bluuebunny/crossref_metadata_2025_split huggingface dataset:
ET-6 Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax
Authors: Yamamoto Masahiro , Kitanaka Chifumi 
Published: December 2021

Abstract
BACKGROUND: Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We have demonstrated that malignant meningioma cells are exquisitely sensitive to gemcitabine due to their increased expression of hENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively (Takeda et al. Oncotarget 8:90996, 2017; Yamamoto et al., Neuro-Oncol 23:945, 2021). Significantly, in support of our findings, the efficacy and safety of gemcitabine have recently been documented in a small case series of patients with recurrent meningiomas, which has further led to a phase 2 clinical trial to evaluate the efficacy of gemcitabine in recurrent high-grade meningiomas (Khaddar et al., South Asian J Cancer 9:261, 2020). Besides its efficacy as a single agent, gemcitabine reportedly has a radiosensitizing effect in pancreatic cancer. However, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells. METHODS: We examined radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts (s.c. and i.c.) and explored the underlying mechanisms. RESULTS: Gemcitabine sensitized malignant meningioma cells remarkably to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug, further enhanced the effects of the combination of gemcitabine and IR in vitro and in vivo by strongly inducing apoptotic cell death in senescent cells. CONCLUSION: These results suggest that gemcitabine is not only a promising radiosensitizer for malignant meningioma but also creates in combination with IR a therapeutic vulnerability of senescent meningioma cells to senolytics. (submitted for publication)
ET-7 Roles for hENT1 and dCK in gemcitabine sensitivity and malignancy of meningioma
Authors: Yamamoto Masahiro , Uchida Hiroyuki , Yonezawa Hajime , Higa Nayuta , Yamada Yuki , Sonoda Yukihiko , Hirano Hirofumi , Yoshimoto Koji , Kitanaka Chifumi 
Published: December 2021

Abstract
Background: High-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors, and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown. Methods: We examined the roles of hENT1 (human equilibrative nucleoside transporter 1) and dCK (deoxycytidine kinase) in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity. Results: hENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients. Conclusions: The present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine.
TB-4 Antitumor effects of a novel curcumin derivative curcumin monoglucuronide on glioblastoma cells in vitro and in vivo
Authors: Fujii Takashi , Yamamuro Shun , Takahashi Masamichi , Kondo Akihide , Narita Yoshitaka , Yoshino Atsuo , Wada Kojiro , Ichimura Koichi , Tomiyama Arata 
Published: December 2021

Abstract
The therapeutic outcome of glioblastomas (GBMs) is still very poor. Therefore, invention of novel therapeutic methods against GBM cases is considered urgent. The antitumor effects of naturally-derived compounds are attracting attention recently, and therapeutic efficacy of curcumin, a plant-derived compound previously used for multiple purpose, has been indicated in many cancer systems; however, clinical application of curcumin is considered difficult because of its poor bioavailability (under 1 %). Curcumin monoglucuronide (CMG), a water-soluble prodrug of curcumin recently developed for overcoming this weakness, has been demonstrated excellent antitumor effects for several malignancies in vitro and in vivo; therefore, we investigated the effects of CMG against GBM cells. CMG induced cell death of human GBM cells lines (T98G, U251MG, and U87MG) by dose dependent manner by triggering multiple forms of cell death such as apoptosis and perthanatos. Immunoblotting of CMG-treated GBM cell lysates demonstrated activation of multiple cell death signaling. Furthermore, immunodeficiency mice harboring intracerebral U87MG cell xenografts systemically treated by CMG showed significantly prolonged survival compared with control mice. These results suggest CMG would be a novel therapeutic agent against GBM cases.
TB-9 An attempt to establish a patient-derived brain tumor culture model by organoid culture method
Authors: Kuroda Hideki , Kijima Noriyuki , Nakagawa Tomoyoshi , Hirayama Ryuichi , Okita Yoshiko , Kagawa Naoki , Kisima Haruhiko 
Published: December 2021

Abstract
Background: Molecular heterogeneity among and within tumors are one of the reasons for the poor survival rate of brain tumors even with the current standard therapy. However, monolayer culture and neuro-sphere culture (NS) use exogenous growth factors, so may not show the true nature of the tumor. And the culture establishment rate is low, especially low-grade tumors. Therefore, we used the glioblastoma organoid (GBO) culture method showed by Fadi to create culture models of various brain tumors and investigated their characteristics.
Methods: We examined the establishment rate in pathological and genotypic types of 56 patients who underwent brain tumor resection at our hospital between January 2020 and June 2021 and were cultured with GBO or NS. If tumor cells are increased visually at 1 month after culture, we defined establishment.
Results: There were 15 cases of glioblastoma, 7 cases of anaplastic astrocytoma, 7 cases of diffuse astrocytoma, 3 cases of diffuse midline glioma, 2 cases of anaplastic oligodendroglioma, 5 cases of oligodendroglioma, and 16 cases of others. The establishment rate was 76.5% by the GBO method and 40% by the N S method. By histological type, GBO: 80% in glioblastoma, NS: 58.3% in glioblastoma, GBO: 83.3% in AA, NS: 40% in AA, and GBO: 100% in DA. The IDH mutation and pTERT mutation were investigated in GBO: IDHwt/TERT+ 87.5%, IDHwt/TERT- 64.3%, IDHmt/TERT- 100%, and in NS: IDHwt/TERT+ 75%, IDHwt/TERT- 33.3%, IDHmt/ TERT- 20% in NS. In addition, establishment was observed in GBO 2 case in medulloblastoma, 1 case in ependymoma.
Discussion and Conclusion: This suggest that GBO can be used to establish culture models for low-grade tumors. In addition, GBO can establish culture earlier, so it is expected to be applicable to personalized therapies such as preclinical drug efficacy studies tailored to individual patients.
IM-7 Identification of novel glioblastoma specific antigen using patient derived tumor cell for CAR-T cell therapy
Authors: Nakagawa Tomoyoshi , Kijima Noriyuki , Hasegawa Kana , Kuroda Hideki , Hirayama Ryuichi , Okita Yoshiko , Kagawa Naoki , Kanemura Yonehiro , Hosen Naoki , Kishima Haruhiko 
Published: December 2021

Abstract
Chimeric antigen receptor T (CAR-T) cell therapy is a newly developed antitumor immunotherapy presenting remarkable clinical response with leukemia, and is expected to be applied to other malignant solid tumors including glioblastoma (GBM). However, for development of CAR-T therapy against GBM, identification of novel and suitable tumor specific antigen is required to expect higher therapeutic efficacy. Herein, we developed our original method to detect novel GBM specific antigen using patient derived GBM (PD-GBM) cells. First, BALB/c mice were immunized by footpad injection of PD-GBM cells. B cells were extracted from lymph nodes of the mice, fused with murine myeloma cells, and then cultured to produce monoclonal antibodies for GBM cells. About 500 GBM binding monoclonal antibody lines were established, and then each antibody was again analyzed by flow cytometry with multiple PD-GBM cells and human non-tumor brain cells to find out GBM specific antibodies. Consequently, two GBM specific antibody lines were selected and genetically analyzed to identify the recognized antigen. CAR-T cells targeting the detected antigens were successfully generated, and the cytotoxicity against GBM cells was confirmed by chromium releasing assay and bioluminescent cytokine assay. Remarkably, one of the identified tumor specific antigens proved to be B7-H3, which is known pan-cancer antigen expected to be one CAR-T therapeutic target for malignant solid tumors, also expressed in most GBM cells. This result confirms that our experimental method using murine antigen-antibody reaction is feasible for detecting antigen as a novel CAR-T therapeutic target for GBM. Moreover, this method can also detect antigens derived from post-translational conformational changes such as glycosylation, which might have been overlooked by conventional methods. In addition, these results suggest our method using PD-GBM cells can identify potential targets of CAR-T therapy for each GBM patients respectively, thus leading to precision immunotherapy for GBM.
IM-8 Significance of IL-1 pathways in Glioblastoma
Authors: Kai Keitaro , Komohara Yoshihiro , Yamamoto Takahiro , Uekawa Ken , Takezaki Tatsuya , Kuroda Junichiro , Shinojima Naoki , Mukasa Akitake 
Published: December 2021

Abstract
Purpose: Previous studies have revealed that macrophages affect the prognosis of glioblastoma. However, there are still many unknown parts about the mechanism. In this study, we conducted an experiment with the aim of elucidating the mechanism by which tumor associated macrophages (TAM) work on tumors in the tumor microenvironment (TME).
Method: Experiments were carried out using two glioblastoma cell strains, T98G, and U251. For clinical data, we analyzed it based on databases such as Protein Atlas, Ivy Glioblastoma Atlas, brain TIME database.
Results: In 3D culture, we confirmed that IL-1β stimulation promoted glioblastoma cell proliferation and sphere formation. The addition of IL-1β increased mRNA expression of various cytokines such as IL-6 and CXCL8, and increased phosphorylation of STAT3 in arrays. When we administered IL-6 and CXCL8, the growth was significantly increased in cells administered with IL-6 and CXCL8. As a result, we speculated that STAT3 pathway and NFκB pathway via IL-6 and CXCL8 are involved in cell proliferation by IL-1β. In order to confirm these things, western blot was performed, and it was confirmed that phosphorylation of STAT3 and NFκB were increased. In addition, STAT3 inhibitors and NFκB inhibitors suppressed tumor growth. Clinically analysis was carried out based on the database, and it was found that IL-1β and macrophages were related. Furthermore, IL-1β was found in many cases around tumor necrosis.
Discussion: This study clarifies some of the effects of IL-1β on glioblastoma. However, there are still many unknown points, and it is necessary to continue to consider them in the future.
ACT-1 Multicenter investigator-initiated registration-directed Phase 2 study of E7090 in subjects with advanced or recurrent solid tumors with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial
Authors: Takahashi Masamichi , Chiba Yohei , Sudo Kazuki , Kojima Yuki , Okuma Hitomi , Kohsaka Shinji , Ichimura Masahiko , Okita Natsuko , Nakamura Kenichi , Machida Ryunosuke , Kinoshita Ichiro , Takahashi Masanobu , Matsubara Junichi , Kusaba Hitoshi , Yonemori Kan 
Published: December 2021

Abstract
Background: Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, 2021), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods: The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043, ClinicalTrials.gov: NCT04962867)
ACT-3 Reactor-based boron neutron capture therapy with add-on bevacizumab for recurrent malignant glioma: The final report
Authors: Furuse Motomasa , Kawabata Shinji , Wanibuchi Masahiko , Shiba Hiroyuki , Takeuchi Koji , Kondo Natsuko , Tanaka Hiroki , Sakurai Yoshinori , Suzuki Minoru , Ono Koji , Miyatake Shin-Ichi 
Published: December 2021

Abstract
Background: Re-irradiation had a higher rate of radiation injury because recurrent MG had already irradiated in the first-line treatment. Recently, combination therapy of re-irradiation and bevacizumab showed a lower incidence of radiation injury than re-irradiation alone. Boron neutron capture therapy (BNCT), a tumor-selective particle radiation therapy, also increased radiation injury for recurrent MG, despite the greater focus on tumor cells. In this study, we evaluated the efficacy of BNCT plus bevacizumab with early induction after BNCT.
Methods: Patients with recurrent MG were prospectively enrolled in this study. BNCT was performed using Kyoto University Research Reactor as a neutron source. Bevacizumab of 10 mg/kg was initiated 1–4 weeks after BNCT and was continued every 2–3 weeks until disease progression. Newly-diagnosed (de novo) glioblastoma was categorized as primary GBM (pGBM). Other MG were categorized as non-pGBM.
Results: Kyoto University Research Reactor stopped irradiation for clinical use in February 2019. Twenty-five patients (14 pGBM and 11 non-pGBM) were treated with this combination therapy between June 2013 and February 2019. The median Overall survival (OS) after BNCT was 21.4 months for pGBM and 73.6 months for non-pGBM, respectively (p = 0.0428). The median progression-free survival (PFS) after BNCT was 8.3 months for pGBM and 15.6 months for non-pGBM, respectively (p = 0.0207). The objective response rate was 72 %. Alopecia occurred in all patients. Adverse events ≥ grade 3 were grade 3 proteinuria in four patients, grade 5 myocardial infarction in one patient, and grade 5 meningitis in one patient.
Conclusion: BNCT plus bevacizumab showed a long OS and a long PFS, compared to our previous studies of BNCT alone for recurrent MG. Bevacizumab could provide beneficial effects not only for tumor itself, but also radiation injury. Further research with a larger sample using accelerator-based BNCT and bevacizumab is required to elucidate the efficacy and safety of this combination therapy.
ACT-8 Current status and prospects for the treatment of malignant glioma using cancer gene panel tests
Authors: Koizumi Shinichiro , Makita Ippei , Sameshima Tetsuro , Kurozumi Kazuhiko 
Published: December 2021

Abstract
Introduction: The cancer gene panel test was covered by insurance in June 2019. Our institution started the test in May 2020 and has experienced 10 cases, so we will report on the current status and future prospects. Methods: The subjects were 10 patients who underwent the cancer gene panel test using FoundationOne CDx. Results:The cases included 8 glioblastomas, an anaplastic astrocytoma, and an anaplastic oligodendroglioma. The total number of tumor mutational burden (TMB) was judged to be low in all cases, and the microsatellite instability test (MSI) showed no instability in all cases (MSI-Stable). The total number of genetic changes detected was 11 ± 5.0, oncogene mutations were 5.3 ± 2.4, and gene mutations of unknown relevance to cancer were 5.7 ± 2.8. Major oncogene mutations were IDH1 mutation in 4 cases, ATRX mutation in 2 cases, TP53 mutation in 6 cases, and BRAF V600E mutation in 1 case. Based on the test results, a 25-year-old man with BRAF V600E mutation was initiated into the NCCH1901 study (Patient-Proposed Healthcare Services). A case with IDH1 mutation (47-year-old male) entered a phase I clinical trial of a mutant IDH1 inhibitor. It is estimated that the chance of finding an appropriate drug by cancer gene panel test is about 10–20%. However, in cases that are resistant to standard treatment, the benefits can be expected if the drugs associated with the cancer gene panel test can be used. Conclusions: Although Malignant gliomas are often TMB-low and MSI-stable and the response rate to molecular-targeted drugs and other therapies is not high, there are some cases that can be salvaged by performing the cancer gene panel test. It is suggested that the active use of cancer gene panel test may contribute to the development of new drugs with high response rates and the improvement of prognosis.
PEDT-9 A study of NovoTTF-100A to expand the regulatory indication for childhood glioblastoma through a pediatric clinical trial based on the Advanced Medical Care system
Authors: Yuza Yuki , Nishikawa Ryo , Terashima Keita , Fujisaki Hiroyuki , Kurihara Jun , Morikawa Yoshihiko , Ihara Satoshi , Makimoto Atsushi 
Published: December 2021

Abstract
Background: Tumor-treating fields (TTF) are alternating electric fields applied continuously to the brain by attaching 2-pair arrays on the scalp. Although TTF therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. In Japan, off-label use of medical devices is almost impossible because the national health insurance system does not cover the cost of off-label use of drugs and medical devices. Therefore, TTF therapy cannot be applied to the treatment of pediatric GBM.
[Objectives] The investigator-initiated clinical trial aims to expand regulatory approval of TTF therapy for pediatric GBM treatment based on safety and exploratory efficacy data.
Methods: Patients aging between 5 and 17 years with histopathological diagnosis of GBM (either newly diagnosed or first-recurrence), which located in the supratentorial region would be included. All the patients will receive TTF therapy for 28 days per course for up to 26 courses until the end-of-therapy criteria are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various time-to-event measures and QoL. In total ten patients will be enrolled.
Current Status: Discussions with the Pharmaceuticals and Medical Devices Agency (PMDA) led to a tentative consensus that the accumulated data on the efficacy of NovoTTF-100A for adult GBM may be extrapolatable to pediatric GBM if the trial is able to demonstrate efficacy equivalent to that found in previous, adult studies. On the other hand, the combination of the pediatric safety data gathered in this trial and the findings of international studies, including clinical trials and post-marketing surveillance studies, may expedite approval of the device for pediatric GBM treatment. The trial started patient enrollment in April, 2021 with the supervision of the Advanced Medical Care administration system and is currently awaiting the first eligible patient.
STMO-14 Clinical experience of brain tumor surgery using middleware “OPeLiNK”
Authors: Fujii Yu , Ogiwara Toshihiro , Goto Tetsuya , Muragaki Yoshihiro , Hongo Kazuhiro , Horiuchi Tetsuyoshi 
Published: December 2021

Abstract

PURPOSE
The removal of brain tumors requires not only imaging information such as MRI and navigation systems, but also a variety of other information such as neurological function and biological information. To integrate this information, a novel operating room, “Smart Cyber Operating Theater (SCOT)”, which connects the medical devices in the operating room via a network has developed. In this SCOT, the intraoperative information is time-synchronized, recorded, and stored by the middleware “OPeLiNK”. Clinical experience of brain tumor surgery using OPeLiNK in our institute is reported.

Methods
Brain tumor surgeries performed at SCOT, which had been started since July 2018, was enrolled. In all surgeries intraoperative information was integrated by OPeLiNK. Surgical procedure was discussed between main surgeon and supervising surgeon in the Strategy Desk through OPeLiNK intraoperatively, if necessary. Clinical and radiological data from patients who underwent resection at SCOT were analyzed retrospectively.

Results
Sixty patients were involved. Histopathological diagnosis was glioma in 29 patients, pituitary adenoma in 29 patients, acoustic tumor in 1 patient and intravascular lymphoma in 1 patient. Intraoperative discussion with Strategy Desk through OPeLiNK was useful for not only surgeons but also for medical staff in operation room. Advice for extent of resection and craniotomy from Strategy Desk was conducted by OPeLiNK using conversation and drawing. Intraoperative comment was useful for postoperative review. OPeLiNK, which display multiple intraoperative information, was also used at postoperative conference.

Conclusion
We have reported clinical experience with OPeLiNK for brain tumor surgery in our institute. OPeLiNK was useful for not only sharing intraoperative information with doctors outside the operation room but also postoperative review and education for young doctors.