bluuebunny/crossref_metadata_2025_split huggingface dataset:
SL-1 Activity on Nationwide Cancer Genome Screening Project for Advanced Solid Tumors; SCRUM-Japan GI-/MONSTAR-SCREEN
Authors: Yoshino Takayuki 
Published: November 2020

Abstract
Advances in precision oncology have made genotyping mandatory for most advanced solid tumors to ensure proper therapy selection. However, the innovations remains limited by the realities of patient identification-actionable targets are present in only a small fraction of patients. We initiated a nationwide cancer genome screening project, SCRUM-Japan GI- (from 2015 to 19)/MONSTAR-SCREEN (since 2019) with the purpose of matching patients with interventional IND trials. We revealed requirement for tissue samples hampers recruitment, and genotyping using archival tumor samples provides information only at a single spatial and temporal point and fail to detect chronological tumor evolution and intratumoral heterogeneity, both of which are obstacles for proper therapy selection. We also demonstrated circulating tumor DNA (ctDNA) analysis using next-generation sequencing (NGS)-based methods have the potential of ctDNA analysis for genomic profiling as an alternative for tissue genotyping. Recently, gut microbiome has the promise in predictive value of therapy. Serial analyses with ctDNA and microbiome at pre- and post- cancer therapies are ongoing. Updated results will be presented.
SS-1 Therapeutic challenges for glioblastoma: Temozolomide and its issues?
Authors: Nagane Motoo 
Published: November 2020

Abstract
Glioblastoma (GBM), the most malignant form (WHO grade IV) of gliomas, remains incurable despite recent advances in medical technologies and molecular knowledge, with 5-year survival rate being just beyond 10%, thus undoubtedly leaving unmet needs to develop effective therapeutics to improve outcome. Current standard of care for patients with newly diagnosed GBM is maximum safe resection of the enhancing tumor bulk, followed by involved-field radiotherapy with temozolomide (TMZ) given concomitantly and as an adjuvant therapy thereof with or without Tumor-Treating Fields (TTF). The efficacy of TMZ for GBM was proved in 2005 by a randomized phase III trial (EORTC25981) for the first time ever in history, since then, however, any other agents have failed to show benefit to improve survival until now. O6-methylguanine-DNA methyltransferase (MGMT), a specific DNA repair enzyme, has been shown to restore the cytotoxic O6-methylguanine lesion induced by TMZ to normal, responsible for a major reason of TMZ resistance. Expression of MGMT is tightly regulated by methylation of the promoter region of the MGMT gene, where promoter methylation results in suppression of its expression. Accordingly, the promoter methylation of the MGMT gene (meth-MGMT) has been consistently associated with a better response to and outcome by TMZ treatment, and furthermore a favorable prognostic factor for patients with newly diagnosed GBM in a number of prospective clinical trials. In this line, efforts have been made to overcome TMZ resistance including intensifying dose schedulings of TMZ, one of which has been currently tested in a multi-institutional prospective phase III trial in Japan (JCOG1308C). TMZ has also been investigated in lower grade gliomas. A major issue in treating lower grade glioma with TMZ is potential development of the hypermutated tumors by virtue of O6-methylguanine-induced mutagenesis. The clinical and molecular consideration related to TMZ in glioma treatment will be presented.
SS-3 Tumor Treating Fields: from the Petri dish to the patient
Authors: Giladi Moshe 
Published: November 2020

Abstract
Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, antineoplastic treatment modality targeting rapidly dividing cancer cells using low intensity, alternating electric fields at cell-type-specific intermediate frequencies (100–500 kHz). TTFields therapy is approved for the treatment of newly-diagnosed and recurrent glioblastoma as well as malignant pleural mesothelioma, following clinical trials demonstrating efficacy and a favorable safety profile. Using novel in vitro and in vivo systems for TTFields application, research activities are being conducted to extend the understanding of the underlying mechanisms of action (MoA) and to assess additional means to improve treatment outcomes. The demonstrated antimitotic effects of TTFields discerned the positive combinatorial potential of TTFields with other agents targeting the division process. Subsequent to elucidation of anti-mitotic effects, other downstream effects of TTFields include induction of endoplasmic reticulum stress, up-regulation of autophagy and cell death, thus driving immunogenic cell death. Indeed, in several preclinical models, combining TTFields with immunotherapeutics demonstrated enhanced efficacy. Recently, additional novel effects of TTFields were characterized, including inhibition of DNA damage repair responses and induction of transient and reversible permeabilization of the blood brain barrier (BBB). These new findings offer potentially innovative means to optimize treatment outcomes by combining TTFields with radiation therapy and DNA damaging agents, as well as improved delivery of impermeant agents across the BBB. These scientific findings were instrumental in advancing the clinical pipeline of TTFields, which includes conduct of ongoing trials combining TTFields with a variety of modalities, in approved indications and in other solid malignant tumor types. The aim of this talk is to describe TTFields’ preclinical research activities and tools, and to specify how these study outcomes have defined and advanced the clinical pipeline.
SS-4 High dose chemotherapy with autologous hematopoietic stem cell transplantation for CNS lymphoma
Authors: Kondo Eisei 
Published: November 2020

Abstract
High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT-ASCT) is listed as a consolidation therapy option for primary central nervous system (CNS) lymphoma in the guidelines of western countries. The advantages of HDT-ASCT for primary CNS lymphoma as consolidation are believed to be high rates of long-term remission and lower neurotoxicity, even though its eligibility is limited to younger fit patients. In the Japanese guideline, HDT-ASCT for primary CNS lymphoma is however not recommended in daily practice, mainly because thiotepa was unavailable since 2011. The Japanese registry data for hematopoietic transplantation have shown that primary CNS lymphoma patients were treated with various HDT regimens and thiotepa-containing HDT was associated with better progression free survival (P=.019), lower relapse (P=.042) and a trend toward a survival benefit (Kondo E et al, Biol Blood Marrow Transplant 2019). A pharmacokinetic study of thiotepa(DSP-1958) in HDT-ASCT for lymphoma was conducted in 2017, and thiotepa was approved for HDT-ASCT in lymphoma this March, meaning that optimal HDT regimen for CNS lymphoma is now available in Japan. The treatment strategy of CNS lymphoma needs further development to improve survival and reduce toxicity.
KNL-1 Pathologic diagnosis of brain tumors in the molecular era
Authors: Hirose Takanori 
Published: November 2020

Abstract
The WHO Classification of CNS Tumors, first published in 1979, was revised four times during the recent four decades. The revision was based on the refinement of tumor entities and introduction of new entities, which were facilitated by the development of new investigative techniques, such as immunohistochemistry and molecular cytogenetics. More sophisticated approaches including NGS and methylation analysis will introduce more molecularly defined entities in the next WHO Classification. The molecular analyses are a very powerful tool for brain tumor research. They have disclosed molecular mechanisms of several tumors and discovered unrecognized tumor entities till then. More precise biologic behavior could be estimated by molecular profiles. Furthermore, the development of novel molecular-targeted therapies will be expected. In the clinical practice, brain tumors should be diagnosed stepwise. First, clinical and image information is mandatory. Histopathologic and immunohistochemical findings should be evaluated within the clinical context. For molecularly defined tumors, genetic analyses are necessary. Following the stepwise procedures, the risk of falling in pit-falls may be decreased. In the molecular era, the integrated diagnosis, combined histopathologic and molecular information, of brain tumors is necessary. Recently, the Japanese Society of Pathology (JSP) has started the project which foster next-generation pathologists interested in rare cancers including brain tumors. In addition, some molecular information could be gained through the consultation system run by JSP and the National Cancer Center Japan. To adapt the next, more detailed molecular classification, it may be necessary that the cancer genome panel test become available within the national health insurance system.
ES-1 Clinical results of tumor treating fields in patients with glioblastoma in Japan, compared with global surveillance
Authors: Muragaki Yoshihiro , Nitta Masayuki , Saito Taiichi , Tutsuki Shunichi , Fukui Atsushi , Kawamata Takakazu 
Published: November 2020

Abstract
INTRODUCTION: The tumor treatment field induces apoptosis of tumor cells by providing a low intensity, intermediate frequency, alternating current electric field via a transducer array. TTFields is based on Phase 3 EF-11 and EF-14 trials for glioblastoma in the US FDA and Japan PMDA. Therefore, I will report the statistics of TTFields use in Japan along with recent papers. METHODS: 410 patients were treated with TTFields in Japan (December 2017-), of which 17 were at Tokyo Women’s Medical University. We also referred to papers about global post-marketing surveillance and recent studies. RESULTS: Of the 410 patients, 409 (99.8%) were diagnosed with ndGBM(male: female, 66.8%: 33.2%). As of June 2020, 222 patients (54.1%) were on treatment and 188 (45.9%) were discontinued. In 17 cases at TWMU, the average age was 46.3 years. The average treatment period was 218 days, with 6 patients (35%) continuing treatment, 6 patients (35%) discontinuing due to patient wishes, and 5 patients (30%) discontinuing treatment due to recurrence. Side effects were contact dermatitis under the array in 9 patients (57%) and mild malaise in 7 patients (43%). We experienced long-term progression-free cases with TTF use of 25 months (survival 30 months after surgery) with a glioma partially resected and 21 months (survival 27 months after surgery) with a biopsied glioma. In the biopsy case, bevacizumab was used in combination during the treatment. Conclusion: In global surveillance, use for rGBM accounts for 39%, but Japan is limited to use for ndGBM due to insurance coverage. In terms of side effects, it showed a good safety profile comparable to previous trials. Long-term progression-free cases have been observed, and it is necessary to examine the characteristics of patients who respond to treatment and the effect of concomitant use with bevacizumab by prospective studies
SPDR-01 Paired epithelioid glioblastoma patient-derived xenograft models to evaluate resistant mechanism for molecular target therapy
Authors: Sasame Jo , Tateishi Kensuke , Ikegaya Naoki , Miyake Yohei , Nakamura Taishi , Udaka Naoko , Yamanaka Shoji , Yamamoto Tetsuya 
Published: November 2020

Abstract
Epithelioid glioblastoma (E-GBM) arises at younger age, commonly disseminates to cerebrospinal fluid, and results in dismal prognosis. About half of E-GBM harbors BRAF V600E mutation, thus BRAF/MEK inhibitors are expected to be specifically sensitive to E-GBM like other BRAF V600E mutant carcinomas. However, therapeutic effect is limited by the emergence of drug resistance. To overcome this issue, it is crucial to elucidate the treatment resistance mechanisms by clinically representative models. Herein, we establish 2 paired E-GBM patient-derived xenograft (PDX) models from young adult patients (YMG62 and YMG89) with BRAF V600E, TERT promoter mutations and CDKN2A homozygous deletions. The YMG62 patient received dabrafenib with trametinib, while YMG89 patient received dabrafenib monotherapy after recurrence with standard treatment. The YMG62 patient was refractory to combination therapy. The YMG89 patient was initially responded to dabrafenib, but gradually became resistant and the 2 patients died due to CNS dissemination. Paired PDX models were established from tumors prior and after molecular target therapy. All PDXs were formed as CNS dissemination model, which were recapitulated to the patient characteristics. BRAF/MEK inhibitors strongly suppressed cell viability in primary tumor (YMG89P). However, BRAF/MEK inhibitors became resistant in recurrent tumor (YMG89R). YMG62 paired PDXs were resistant to molecular target therapy. Western blotting indicated retained MAPK signaling pathway and/or increased AKT phosphorylation after BRAF/MEK inhibitors treatment in refractory and recurrent cells, which indicates crucial role of re-activation in the MAPK signaling pathway and/or PI3 kinase pathway for tumor maintenance in BRAF V600E mutant E-GBM. We have done high throughput drug screening to identify compounds to overcome resistant to molecular target therapy. Our established E-GBM paired PDX models recapitulate patient characteristics, which may uncover treatment resistant mechanism and novel therapeutic target in E-GBM.
GEN-09 Pursuing the function of microRNA targeting (Pro)renin receptor against glioma
Authors: Ogawa Daisuke , Fujimori Takeshi , Toyota Yasunori , Hatakeyama Tetsuhiro , Okauchi Masanobu , Kawanishi Masahiko , Miyake Keisuke , Masaki Tsutomu , Nishiyama Akira , Tamiya Takashi 
Published: November 2020

Abstract
(Pro)renin receptor((P)RR) is a part of the Wnt receptor complex. Wnt/β-catenin signaling pathway (Wnt signaling) plays important role in pathogenesis and self-renewal of glioblastoma (GBM), or differentiation of glioma stem cell. We previously reported that (P)RR activated Wnt signaling, (P)RR expression correlated with malignancy of glioma, and treatment with (P)RR siRNA reduced the proliferative capacity. This time, we have searched for over 2632 microRNAs by microRNA microarray that its expression is affected by (P)RR whether overexpressed or suppressed and examined their effects in GBM cell lines or its glioma stem cells.
ET-03 Convection-enhanced delivery of EZH2 inhibitor for the treatment of diffuse midline glioma
Authors: Sasaki Takahiro , Katagi Hiroaki , Oren Becker , Stewart Goldman , Nakao Naoyuki , Hashizume Rintaro 
Published: November 2020

Abstract
Background: Diffuse midline glioma (DMG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. Objective: This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DMG xenograft models. Methods: The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography mass spectrometry (LC/MS). We treated mice bearing human DMG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival. Results: LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = 0.0475). Conclusion: Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DMG.
ET-05 Alectinib and ceritinib, the second-generation ALK inhibitors, effectively induce glioblastoma cell death
Authors: Kawauchi Daisuke , Takahashi Masamichi , Yamamuro Shun , Kobayashi Tatsuya , Uchida Eita , Iwadate Yasuo , Ichimura Koichi , Tomiyama Arata 
Published: November 2020

Abstract
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that only expresses in the developmental stage of the central and peripheral nervous system. A variety of ALK gene alterations, such as oncogenic fusion, activating point mutation, or wild type gene amplification, have been recently discovered as the powerful oncogene in various tumors. These ALK mutations are expected as potential therapeutic targets. Some ALK inhibitors have already been approved and used for the clinical treatment of non-small cell lung cancers harboring oncogenic ALK fusion.
Previously, we reported classical ALK inhibitors triggered cell death in human glioblastoma (GBM) cells, which did not express ALK, via suppression of transcription factor STAT3 activation but not in normal tissue-derived cells.
In this study, we investigated the anti-tumor effect of newly-developed ALK inhibitors in GBM cells. As a result, second-generation ALK inhibitors, alectinib and ceritinib, induced cell death in various human GBM cell lines with lower concentrations than other ALK inhibitors. Also, alectinib and ceritinib suppressed STAT family activity in these GBM cell lines. We consider alectinib and ceritinib might be a novel therapeutic agent against GBMs. Further investigation about the specific anti-tumor mechanism of these second-generation ALK inhibitors in GBM cells is currently on-going.
ET-06 Suppression of glioblastoma through novel drug based on “Gene Switch Technology”
Authors: Yamamoto Etsuko , Arakawa Yoshiki , Mineharu Youhei , Mikami Masamitsu , Matsui Yasuzumi , Sugiyama Hiroshi , Miyamoto Susumu , Adachi Souichi , Kamikubo Yasuhiko 
Published: November 2020

Abstract
Glioblastoma (GBM) is the most common and aggressive malignancy primarily affecting adults. Despite intensive multimodal therapies, the prognosis of GBM is dismal and a novel therapy is needed. Here, we focused on RUNX, a transcription factor involved in the malignant transformation of GBM, and developed a novel Chlorambucil-conjugated PI-polyamides (Chb-M’), which “switches off” RUNX family. Chb-M’ specifically recognizes the consensus RUNX-binding sequences (TGTGGT) and alkylates it to inhibit transcription of the downstream gene of RUNX family. Chb-M’ has been shown to induce apoptosis and suppress proliferation in a variety of cancers including leukemia, and in this study, similar results were found for glioblastoma cells in vitro. Specific inhibition of RUNX1 led to a marked inhibition of tumor growth through cell cycle arrest and apoptosis. By using apoptosis array, we isolated several candidate genes which regulated by RUNX1. And some types of glioblastoma cell lines treated with Chb-M’ showed elevated expression of p21 and decreased survivin. From in silico analysis using glioma patient cohorts, survivin expression was significantly higher in GBM and it was possibly involved in maintaining the malignancy of GBM. Mechanistically survivin was found to be directly transcriptionally regulated by RUNX1 through ChIP assay and reporter assay. In addition, survivin K/D cells upregulated p21 expression and accelerated apoptosis. Taken together, we hypothesized that the RUNX1-survivin-p21 pathway can potentially be exploited in the management of this malignancy. Chb-M’ mediated regulation of RUNX1 can be a novel therapeutic strategy against GBM.
ACT-02 Changes in Recurrence Pattern and Prognosis of Glioblastoma after Approval of Bevacizumab as First-line Application
Authors: Funakoshi Yusuke , Hata Nobuhiro , Kuga Daisuke , Hatae Ryusuke , Sangatsuda Yuhei , Fujioka Yutaka , Takigawa Kosuke , Mizoguchi Masahiro 
Published: November 2020

Abstract
Introduction: There exist controversies on recurrence and aggressiveness after use of first-line bevacizumab (BEV) which has been approved in Japan and proven to be beneficial. Therefore, we analyzed the clinical impact of BEV approval by investigating the overall clinical course and glioblastoma (GBM) relapse pattern.
Methods: We included 100 patients with IDH-wildtype GBM between September 2006 and February 2018 from our institution. They were subdivided into pre-BEV (n=51) and post-BEV (n=49) groups. Overall, progression-free, deterioration-free, and post-progression survivals (OS, PFS, DFS, and PPS, respectively) were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were confirmed.
Results: Significant improvements in DFS (median DFS in the pre-BEV and post-BEV eras: 8.5 and 13.8 months, P=0.0046), and PFS (7.5 and 9.9 months, P=0.0153) after BEV approval were observed. These survival prolongations were strongly correlated (r: 0.91, P&lt;0.0001). Non-enhancing tumor emerged as a novel recurrence pattern in the post-BEV era (five of 33; 15.2%). Changes in relapse pattern did not significantly impact OS, PFS, and DFS. No significant difference in PPS between pre-BEV and post-BEV eras was observed (6.7 and 5.5 months, P=0.2319). The rate of early (within 6 months) focal recurrence was significantly lower (P=0.0155) in the post-BEV era (four of 33; 12.1%) than in the pre-BEV era (18 of 39; 46.2%). A significant decrease in early focal recurrence after BEV approval was observed exclusively in patients with unresectable tumors (P=0.0110). Treatment era was the only parameter significantly correlated with decreased early focal recurrence rate (P=0.0021, univariate analysis; P=0.0144, multivariate analysis).
Conclusions: We found that, first-line BEV in Japan for unresectable tumors has a positive impact on the prevention of early progression and clinical deterioration of GBM without accelerating the clinical course after recurrence.
ACT-05 Present and future of precision-based medicine using cancer genome panels
Authors: Natsumeda Manabu , Kanemaru Yu , On Jotaro , Saito Shoji , Tsukamoto Yoshihiro , Okada Masayasu , Hiraishi Tetsuya , Oishi Makoto , Fujii Yukihiko 
Published: November 2020

Abstract
Background: Two cancer genome panels were approved for use in Japan in 2019, and their application in brain tumors are awaited. We have used CANCERPLEXR and FoundationOne CDx (F1) panels for the realization of precision-based medicine in brain tumors. Patients and methods: From August 2017 to present, we have applied cancer genome panels in 11 times to tumors in 9 patients. We assessed patient data including age, sex, pathology, reason for using the panel and actionability. Results: The range of age of 4 to 69 years (mean 45.2 years), and 5 men and 4 women were studied. Pathological diagnosis was epithelioid glioblastoma (GBM), giant cell GBM, anaplastic ependymoma, anaplastic meningioma, anaplastic large cell type lymphoma, meningeal melanomatosis, enterogeneous carcinoma, choroid plexus carcinoma and pineoblastoma. CANCERPLEXR was performed 7 times and F1 panel 4 times and the reasons included confirmation specific gene mutations such as BRAF V600E and TP53, young (pediatric) age and patient request. In one patient, by analyzing primary and recurrent tissue, we were able to assess genetic hits involved in malignant transformation. Actionable targets were found in 4 (44%) of cases, and action was taken in only 1 epithelioid GBM patient with BRAF V600E mutation, albeit with dramatic response (Kanamaru et al., Acta Neuropathol Commun, 2019). All tumors were microsatellite stable. Conclusions: We were able to understand tumor biology in rare brain tumors using 2 genome panels. We need to increase the percentage of patients actually treated. I will also like to touch briefly on how use genome panels for translational research on brain tumors.