data with such methods has often proved to be erroneous, with further manual inspections required. In addition, network construction as well as preparation of training data sets for effective RFI flagging has imposed significant additional workloads. Therefore, rapid deployment and adjustment of AI approaches for different observations is impractical to implement with existing algorithms. To overcome such problems, we propose a model called RFI-Net. With the input of raw data without any processing, RFI-Net can detect RFI automatically, producing corresponding masks without any alteration of the original data. Experiments with RFI-Net using simulated astronomical data show that our model has outperformed existing methods in terms of both precision and recall. Besides, compared with other models, our method can obtain the same relative accuracy with fewer training data, thus reducing the effort and time required to prepare the training data set. Further, the training process of RFI-Net can be accelerated, with overfittings being minimized, compared with other CNN codes. The performance of RFI-Net has also been evaluated with observing data obtained by FAST and the Bleien Observatory. Our results demonstrate the ability of RFI-Net to accurately identify RFI with fine-grained, high-precision masks that required no further modification.
The impact of star formation sampling effects on the spectra of lensed z > 6 galaxies detectable with JWST
Authors: Vikaeus Anton , Zackrisson Erik , Binggeli Christian
Published: December 2019

The upcoming James Webb Space Telescope (JWST) will allow observations of high-redshift galaxies at fainter detection levels than ever before, and JWST surveys targeting gravitationally lensed fields are expected to bring z ≳ 6 objects with very low star formation rate (SFR) within reach of spectroscopic studies. As galaxies at lower and lower star formation activity are brought into view, many of the standard methods used in the analysis of integrated galaxy spectra are at some point bound to break down, due to violation of the assumptions of a well-sampled stellar initial mass function (IMF) and a slowly varying SFR. We argue that galaxies with SFR ∼ 0.1 M⊙ yr−1 are likely to turn up at the spectroscopic detection limit of JWST in lensed fields, and investigate to what extent star formation sampling may affect the spectral analysis of such objects. We use the slug spectral synthesis code to demonstrate that such effects are likely to have significant impacts on spectral diagnostics of, for example, the Balmer emission lines. These effects are found to stem primarily from SFRs varying rapidly on short (∼Myr) time-scales due to star formation in finite units (star clusters), whereas the effects of an undersampled IMF is deemed insignificant in comparison. In contrast, the ratio between the He ii- and H i-ionizing flux is found to be sensitive to IMF-sampling as well as ICMF-sampling (sampling of the initial cluster mass function), which may affect interpretations of galaxies containing Population III stars or other sources of hard ionizing radiation.
The evolution of dust in discs influenced by external photoevaporation
Authors: Sellek Andrew D , Booth Richard A , Clarke Cathie J
Published: December 2019

Protoplanetary discs form and evolve in a wide variety of stellar environments and are accordingly exposed to a wide range of ambient far-ultraviolet (FUV) field strengths. Strong FUV fields are known to drive vigorous gaseous flows from the outer disc. In this paper we conduct the first systematic exploration of the evolution of the solid component of discs subject to external photoevaporation. We find that the main effect of photoevaporation is to reduce the reservoir of dust at large radii and this leads to more efficient subsequent depletion of the disc dust due to radial drift. Efficient radial drift means that photoevaporation causes no significant increase of the dust-to-gas ratio in the disc. We show that the disc lifetime in both dust and gas is strongly dependent on the level of the FUV background and that the relationship between these two lifetimes just depends on the Shakura–Sunyaev α parameter, with the similar lifetimes observed for gas and dust in discs pointing to higher α values (∼10−2). On the other hand, the distribution of observed discs in the plane of disc size versus flux at 850 μm is better reproduced by lower α (∼10−3). We find that photoevaporation does not assist rocky planet formation but need not inhibit mechanisms (such as pebble accretion at the water snow line) which can be effective sufficiently early in the disc’s lifetime (i.e. well within a Myr).
Type II migration strikes back – an old paradigm for planet migration in discs
Authors: Scardoni Chiara E , Rosotti Giovanni P , Lodato Giuseppe , Clarke Cathie J
Published: December 2019

In this paper, we analyse giant gap-opening planet migration in proto-planetary discs, focusing on the type II migration regime. According to standard type II theory, planets migrate at the same rate as the gas in the disc, as they are coupled to the disc viscous evolution; however, recent studies questioned this paradigm, suggesting that planets migrate faster than the disc material. We study the problem through 2D long-time simulations of systems consistent with type II regime, using the hydrodynamical grid code fargo3d. Even though our simulations confirm the presence of an initial phase characterized by fast migration, they also reveal that the migration velocity slows down and eventually reaches the theoretical prediction if we allow the system to evolve for enough time. We find the same tendency to evolve towards the theoretical predictions at later times when we analyse the mass flow through the gap and the torques acting on the planet. This transient is related to the initial conditions of our (and previous) simulations, and is due to the fact that the shape of the gap has to adjust to a new profile, once the planet is set into motion. Secondly, we test whether the type II theory expectation that giant planet migration is driven by viscosity is consistent with our simulation by comparing simulations with the same viscosity and different disc masses (or vice versa). We find a good agreement with the theory, since when the discs are characterized by the same viscosity, the migration properties are the same.
SL1 GENETICS OF PEDIATRIC BRAIN TUMORS: RECENT ADVANCES AND FUTURE PERSPECTIVES
Authors: Jones David T W
Published: December 2019

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

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

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

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

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

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

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

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

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 < 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

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

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

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.
TB-08 PATIENT DERIVED XENOGRAFT’S BIOBANK FROM KANSAI MOLECULAR DIAGNOSIS NETWORK FOR CENTRAL NERVOUS SYSTEM TUMORS
Authors: Kijima Noriyuki , Kanematsu Daisuke , Shofuda Tomoko , Nonaka Masahiro , Iwata Ryoichi , Fukai Junya , Inoue Akihiro , Sasayama Takashi , Tsuyuguchi Naohiro , Kawashima Toshiyuki , Higuchi Yuichiro , Suemizu Hiroshi , Mori Kanji , Kishima Haruhiko , Kanemura Yonehiro
Published: December 2019

Patient-derived xenografts (PDXs) are essential tools for translational research for brain tumors. However, it is sometimes difficult for each institution to establish PDXs because it needs experiences and techniques and it also takes a lot of works to establish them. Thus we aim to establish patient derived xenograft’s biobank among institutions of Kansai Molecular Diagnosis Network for Central Nervous System (CNS) Tumors, Osaka, Japan. We have already began sharing two anaplastic astrocytoma PDXs, twelve glioblastoma IDH wild type PDXs, two medulloblastoma Shh subgroup PDXs, one atypical teratoid/rhabdoid tumor (AT/RT) PDX, and three metastatic brain tumor PDXs. Furthermore these PDXs can also be cultured in vitro, except 2 medulloblastoma SHH subgroup PDXs, 1 AT/RT PDX. However, we have not yet established any PDXs from low grade glioma, ependymoma, primary central nervous system lymphoma (PCNSL), diffuse intrinsic pontine glioma (DIPG).

We began sharing these PDXs among the institutions of Kansai Molecular Diagnosis Network for CNS Tumors, Osaka, Japan. However, further improvement is necessary to succeed in establishing PDX from low grade glioma, PCSNL, DIPG, etc. and get enough number of PDXs so we can share PDXs from almost all of the brain tumors.
BOT-03 INVESTIGATION OF NOVEL SPRAY TYPE FLUORESCENT PROBE FOR GLIOBLASTOMA DETECTION
Authors: Kitagawa Yosuke , Tanaka Shota , Kuriki Yugo , Yamamoto Kyoko , Hana Taijun , Koike Tsukasa , Kushihara Yoshinori , Yamazawa Erika , Takayanagi Shunsaku , Kamiya Mako , Urano Yasuteru , Saito Nobuhito
Published: December 2019

PURPOSE

5-ALA is commonly used as an intraoperative tool in malignant glioma surgery, which has been proven effective for radical tumor resection and extended progression-free survival. However, there are some limitations in its use, such as false positivity, false negativity, and inability of re-administration. We aim to develop a novel fluorescent labeling system which can be repeatedly administered by spray during surgery, using hydroxymethyl rhodamine green (HMRG) as fluorescent scaffold originally designed at our university for cancer detection.

METHODS

Primary probe screening was performed using the homogenized glioblastoma (GBM) samples with the fluorescent probe library comprised of more than 320 kinds of HMRG fluorescent scaffold combined with various types of dipeptides. Second probe screening was performed using fresh GBM specimens and the selected probes in primary screening. To identify the responsible enzymes, diced electrophoresis gel (DEG) assay was performed. This method utilizes the combination of two dimensional electrophoresis (isoelectric point and molecular weight) and a multiwell-plate-based fluorometric assay to find protein spots with the specified activities.

RESULTS

The prominent probes were selected based upon the above two-step screenings. We identified two enzymes by proteome analysis and experiments using inhibitors, which was further confirmed with real-time PCR and western blotting.

DISCUSSION

This screening methodology is innovative in that it is based on selecting probes from the probe library that respond to clinical samples rather than creating probes from the responsible enzymes. Practical fluorescent probes can be established even for low-grade gliomas, which would be a breakthrough for rapid intraoperative diagnosis in glioma surgery.

CONCLUSION

HMRG-based aminopeptidase fluorescent probes may be effective for GBM detection.
ACT-02 BORON NEUTRONS CAPTURE THERAPY FOR RECURRENT HIGH-GRADE MENINGIOMAS, FROM REACTOR TO ACCELERATOR
Authors: Miyatake Shin-Ichi , Kawabata Shinji , Wanibuchi Masahiko , Suzuki Minoru , Sakurai Yoshinori , Tanaka Hiroki , Aihara Teruhito , Akita Kazuhiko , Ko Naonori , Ono Koji
Published: December 2019

INTRODUCTION

Recurrent high-grade meningiomas (rHGM) are difficult to control. We have applied tumor-selective particle radiation, reactor-based boron neutron capture therapy (BNCT) with excellent tumor control.

METHODS

Forty-six recurrent and treatment-refractory high grade meningiomas were treated with reactor-based BNCT by Osaka Medical College (OMC) and Kyoto University Research Reactor team collaboratively until February 2019. Tumor shrinkage, overall survival (OS), progression free survival (PFS), Lesion/Normal (L/N) ratio in boronophenylalanine positron emission tomography (BPA-PET) and causes of treatment failures are analyzed.

RESULTS

Subjects had been almost always treated heavily, high-risk patients for prognosis. They were received surgery 3 times and some radiotherapy 2 times averagely, prior to BNCT. All cases responded well and markedly shrunk by BNCT. The mean L/N ratio in BPA-PET was 4.0 which is higher than glioblastomas. Two-year PFS was 49.0% (95% CI: 28.84–66.49). Unfortunately follow-up was insufficient and 2 year OS was very similar to 2 year PFS. Treatment failures were observed as recurrence out of fields of neutron irradiation, systemic metastasis and in field local recurrence almost equally.

SUMMARY AND PROSPECTS

Median PFS and OS of rHGM are 5 months and 2 years respectively in literatures. We achieved relatively favorable results by reactor-based BNCT. On the other hand, we performed accelerator-based BNCT clinical trial for recurrent glioblastomas steadily first in the world. Based on these backgrounds, we applied investigator-lead, clinical trial of accelerator-based BNCT for rHGM as RCT design. Government (PMDA and AMED) has approved our proposal. We start this trial with the primary endpoint as PFS, from August 2019. Treatment arm is BNCT and control one is best-supportive care. If the subjects in control arm show progress disease in follow-up, they can be treated by BNCT as rescue treatments. We will introduce details of this trial in our presentation.
ACT-05 PREDICTIVE FACTORS RELATING TO OUTCOME AFTER RESECTION OF LOW-GRADE GLIOMAS WITHOUT CHEMOTHERAPY OR RADIOTHERAPY
Authors: Ikuta Soko , Maruyama Takashi , Saito Taiichi , Nitta Masayuki , Tsuzuki Syunsuke , Fukui Atsushi , Kawamata Takakazu , Muragaki Yoshihiro
Published: December 2019

BACKGROUND

There are several treatment options, including observation, after surgical removal of low-grade gliomas (LGG). If postoperative chemotherapy and/or radiotherapy are not provided, resection-alone approach will probably be alternative to a natural course of LGG under observation. The objective of this study was evaluation of prognostic factors associated with overall survival (OS) of patients with LGG treated with surgery alone.

METHODS

A consecutive series of 236 adult patients who underwent surgery for LGG without adjuvant therapy was analyzed retrospectively. In 193 cases (82%) histopathology of the tumor was re-classified based on evaluation of IDH1 mutational status and 1p/19q co-deletion according to criteria of WHO classification 2016. Cox proportional hazards model was used for statistical analysis.

RESULTS

Median extent of resection (EOR) was 95% (range, 1–100%) and in 210 cases (89%) EOR was >=90%. During postoperative follow-up tumor progression was noted in 106 patients, and 30 patients died of disease. Overall, 10-year OS rate was 82.0%. There was statistically significant difference (P <0.001) in OS among molecularly re-classified tumors, with 10-year OS rates of 90%, 79%, and 75% in cases of OD, DA IDH1-mutant, and DA IDH1-wild, respectively. In patients with EOR >=90% 10-year OS rate was 75%. Multivariate analysis revealed that only EOR >=90% (RR, 0.23; 95% CI, 0.09–0.66; P<0.007) and presence of 1p/19q co-deletion (RR, 0.41; 95% CI, 0.16–0.97; P = 0.042) are independently associated with OS. In patients with EOR >=90% such factors as type of disease manifestation, time interval between onset of symptoms and surgery, and molecular subtype of the tumor did not show significant associations with OS.

CONCLUSION

Survival outcome in patients with LGG who underwent surgical resection alone may be predicted by EOR and presence of 1p/19q co-deletion. In cases with EOR >=90% molecular subtype of the neoplasm does not impact OS.
ACT-14 A FIRST-IN-HUMAN STUDY OF MUTANT IDH1 INHIBITOR DS-1001B IN PATIENTS WITH RECURRENT GLIOMAS
Authors: Arakawa Yoshiki , Mineharu Yohei , Wakabayashi Toshihiko , Natsume Atsushi , Miyakita Yasuji , Narita Yoshitaka , Yamasaki Fumiyuki , Sugiyama Kazuhiko , Hata Nobuhiro , Muragaki Yoshihiro , Nishikawa Ryo , Shinojima Naoki , Kumabe Toshihiro , Saito Ryuta , Ito Kazumi , Tachibana Masaya , Kakurai Yasuyuki , Yamaguchi Tomoyuki , Nishijima Soichiro , Tsubouchi Hiroshi
Published: December 2019

BACKGROUND

WHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in intratumoral accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier.

METHODS

In this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and D-2-HG levels.

RESULTS

Between Jan 2017 and May 2019, DS-1001b (125–1400 mg bid) had administered for 47 pts, and 15 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1–2. Gr 3 AEs were observed in 40% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Of 35 evaluable pts with contrast enhancing gliomas, one, five and 11 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable 12 pts with contrast non-enhancing gliomas, four achieved minor response and eight achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently.

CONCLUSIONS

DS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. The latest data will be updated. Funding source: This study was funded by Daiichi Sankyo Co., Ltd.
ACT-26 ABT-414 (DEPATUX-M) IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: WHERE DO WE STAND?
Authors: Preusser Matthias
Published: December 2019

Epithelial growth factor receptor (EGFR) amplifications are found in approximately half of glioblastoma cases and targeting of the EGFR axis is an attractive treatment paradigm in this tumor type. However, several anti-EGFR drugs have failed to achieve significant and meaningful improvements in clincial trials. ABT-414 (Depatux-M) is an antibody-drug conjugate (ADC) that combines a cytotoxic agent with an antibody targeting EGFR, thus aiming at specific tummor cell killing through intracellular toxin delivery. The activity of ABT-414 has been evaluated in two large clinical trials enrolling glioblastoma patients. Intellance-2 enrolled 260 patients with first recurrence of EGFR-amplified glioblasoma into a chemotherapy control arm (temozolomide or lomustine) or one of two experimental arms (ABT-414 monotherapy or ABT-414 combined with temozolomide). Depatux-M in combination with temozolomide showed a trend towards improved survival times compared to temozolomide/lomustine alone, with patients relapsing more than 4 months after the last adjuvant temozolomide cycle deriving the greatest benefit. Intellance-1 was a randomized, placebo-controlled Phase 3 study and was designed to evaluate the efficacy and safety of Depatux-M versus placebo when administered with concurrent radiation and temozolomide and with adjuvant temozolomide in subjects with newly diagnosed EGFR-amplified glioblastoma. The primary endpoint was overall survival. Recently, it was announced that a preplaned interim analysis based on data from 639 patients showed the lack of a survival benefit for patients exposed to Depatux-M. In summary, the currently available data do not support routine use of Depatux-M in glioblastoma patients and further studies are needed to understand resistance mechanisms limiting therapeutic efficacy of EGFR-targeting in glioblastoma.
MPC-01 PROGNOSTIC ROLE OF TERT PROMOTER IMPROVES THE STRATIFICATION OF IDH-MUTATED LOWER GRADE GLIOMA
Authors: Arita Hideyuki , Ohno Makoto , Nakamura Taishi , Tanaka Shota , Miyake Yohei , Saito Kuniaki , Tamura Kaoru , Okita Yoshiko , Fukai Junya , Uda Takehiro , Hata Nobuhiro , Amura Sabit , Kurozumi Kazuhiko , Eriel Sandika , Yamaguchi Shigeru , Kanamori Masayuki
Published: December 2019

TERT promoter mutation is associated with favorable prognosis and 1p/19q codeletion in IDH-mutated gliomas. The current diagnostic system, however, did not incorporate this change as a diagnostic marker in this entity. We investigated the value of prognostication incorporating TERT using the Japanese original cohort of 560 IDH-mutated adult gliomas. We collected the information of molecular status of IDH, TERT and 1p/19q and patient clinical data including Karnofsky performance status (KPS). TERT mutation and 1p/19q codeletion were found in 303 and 285 cases, respectively. For the purpose of this study, the patient cohort was divided into four groups by a combination of 1p/19q and TERT status, and the characteristics of 1p/19q intact-TERT mutated group (Astro-TERT group) (n=24) were dissected in light of the differences comparing with 1p/19q intact-TERT wild (Astro-group, n=251) or 1p/19q codeleted-TERT mutated (Oligo-group, n=279) cases. Astro-TERT group with any grade showed intermediate overall survival between the Oligo-group and Astro-group although the survival differences were not statistically significant (median OS: not reached (NR) versus NR, and 106 months, respectively. p>0.05). In grade II-III gliomas, the survival curve of the Astro-TERT group overlapped with that of the Oligo-group while the Astro-TERT group showed short survival as well as the Astro-group. We further conducted subgroup analysis by adjusting KPS in grade II-III tumors. In the subgroup with favorable KPS (90–100) and gradeII-III (n=438), The OS of Astro-TERT group (median NR) was significantly longer survival than that of Astro-group (median NR p=0.032), and was comparable with that of the Oligo-group (median NR, p>0.05). Thus, TERT promoter status provides the additional information for prognostication at least in grade II-III gliomas in the current diagnostic system.