bluuebunny/crossref_metadata_2025_split huggingface dataset:
10136- GEN-7 ADDED CLINICAL VALUE OF WHOLE GENOME SEQUENCING FOR PEDIATRIC GLIOMA AND GLIONEURONAL TUMOR
Authors: Yajima Hirohisa , Takami Hirokazu , Watanabe Kentaro , Shiraishi Yuichi , Yamasaki Kai , Yoshioka Takako , Hirato Junko , Kato Shota , Takasugi Nao , Nakano Yoshiko , Okita Hajime , Katayama Kotoe , Imoto Seiya , Arakawa Yoshiki , Yoshida Kenichi , Kumabe Toshihiro , Saito Nobuhito , Kato Motohiro , Ichimura Koichi 
Published: November 2024

Abstract

BACKGROUND
The fifth edition of the WHO Classification of Tumors of the Central Nervous System incorporates numerous genetic findings in pediatric brain tumor classification, emphasizing the significance of molecular diagnostics. In Japan, Japan Children’s Cancer Group (JCCG) Brain Tumor Committee organizes a central diagnostic system for pediatric brain tumors, including histopathology review and molecular diagnostics through a limited targeted gene analysis. However, comprehensive genome-wide analysis has not been conducted.

OBJECTIVE
To evaluate the clinical utility of whole genome sequencing (WGS) in pediatric glioma/glioneuronal tumor (GNT).

METHODS
WGS (62 cases) and RNA-seq (46 cases) were performed as part of the “ Action Plan for Whole Genome Analysis” and compared with central molecular diagnosis results (62 cases).

RESULTS
Central diagnostics identified 28 low-grade gliomas (44.4%), 26 high-grade gliomas (41.3%), and 8 GNTs (14.3%), with pilocytic astrocytoma accounting for 16 cases (25.8%). Adding WGS to central molecular diagnosis identified new driver mutations in 26/62 cases (41.9%). Notably, 5 additional KIAA1549::BRAF and 2 NTRK2 fusion genes were detected. In comparison with RNA-seq analysis, several cases were found in which KIAA1549::BRAF could be detected only by WGS. Additionally, PATZ1 fusion genes and several novel RAF1 fusion genes were identified.

CONCLUSION
WGS is useful in detecting genetic alterations that may contribute to diagnostic and therapeutic decision-making for pediatric gliomas/GNT. Incorporating WGS into the current diagnostic procedure could help develop more precise treatment strategies for pediatric glioma/GNT.
10000- ET-1 STEM CELL-BASED GENE THERAPY FOR MALIGNANT GLIOMA USING GENOME-EDITED HUMAN INDUCED PLURIPOTENT STEM CELLS
Authors: Tamura Ryota , Yo Masahiro , Okano Hideyuki , Toda Masahiro 
Published: November 2024

Abstract
Malignant glioma is the most aggressive primary brain tumor with dismal prognosis, characterized by diffuse infiltration into the normal brain parenchyma. Invasive glioma stem cells (GSCs) are thought to be an underlying cause of therapeutic resistance and tumor recurrence. Therefore, development of new therapeutic modalities is urgently needed. We demonstrated that human induced pluripotent stem cells (iPSCs)-derived neural stem cells (NSCs) possess the higher tumor-tropic migratory capacity than mesenchymal stem cells. Therefore, we established the concept of suicide gene therapy using iPSCs-derived NSCs as a cellular delivery vehicle for the treatment of malignant glioma. We first used a lentiviral vector for transduction of the yeast cytosine deaminase (yCD)- uracil phosphoribosyl transferase (UPRT) suicide gene into iPSCs, because of the high efficacy and safety. However, lentiviral vectors integrated randomly into the host genome, raising concerns about insertional mutagenesis, oncogene activation, and transgene silencing. In order to improve safety and to achieve stable transgene expression, yCD-UPRT was inserted into a housekeeping gene locus (ACTB) in iPSCs using CRISPR/Cas9-mediated genome editing, resulting in a significantly better anti-tumor effect for human glioma and glioma stem xenograft mice than temozolomide (standard chemotherapy). In the near future, NSCs derived from clinical grade human iPSCs with yCD-UPRT are established. Quality, safety and efficacy is evaluated, leading to obtain preclinical proof of concept. We prepare for the investigator initiated clinical trial.
10059- IM-3 IDENTIFICATION OF THERAPEUTIC TARGET ANTIGENS USING PATIENT DERIVED GLIOBLASTOMA AND THEIR APPLICATION TO CAR-T THERAP
Authors: Kuroda Hideki , Kijima Noriyuki , Nakagawa Kanji , Murakami Koki , Tachi Teturou , Hosen Naoki , Kishima Haruhiko 
Published: November 2024

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. In the brain, EGFRv3 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 nonclonally 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. Then, we generated CAR-T cells derived from the obtained antibody and confirmed anti-tumor effect of CAR-T cells in vitro and in vivo.

RESULTS
Approximately 25,000 antibody-producing strains were generated. From these, we selected the antibody, which reacted with several glioblastomas and did not react with several normal brain cells. Finally, we identified the antibody as Prostaglandin F2 receptor negative regulator (PTGFRN) by using expression cloning. CAR-T cells derived from PTGFRN produced cytokines and exerted cytotoxicity upon co-culture with tumor cells from patients with GBM. Furthermore, intracranial injection of 5E17-CAR-T cells demonstrated antitumor effects in an orthotopic xenograft murine model with patient-derived GBM cells.

DISCUSSION
In this study, we identified PTGFRN as a tumor-specific surface antigen and confirmed its antitumor effect in vitro and in vivo. PTGFRN is involved in the control of cell proliferation, migration, invasion, cell cycle, and apoptosis, and is expressed in multiple cancers. Cell surface PTGFRN is a candidate target for intracranial CAR-T-cell therapy for GBM.
10018- ACT-2 REGIONAL HEALTH DISPARITIES IN THE ERA OF COMPLEX GLIOBLASTOMA TREATMENT
Authors: Momii Yasutomo , Hata Nobuhiro , Fudaba Hirotaka , Yonezawa Hajime , Shinojima Naoki , Negoto Tetsuya , Ujifuku Kenta , Nagamine Hideki , Kuga Daisuke , Nakahara Yukiko , Yamashita Shinji , Nakano Yoshiteru , Emoto Toshiyuki , Hanaya Ryosuke , Mukasa Akitake , Morioka Motohiro , Matsuo Takayuki , Hamasaki Tadashi , Yoshimoto Koji , Abe Tatsuya , Okita Yoshiko , Yamamoto Junkoh , Abe Hiroshi , Fujiki Minoru ,   Research Group Kyushu Brain Tumour
Published: November 2024

Abstract
Glioblastoma, a highly aggressive brain tumor, typically has a poor prognosis. However, advancements in combined treatments have significantly improved patients’ activities of daily living (ADL) and overall prognosis. Despite these advancements, patients in regional areas face challenges. Frequent hospital visits for BEV (bevacizumab) administration from remote locations often hinder the continuation of early treatment, leading to poorer outcomes. This study, conducted by the Kyushu Brain Tumour Study Group, analyzed data from patients treated at 11 hospitals in Kyushu between 2010 and 2023. The study compared survival rates based on the distance of patients’ residences from treatment centers. Prognostic factors were evaluated using both univariate and multivariate analyses. The Kaplan-Meier method was employed to compare survival rates. The findings indicated that rural glioblastoma patients may experience worse prognoses due to the long travel distances required for treatment. While consolidating treatment facilities is ideal, ensuring that such facilities are within accessible distances in rural areas is crucial for improving patient outcomes.
10052- IMT-2 TRANSRATIONAL RESEARCH FOR A MULTICENTER CLINICAL TRIAL OF TUMOR-FUSED DENDRITIC CELL IMMUNOTHERAPY
Authors: Akasaki Yasuharu , Takei Jun , Yamamoto Yohei , Teshigawara Akihiko , Tomoto Kyoichi , Koseki Hirokazu , Tanaka Toshihide , Murayama Yuichi 
Published: November 2024

Abstract

OBJECTIVE
Although an immunotherapy using tumor-fused dendritic cells (TFDC) is considered promising as one of the multimodality therapies for malignant gliomas, it has not been able to perform it in hospitals without a cell processing facility because the method of transporting a raw material and preserving the final product have not been established. We performed a non-clinical study to address these challenges with the aim of conducting a multicenter investigator-initiated clinical trial.

METHODS
In a study for establishing a transport method of raw material, removed glioma tissue in a surgery was transported under refrigerated storage from an affiliated hospital of the Jikei University to the JIEKI-CPF that is a manufacturing base of TFDC located at a remote place. Cultured tumor cells were tried to establish using the tissues refrigerated for 24, 48, and 72 hours. In a study for establishing a cryopreserve method of TFDC, TFDC was manufactured using established cultured tumor cells and dendritic cells of the same patient, suspended in a cryoplastic solution on the day after manufacture, frozen in gas-phase liquid nitrogen for 13 weeks, and thawed to confirm its viability. An analysis of mixed lymphocyte reaction was performed to confirm the function of TFDC after thawing.

RESULTS
Cultured tumor cells were successfully established from the tumor tissues of all registered 4 cases (3 cases of glioblastoma, 1 case of anaplastic oligodendroglioma) at all refrigerated periods. Count and viability of TFDC cryopreserved for 13 weeks were achieved the target values. Increased secretion of IFNγ induced by TFDC was confirmed in an analysis of mixed lymphocyte reaction.

CONCLUSIONS
Despite the high efficacy and safety of TFDC immunotherapy, its un-versatility has limited its use to single centers. We aim to conduct an investigator-initiated multicenter clinical trial based on the data from this non-clinical study.
10040- STMO-2 ASSOCIATED FACTORS LEADING TO INTRAOPERATIVE HYPOTENSION DUE TO THE USE OF 5-AMINOLEVLINIC ACID
Authors: Tomoto Kyoichi , Teshigawara Akihiko , Tanaka Toshihide , Hasegawa Yuzuru , Murayama Yuichi 
Published: November 2024

Abstract

INTRODUCTION
Photodynamic diagnosis using 5-aminolevulinic acid (5ALA) for gliomas has contributed to improved resection rates and extended progression free survival and is widely used in Japan. However, there have been multiple reports of marked hypotension during anesthesia induction after 5ALA administration, leading to its listing as a significant adverse effect from April 2020. In this study, we retrospectively analyzed factors contributing to intraoperative hypotension (IOH) caused by 5ALA use.

MATERIALS AND METHODS
We included 148 cases of glioma that underwent surgery at our hospital from 2015 to 2024. The cases were stratified into the 5ALA administration group and the non-administration group. IOH was defined as a mean arterial pressure below 60 mmHg after anesthesia induction. We compared the incidence of IOH between the two groups and evaluated potential risk factors such as age, body weight, and preoperative antihypertensive medication use using the Chi-square test.

RESULTS
The 5ALA group included 72 cases (48.6%), while the non-5ALA group included 76 cases (51.4%). There was no significant difference in the incidence of IOH between the groups (p=0.296). In the elderly group (&gt;60 years), the incidence of IOH was significantly higher in the 5ALA group (p=0.029). For patients weighing &lt;75 kg, the 5ALA group had a significantly higher incidence of IOH (p=0.039), whereas for those weighing &gt;76 kg, the non-5ALA group had a higher incidence (p=0.049). Additionally, in patients taking calcium channel blockers (CCBs) or angiotensin receptor blockers (ARBs), or both, the incidence of IOH was significantly higher with 5ALA administration (p=0.033, 0.015, 0.023, respectively).

CONCLUSION
Elderly patients, those weighing &lt:75 kg, and those taking CCBs/ARBs are at a higher risk of IOH, suggesting the need for careful blood pressure management during and after surgery in these populations.
10012- MPC-2 DIFFERENCE BETWEEN HISTOLOGICAL AND INTEGRATED DIAGNOSES; IMPLICATIONS FOR TREATMENT
Authors: Kurose Akira , Asano Kenichiro , Kamataki Akihisa , Nakagawa Runa , Hirayama Akane 
Published: November 2024

Abstract
The difference between histological and integrated diagnoses according to WHO2021 is necessary to clarify the disadvantage of not having molecular information, since molecular analysis is currently available only in a few centers and treatment selection for many cases depends on histological diagnosis. We analyzed 70 cases of glioma. Molecular analysis included IDH, ATRX, and p53 by IHC, IDH, TERTp by sequencing, 1p/19q, CDKN2A/B, PDGFRA, EGFR, PTEN by MLPA. The gliomas were histologically classified into astrocytoma (A) (n=5), oligoastrocytoma (OA) (12), oligodendroglioma (O) (7), and glioblastoma (Gb) (46). Molecular analysis classified A into astrocytoma, IDH-mut, grade 2/3 (4) and molecular Gb (1); OA into A, IDH-mut, grade 2/3 (4), O (6) and molecular Gb (2); O into A, IDH-mut, grade 4 (1), O (5) and molecular Gb (1); Gb into A, IDH-mut, grade 4 (2) and Gb, IDH-wt (44). Of the 70 cases, 65 had no significant difference between histological and the integrated diagnoses, however, 5 patients including A (1), OA (2) and O (2) were changed from grade 2/3 to grade 4, which may have a significant implication on the choice of treatment and the necessity for molecular analysis to improve the overall prognosis of glioma is clear. In order to make the histological diagnosis closer to the integrated diagnosis, it is necessary to histologically observe as wide an area of the tumor as possible. In addition, the cases in which the integrated diagnosis reveals an increase in grade should continue to be investigated to clarify the specific histological findings.
10076- MPC-8 MOLECULAR DIAGNOSIS OF MEDULLOBLASTOMA: CHARACTERISTICS OF JAPANESE CASES AND DIAGNOSTIC METHODS FOR WNT MBS.
Authors: Go Kohichi , Katsuma Asako , Makino Yasuhide , Yamamoto Etsuko , Yoshioka Ema , Shofuda Tomoko , Kanematsu Daisuke , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Kodama Yoshinori , Mano Masayuki , Ichimura Koichi , Sasaki Atsushi , Hirato Junko , Inoue Takeshi , Nishikawa Ryo , Date Isao , Nonaka Masahiro , Nagane Motoo , Arakawa Yoshiki , Kanemura Yonehiro 
Published: November 2024

Abstract

BACKGROUND
Medulloblastomas have been subdivided into pathological morphological groups, but since 2012, consensus has been reached on four different molecular subgroups, including wingless (WNT)-activated, sonic hedgehog (SHH)-activated, groups 3 and 4, which have been included in the WHO classification since 2016 and have been to date, the era has seen a greater emphasis on molecular genetic diagnosis. Although DNA methylation arrays are used as the Golden Standard in many developed countries, in many Asian countries, including Japan, and in clinical practice in developing countries, the diagnosis of the name and type of disease is often based on pathological findings and immunostaining. WNT MB is known as a group with a particularly good prognosis if treated appropriately, and the reliable diagnosis (salvage) of WNT MB patients without omissions is extremely important for future clinical trials. However, no consensus has yet been reached on the optimal method for correct and leak-free diagnosis.

METHODS
JPMNG: 267 cases registered since 2012 at 43 facilities in Japan participating in the Japanese Pediatric Molecular Neuro-oncology group (244 cases were analyzed in the final analysis). Molecular genetic diagnosis was performed using Nano string, DNA sequencing, DNA methylation array, etc., to classify the patients into four types.

RESULTS
The four typing groups were WNT: 39 (16%), SHH: 61 (25%), Group3: 42 (17%) and Group4: 102 (41.8%) cases, respectively. Of these, all cases were positive for (1) CTNNB1 in 39 of 39 cases (100%) and (2) monosomy6 in 35 of 35 cases (100%), especially in the diagnosis of WNT.

CONCLUSIONS
The molecular genetic features of WNT MB were analyzed from 244 cases of medulloblastoma accumulated at the JPMNG. The diagnosis of WNT MB can be made more conveniently and accurately by utilizing multiple modality approaches, in addition to the use of DNA methylation arrays.
10098- MPC-11 THE GENETIC DUET OF BRAF V600E AND TERT PROMOTER MUTATIONS IN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMAS AND EPITHELIOID GLIOBLASTOMAS
Authors: Uzuka Takeo , Shibao Shunsuke , Sumi Takuma , Matsuda Hadzuki , Akutsu Hiroyoshi 
Published: November 2024

Abstract

OBJECTIVE
Pleomorphic xanthoastrocytoma (PXA), anaplastic PXA (aPXA), and epithelioid glioblastoma (E-GBM) are known to frequently harbor the BRAF V600E mutation and share numerous pathological and clinical similarities. This study investigates the molecular biological and clinical features of these tumors.

METHODS
Cases diagnosed morphologically as PXA/aPXA/E-GBM with reported BRAF V600E/TERT promoter (TERTp) mutations/prognostic outcomes were included. Information regarding tumor location, cerebrospinal fluid (CSF) dissemination, and CDKN2A/B co-deletions was also collected.

RESULTS
A total of 104 cases (54 females, 49 males, 1 unspecified; from 14 literature sources and 7 own cases) were included. Patients ranged from 5 to 80 years old (median age 39). PXA was observed in 32 cases (30.8%), aPXA in 27 cases (26.0%), and E-GBM in 45 cases (43.3%). Temporal lobe localization was found in PXA in 13/27 (48.1%) cases, aPXA in 6/18 (33.3%) cases, and E-GBM in 14/44 (31.8%) cases. The BRAF V600E mutation was identified in PXA 23/32 (71.9%), aPXA 21/27 (77.8%), and E-GBM 27/45 (60.0%). TERTp mutations were present in PXA 23/32 (0%), aPXA 6/27 (22.2%), and E-GBM 19/31 (61.3%). The oncogene duet (BRAF V600E and TERTp) was observed in 5/27 (18.5%) aPXA cases and 19/45 (42.2%) E-GBM cases. Median overall survival (MOS) was 160 months for PXA, 67 months for aPXA, and 12 months for E-GBM. The MOS for the oncogene duet group was 11 months. CSF dissemination was noted in 28 out of 32 (87.5%) E-GBM cases.

DISCUSSION
The oncogene duet was more prevalent in E-GBM compared to aPXA. Since more than half of the E-GBM cases did not show the oncogene duets, E-GBM is considered a heterogeneous group. Despite this heterogeneity, the high incidence of CSF dissemination and poor prognosis in E-GBM cases underscore the potential clinical significance of maintaining E-GBM as a distinct diagnostic category.
10184- MPC-17 CHARACTERISTICS AND OUTCOMES OF DIFFUSE NON-MIDLINE GLIOMAS WITH H3F3A GENE MUTATION IN THE KANSAI MOLECULAR DIAGNOSIS NETWORK FOR CNS TUMORS (KANSAI NETWORK)
Authors: Nakatogawa Hirokazu , Fukai Junya , Kawaji Hiroshi , Hayashi Nobuhide , Kijima Noriyuki , Yoshioka Ema , Kanematsu Daisuke , Katsuma Asako , Sumida Miho , Shofuda Tomoko , Mori Kanji , Inenaga Chikanori , Kanemura Yonehiro 
Published: November 2024

Abstract

PURPOSE
Diffuse gliomas with H3F3A gene mutation such as H3.3 K27M and G34R/V in cerebral hemisphere can be found in diffuse gliomas rarely. These tumors may be called histone H3 K27M-mutant diffuse non-midline gliomas (NDMG) and H3 G34-mutant diffuse hemispheric gliomas (DHG), respectively. This study investigates clinical, radiological and molecular characteristics as well as treatment outcomes of patients with H3 K27-mutant NDMG compared with H3 G34-mutant DHG.

METHODS
We collected histone H3-mutant diffuse glioma cases at non-midline location and enrolled in Kansai Molecular Diagnosis Network for CNS Tumors. Clinical, radiological pathological characteristics and DNA methylation were analyzed retrospectively and compared between NDMG and DHG cases. Various factors were evaluated to examine their effects on overall survival.

RESULTS
A total of 16 patients with H3 K27M-mutant NDMG and 9 patients with H3 G34R/V-mutant DHG were included in this study. Patients with NDMG were older than those with DHG (median age = 45 vs. 25 years old). Overall survival times (OS) of patients with NDMG was comparable to those of DHG (median OS = 20.0 vs. 22.5 months). Female gender, preoperative KPS score 80 and over and extensive surgical resection tended to improve prognoses of the patients with these tumors. H3 K27M-mutant NDMGs possess are similar DNA methylation property to H3 K27M-mutant DMGs.

CONCLUSIONS
Diffuse gliomas harboring histone H3 K27M mutation can arise at cerebral hemisphere in the older adults. H3 K27M-mutant NDMG could be a different tumor type from DMG or DHG defined in CNS WHO 2021.
10118- NI-8 RADIOLOGICAL AND MOLECULAR ANALYSIS OF EARLY-STAGE GLIOBLASTOMA REVEAL THE RADIOLOGICAL INITIATION OF IDH WILDTYPE GLIOBLASTOMA
Authors: Shibahara Ichiyo , Shigeeda Ryota , Orihashi Yasushi , Tanihata Yoko , Fujitani Kazuko , Hyakutake Yuri , Toyoda Mariko , Inukai Madoka , Sato Sumito , Hide Takuichiro , Kumabe Toshihiro 
Published: November 2024

Abstract
Glioblastoma (GB), IDH wildtype, is an aggressive and malignant tumor that necessitate early surgical intervention upon radiological suspicion. Consequently, the natural growth dynamics of GB remain not fully understood. Previous studies have examined GB growth using multiple MRIs between initial radiological diagnosis of GB and preoperative MRI, but these studies have short-term intervals between MRIs (defined as shortGB-cohort). Therefore, the shortGB-cohort requires extrapolations to determine radiological initiation which harbors greater uncertainty. In this study, we focused on early-stage GB (eGB), characterized by small, nonspecific lesions on MRI that eventually progress to classic GB findings. We compared three cohorts: 49 cases of eGB. 68 cases of shortGB, and 23 cases of eGB from previous publications (other-eGB). Molecular analyses revealed that TERT promoter mutations, EGFR amplification/gain, CDKN2A hemi/homozygous deletion, and PTEN hemi/homozygous deletion were consistent between eGB and shortGB. Our analysis indicated that the radiological initiation of GB in eGB was -0.84 years (95% confidence interval (CI): -1.09 to -0.68), compared to -0.35 years (95%CI: -0.46 to -0.28) in shortGB. In eGB, factors such as age&lt;65, MIB1&gt;30%, TERTp mutation, and the presence of copy-number alterations (CNA) in EGFR/PTEN/CDKN2A, with or without TERTp mutation, correlated with faster tumor progression. In cases without these alterations, the estimated radiological initiation was -2.31 years (95%CI: -100 to -0.80), indicating slower progression. The ShortGB-cohort did not show any significant changes based on these factors, suggesting it does not actually reflect tumor origin. The other-eGB cohort presented radiological initiation between -0.92 and -0.15 year, consistent with our eGB-cohort. This study investigates the radiological origin of GB using extremely rare cases of eGB. This cohort minimizes the extrapolations, providing insights into the radiological pathophysiology and its association with molecular alterations in IDH-wildtype GB.