bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of laboratory holding time and diet type on labile traits in the crabCancer irroratusSay, 1817 (Decapoda: Brachyura: Cancridae)
Authors: Matveev Evgeni , McGaw Iain J
Published: December 2021

Collecting animals from the field and bringing them into the laboratory elicits acute and chronic stress responses that may affect the interpretation of experimental outcomes. The effects of prolonged laboratory holding (three months) on labile traits (metabolic rate and spontaneous activity) were quantified for the Atlantic rock crab Cancer irroratusSay, 1817. The effects of diet (heterogenous versus homogenous) on crab condition (hemolymph protein density, crab mass, and chelal compression strength) were also assessed. When offered a heterogeneous diet C. irroratus displayed a clear preference for mussels and an aversion to herring and algae. The amount crabs ate in the laboratory was negatively correlated to the density of hemolymph protein at the time of collection, which affirms the strong link between nutritional status and hemolymph protein in crustaceans. It also suggests that crabs in good nutritional condition may forgo eating even a high-quality meal if they are stressed. Overall, providing a heterogenous diet did not significantly improve survival rates or affect labile-trait responses in crabs. In contrast, prolonged holding in the laboratory had considerable effects on labile traits: resting metabolic rate (RMR) was highest after one week, but declined over the holding period. There was also a reduction in variation of locomotor activity for approximately 4 weeks. Acute stress responses (increased RMR and activity) also occurred after transfer from holding tanks to experimental chambers, likely due to animal handling. Given the increasing attention paid to animal sentience and welfare, especially for decapod crustaceans, the amount of time that wild crustaceans are held in the laboratory should be considered carefully.
Polyphenism in Antennal Sensilla Among Different Adult Morphs of Nonhost-Alternating, Holocyclic Sitobion avenae (Hemiptera: Aphididae)
Authors: Wu Yuting , Wu Mengchu , Hui Zi , Hu Xiangshun , Xu Xiangli
Published: December 2021

Aphids, mainly distributed in temperate zones, exhibit seasonal generation-alternating phenomena. Across the life cycle, different morphs are produced. Sitobion avenae (Fabricius 1775) is a major pest of wheat worldwide. To elucidate olfactory perception of morph-specific behavior across their life cycle, we investigated antennal sensilla among seven morphs using scanning electron microscopy. Trichoid, placoid, coeloconic, and campaniform sensilla were identified. Trichoid sensilla, big multiporous placoid sensilla (primary rhinarium), a group of sensilla (primary rhinaria), and campaniform sensilla showed similar distribution and resemblance among morphs, whereas small multiporous placoid sensilla (secondary rhinaria) exhibited obvious differences. Compared to apterous morphs, alate morphs possessed a greater abundance of secondary rhinaria, with the greatest found in males on antennal segments III–V. Alate virginoparae and alate sexuparae ranged from six to fourteen rhinaria on antennal segment III. Fundatrices, apterous virginoparae and apterous sexuparae only had one or two secondary rhinaria on antennal segment III while they disappeared in oviparae. Secondary rhinaria, lying in a cuticle cavity, are convex or concave in their central part. In males, both forms were present, with a greater proportion of convex form than that of the concave form. Fundatrices and virginoparae had the convex form while sexuparae had the concave form. Polyphenism of secondary rhinaria might suggest their association with the olfactory functions of morph-specific behavior. These results have improved our understanding of the adaptive evolution of the antennal sensilla in nonhost-alternating, holocyclic aphids.
IL2 Neural stem cell regulation and brain development
Authors: Gotoh Yukiko
Published: December 2021

Quiescent neural stem cells (NSCs) in the adult mouse brain are the source of neurogenesis that regulates innate and adaptive behaviors. Adult NSCs in the subventricular zone (SVZ) are derived from a subpopulation of embryonic neural stem-progenitor cells (NPCs) that is characterized by a slower cell cycle relative to the more abundant rapid cycling NPCs that build the brain. We have previously shown that slow cell cycle can cause the establishment of adult NSCs at the SVZ, although the underlying mechanism remains unknown. We found that Notch and an effector Hey1 form a module that is upregulated by cell cycle arrest in slowly dividing NPCs. In contrast to the oscillatory expression of the Notch effectors Hes1 and Hes5 in fast cycling progenitors, Hey1 displays a non-oscillatory stationary expression pattern and contributes to the long-term maintenance of NSCs. These findings reveal a novel division of labor in Notch effectors where cell cycle rate biases effector selection and cell fate. I will also discuss the heterogeneity of slowly dividing embryonic NPCs and the lineage relationship between adult NSCs and ependymal cells, which together form the niche for adult neurogenesis at the SVZ.
CBMS-5 One-carbon metabolism protect glioma cells under glutamine starvation through upregulation of MTHFD2
Authors: Tanaka Kazuhiro , Nagashima Hiroaki , Uno Takiko , Fujita Yuichi , Iwahashi Hirofumi , Sasayama Takashi
Published: December 2021

Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around pseudopalisading necrosis. Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results suggest new therapeutic targets for glioma cells adapting to a low-nutrient microenvironment.
GEN-7 Liquid biopsy in brain tumor patients -The present and future-
Authors: Natsumeda Manabu , On Jyotaro , Watanabe Jun , Tsukamoto Yoshihiro , Okada Masayasu , Oishi Makoto , Fujii Yukihiko
Published: December 2021

We have previously published liquid biopsy for the diagnosis of brain tumors including PCNSL (JCO Precision Oncology, 2019; Leukemia and Lymphoma, 2019) and diffuse midline gliomas (DMG) (Diagnostics, 2021). We used the Maxwell RSC cfDNA extraction kit to extract circulating tumor DNA (ctDNA from) 1 milliliter of cerebrospinal fluid (CSF), and droplet digital PCR to detect MYD88 L265P mutations in PCNSL and H3F3A K27M mutations in DMG. From our initial experience, we were able to detect a high rate of MYD88 mutations in PCNSL, but not H3F3A mutations in DMG. We also observed that higher concentrations of ctDNA were obtained when prompt centrifugation and storage were done after obtaining CSF. Application of liquid biopsy to early detection of relapse and monitoring of treatment relapse are highly anticipated. In cases of PCNSL, we perform liquid biopsy when relapse is suspected on post-contrast MRI. However interestingly, the rate of MYD88 mutations detected is lower than that of newly-diagnosed cases. We would also like to share our experience performing liquid biopsy in conjunction with CSF cytology in brain tumor patients with evidence of leptomeningeal disease. From our initial experience, we would like to discuss the present limitations and future prospects of liquid biopsy in brain tumor patients.
GEN-8 Real-time PCR based intraoperative genetic analysis for gliomas
Authors: Takabayashi Katsuhiro , Tateishi Kensuke , Hayashi Takahiro , Sasame Jo , Isoda Masataka , Miyake Youhei , Oshima Akito , Honma Hirokuni , Yamamoto Tetsuya
Published: December 2021

An individual therapeutic strategy based on the genetic characterization is important in gliomas. However, it has been difficult to obtain genetic features during surgery. In this study, we present an overview of intraoperative genetic analysis using modified real-time PCR method. The tumor specimen was crushed with liquid nitrogen, then extract DNA within 60 minutes. Reagents of real-time PCR for detecting IDH, TERT, and BRAF hot spot mutations were stocked and real-time PCR was performed after mixing the extracted DNA. We used PNA and LNA to detect single nucleotide variant (SNV). The average time from tumor extraction to intraoperative tentative judgement was approximately 100 minutes. Using this system. we preliminary performed intraoperative genomic analysis in10 glioma patients. We confirmed that 8 of 10 cases (80%) of intraoperative genomic diagnosis were consistent with post-operative diagnosis by Sanger sequencing. However, we experienced 2 (20%) unmatched cases due to low allele of SNV, which indicates that more advanced system is required for clinical application.
ET-6 Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax
Authors: Yamamoto Masahiro , Kitanaka Chifumi
Published: December 2021

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

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

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

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

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

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

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

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

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

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

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.
STMO-21 The Outcome of tumor resection followed by photodynamic therapy for recurrent glioblastoma
Authors: Kobayashi Tatsuya , Nitta Masayuki , Shimizu Kazuhide , Saito Taiichi , Maruyama Takashi , Komori Takashi , Muragaki Yoshihiro , Kawamata Takakazu
Published: December 2021

Recurrent glioblastoma remains a clinical problem with no standard treatment and quite a few effective treatment options. We evaluated the efficacy of photodynamic therapy (PDT) using talaporfin sodium (TS) as a treatment for recurrent glioblastoma in a retrospective analysis of 70 patients who underwent PDT with surgery (PDT group) between 2014 and 2018, and 38 patients who underwent surgery alone (control group) during the same period. The median overall survival (OS) of the PDT and control groups were 16.03 and 12.75 months, respectively (P=0.0311). The median progression-free survival (PFS) of these two groups were 5.67 and 2.2 months, respectively (P=0.00428). Univariate and multivariate analyses showed PDT with surgery and preoperative Karnofsky Performance Scale as significant independent prognostic factors for both PFS and OS.On the other hand, IDH mutation and previous pathology before recurrence were not significant prognostic factors in this study. In the PDT group, there was no significant difference in PFS and OS between patients with GBM from the previous pathology before recurrence and those with malignant transformation to GBM from lower-grade glioma. Furthermore, there was also no significant difference in TS accumulation in the tumor between these two groups. These results suggest that additional PDT treatment for recurrent glioblastoma can have potential survival benefits and that its efficacy is independent of the pathology before recurrence or IDH status.
NI-8 Molecular diagnostic prediction combining T2-FLAIR mismatch sign, calcification, and methionine PET in grade II and III gliomas
Authors: Ebiko Yusuke , Tamura Kaoru , Hara Shoko , Inaji Motoki , Tanaka Yoji , Nariai Tadashi , Ishii Kenji , Maehara Taketoshi
Published: December 2021

Background: The 2016 WHO Classification classified grade II and III gliomas into three molecular subtypes depending on the presence of IDH mutation and 1p/19q codeletion. We combined T2-FLAIR mismatch sign, tumor calcification, and methionine PET uptake to examine whether molecular diagnosis could be predicted.

Methods: 53 grade II and III glioma patients with preoperative MRI, CT, and MET-PET who underwent surgical resection or biopsy during 2000–2019 were included in this study. Out of the 53 cases, astrocytic tumors (A group: IDH-mutant, 1p19q non-codeleted) were 17, oligodendroglial tumors (O group: IDH-mutant, 1p19q codeleted) were 15, and IDH wild tumors (W group) were 21. MR and CT scans were evaluated by 3 independent reviewers to assess presence/absence of T2-FLAIR mismatch sign and calcification in the tumor, respectively. The tumor-to-normal (T/N) ratio of methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain.

Results: Out of the 53 cases, T2-FLAIR mismatch sign was present in 6 cases in group A and 9 cases in group W (p=0.008). Calcification in tumor was present in 2 cases in group A, 7 cases in group O, and 3 cases in group W (p=0.046). In the T2-FLAIR mismatch-positive cases, assuming MET-PET T/N>1.401 was group W and <1.401 was group A, sensitivity was 100% and specificity was 67%. In the T2-FLAIR mismatch-negative and calcification-positive cases, assuming those group O, the diagnostic predictive value was 70%. In the T2-FLAIR mismatch-negative and calcification-negative cases, assuming MET-PET T/N>2.349 was group W and <2.349 was group A or O, sensitivity was 60% and specificity was 94%.

Conclusions: Combined diagnostic prediction of T2-FLAIR mismatch, calcification, and MET-PET T/N may be useful for preoperative molecular diagnosis of grade II and III gliomas.
NI-16 Verification of APT image and relationship with T2/FLAIR mismatch sign in WHO2016 brain tumor pathology classification
Authors: Shirota Masami , Nitta Masayuki , Saito Taiichi , Tsuduki Syunsuke , Fukui Atsushi , Ikuta Souko , Yoshida Ayako , Muragaki Yoshihiro , Kawamata Takakazu
Published: December 2021

Introduction: Amide Proton Transfer Imaging(APT)is an MRI imaging method that images the increased concentration of amide groups in tumors and is expected to be clinically applied to the diagnostic imaging of gliomas.On the other hand,T2/FLAIR mismatch sign(T2/FLms)has been proposed as an MRI finding specific to astrocytoma with IDH gene mutation.This time,in the WHO2016 Brain Tumor Pathological Classification,we report the verification of the pathological gene classification of APT and the retrospective verification based on the pathological diagnosis results of whether there is a relationship between APT and T2/FLms. Method: We examined 88 cases of preoperative glioma (Grade:G2/3/4)in which APT/T2/FLAIR was imaged.resultIt showed a high value in high malignancy and a significant difference was observed.In the verification of genetic classification, the measured APT values were 1.91 ±0.71 for oligodendroglioma(16 cases),2.58±0.17 for astrocytoma(2 cases),2.40±0.90 for anaplastic oligodendroglioma(12 cases),Anaplastic astrocytoma(20 cases)2.63±0.42,The oligodendroglioma system showed lower values than the astrocytoma system.For anaplastic astrocytoma IDH mutant and glioblastoma IDH mutant,APT measurement values were measured after evaluating the presence or absence of T2/FL ms. APT measured values are anaplastic astrocytoma IDH mutant T2/FL ms present(7 cases) 2.63±0.38,T2/FL ms not (5 cases) 2.76±0.37, glioblastoma IDH mutant T2/FL ms present(5 cases)2.67±0.50, no T2/FL ms(3 cases)3.48±0.27,suggesting low APT measured values with T2/FL ms,respectively.ConclusionIn the verification of genetic classification, the oligodendroglioma system shows a lower value than the astrocytoma system,and it is considered that it can be one of the options such as treatment policy.Regarding the relationship between T2/FL ms and APT,it was suggested that the APT measured value with T2/FL ms tended to be low,but since it wasreported that the sensitivity of T2/FL ms was 30%,it was verified by accumulating cases.is required.
NQPC-7 Rehabilitation program toward reinstatement support based on network construction among related departments for the patients after treatment of brain disease including brain tumor
Authors: Ideguchi Makoto , Matsutani Masao , Sato Akira , Muraya Shoichi , Takahashi Toshiko , Omata Akiko
Published: December 2021

Introduction: We have conducted a rehabilitation program to support a return to work for patients with brain disease since 2019. The program focuses on independence in the home environment; physical ability for desk work, commuting and conversation; and concentration and executive ability in the office. The “Promotion of Health and Employment Support” document of the Ministry of Health, Labour and Welfare has been used to update the program since May 2021. Here, we report the status of this program.Methods: Patients desiring employment reinstatement attended the program. A doctor first gave an overview. Social workers then used the QLQ-C30/BN-20 questionnaire to assess mental and physical health, a therapist evaluated physical and higher cognitive function, and nurses advised on work-life balance and mental state. This information was used to develop suitable rehabilitation for each patient. The employment situation was surveyed after discharge. Results: The program included 77 patients (55 men, 22 women, mean age 54) from January 2019 to July 2021, after treatment for stroke (n=55), brain tumor (n=14), and traumatic brain injury or other conditions (n=8). FIM (94.2) and MMSE (26.3) at admission indicated that almost all patients were independent in ADL. A return to work was achieved by 25 (83%) of the 30 patients that could be investigated, including all 4 with brain tumors. The period until reinstatement was <1 month in 16 cases, but >1 month in 3 with brain tumors. The program was found useful by 26 patients (86%). Employment reinstatement was not achieved due to company reasons and family circumstances. Only 4 patients were interviewed by an industrial physician. Conclusion: The physical and cognitive functions of patients wishing for employment reinstatement were relatively well maintained. Cooperation with the company, information sharing with an industrial physician, and adjustment to the home environment were also important for reinstatement.
ML-13 Primary central nervous system malignant lymphoma in a patient with rheumatoid arthritis receiving tocilizumab
Authors: Ohno Masasuke , Kuramitsu Syunichiro , Ito Syohei , Kimata Masayuki , Asai Takumi , Suzaki Noriyuki , Kajita Yasukazu , Takahashi Tastuo
Published: December 2021

Background: Although the risk of developing malignant lymphoma is higher in patients with rheumatoid arthritis (RA) than in the general population, the occurrence of primary central nervous system lymphoma (PCNSL) in patients with RA is extremely rare. In recent years, there has been concern that biological disease-modifying antirheumatic drugs (DMRADs), which are widely administered to patients with RA, may increase the risk of developing cancer. We report the first case of PCNSL in a patient with RA who was treated with the biological DMRADs, tocilizumab. Case description: A 70-year-old man, who was diagnosed with RA in 2010 was treated with low-dose methotrexate from 2010 to 2015. He was started on tocilizumab in 2012. In 2018, he suffered from gait disturbance and was diagnosed with lumbar spinal stenosis. He underwent L2/3 posterior fusion surgery, but his paraplegia gradually deteriorated. Two months after the surgery, a head Gd-MRI showed multiple contrast-enhanced lesions in the basal ganglia and brain stem. A stereotactic brain biopsy was performed and DLBCL was diagnosed, and finally PCNSL was diagnosed because of no neoplastic lesions in other organs. He was treated with 5 courses of MTX 3.5g/m2 with rituximab and has been in remission for 23 months. He has maintained an independent life with residual paraplegia, but his ADLs gradually worsened. He was restarted on tocilizumab with a diagnosis of worsening RA. Conclusion: Low-dose methotrexate and biological DMRADs including tocilizumab, have been concerned to increase the risk of cancer in patients with RA, but there is no solid evidence. Since it has been a short time since the use of biological DMRADs, further accumulation of cases and careful follow-up are necessary.
ML-18 High-dose chemotherapy supported by autologous stem cell transplant in relapsed and refractory primary CNS lymphoma
Authors: Nagane Motoo , Sasaki Nobuyoshi , Saito Kuniaki , Kobayashi Keiichi , Onoda Ryo , Seiya Yosuke , Yamagishi Yuki , Nakatomi Hirofumi , Ohnishi Hiroaki , Takayama Nobuyuki , Shiokawa Yoshiaki
Published: December 2021

While whole brain radiation therapy (WBRT) has been performed as consolidation therapy in primary central nervous system lymphoma (PCNSL), high-dose chemotherapy supported by autologous stem cell transplant (HDC/ASCT) is widely investigated today as an alternative treatment strategy, given the high risk for radiation-induced neurotoxicity in WBRT. Various conditioning regimens have been investigated in phase II trials, which report non-inferiority of HDC/ASCT in efficacy and preservation of neurocognitive function in comparison with WBRT. Besides its promising efficacy, treatment-related deaths are reported in 11% in patients treated by a conditioning regimen using thiotepa, busulfan and cyclophosphamide (TBC), which raises a concern for safety. Among several conditioning regimens, analysis using registry data of Japan Society for Hematopoietic Cell Transplantation has revealed that the use of conditioning regimens containing thiotepa was a positive factor for longer PFS. According to the result of a phase I trial in Japan which investigated HDC/ASCT using thiotepa and busulfan (BuTT), thiotepa was approved by the pharmaceuticals and medical devices agency (PMDA) on March 2020. In comparison with the TBC regimen, cyclophosphamide is omitted, and the dose of thiotepa is lower (250 mg/m2, 3 days in TBC; 5 mg/kg, 2 days in BuTT) in BuTT, therefore BuTT could be less toxic in comparison with TBC, and no treatment-related deaths were observed in the phase I study in Japan. Further investigation on the efficacy and safety of BuTT in actual clinical practice is warranted. We have constituted a multi-disciplinary team in our institution in order to perform HDC/ASCT using BuTT in relapsed/refractory PCNSL. Treatment indications are as follows; 65 years old or younger, previously treated by rituximab, methotrexate, procarbazine and vincristine (R-MPV), good organ function and neurological status. Future directions along with preliminary treatment results will be discussed at the meeting.
MET-3 A Case of Intrapituitary Adenoma Metastasis from Advanced gastric cancer
Authors: Fujita Shohei , Kawanishi Yu , Fukuda Hitoshi , Fukui Naoki , Ueba Tetsuya
Published: December 2021

Metastasis from extracranial tumor into a pituitary adenoma is a rare case. We report a case of metastasis from gastric cancer to a giant pituitary tumor. A 65-year-old man had been drinking more water and had an increased frequency of urine in 10 years. From that time, the patient was gradually aware of the pain in his left eye. In 20XX the patient had a sudden severe headache and pain of his eyes and visited an ophthalmologist. The patient was referred to our institution with general malaise and nausea, vomiting. A cerebral MRI disclosed Extensive neoplastic lesions from the base of the skull to the nasal cavity. The left eye had esotropia and abduction disorder. Laboratory test demonstrated hyponatremia (Na 126mEq/L) and decreased in plasma osmolality (273mOsm/kg), D-dimer, fibrinogen and CA19-9 were high level. One week after admission, the patient’s symptom was getting worse. The patient underwent FDG PET/CT, which showed FDG avid in the gastric wall and clivus tumor. The lesion was suspected gastric cancer and performed Esophagogastroduodenoscopy. The biopsy-based pathology was showed cubic and round cells with high NC ratio and signet-ring cells containing mucin. And clivus tumor was biopsied at an otolaryngologist because part of the tumor was exposed from the nasal cavity. The biopsy-based pathology was showed a small amount of adenocarcinoma cells which is surrounded by pituitary adenoma. The patient was diagnosed as intrapituitary adenoma metastasis from advanced gastric cancer and has been started radiation therapy. But the level of consciousness dropped sharply, so radiation therapy had become difficult to continue. The patient transferred to palliative care ward and died 3 months after his first visit. In this case, diagnosis and treatment were difficult due to the that the image was a finding a malignant tumor and the rapid progression of symptoms.