bluuebunny/crossref_metadata_2025_split huggingface dataset:
TB-8 Genetic and molecular properties of long-term proliferating tumorsphere -forming glioma derived cells
Authors: Kijima Noriyuki , Kanematsu Daisuke , Shofuda Tomoko , Yoshioka Ema , Yamamoto Atsuyo , Handa Yukako , Fukusumi Hayato , Katsuma Asako , Sumida Miho , Moriuchi Shusuke , Nonaka Masahiro , Okita Yoshiko , Tsuyuguchi Naohiro , Uda Takehiro , Kawashima Toshiyuki , Fukai Junya , Kodama Yoshinori , Mano Masayuki , Higuchi Yuichiro , Suemizu Hiroshi , Kanemura Yonehiro 
Published: December 2021

Abstract
Long-term proliferating tumorsphere-forming glioma derived cells (LTP-TS-GDCs) and patient derived xenografts (PDXs) are essential tools for translational research for glioma. However, only small subsets of glioma samples are established as LTP-TS and/or PDXs and little is known about the genetics and molecular properties of LTP-TS -forming GDCs and PDX. In this study, we aim to analyze the characteristics of LTP-TS -forming GDCs and PDXs. We tried primary sphere cultures from 56 glioma patient-derived samples and established 11 LTP-TS-GDCs out of 45 glioblastoma samples and no long-term sphere culture was isolated from grade3 and grade 2 gliomas. LTP-TS-GDCs had self-renewal ability and possessed certain multipotency. However, they significantly less expressed SOX1 FOXG1 and TUBB3, whereas they expressed LGALS1 and EN1 significantly higher than normal neural stem/progenitor cells. In addition, we found that LTP-TS-GDCs shared the same genetic profiles with original patients’ tumors. Furthermore, we investigated the genetic differences between the glioma tissues which were successfully established as LTP-TS-GDCs and those which were not. We found that glioma tissues with TERT promotor mutations and triple copy number alteration (CNA) [EGFR, CDKN2A, and PTEN loci] are significantly established as LTP-TS-GDCs. Lastly, we next investigated in vivo characteristics of glioma PDXs. We have injected glioma PDXs lines into immunodeficient mice brains and histopathologically analyzed the characteristics of xenografts. Each xenograft well recapitulated histological features of original patients’ tumors and tumor cells remarkably invade through subventricular zone. In conclusion, each LTP-TS-GDCs and PDXs had various gene expression profiles, reflecting intratumoral and interpatient heterogeneities of glioma. In addition, TERT promotor mutations and triple CNA significantly correlated with success rate of LTP-TS-GDCs. These findings will be of use and advance the preclinical and translational researches of glioma.
IM-4 Impact of oHSV activated NOTCH signaling in tumor microenvironment and its impact on anti-tumor immunity
Authors: Yoshihiro Otani , Yoo Ji Young , Lawler Sean E , Chiocca Antonio E , Kaur Balveen 
Published: December 2021

Abstract
Oncolytic herpes simplex virus-1 (oHSV) is novel FDA-approved immunotherapy for advanced melanoma patients in US. Also, oHSV is recently approved for the treatment of recurrent GBM in Japan. We have shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells via HSV-1 microRNA-H16 (Otani Y and Yoo JY, Clin Cancer Res, 2020), however, the consequences of NOTCH on immunotherapy in GBM is unknow. Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment (TME). Analysis of TCGA GBM data and experimental murine models revealed NOTCH induced immunosuppressive myeloid cell recruitment and limited anti-tumor immunity. In oHSV treated tissue, viral infection educated tumor associated macrophages to secrete CCL2 which recruited monocytic myeloid derived suppressor cell (MDSC) that attenuated anti-tumor immunity. Consistent with this, CCL2 induction was also observed in serum of recurrent GBM patients treated with oHSV (NCT03152318). Importantly, blockade of NOTCH signaling reduced the oHSV induced immunosuppressive environment and activated a CD8 dependent anti-tumor memory response. These findings present the opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity in GBM.
BOT-5 Chrysanthemum morifolium extract improves doxorubicin-induced cardiomyopathy by suppressing apoptosis in mouse heart
Authors: Ono Masaya , Mochizuki Saho , Tsuchitani Kanako , Iwashimizu Sonoka , Sunagawa Yoichi , Funamoto Masafumi , Shimizu Kana , Shimizu Satoshi , Katanasaka Yasufumi , Hasegawa Koji , Morimoto Tatsuya 
Published: December 2021

Abstract
Background: Doxorubicin is widely used for the treatment of various malignant tumors. However, doxorubicin causes cumulative and dose-dependent cardiotoxicity, ranging from occult changes in myocardial structure and function to severe cardiomyopathy and congestive heart failure. Since this problem affects the QOL and survival of cancer patients, solutions for this problem are urgently needed. Recently, it has been reported that Chrysanthemum morifolium extracts (CME) have antioxidant and anti-inflammatory activities. The purpose of this study is to clarify whether CME decreases doxorubicin-induced cardiotoxicity and prevents the development of heart failure. Methods and Results: H9C2 cardiomyoblast cells were treated with CME (0.3, 1 mg/mL) for 2 hours and then stimulated with doxorubicin. After 24 hours incubation, surviving cells were evaluated by MTT assay. CME dose-dependently decreased doxorubicin-induced cardiotoxicity in H9C2 cells. Western blotting showed that CME significantly suppressed doxorubicin-induced increases in four markers of apoptosis: p53, phosphorylated p53, and cleaved caspase-9 and -3. Next, to investigate the effects of CME on doxorubicin-induced cardiomyopathy in vivo, C57BL6 mice were orally administered with CME (400 mg/kg/day) or vehicle daily from 2 days before doxorubicin treatment and then treated once intraperitoneally with doxorubicin (20 mg/kg). The survival ratio of the CME-treated group was significantly higher than that of the vehicle-treated group. Echocardiographic analysis at 7 days after doxorubicin stimulation revealed that CME had significantly improved doxorubicin-induced left ventricular systolic dysfunction. Apoptotic cells in mouse heart tissue were detected by TUNEL assay, which showed that CME significantly suppressed doxorubicin-induced apoptosis. Discussion: These results indicate that CME decreases doxorubicin-induced cardiotoxicity both in vitro and in vivo, suggesting that CME might possess the therapeutic potency to reduce doxorubicin-induced cardiotoxicity in cancer patients. Further studies are required to assess the effectiveness of CME for preventing doxorubicin-induced heart failure in clinical settings.
ACT-6 Clinical manifestations of the patients with relapsed glioblastoma after bevacizumab treatment
Authors: Kikuchi Miyu , Takahashi Masamichi , Yanagisawa Syunsuke , Ono Makoto , Miyakita Yasuji , Tamura Yukie , Kawauchi Daisuke , Narita Yoshitaka 
Published: December 2021

Abstract
Introduction:The outcome of glioblastoma (GBM) is improving recently, but still only temozolomide and bevacizumab (BEV) are recognized as the effective agents that are reimbursed in Japan. On large clinical trials, BEV prolonged progression free survival (PFS) but the remaining survival period from the relapse after BEV is only 3–5 month. On this study, we retrospectively analyzed the data of GBM patients who were treated with BEV to explore the best usage of BEV.Methods:230 patients were diagnosed as GBM and received BEV from July 2013 to March 2021 in our institution. Among them, 104 patient, whose clinical courses were followed, were included in this study. (M:F=59:45, median age was 65.5) Results:The patients were divided into three groups by when they used BEV; upfront group at first line therapy, 1st relapse group at second line, and 2nd+ relapse group at more than third line. There were 42, 35, 27 patients in each group. The median overall survival (OS) was 17.6, 24.7, 46.1 month (p&lt;0.0001), median PFS after BEV treatment (PFSpBEV) was 8.8, 5.1, 5.0 month (p=0.2532), and the median survival after BEV treatment (OSpBEV) was 15.0, 9.9, 9.2 month (p=0.4437), respectively. There were 64 patients (22, 25, 17 in each group) who reached progressive disease (PD) after BEV. The median survival after PD (OSpBEVpPD) was 4.5, 5.8, 4.3 month (p=0.1590), respectively.Discussion:At the first onset, we use BEV only when the patients have low PS. Our results showed that OS was significantly longer when BEV was used in the later stage, but there was no significant difference in OS or PFS after BEV treatment. Especially OSpBEVpPD was 4–6 month regardless of the timing of BEV. To improve the treatment outcome of GBM, breakthrough therapy is needed in addition to optimizing the usage of BEV.
PEDT-1 Integrated diagnoses of pediatric gliomas in our institute by cIMPACT-NOW recommendations
Authors: Yamamura Toshihiro , Tamura Kaoru , Kobayashi Daisuke , Inaji Motoki , Tanaka Yoji , Maehara Taketoshi 
Published: December 2021

Abstract
Purpose:Since many genetic abnormalities in glioma have been revealed in recent years, Integrated diagnoses are necessary in the updated fourth edition of the WHO Classification of Tumors of the Central Nervous System(CNS) published in 2016. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classification. We retrospectively classified pediatric gliomas in our hospital in accordance with cIMPACT-NOW recommendations. Methods: This study includes 13 consecutive glioma patients under the age of 18 who underwent surgical resection at our hospital from 2000 to 2021. Histopathological diagnoses and molecular status such as IDH, H3F3A and BRAF were analyzed. Results: There were four females and nine males, ranging in age from 0 to 17 years, median 9.0 years. Three pilocytic astrocytomas (PA) and a polymorphous low-grade neuroepithelial tumor of the young (PLNTY) had BRAF fusion. Four cases were classified as Diffuse midline glioma, H3K27M-altered. Two cases were classified as Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. No genetic alteration was observed in two diffuse astrocytoma cases. An anaplastic oligodendroglioma case with PDGFRA amplification could not be classified as any new entity. All three PA cases with BRAF fusion occurred in cerebellum and all four H3K27M altered cases occurred in midline location such as thalamus, brainstem and cervical spinal cord. Six cases which were classified as pediatric-type diffuse high grade gliomas had poor prognosis. Conclusion:Genetic status is associated to tumor location and patients prognosis. Integrated diagnoses are important in pediatric glioma patients.
STMO-3 Mid- to long-term outcome of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study
Authors: Hirono Seiichiro , Ozaki Ko , Kobayashi Masayoshi , Hara Ayaka , Yamaki Tomohiro , Matsutani Tomoo , Iwadate Yasuo 
Published: December 2021

Abstract

Purpose
Mid- to long-term outcome in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection both of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-Met positron emission tomography (Met-PET), are not clarified.

Methods
A retrospective, single-center review was performed in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was completely resected. Only patients who were operated on until November 2019 were included for evaluation of mid- to long-term outcome. Following resection, all patients underwent standard radiotherapy and temozolomide treatment, and were followed for progression-free survival (PFS) and overall survival (OS).

Results
Among the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median PFS in the GTR and SupTR groups was 8.8 months (95% confidence interval [CI], 5.2–14.9) and 27.8 months (95% CI, 6.0-not estimable) respectively (p=0.08 by log-rank test). Median OS was 17.7 months (95% CI, 14.2–35.1) in GTR and not reached (95% CI, 30.5-not estimable) in SupTR, respectively; this difference was statistically significant (p=0.03 by log-rank test). No postoperative neurocognitive impairment was observed in SupTR patients.

Conclusion
Compared to GTR alone, SupTR strategy with aggressive resection of both CE tumors and Met uptake area in GBM patients under awake craniotomy with functional preservation results in a survival benefit associated with better local control.
STMO-12 Efforts for safe malignant brain tumor surgery at our hospital
Authors: Kobayashi Yusuke , Satou Yosuke , Kon Takashi , Tanioka Daisuke , Shimizu Katsuyoshi , Mizutani Tohru 
Published: December 2021

Abstract
Although maximal safe resection is the current standard for glioblastoma surgery, its safety and removal rate conflict with each other. Electrophysiological monitoring, such as motor evoked potential monitoring and awake craniotomy, can be utilized as safety measures; not all facilities can perform them. Herein, we present a representative case report on our efforts for a safe malignant brain tumor surgery.
Case: A 77-year-old woman with glioblastoma in the premotor cortex presented with seizure of the upper left lower limb. Her pyramidal tract ran from the medial bottom to the posterior of the tumor. We performed excision from the site using the lowest gamma entropy. We then removed all parts of the tumor, with the exception of the pyramidal tract infiltration, and no paralysis was observed. She was definitively diagnosed with glioblastoma and is currently on maintenance chemotherapy.
As a preoperative examination, we performed cerebrovascular angiography. We then performed various other tests to ascertain the patient’s condition. Considering lesions that affect language, Wada tests were performed regardless of laterality. For all patients with epilepsy onset, preoperative 256-channel electroencephalogram measurement and intraoperative the gamma entropy analysis were performed to confirm epileptogenicity. Considering lesions that affect eloquence, subdural electrodes were placed and brain function mapping was performed the next day. Based on the results, the safest cortical incision site and excision range were determined, and excision was performed on the following day.
Of the 14 operated glioblastoma cases after November 2018, more than 85% of the contrast-enhanced lesions were completely removed in 7 cases, partially removed in 5 cases, and underwent biopsy in 2 cases. Postoperative Karnofsky performance status scores remained unchanged in 11 cases, improved in 1 case, and deteriorated in 2 cases.
Our efforts have resulted in safe and sufficient removal of malignant brain tumors during surgery.
NI-12 The ratio of T1-Weighted to T2-Weighted Signal Intensity and IDH mutation in glioma
Authors: Sanada Takahiro , Yamamoto Shota , Sato Hirotaka , Sakai Mio , Saito Masato , Mitsui Nobuyuki , Hiroshima Satoru , Anei Ryogo , Kanemura Yonehiro , Nakanishi Katsuyuki , Kishima Haruhiko , Kinoshita Manabu 
Published: December 2021

Abstract
Introduction: Prediction of IDH mutation status for Lower-grade glioma (LrGG) is clinically significant. The purpose of this study is to test the hypothesis that the T1-weighted image/T2-weighted image ratio (rT1/T2), an imaging surrogate developed for myelin integrity, is a useful MRI biomarker for predicting the IDH mutation status of LrGG.
Methods: Twenty-five LrGG patients (IDHwt: 8, IDHmt: 17) at Asahikawa Medical University Hospital (AMUH) were used as an exploratory cohort. Twenty-nine LrGG patients (IDHwt: 13, IDHmt: 16) from Osaka International Cancer Institute (OICI) and 103 patients from the Cancer Imaging Archive (TCIA) / Cancer Genome Atlas (TCGA) dataset (IDHwt: 19, IDHmt: 84) were used as validation cohorts. rT1/T2 images were calculated from T1- and T2-weighted images using a recommended signal correction. The region-of-interest was defined on T2-weighted images, and the relationship between the mean rT1/T2 (mrT1/T2) and the IDH mutation status was investigated.
Results: The mrT1/T2 was able to significantly predict the IDH mutation status for the AMUH exploratory cohort (AUC = 0.75, p = 0.048). The ideal cut-off for detecting mutant IDH was mrT1/T2 &lt; 0.666 ~ 0.677, with a sensitivity of 58.8% and a specificity of 87.5%. This result was further validated by the OICI validation cohort (AUC = 0.75, p = 0.023) with a sensitivity of 56.3% and a specificity of 69.2%. On the other hand, the sensitivity was 42.9% and the specificity was 68.4 % for the TCIA validation cohort (AUC = 0.63, p = 0.068).
Conclusion: Our results supported the hypothesis that mrT1/T2 could be a useful image surrogate to predict the IDH mutation status of LrGG using two domestic cohorts. The decline of the accuracy for the TCIA cohort should be further investigated.
NI-14 estimation of property of MRI non-contrast enhanced lesion of Glioblastoma using T1/T2 ratio
Authors: Yamamoto Shota , Sanada Takahiro , Sakai Mio , Arisawa Atsuko , Shimosegawa Eku , Nakanishi Katsuyuki , Kanemura Yonehiro , Kagawa Naoki , Kishima Haruhiko , Kinoshita Manabu 
Published: December 2021

Abstract
Background: Tumor mass of glioblastoma is considered to exist beyond gadolinium-enhancing lesion into T2/FLAIR-high intensity lesions (T2/FL-HIL) on MRI. However, it is challenging to differentiate non-enhancing tumor region (NET) from pure brain edema for T2/FL-HIL. The T1/T2 ratio (rT1/T2) is an MRI metric considered to semi-quantify the tissue relaxation time on MRI. This research tested the hypothesis that rT1/T2 is useful for identifying NET within T2/FL-HIL by comparing it with 11C-methionine positron emission tomography (MET-PET). Method: Forty-six glioblastoma (GBM) patients at Osaka International Cancer Institute and Osaka University Hospital where T1-, T2- and contrast-enhanced T1-weighted MRI and MET-PET were available were included in this study. rT1/T2 maps were obtained after signal corrections were performed, as reported previously. Region-of-interests (ROIs) were defined within T2/FL-HILs beyond the gadolinium-enhanced lesion. MET-PET and rT1/T2 maps were co-registered to the same coordinate system, and the relationship between methionine uptake and rT1/T2 values was examined in a voxel-wise manner.ResultApproximately three million voxels were included for analysis. Lesions with methionine uptake higher than 5.0 on T/N showed 0.7 &lt rT1/T2 &lt 0.98. For those with methionine uptake higher than 3.0, rT1/T2 was between 0.70 and 1.04.DiscussionThis report suggested that rT1/T2 represents histological characteristics of the glioblastoma within T2/FL-HIL. It also indicated that rT1/T2 could be a useful biomarker for detecting NET within T2/FL-HIL for glioblastoma.
NI-19 A case of Leber’s hereditary optic neuropathy with diffuse white matter changes mimicking gliomatosis cerebri
Authors: Saruta Wakiko , Shibahara Ichiyo , Inukai Madoka , Kanayama Shunsuke , Akiyama Hisanao , Ishikawa Hitoshi , Sato Sumito , Hide Takuichiro , Kumabe Toshihiro 
Published: December 2021

Abstract
BACKGROUND: Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by bilateral severe subacute central vision loss and a mutation in the mitochondrial DNA (mtDNA). The cranial magnetic resonance imaging (MRI) of LHON patients varies from subtle to multiple white matter changes. However, they rarely present with diffuse infiltrative white matter changes. CASE REPORT: We report a case with diffuse white matter changes mimicking gliomatosis cerebri (GC). The histological findings included only mild glial hyperplasia without immunohistochemical positivity supporting the diagnosis of glial tumors. Analysis of mtDNA obtained from the blood and brain tissue revealed mutation of m.11778G&gt;A in the NADH dehydrogenase 4 gene, which confirmed the case as LHON. Immunohistochemistry of the brain tissue revealed 8-hydroxy-2’-deoxyguanosine positivity, suggesting the presence of oxidative stress. CONCLUSION: LHON is extremely difficult to diagnose unless we suspect or know the disease. The present case brings attention not only to LHON but other mtDNA mutated diseases that need to be considered with diffuse white matter changes or GC.
ML-3 A Case of Primary Central Nervous System Anaplastic Lymphoma Kinase Positive Anaplastic Large cell Lymphoma at Neurohypophysis and Pineal Gland
Authors: Kohno Shohei , Omae Ryo , Shinko Aiko , Takahashi Kazuya 
Published: December 2021

Abstract
The majority of primary central nerve system (CNS) lymphomas (PCNSL) are diffuse large B-cell lymphomas. Anaplastic large cell lymphoma (ALCL) that is a type of T-cell tumor is very rare in the PCNSL. ALCLs are divided into two entities: anaplastic lymphoma kinase (ALK)-positive and ALK-negative. We report a case of a 26-year-old woman who presented with a one month historyof headache and nausea. Magnetic resonance imaging (MRI) of the brain revealed pituitary and pineal gland mass diagnosed as ALK-positive ALCL by endoscopic brain biopsy. She underwent chemotherapy following methotrexate (MTX) and cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP). The follow-up contrast-enhanced brain MRI showed no recurrent lesion after chemotherapy. In previous reports, most of the lesions were in cerebral hemisphere, dura mater and spinal cord. Many of these patients were given primary diagnoses of meningitis. To our knowledge, there is no case report of initial diagnosis of germinoma due to lesions in Neurohypophysis and pineal gland as in this case.
ML-16 First clinical experience of administration of Tirabrutinib for the patients with newly diagnosed primary central nervous system lymphoma
Authors: Onodera Sho , Akimoto Jiro 
Published: December 2021

Abstract
Tirabrutinib (TIR), a Burton’s tyrosine kinase inhibitory drug, has been approved in Japan for treating relapsed/refractory primary central nervous system lymphoma (PCNSL). The authors recently encountered three patients with newly diagnosed refractory PCNSL using TIR.
Three patients, 48, 78 and 88 years-old males, diagnosed with PCNSL by histologically verification were firstly treated with high dose Methotrexate based chemotherapy (HD-MTX) and/or radiotherapy, however these cases were refractory for these standard treatments, demonstrated early cerebrospinal fluid dissemination or accompanied with severe adverse event. The authors decided to administrate TIR to these patients with a full informed consent. TIR demonstrated dramatic reduction of the volume of tumor on MRI within one month after administration of TIR, and improved the patient’s performance status. However, one case demonstrated liver dysfunction and multiple brain abscess due to aspergillus infection, and one case demonstrated early progression of the tumor 49 days after starting TIR.
Administration of TIR for the patients with newly diagnosed refractory PCNSL demonstrated a rapid and dramatic clinical response, and presented with several clinical implications for this complicated condition.