bluuebunny/crossref_metadata_2025 huggingface dataset:
A mutation in DNA polymerase γ harbors a shortened lifespan and high sensitivity to mutagens in the filamentous fungus Neurospora crassa
Authors: Yoshihara Ryouhei , Shimakura Yuzuki , Kitamura Satoshi , Satoh Katsuya , Sato Manami , Aono Taketo , Akiyama Yu , Hatakeyama Shin , Tanaka Shuuitsu
Published: November 2024

Hyphal elongation is the vegetative growth of filamentous fungi, and many species continuously elongate their hyphal tips over long periods. The details of the mechanisms for maintaining continuous growth are not yet clear. A novel short lifespan mutant of N. crassa that ceases hyphal elongation early was screened and analyzed to better understand the mechanisms for maintaining hyphal elongation in filamentous fungi. The mutant strain also exhibited high sensitivity to mutagens such as hydroxyurea and ultraviolet radiation. Based on these observations, we named the novel mutant “mutagen sensitive and short lifespan 1 (ms1).” The mutation responsible for the short lifespan and mutagen sensitivity in the ms1 strain was identified in DNA polymerase γ (mip-1:NCU00276). This mutation changed the amino acid at position 814 in the polymerase domain from leucine to arginine (MIP-1 L814R). A dosage analysis by next-generation sequencing reads suggested that mitochondrial DNA (mtDNA) sequences are decreased nonuniformly throughout the genome of the ms1 strain. This observation was confirmed by quantitative PCR for 3 representative loci and restriction fragment length polymorphisms in purified mtDNA. Direct repeat-mediated deletions, which had been reported previously, were not detected in the mitochondrial genome by our whole-genome sequencing analysis. These results imply the presence of novel mechanisms to induce the nonuniform decrease in the mitochondrial genome by DNA polymerase γ mutation. Some potential reasons for the nonuniform distribution of the mitochondrial genome are discussed in relation to the molecular functions of DNA polymerase γ.
The Alexander Trick for Homology Spheres
Authors: Galatius Søren , Randal-Williams Oscar
Published: November 2024

We show that the group of homeomorphisms of a compact contractible $d$-manifold that fix the boundary is contractible, as long as $d \geq 6$. We deduce this from a strong uniqueness statement for one-sided $h$-cobordisms.
10054- CBMS-1 TARGETING POLY(ADP-RIBOSE) TO INDUCE SELECTIVE CELL DEATH IN IDH-MUTANT GLIOMAS
Authors: Kitagawa Yosuke , Nasser Ali , Wetzel Ethan , Miller Julie , Wakimoto Hiroaki , Daniel Cahill
Published: November 2024

To develop a novel therapeutic approach targeting DNA repair mechanisms for isocitrate dehydrogenase (IDH) mutant gliomas, we examined the combined effects and mechanisms of poly(ADP-ribose) glycohydrolase (PARG) inhibitors (PARGi) and radiation therapy (IR). Poly(ADP-ribose) polymers (PAR chains) are essential DNA repair enzymes synthesized by poly(ADP-ribose) polymerase (PARP) using nicotinamide adenine dinucleotide (NAD) as a substrate. PAR chains are degraded by PARG, and their length is precisely controlled by the balance of PARP and PARG activities, playing crucial roles in DNA damage response and cellular stress reactions. Previous studies showed that the combination of PARGi and temozolomide (TMZ) exhibited selective cytotoxicity in IDH mutant glioma cells, and our study confirmed cell death due to a novel DNA repair vulnerability independent of NAD depletion. Experiments using patient-derived IDH mutant glioma cell lines demonstrated that the combination of PARGi and IR exhibited strong cytotoxicity towards IDH mutant cells. Additionally, lentivirus-mediated PARG knockout (KO) experiments showed high radiation sensitivity in PARG KO cells, and partial recovery of cytotoxicity with IDH inhibitors. These results suggest that the combination of PARGi and IR has synergistic effects specifically in IDH mutant cells. Furthermore, we analyzed the expression of DNA damage markers PAR and γH2AX over time using western blotting and immunofluorescence, and confirmed tumor reduction in a mouse model with IDH mutant PARG-KO cell lines treated with IR. PARGi, which have high selectivity and bioavailability, are expected to have lower systemic toxicity compared to conventional alkylating agents, and the synergistic cytotoxic effects could potentially reduce postoperative radiation doses. Particularly, since recurrent tumors after TMZ treatment often acquire mutations in DNA repair enzymes, this therapeutic strategy offers a promising new approach based on novel mechanisms.
10124- GEN-6 ANALYSIS OF DNA METHYLATION IN DIFFERENTIATION AND DEDIFFERENTIATION MECHANISMS OF GLIOMA STEM-LIKE CELLS
Authors: Sano Emiko , Yoshikawa Masaaki , Hino Hirotsugu , Ohyama Kentaro , Sumi Koichiro , Nishide Takuma , Aida Yumi , Nara Kaoru , Yamamuro Shun , Hara Hiroyuki , Hirai Shuichi , Yoshino Atsuo
Published: November 2024

The presence of glioma stem cells, capable of self-renewal and multilineage differentiation, is one of the reasons why brain tumors are difficult to treat. Gliomas are predicted to arise from the accumulation of genetic abnormalities in glial cells or their progenitor cells at the origin of tumorigenesis. It has been suggested that these glioma stem cells can acquire different properties through epigenomic reprogramming by interacting with the surrounding environment. In this study, we investigated whether DNA methylation, an epigenomic factor, is involved in the mechanism of glioma differentiation and dedifferentiation. DNA methylation was analyzed by real-time methylation-specific PCR (MSP). The promoter region (CpG island) of EZH2 (histone H3 lysine 27 (H3K27) methyltransferase), which has been reported to be involved in the mechanism of differentiation and dedifferentiation, was examined. 0125-GSC and 0222-GSC which are established from patient tumors were cultured in neurobasal medium with supplements and used as glioma stem-like cells. These cells formed sphere and expressed stem cell markers. S0125 and S0222 were adherent and cultured in D-MEM with 10 % fetal calf serum. The DNA methylation rate of EZH2 was increased in S0125 and S0222. Furthermore, real-time PCR analysis revealed that the expression of EZH2 mRNA was decreased in S0125 and S0222. These results suggest that changes in DNA methylation and gene expression of EZH2 may be involved in the differentiation and dedifferentiation of glioma cells.Keyword: Glioblastoma stem-like cell, Differentiation, EZH2 methylation
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

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

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

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

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

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

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 (>60 years), the incidence of IOH was significantly higher in the 5ALA group (p=0.029). For patients weighing <75 kg, the 5ALA group had a significantly higher incidence of IOH (p=0.039), whereas for those weighing >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 <: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

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

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

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

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

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<65, MIB1>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.
10217- NI-17 COMPARISON OF DYNAMIC SUSCEPTIBILITY CONTRAST PERFUSION MRI WITH 11C-METHIONINE PET IN ADULT NON-CONTRAST ENHANCED GLIOMAS
Authors: Imai Naoya , Yano Hirohito , Yasuda Shoji , Ikegame Yuka , Kumagai Morio , Shinoda Jun
Published: November 2024

OBJECTIVE

This study examined the correlation between cerebral blood volume (CBV) and MET PET.

SUBJECTS AND METHODS

108 non-contrast-enhanced gliomas (41.8±12.3 years old, 58 males) examined between April 2012 and December 2022 were included. The pathological diagnosis was Glioblastoma, IDH-wildtype (G): 21 cases, Astrocytoma, IDH-mutant (A): 52, Oligodendroglioma, IDH-mutant and 1p/19q codeleted (O): 35. T2 region (the high signal region on T2WI) on MRI and high-MET region (tumor maximum SUV/normal frontal cortex SUV (T/N) ratio > 1.3) on MET PET were defined. The rCBV (regional mean CBV/normal white matter mean CBV) was calculated using dynamic-susceptibility-contrast perfusion MRI to compare each region.

RESULT

The rCBV (3.22±0.95) in the T2 region in 67 patients with MET accumulation was significantly higher than those (2.47±0.64) in 41 patients without MET accumulation (p<0.0001). The cutoff rCBV value obtained from the ROC curve for MET accumulation was 2.79, with a sensitivity of 61.2%, specificity of 75.6%, and AUC of 0.73. The rCBV in the T2 region was (G: 3.60±1.0 A: 2.53±0.69 O: 3.14±0.89) significantly higher in group G (p<0.0001). In the 69 patients with MET accumulation (G: 16, A: 21, O: 30), the rCBV was 3.23±0.96 in the T2 region and 3.48±1.13 in the high-MET region, significantly higher in the latter (p<0.0016). The rCBV was significantly higher in the group G both in the T2 region (G: 3.82±0.97 A: 2.77±0.68 O: 3.22±0.93, p=0.0026) and in the high-MET region (G: 4.12±1.18 A: 3.29±1.0 O: 3.27±1.1, p=0.031). The difference was most in the group A (p=0.016). The rCBV significantly correlated with T/N ratio in both the T2 region (r=0.41, p=0.0005) and the high-MET region (r=0.49, p<0.0001), mainly observed in groups A and O.

DISCUSSION

The rCBV and MET accumulation correlated in non-contrast-enhanced gliomas. The CBV may be an alternative to MET PET in imaging gliomas.
10226- MET-20 PRIMARY UNKNOWN CANCER THAT WAS DIFFICULT TO DIAGNOSE EVEN WITH A CANCER PANEL TEST, PRESENTING AS LEPTOMENINGEAL CARCINOMATOSIS
Authors: Koga Nanako , Yamamoto Etsuko , Matsubara Jyunichi , Takeuchi Yasuhide , Makino Yasuhide , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Youhei , Arakawa Yoshiki
Published: November 2024

CASE REPORT

The patient was a 59-year-old male. Three years prior to the current presentation, he developed left peripheral facial nerve palsy. In October of the year before his presentation, his left facial nerve palsy rapidly progressed, and by December, MRI revealed an enhancing lesion in the left cerebellopontine angle, leading to a referral to our hospital. Gadolinium enhanced lesions were located at bilateral cerebellopontine angles, auditory nerves and trigeminal nerves. There were multiple small nodular lesions at cerebellar surface and spinal cord. In March of the current year, the patient underwent biopsy, and the pathological diagnosis was mucinous adenocarcinoma. Despite various examinations, the primary site of the cancer could not be identified. Genetic testing with FoundationOne revealed amplifications of CDK4, MDM2, and ERBB3, along with ATM mutations and STK11 deletions, but a definitive diagnosis was not available. The patient was treated with nivolumab and radiation therapy to the lesion of left cerebellopontine angle, which showed significant enhancement on imaging. While local control was achieved with radiation, the leptomeningeal carcinomatosis progressed, leading to a determination that the disease had progressed. By June of the current year, the patient experienced worsening hearing loss, tinnitus, and back pain due to spinal cord lesions, resulting in a rapid decline in ADL. Radiation therapy was administered for the spinal cord lesions, and the patient passed away about a week later.

DISCUSSION AND CONCLUSION

In this case, despite a pathological diagnosis of mucinous adenocarcinoma, the primary site of the tumor could not be identified. The results from FoundationOne suggested possible origins in the gastrointestinal tract or lung, but a definitive diagnosis was not reached. Molecular diagnostic methods should be developed for difficult-to-diagnose cancers of unknown primary.
10036- MNG-3 EVALUATION OF THE CORRELATION BETWEEN PET STUDIES AND PATHOLOGICAL FINDINGS IN MENINGIOMAS, AND THEIR IMPACT ON RECURRENCE
Authors: Tatano Masaki , Kanda Takahiro , Suzuki Kenta , Ogawa Daisuke , Hatakeyama Tetsuhiro , Miyake Keisuke
Published: November 2024

OBJECTIVE

Meningiomas are the most common primary brain tumors, typically following a benign course. However, some cases recur after surgery, necessitating further treatment or reoperation. This study aims to examine the relationship between PET studies and pathological findings, and their impact on recurrence.

METHODS

We included cases of newly diagnosed meningiomas treated surgically in our department from August 2008 to August 2022. The correlation between preoperative FDG-PET and methionine-PET accumulations with pathological findings (WHO grade, Ki-67 index), as well as the impact on recurrence, was investigated.

RESULTS

The study included 55 cases (22 males, 33 females), aged 17-87 years (median 61.8). The WHO grade was grade 1 in 34 cases and grade 2 in 21 cases, with no grade 3 cases observed. Recurrence occurred in 20 cases during follow-up, necessitating additional treatment. A significant correlation was observed between the tumor T/N ratio and the Ki-67 index for both tracers. Regarding WHO grade, the T/N ratio for FDG was 0.64 in the grade 1 group and 1.04 in the grade 2 group (p<0.01), while for MET, it was 4.8 in the grade 1 group and 6.39 in the grade 2 group (p<0.01), with both tracers showing significantly higher values in the grade 2 group. For postoperative recurrence, the T/N ratio for FDG was 0.97 in the recurrence group and 0.69 in the non-recurrence group (p=0.01), while for MET, it was 6.38 in the recurrence group and 4.66 in the non-recurrence group (p<0.01), with both tracers showing significantly higher values in the recurrence group.

CONCLUSION

The study demonstrated a significant correlation between preoperative PET studies and pathological findings in meningiomas, as well as an association with recurrence. PET studies were significantly correlated with the tumor malignancy and were considered predictors of postoperative recurrence.
10023- COT-4 THE LANDSCAPE OF REGIONAL COLLABORATION OF MEDICAL NETWORK IN SUPPORTIVE CARE FOR BRAIN TUMOR PATIENTS
Authors: Nishiyama Jun , Kanno Mai , Yonemochi Takuya , Sano Fumiya , Nozue Kyoko , Horie Osamu , Ozaki Satoshi , Takahashi Masamichi
Published: November 2024

The physical and mental burden suffers patients and their families in the treatment of malignant brain tumors, which needs close collaboration and intervention by multiple local medical professionals. What both patients and their families want to know is “prognosis,” and healthcare providers need to promptly integrate the information obtained through Advanced Care Planning for patients and their families, identify physical and social problems, and prepare for a quick and smooth transition from core hospital to home health care or local hospital. In our hospital, many professionals participate in the grand conference of Department of Neurosurgery to understand patient’s condition and share goals and challenges interactively. Attending physicians hold ward conferences twice a month with the nurses to share information on the patient’s treatment plan, general condition, discharge issues, and family background. At the same time, while setting a discharge date with the nurses at the patient support center, preparations are made from various angles regarding the patient’s issues and necessary home care support. It should be noted that the attending physician here is also engaged in home health care, enabling close and intimate collaboration between the university hospital and the local community. We report here how we are making a seamless transition from center hospital to community medical network collaboration, based on our clinical experience.
10119- COT-12 ROLE OF GLUCARPIDASE IN DELAYED METHOTREXATE EXCRETION, BASED ON OUR EXPERIENCE
Authors: Tanimura Kazuki , Okada Keiko , Kayatani Rishu , Ueda Kazuhiro , Matsuoka Yuki , Yamasaki Kai , Nitani Chika , Fujisaki Hiroyuki , Hara Junichi
Published: November 2024

INTRODUCTION

High-dose methotrexate (HD-MTX) is widely used to treat primary central nervous system lymphomas and medulloblastoma in infants. A key problem associated with this regimen is slow elimination, which can rapidly cause renal and hepatic damage. Glucarpidase was launched in January 2024 as a treatment for delayed elimination, but to date no guidelines have been established for its administration in Japan. Thus, we retrospectively examined data from cases of glucarpidase use in our department, including patients enrolled in the clinical trial.

PATIENTS AND METHODS

This study included 14 patients (10 males and four females) who received glucarpidase to counter delayed elimination during HD-MTX therapy between January 2015 and July 2024.

RESULTS

Median patient age was 7.5 years (range: 1.5-79 years) and the treated disease was acute leukemia in seven patients, lymphoma in four, osteosarcoma in two, and medulloblastoma in one. During glucarpidase administration, seven patients were experiencing renal impairment and three had elevated hepatic enzyme levels. The median blood MTX concentration at the first dose of glucarpidase was 4.9 μM (range: 1.02-24.1 μM). This decreased to 0.22 μM (range: 0.07-1.66 μM) at 48 h post-administration. Glucarpitase was re-administered in one patient. Median time to <0.2 μM was 96 h (range: 24-336 h). Peak renal impairment occurred at a median of 24 h (range: 0-96 h), and median time to normalization was 456 h (range: 96-648 h). Six of 12 patients were re-treated with HD-MTX. Four of these showed delayed elimination but did not require glucarpidase re-administration.

DISCUSSION

This study confirmed the efficacy and safety of glucuronidase for delayed elimination during HD-MTX therapy in real-world clinical practice. Timely detection of delayed elimination and examination of the indications for this agent are important to improve HD-MTX therapy safety.
10203- COT-21 DIFFERENCES IN THE RISK OF BRAIN TUMOR OCURRENCE ACCORDING TO REGIONAL DIFFERENCES AND EMPLOYMENT HISTORY
Authors: Murakami Tomoaki , Toyota Shingo , Achiha Takamune , Okochi Kosei , Nakashima Koichi , Okuhara Shuki , Tohara Kazuhiro , Yamada Shuhei , Kobayashi Maki
Published: November 2024

We investigated the relationship between occupational history and regional differences in the risk of brain tumor occurrence using the Inpatient Clinico-Occupational Database of the Rosai Hospital Group. 8546 patients hospitalised with primary brain/spinal cord tumors excluding metastatic brain/spinal cord tumors from 1996 to 2021 at the Rosai Hospital Group were included. Patients were divided into two groups: ICD codes for ‘malignant’ tumors (malignant group) and benign and other ICD codes (non-malignant group), and patient backgrounds, occupational classification (current occupation) and regional characteristics were compared. 2448 patients in the malignant group and 6098 patients in the non-malignant group. Comparing the patient backgrounds of the two groups, the age at admission was higher in the malignant group and the proportion of women was higher in the non-malignant group. There was no correlation with history of smoking, alcohol and medical history. With regard to the proportion of occupational categories (current occupation) in each group, Agricultural workers were significantly more in the malignant group. (P=0.0001, Odds ratio: 1.820; 1.328 to 2.488) Also, regarding regional differences, in the majority of regions the non-malignant group had approximately 1.2-2.5 times as many cases as the malignant group, while in the Kanto region the non-malignant group had approximately five times as many cases as the malignant group (2618 vs 518, p<0.0001)The present study suggests an association between agricultural workers and the malignant group. Although there have been previous reports on the association between agricultural workers and brain tumours, none have noted an association between agricultural workers and ‘malignant’ brain/spinal cord tumours. With regard to regional characteristics, the number of cases in the non-malignant group was overwhelmingly higher in the Kanto region. This could be due to differences in the number of hospitals, characteristics between hospitals, surgeons, MRI coverage and asymptomatic lesion detection rates.
IL-6 RESEARCH INTO INTRACTABLE CANCER AIMING FOR IMPLEMENTATION
Authors: Saya Hideyuki
Published: November 2024

Many people believe that “excellent basic research results will inevitably lead to practical applications,” but this is not necessarily true. Although it is undeniable that the drugs and medical devices that have been put into practice are the result of excellent research, having excellent research does not guarantee that it will be put into practice. There are countless research seeds that disappear without being implemented. In other words, bridging the gap between basic research and application is as challenging as building a bridge over a turbulent river, and it is not a problem that can be solved by academics and scientists alone. Translational research requires more than just academic rigor. It also involves addressing regulatory and intellectual property issues, securing funding, procuring necessary materials, and most importantly, assembling specialized personnel and support staff to drive the project forward. Bringing all these resources together is no easy feat. Drug discovery and medical device development once took place in large corporations, but as medical science has become more complex, development has shifted entirely to academia. This reality highlights the challenges of creating new medicines, but also the opportunity to solve even the smallest clinical problems (needs) yourself. In this educational talk, I will explore the importance and strategies for translating insights from basic research and clinical practice into practical applications, drawing from my own experience.
Hesperidin produces antidepressant effects by activating AMPA receptor: enhancing synaptic proteins to promote hippocampal neuronal activities
Authors: Pang Bo , Cao Ting
Published: November 2024

Hesperidin treatments reduce depressive symptoms in mouse models of depression, but the mechanism that mediates its antidepressant effects is unclear. This study shows that hesperidin exerts its antidepressant effects by activating α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor to promote synaptic and neuronal function in the hippocampus. The optimal dose of hesperidin (10 mg/kg) for the antidepressant potential was determined after 7 consecutive days of treatments, demonstrating decreased latency to eat and increased food consumption in novelty suppressed feeding, and decreased immobility time in tail suspension test (TST). Moreover, the optimal dose also reversed the depressive phenotypes of Institute of Cancer Research mice exposed to chronic unpredictable mild stress (CUMS), including reduced immobility time in the TST and increased sucrose preference in the sucrose preference test. In addition, hesperidin increased the expression of AMPA receptor protein (Glur1) and synaptic proteins (BDNF, PSD95, synapsin1) in the hippocampus of CUMS-exposed mice. Furthermore, inhibition of AMPA receptor activity by NBQX blocked the effect of hesperidin in reversing the depressive phenotypes, upregulated the expression of synaptic proteins (BDNF, PSD95, synapsin1) and cFOS-positive cells in the hippocampus, and increased the number of Ki67-positive cells in the dentate gyrus of the hippocampus of CUMS-exposed mice. These results help to further understand the antidepressant mechanism of hesperidin and provide new ideas for the future development of antidepressant drugs.
Establishment and validation of diagnostic model in immunoglobulin A nephropathy based on weighted gene co-expression network analysis
Authors: Liu Haibo , Dai Lingling , Liu Jie , Duan Kai , Yi Feng , Li Zhuo
Published: November 2024

Bioinformatics analysis helps to understand the underlying mechanisms and adjust diagnostic and treatment strategies for immunoglobulin A nephropathy (IgAN) by screening gene expression datasets. We explored the biological function of IgAN, and established and validated a diagnostic model for IgAN using weighted gene co-expression network analysis. Using the GSE93798 and GSE37460 datasets, we performed differential expression analysis, Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, constructed a protein-protein network, and identified hub genes. A diagnostic model was built using a receiver operating characteristic curve, calibration plot, and decision curve analysis. Two Gene Expression Omnibus (GEO) datasets were integrated to screen 38 differentially expressed genes between patients with IgAN and normal kidney donors in glomerular samples. KEGG enrichment analysis showed that the differentially expressed genes were mainly enriched in the IL-17 and relaxin signaling pathways. We constructed a protein–protein interaction (PPI) network of differentially expressed genes using the STRING database and cross-compared it with the results of weighted gene correlation network analysis to screen out the top 10 key genes: FOS, EGR2, FOSB, NR4A1, BR4A3, FOSL1, NR4A2, ALB, CD53, C3AR1.We also found that the immune infiltration level was remarkably increased in IgAN tissues. We established a 5-gene panel diagnostic model (ACTA2, ALB, AFM, ALDH1L1, and ALDH6A1). The combined diagnostic ability was high, with the area under the curve (AUC) was 0.964. Based on these 5 genes, we also developed a risk-scoring evaluation system for individuals. The calibration plot indicated that the nomogram-predicted probability of nonadherence was highly correlated with actual diagnosed nonadherence, and the decision curve analysis indicated that patients had a relatively good net benefit. The model and gene expression were also validated using an external dataset. Our study provides directions for exploring the potential molecular mechanisms of IgAN as well as diagnostic and therapeutic strategies.