bluuebunny/crossref_metadata_2025_split huggingface dataset:
ET-4 BASIC RESEARCH OF BORON NEUTRON CAPTURE THERAPY USING A NOVEL BORON COMPOUND TARGETED TO INTEGRIN
Authors: Tsujino Kohei , Kawabata Shinji , Kashiwagi Hideki , Yoshimura Kohei , Kayama Ryo , Fukuo Yusuke , Kanemitsu Takuya , Hiramatsu Ryo , Hu Naonori , Miyatake Shin-Ichi , Nishimura Kai , Takata Takushi , Tanaka Hiroki , Suzuki Minoru , Nakamura Hiroyuki , Wanibuchi Masahiko 
Published: December 2022

Abstract

Background
Boron neutron capture therapy (BNCT) is a particle radiation modality capable of selectively destroying tumor cells. The most commonly used boron compound for BNCT is boronphenylalanine (BPA). BPA is taken up into the tumor cell via the L-type aminoacid transporter (LAT-1). However, there are some BPA-refractory situations. Therefore, a novel boron compound is expected to improve the therapeutic performance of BNCT. We focused on integrinαvβ3, which is overexpressed in malignant gliomas as in many cancer cells, and have developed cRGD-MID-AC, a conjugate of cyclic RGD (cRGD), which selectively inhibited integrinαvβ3, and MID-AC, which we have already reported as effective on BNCT as BPA as a boron compound in F98 rat glioma models. We evaluated the efficacy of BNCT using this novel compound.Methods: F98 glioma cells were exposed to BPA, cRGD-MID-AC, and cRGD-MID for cellular uptake and neutron irradiation experiment. Intracellular boron concentrations and compound biological effectiveness (CBE) for each boron compound was calculated. After intravenous administration (i.v.) of cRGD-MID-AC or BPA, the biodistribution of boron compounds was measured and neutron irradiation experiment were performed in F98 rat glioma models.

Results
Intracellular boron concentrations of BPA and cRGD-MID-AC were increased gradually at all exposed time, and CBE for cRGD-MID-AC was comparable to that for BPA. In cRGD-MID-AC, the boron concentration in the tumor was the highest at 8 h after i.v. and tended to be retained longer at 24h. In vivo neutron irradiation experiment, long-term survival was observed only in the group irradiated 8 h after cRGD-MID-AC i.v.. These experiments suggest that cRGD-MID-AC has sufficient cell-killing effect and may be more effective in vivo.

Conclusion
cRGD-MID-AC has a tumor accumulation mechanism different from that of BPA, and could be an effective boron carrier in BNCT for malignant gliomas.
ET-5 POTENT BYSTANDER EFFECT IN SUICIDE GENE THERAPY USING TK-EXPRESSING STEM CELLS FROM HUMAN EXFOLIATED DECIDUOUS TEETH
Authors: Koizumi Shinichiro , Horikawa Makoto , Yamamoto Taisuke , Oishi Tomoya , Yamasaki Tomohiro , Kida Satoru , Namba Hiroki , Kurozumi Kazuhiko 
Published: December 2022

Abstract

Introduction
We investigated HSVTK/GCV suicide gene therapy for malignant glioma, and demonstrated the migration ability and antitumor effect of various tissue-derived pluripotent stem cells. In recent years, stem cells from human exfoliated deciduous teeth (SHED), which have excellent ethical and self-renewal ability, have attracted attention, especially in regenerative medicine. In this study, using SHEDTK transfected with TK, we examined the migration ability and antitumor effect against malignant glioma and metastasis models.

Methods
In vitro assay: Using Matrigel chamber, the migration ability of SHEDTK to conditioned medium (CM) of glioma cells, lung carcinoma cells, and various tumor growth factors (TGF) was examined. The antitumor effect was examined for cell viability by co-culturing SHEDTK and each tumor cell under the addition of GCV. in vivo assay: Using glioma model mice, SHEDTK migrating around the tumor was confirmed in brain sections. In addition, we co-implanted SHEDTK and administered GCV to glioma and metastasis model as therapeutic models, evaluated tumor reduction effect by bioluminescence, and confirmed survival curves.

Results
In vitro assay: SHEDTK significantly migrated to CM and TGF compared to control. The antitumor effect was observed even when the ratio of each tumor cell to SHEDTK was 128-256 times. in vivo assay: In glioma model mice, SHEDTK migrated around contralateral tumor. In the treatment experiment, the control group died of tumors, whereas the tumor in the treatment group disappeared within the period of GCV administration, and they survived without neurological deficits until 100 days later, and the overall survival time was improved with a statistically significant difference.

Conclusions
We confirmed the migration ability and antitumor effect of SHEDTK on malignant glioma and metastasis models. Suicide gene therapy using SHEDTK was suggested as novel gene therapy. In the future, we plan to conduct translational research such as preclinical studies and physician -initiated clinical trials.
ET-6 EFFICACY OF NEAR-INFRARED PHOTOIMMUNOTHERAPY TARGETING PODOPLANIN IN MALIGNANT GLIOMAS
Authors: Natsumeda Manabu , On Jotaro , Watanabe Jun , Ando Kazuhiro , Tsukamoto Yoshihiro , Okada Masayasu , Ogura Ryosuke , Oishi Makoto , Fujii Yukihiko 
Published: December 2022

Abstract

Background
Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment based on a conjugate of photosensitizer IR700 and an antibody which selectively binds to the surface antigen of cancer cells. Upon exposure to near infrared light, which does not harm normal tissues, cancer cells are selectively killed. Clinical application for EGFR amplified head and neck cancer has already been realized but is still in the preclinical stages of research for brain tumors. Finding a surface antigen which is selective to cancer cells is key to the effective application of NIR-PIT. In IDH-wildtype gliomas, we found that podoplanin (PDPN) is a promising candidate. PDPN is a transmembrane sialoglycoprotein highly expressed in IDH-wildtype gliomas and other cancers.

Methods
Three PDPN-positive (NGT-11, NGT-41, LN319) and three PDPN-negative (T98G, U87MG, U251MG) glioblastoma cell lines were treated with PDPN-IR700 conjugate and exposed to near infrared light. Cytotoxicity was assessed by cell viability assays. Next, we treated subcutaneous mouse xenografts by NIR-PIT.

Results
Cytotoxicity was only observed after NIR-PIT using PDPN-conjugate in cell lines expressing PDPN. This cytotoxicity was dose-dependent to near infrared light exposure, and most pronounced in LN319 cell line, which expressed the highest levels of PDPN. Time lapse videos revealed instantaneous expanding, followed by rounding of dead cells after treatment. NIR-PIT treated subcutaneous xenografts showed significantly smaller tumor sizes compared to control, and pathological investigation revealed selective and extensive necrosis of tumor tissue.

Discussion/conclusion
PDPN is highly expressed in IDH-wildtype gliomas, and we found that NIR-PIT was highly effective in treating PDPN expressing glioblastoma cell lines. NIR-PIT is anticipated to be more selective and cytotoxic than photodynamic therapy and is a promising new treatment strategy for IDH-wildtype gliomas.
TB-1 ADDITIONAL GENETIC ALTERATIONS DIFFERENTIALLY ALTER THE TRANSCRIPTOMIC LANDSCAPE OF H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Miki Shunichiro , Koga Tomoyuki , Skinner Kasey R , Gruener Robert F , Kawauchi Daisuke , Huang R Stephanie , Miller C Ryan , Furnari Frank 
Published: December 2022

Abstract
Histone H3 K27M mutation is a hallmark mutation for H3 K27M-mutant diffuse midline glioma (DMG), but targeting this mutation has yet to achieve a significant survival benefit in clinical trials. Recent analyses revealed alterations in several genes, such as NF1 and PDGFRA, are observed in substantial subpopulations of H3 K27M-mutant DMG patients in addition to H3 mutation and recurrent TP53 mutations, indicating patient-to-patient tumor heterogeneity and the potential necessity of tailored target therapy for the treatment of this disease. Here, using our human induced pluripotent stem cells (iPSC)-derived glioma avatar platform, we designed DMG models by introducing TP53R248Q with or without heterozygous H3 K27M mutation in combination with further genetic modifications of either NF1 knockout or PDGFRAD842V overexpression to recapitulate DMG subpopulations. Mice with TP53R248Q; H3F3AK27M (QM) tumors survived significantly longer than those harboring QM;NF1-/- (QMN) tumors and QM; PDGFRAD842Voe (QMP) tumors. RNA-sequencing of those induced DMG (iDMG) neurospheres revealed altered patterns of upregulation of MAPK pathway genes both in QMN and QMP-iDMG neurospheres compared to their H3 wildtype counterparts with the same combinations of genetic alterations, suggesting that those additional mutations modifies the oncogenic signaling associated with H3 K27M mutation. Further, differential expression analysis comparing QMN and QMP-iDMG neurospheres revealed 405 differentially expressed genes. Gene set enrichment analysis showed upregulation of transcriptional programs related to mesenchymal signature in QMN-iDMG neurospheres and proneural signature in QMP-iDMG neurosphere as expected. These data show that NF1 deletion and PDGFRAD842V overexpression significantly alter gene expression in H3 K27M-mutant iDMG tumors, potentially opening up a new therapeutic avenue in these devastating tumors with patient-to-patient heterogeneity. Further work using these models will shed light on the development of tailored therapy based on detailed genetic information on each patient sample, such as combining targeted kinase inhibition with HDAC inhibitors that have shown promise in the clinic.
TB-3 A GINGER EXTRACT COMPOUND A REVEALED ANTITUMOR ACTIVITY AGAINST GLIOMA
Authors: Inai Kyoko , Ono Masaya , Iwashimizu Sonoka , Hamabe-Horiike Toshihide , Sunagawa Yoichi , Katanasaka Yasufumi , Arakawa Yoshiki , Hasegawa Koji , Morimoto Tatsuta 
Published: December 2022

Abstract

Purpose
Malignant neoplasms arising in the brain and central nervous system have a poor prognosis and present with symptoms such as headache, epileptic seizures, and paralysis of the arms and legs. Treatment of glioma, the most frequent primary brain tumor, is based on surgical removal of the tumor, radiation therapy, and chemotherapy. However, since gliomas grow invasively, surgical removal of the entire tumor is considered difficult. In addition, the standard treatment, temozolomide, possesses the problem of resistance. Therefore, the risk of recurrence is high, and the development of noble therapeutic agents for Glioma is required. We have screened for compounds with anti-tumor activity against Glioma from our natural compound library and focused on ginger extract, Compound A. In this study, we investigated the effect of Compound A on Glioma cell lines.

Methods and Results
To evaluate the antitumor activity of Compound A on Glioma in vitro , MTT assay was performed. Human glioma cell lines U87-MG and U251 cells were treated with Compound A. After 96 hours, cell viability was evaluated using CCK-8. The IC50 value of Compound A in U87-MG cells was calculated to be 16.3 μM. The IC50 of Compound A in U251 cells was 10.8 μM. Next, to examine the effect of Compound A on normal cells, we performed the same MTT assay using primary cultured rat astrocytes. The MTT assay showed no decrease in cell viability in primary cultured rat astrocytes at 15 μM, whereas an antitumor effect was observed in a human glioma cell line.

Discussion
In this study, Compound A showed antitumor activity against Glioma without affecting normal cells. In the future, we will examine the effects of Compound A in an immunocompromised mouse brain in which U87-MG-RFP cells are implanted, which may lead to the development of therapeutic agents against Glioma.
IM-1 THE IMMUNOSUPPRESSIVE ROLE OF MAIT CELLS AND MR1 IN GBM THROUGH THE INDUCTION OF NEUTROPHILS AND MDSCS
Authors: Hana Taijun , Terabe Masaki 
Published: December 2022

Abstract

Background
Glioblastoma (GBM) is a devastating brain tumor, and its immunosuppressive microenvironment has been implicated in the poor prognosis. However, the mechanism of the induction of the microenvironment is not well understood. MHC class I-related protein (MR1) is an antigen-presenting molecule for Mucosal-Associated Invariant T (MAIT) cells. Recently, MR1 transcriptomic level was reported to correlate with glioma’s poor survival, and the infiltration of MAIT cells in GBM was reported previously. However, the role of MAIT cells and MR1 in GBM is poorly understood. We aimed to understand the mechanism by which MR1 levels affect GBM patient survival and any potential involvement of MAIT cells.

Method
RNA-sequencing data from TCGA-GBM was subjected to multi-layered analysis. Multiple methods, including comprehensive gene expression analysis and direct alignment-search using FASTQ data, were used to assess the immunological impact of MAIT cells in GBM. Using data from Pan-cancer TCGA, the role of MAIT cells in other cancer types was assessed.

Result
The survival of GBM patients was negatively correlated with the level of MR1 expression. 8.3% of TCGA-GBM samples were identified to have MAIT cell infiltration, and the expression of MR1, the amount of MAIT cell infiltration, and the activity of tumor-associated neutrophils (TANs)/myeloid-derived suppressor cells (MDSCs) were significantly correlated. Simultaneously, the TAN/MDSC activity was significantly correlated with the poor survival of GBM patients. In four more cancer types, similar relationships between MAIT/MR1 and TANs/MDSCs were observed.

Conclusions
Our observations shed light on the possible immunosuppressive role of MAIT cells and MR1. It was shown that MR1 up-regulation causes MAIT cell activation, which in turn causes TAN/MDSC induction. The current study implied the existence of a novel MAIT/MR1-TAN/MDSC immunosuppressive pathway, whose activation is associated with a worse prognosis for GBM. It was also suggested that a similar pathway might exist in other cancer types.
IM-3 IDENTIFICATION OF THERAPEUTIC TARGET ANTIGENS USING PATIENT DERIVED GLIOBLASTOMA AND THEIR APPLICATION TO CAR-T THERAPY
Authors: Kuroda Hideki , Kijima Noriyuki , Tachi Tetsuro , Utsugi Rena , HIrayama Ryuichi , Okita Yoshiko , Kagawa Maoki , Hosen Naoki , Kishima Haruhiko 
Published: December 2022

Abstract

Introduction
Recently, CAR-T cell (chimertic antigen receptor T-cell) therapy has been attracting and has shown high therapeutic efficacy, especially in the hematological tumors. The T cells from patient are then genetically engineered to specifically bind to and attack the target tumor cell antigen. In the brain, EGFRvIII or HER2 have been used as antigens, but have yet to show positive results. It is necessary to find antibodies that are more specific and have a therapeutic effect.

Methods
A primary culture line was prepared from glioblastoma surgical specimens, and immunized to Balb/c mice with it.The B cells from the mice were fused with myeloma cells, immortalized, and cultured monoclonally to obtain a number of monoclonal antibodies reacted glioblastoma cells. The obtained antibodies were reacted with glioblastoma cells and normal brain cells, and those that specifically react to glioblastoma were selected by flowcytometry to obtain antibody candidates that could be specifically expressed on the surface of glioblastoma cells.

Results
Approximately 20,000 antibody-producing strains were generated. From these, about 3,200 strains were selected as the reacted with immunized glioblastoma. About 560 strains was selected that reacted with at least one other glioblastoma, and from these, we selected 30 strains that did not react with normal brain cells. Finally, the cells were frozen and thawed at least once, and 13 stably growing strains selected.

Discussion
We have been identified one antibody among approximately 500 strains in past our study, and have confirmed that it is B7H3, a pan-tumor antibody. We will generate more antibody candidates in the future, as well as identify antibodies in 13 strains that have already been selected and confirmed to be glioblastoma-specific antibodies. We will also create CAR-T cells targeting these antibodies and confirm their anti-tumor effects.
ACT-1 A PROSPECTIVE MULTICENTER PHASE I/IIA STUDY OF PREOPERATIVE NEOADJUVANT BEVACIZUMAB FOR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Tanaka Toshihide , Tamura Ryota , Takei Jun , Morimoto Yukina , Teshigawara Akihiko , Tohmoto Kyoichi , Kuranari Yuki , Imai Ryotarou , Yamamoto Yohei , Hasegawa Yuzuru , Akasaki Yasuharu , Murayama Yuichi , Miyake Keisuke , Sasaki Hikaru 
Published: December 2022

Abstract

Background
Preoperative neoadjuvant bevacizumab (neoBev) reduces enhancement and perifocal edema by inhibition of angiogenesis and vascular permeability for glioblastoma (GBM). The aim of this study was to investigate safety and efficacy of neoBev for newly diagnosed GBM through an exploratory prospective multi-center study.

METHODS & PATIENTS
15 patients with newly diagnosed GBM were enrolled in the present study. Eligibility was a patient with a brain tumor representing with ring-shaped enhancement and perifocal edema on magnetic resonance imaging (MRI). Based on neuroimage of typical GBM, neoBev and temozolomide (TMZ) were administered prior to craniotomy. Two weeks after neoBev, the tumor volume on T1-weighted gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev and TMZ administration, patients underwent surgical resection. The primary endpoint was feasibility and safety, and the secondary endpoint was efficacy. Adverse events including systemic toxicity and wound healing delay during radiation (RT), TMZ, and Bev combined therapy were carefully monitored throughout clinical course including extent of resection.

RESULTS
Average of tumor regression rate two weeks after neoBev on T1Gd and FLAIR were 37.0% and 54.0%, respectively. Cerebral blood flow and cerebral blood volume were reduced after neoBev. Patients underwent surgical resection safely without excess blood loss due to less vascular and less degree of brain swelling. Two patients underwent awake surgery without any complications. Postoperative MRI showed that the all tumors were totally removed except one with multiple invasive tumors. Histological diagnosis of all patients was GBM, IDH-1 wild-type. Postoperative course was uneventful without neurological deficit and adverse effects except one postoperative hematoma in the resection cavity and one wound infection due to wound dehiscence.

CONCLUSION
Preoperative neoBev for newly diagnosed GBM might contribute to safe surgery. Clinical outcome of this therapeutics is now currently under investigation.
ACT-2 JCOG0911A2 AND ESTABLISHING AN INFRASTRUCTURE FOR RADIOLOGICAL STUDIES FOR JCOG BRAIN TUMOR STUDY GROUP CLINICAL TRIALS
Authors: Kinoshita Manabu , Sasaki Keita , Natsume Atsushi , Wakabayashi Toshihiko , Arakawa Yoshiki , Narita Yoshitaka 
Published: December 2022

Abstract

Background
Radiological information is indispensable to understanding the pathology and correctly assessing the treatment response of malignant brain tumors. Clinical trials conducted outside of Japan have vigorously collected and investigated radiological images of the enrolled patients and published many significant findings, such as the RANO criteria. The authors initiated the JCOG0911A2 study, which is an ancillary analysis of JCOG0911, and established an infrastructure for collecting and analyzing raw radiological images of patients enrolled in clinical trials conducted by the JCOG brain tumor study group. JCOG0911A2 study design and infrastructure for radiological image storage: JCOG0911A2 aims to collect all radiological images related to the JCOG0911 study, conduct radiomics analysis, and complete general radiological research. Among 122 registered patients, 2532 series from 118 cases accounting for 237 GB of data were collected as of June 28, 2022. All collected data were anonymized and stored in Osirix MD with triple data backup. JCOG0911A2's treatment response assessment will be performed according to the RANO criteria. Thus, the authors developed a script in MATLAB that enables semi-automatic treatment response assessment according to the investigators' annotations on Osirix MD.

Data Management
The abovementioned “semi-automatic treatment response assessment script” was not necessary until up to a collection of 30 cases. However, manual management became impossible as more case data arrived, and establishing a sophisticated and systematic data management system was inevitable. The data management system developed for JCOG0911A2 is also used with minor modifications for the ongoing JCOG study.

Conclusion
JCOG0911A2 study established a reliable infrastructure capable of handling radiological images from patients enrolled in JCOG brain tumor study group clinical trials.
ACT-8 A RANDOMIZED PHASE III STUDY OF HYPOFRACTIONATED RADIOTHERAPY COMBINED WITH TEMOZOLOMIDE IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: JCOG1910 (AGEDGLIO-PIII)
Authors: Mineharu Yohei , Uto Megumi , Ichimura Koichi , Matsushita Yuko , Ono Tomohiro , Ito Yoshinori , Nishikawa Ryo , Nishimura Yasumasa , Narita Yoshitaka , Mizowaki Takashi , Arakawa Yoshiki 
Published: December 2022

Abstract

Background
The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy (40 Gy in 15 fractions) with temozolomide. Further reduction of fractionation is expected to reduce the burden for elderly patients without decreasing therapeutic efficacy.

Methods
This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant and adjuvant temozolomide in terms of overall survival (OS) in elderly patients aged 71 or older with newly diagnosed glioblastoma. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. MGMT promoter methylation was included as an adjustment factor, and tumor specimen have been collected soon after the tumor resection and molecular diagnosis has been made centrally before randomization. A total of 270 patients will be accrued from 55 Japanese institutions in 4 years and follow-up will last 2 years.

Results
More than a half of patients (160 /270 cases) have been recruited between August 2020 and July 2022. Molecular diagnosis was made all but one cases, and diagnosis was made centrally within around 7 days after receiving the tumor specimen. There were one grade 4 severe adverse event and one treatment related death.

Discussion
Registration has been made smoothly without substantial delay due to central molecular diagnosis. The study has been safely performed for elderly patients. If the primary endpoint is met, hypofractionated radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma.