bluuebunny/crossref_metadata_2025 huggingface dataset:
CBMS-09 Intercellular communication at glioblastoma stem cell niches
Authors: Hide Takuichiro , Shirakawa Yuki , Jono Hirofumi , Shibahara Ichiyo , Inukai Madoka , Shinojima Naoki , Mukasa Akitake , Kumabe Toshihiro
Published: November 2020

Glioblastoma multiforme (GBM) contains heterogenous population of cells including a small population of GBM stem cells (GSCs), which potentially cause therapeutic resistance and tumor recurrence. GSCs harbored in special microenvironments, such as perinecrotic niche, perivascular niche, border niche. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. Stemness and chemo-radioresistance was promoted by not only additional mutation, but also microenvironment of GBM cells. Previously, we had reported that growth factors and cytokines secreted by oligodendrocyte lineage cells and macrophages/microglia induce stemness and chemo-radioresistance into GBM cells. Recently, Ito et al. reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans-differentiation toward multipotency. Ribosomal proteins exist intra- and extracellularly. There is a possibility that ribosomal proteins promote stemness into cancer cells, we focused on 40S ribosomal protein S6 (RPS6), which is related to cell proliferation in lung and pancreatic cancer, but not reported in GBM. RPS6 was significantly upregulated in high-grade glioma. SiRNA-mediated RPS6 knock-down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and stemness marker expression, such as Nestin and Sox2. RPS6 overexpression enhanced the tumorsphere potential of GSCs. Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data indicated that RPS6 was predominant detected at GSC niches, concurrently with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC-predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemo-radioresistance and GBM recurrence. These results suggested that intercellular communications through growth factors, cytokines, and ribosomes are regarded as new treatment targets of GBM.
CBMS-12 Pro renin receptor antibody regulates glioblastoma stemness
Authors: Fujimori Takeshi , Oagawa Daisuke , Kanda Takahiro , Suzuki Kenta , Shibayama Saki , Miyake Keisuke , Nishiyama Akira , Tamiya Takashi
Published: November 2020

Objective: Glioblastoma multiforme (GBM) is characterized by a strong self-renewal potential and poor differentiated state. We previously reported that (pro)renin receptor (PRR) was a potential target for glioma therapy by silencing the gene of PRR. Here, we have developed the monoclonal antibody of PRR and examined their effects on GBM. Materials and methods: We performed immunohistochemical analysis to detect the protein expression of PRR and SOX-2 in human sample of 56 gliomas. We used human glioma cell lines (U251MG and U87MG) and glioma stem cell line (MGG23) in vitro study. PRR antibody was designed to target the extracellular domain of the PRR with the rat lymph node method. Expression of the Wnt signaling components and stem marker (SOX-2, Oct3/4) in human glioma cell lines and glioma stem cell line treated with PRR antibody were measured using Western blotting. The effects of PRR antibody on cell proliferation, sphere formation, apoptosis, invasion were also examined. Subcutaneous xenografts with U87MG were induced in nude mice. Results: PRR expression showed a positive correlation with SOX-2 expression in glioma samples. Treatment with PRR antibody significantly reduced expression of Wnt signaling components and stem marker. We observed that PRR antibody significantly reduced cell proliferation and decreased sphere formation. Furthermore, PRR antibody suppressed invasion and induced apoptosis. In a subcutaneous U87MG xenograft model, systemic administration of the PRR antibody significantly reduced the size of the tumor volume. Conclusion: PRR has important role for the maintenance of stem cells and contribute to stem cell proliferation. PRR antibody inhibits cell proliferation and cell invasion and induces apoptosis. Treatment with PRR antibody could be an attractive therapeutic strategy for GBM.
GEN-14 Dual regulation of histone methylation by mTOR complexes drives the progression of EGFR-mutant glioblastoma
Authors: Masui Kenta , Harachi Mio , Muragaki Yoshihiro , Mischel Paul , Shibata Noriyuki
Published: November 2020

Trimethylation of histone H3 on lysine 27 (H3K27me3) is essential for ensuring proper gene expression and chromosomal function, and its aberration is associated with the pathogenesis of various brain tumors. However, it remains unclear how histone methylation is regulated in response to genetic mutation and intracellular metabolic status to facilitate the cancer cell survival in the most malignant IDH-wildtype glioblastoma (GBM). We herein report a novel mechanism of the specific regulation of H3K27me3 by cooperative action of two mechanistic target of rapamycin (mTOR) complexes in EGFR-mutant GBM. The level of H3K27me3 is significantly associated with the mutant EGFR signaling (EGFRvIII and EGFR amplification), and integrated analyses with histopathological, NGS and metabolome examinations revealed that both mTOR complexes (mTORC1 and mTORC2) upregulate H3K27me3 downstream of aberrant EGFR signaling. mTORC1 facilitates the protein translation of enhancer of zeste homolog 2 (EZH2), which is known as H3K27-specific methyltransferase. The other mTOR complex, mTORC2, remodels the metabolism of S-adenosylmethionine (SAM), an essential substrate for histone methylation. This synergistic mechanism causes H3K27 hypermethylation which subsequently promotes tumor cell survival both in vitro and in vivo mouse tumor model via regulation of the cell cycle-related tumor suppressor genes. The findings indicate that activated mTORC1 and mTORC2 complexes under aberrant EGFR signaling cooperatively contribute to the progression of IDH-wildtype GBM through specific epigenetic regulation, nominating them as an exploitable therapeutic target against cancer-specific epigenetics.
ET-04 Enhancing drug delivery with MRI-guided focused ultrasound for diffuse intrinsic pontine glioma model
Authors: Ishida Joji , Alli Saira , Bondoc Andrew , Fujita Naohide , Kullervo Hynynen , James Rutka
Published: November 2020

Diffuse intrinsic pontine glioma (DIPG) is surgically unresectable and one of the most devasting tumours in children. To date, there have been no effective chemotherapeutics against DIPG, despite a myriad of clinical trials. The intact blood-brain barrier (BBB) is partly responsible for the limited clinical response to chemotherapy. MRI-guided focused ultrasound (MRgFUS) is a promising non-invasive tissue ablation method for treating CNS tumours. Moreover, MRgFUS allows for temporary and repeatable BBB disruption. Our first objective was to determine the feasibility and safety of temporary BBB disruption within the brainstem using MRgFUS following intravenous administration of microbubbles in vivo. Our second objective was to select effective chemotherapeutics against DIPG cell lines, and to examine their therapeutic effects with MRgFUS in a murine model of DIPG which exhibits an intact BBB. Non-invasive opening of the BBB was determined in the brainstem of normal rodents using physiological monitoring and histological analysis. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics tested against DIPG cell lines. We established SU-DIPG17 orthotopic xenografts which demonstrated diffusely infiltrative tumour growth. By LC-MS/MS analysis, MRgFUS led to a 4-fold increase in doxorubicin concentrations within the brainstem tumours as compared to controls. Moreover, the volumetric tumour growth rate was significantly suppressed in MRgFUS-treated animals, which also exhibited decreased Ki-67 expression. We demonstrated the feasibility and safety of MRgFUS in the rodent brainstem and have shown that MRgFUS increases doxorubicin uptake in the brainstem of a rodent model of DIPG. This preclinical data provides critical support for clinical trials investigating MRgFUS-mediated BBB opening, which may greatly improve chemotherapeutic efficacy against DIPG in children.
CO-01 Prediction of pathological and radiological nature of glioma by mass spectrometry combined with machine learning
Authors: Kawataki Tomoyuki , Hanihara Mitsuto , Suzuki Keiko , Yoshimura Kentaro , Takeda Sen , Kinouchi Hiroyuki
Published: November 2020

BACKGROUND: We have previously developed a medical diagnostic pipeline that employs mass spectrometry and machine learning. It does not annotate molecular markers that are specific to cancer but uses entire mass spectra for predicting the properties of glioma. OBJECT: To validate the power of our diagnostic method in predicting the pathological and radiological properties of glioma with a simple sample preparation procedure. METHODS: Ten patients with glioma and 4 non-glioma patients who went through surgical resection were enrolled in our hospital. A total of 1020 mass spectra were acquired from 88 specimens. In order to examine the prediction power of the diagnostic pipeline that we have developed, we performed ten-fold cross-validation for pathological and radiological findings and calculated agreement rates with the conventional methods such as pathological diagnosis (WHO grading, MIB-1 labeling index (LI), mutations in the isocitrate dehydrogenase (IDH)-1 gene and positive 5-ALA fluorescence) and radiological information (gadolinium (Gd)-enhanced area, high-intensity area on fluid-attenuated inversion recovery (FLAIR) imaging,). RESULTS: Prediction accuracy for WHO malignant grade was 91.37%. Those for MIB-1 LI more than 10% and IDH-1 mutation-positive were 82.84% and 87.75%, respectively. Our method achieved an accurate prediction of 95.00% for the 5-ALA-positive lesion. The present method displayed an accuracy of 82.36% in predicting the area of FLAIR hyperintensity and 81.27% for the Gd enhanced area. CONCLUSION: Our methodology achieved a higher rate of prediction of glioma in terms of pathology and radiology. Research is ongoing to develop a validation cohort to verify the biological profiles of glioma specimens.
TB-02 Comprehensive analysis of expandable benign pituitary adenomas without genetic manipulations
Authors: Yokogami Kiyotaka , Watanabe Takashi , Takeishi Go , Yamashita Shinji , Mizuguchi Asako , Takeshima Hideo
Published: November 2020

Background: Since most pituitary adenomas are benign, there is no model of pituitary adenomas that can be continuously cultured without genetic manipulation. In this study, we analyzed the genetic characteristics of the established cell lines by continuous culture of benign pituitary adenomas without genetic manipulation. Method: The pituitary adenoma was continuously cultured by modifying the conditional reprogramming (CR) method, and the morphology was observed and fluorescent immunostaining (IF) was performed. In addition, genetic characteristics were comprehensively analyzed, differences from the surgical samples were analyzed by enrichment analysis using GSEA, and network analysis was performed using cytoscape based on the protein-protein interaction database. (Results) 1) Of the 14 cases of pituitary adenoma that had undergone primary culture (median MIB-1 labeling index 1.5%), 12 cases were capable of continuous culture for more than 2 months. (6 months or more: 5 cases) 2) After 2 weeks of culturing, the cell morphology changed dramatically. These cultured cells were positive for follicular cell marker s100, ectodermal nervous system markers Nestin, Notch1, and mesodermal marker Vimentin. In these cells, synaptophysin, which was strongly positive in the surgical specimen collected at the same time as the culture, disappeared. 3) Enrichment analysis revealed that gene expression such as epithelial mesenchymal transition(EMT), angiogenesis, IL6 signaling via NFkB, extracellular degradation, integrin cell surface interaction increased in cultured cells, and gene expression such as neurotransmitter including synaptophysin decreased significantly.(Conclusion) 1) The modified CR method allowed continuous culture of pituitary adenoma cells. 2) The cultured cells showed characteristic change of EMT, which was seen in invasive pituitary adenoma.
TB-06 Eribulin prolongs survival in an orthotopic xenograft mouse model of malignant meningioma
Authors: Nakano Tomoyuki , Fujimoto Kenji , Achiha Takamune , Arita Hideyuki , Yasukawa Mami , Masutomi Kenkichi , Takahashi Masamichi , Tomiyama Arata , Maehara Taketoshi , Ichimura Koichi
Published: November 2020

Meningioma is the most common intracranial tumor, and its prognosis is typically favorable. However, patients of malignant meningioma (WHO grade III) most often experience recurrence, undergo multiple surgical treatments, and have poor prognosis. No effective therapy for malignant meningioma has been established yet. We recently reported an efficacy of eribulin (Haraven®) for glioblastoma. Eribulin is considered to target TERT, which is frequently mutated in its promoter. Since TERT promoter mutation is also found in malignant meningioma, this study aims at investigating the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo.

Two meningioma cell lines IOMM-Lee and HKBMM were used in this study. In the viability assay and the flow cytometry, eribulin strongly inhibited cell proliferation by cell cycle arrest. Apoptotic cell death in malignant meningioma cell lines was confirmed by vital dye assay and immunoblotting. Moreover, wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. To assess the effect of eribulin in vivo, orthotopic xenograft mouse models of both malignant meningioma cell lines were constructed. The intraperitoneal administration of eribulin significantly prolonged the survival of meningioma cell lines implanted in the brain (p<0.0001). Furthermore, apoptosis was histologically observed in brain tumor tissue by immunohistochemistry.

Thus, this study suggests that eribulin is a potential therapeutic agent for treating malignant meningioma.
STMO-01 Cerebral edema and perioperative epilepsy due to placement of BCNU wafer for malignant glioma
Authors: Fujii Yu , Ogiwara Toshihiro , Agata Masahiro , Hanaoka Yoshiki , Horiuchi Tetsuyoshi
Published: November 2020

Introduction: Cerebral edema is the most frequent adverse event of BCNU wafer, which is used as local chemotherapy of malignant glioma. However, predictive factor of this event is unknown. Moreover, there is no consensus about cerebral edema and perioperative seizure, which is often observed in glioma. Here, we report risk factor of cerebral edema with BCNU placement and relationship with perioperative seizure in malignant glioma cases.

Material and Method: Thirty-one case of adult malignant glioma who underwent BCNU placement in our institute between March 2013 to March 2019 were investigated. The patients were dichotomized to two groups; patient with postoperative transient cerebral edema (CE+ group) and patient without postoperative transient cerebral edema (CE- group).

Result: Postoperative cerebral edema associated with placement of BCNU was observed in 9 out of 31 patients (29%). Tumor malignancy was significant parameter for postoperative cerebral edema (p=0.003). Other factors such as, age, gender, laterality, tumor location, primary or recurrent, number of BCNU wafers, duration of recurrence were not significant for postoperative cerebral edema. Seizure was seen in 14 patients (45%), and cerebral edema was not significant parameter for seizure. Tumor malignancy was significant parameters for postoperative cerebral edema. Tumor malignancy was significant parameters for seizure (p=0.0004). Although postoperative seizure was observed in 4 patients (44%) with CE+ group, neither maximum volume (mean 61.1 ml) nor change ratio (mean 354%) of FLAIR-high-intensity region were not related with postoperative seizure.

Conclusions: Tumor malignancy was important factor for patients who underwent placement of BCNU wafer with postoperative cerebral edema and seizure. On the other hand, there were no relationship between postoperative cerebral edema and perioperative seizure in patients treated with BCNU wafer.
STMO-02 Efficacy of preoperative embolization for hemangioblastoma
Authors: Hiu Takeshi , Hirayama Kousuke , Baba Shiro , Ujifuku Kenta , Yoshida Koichi , Matsuo Takayuki
Published: November 2020

Introduction: Preoperative transarterial embolization (TAE) for hemangioblastoma carries a risk of cerebral infarction and hemorrhagic complications, and its safety and efficacy are controversial.

Method: Twenty-two cases of hemangioblastoma (cerebellar: 18 cases, medulla oblongata: 3 cases, spinal cord: 1 case) treated via direct surgery in our hospital from 2007 to 2020 were enrolled.

Results: Preoperative TAE was performed in 6 cases of cerebellar hemangioblastoma (1 bilateral case) and 1 case of spinal hemangioblastoma. The cerebellar hemangioblastoma feeders were only superior cerebellar artery (SCA) in 3 cases, SCA/anterior inferior cerebellar artery (AICA)/posterior inferior cerebellar artery (PICA) in 2 cases, AICA/PICA in 1 case, and single drainer in 5 cases. Tumors were ≥30 mm in all cases (25 mm on 1 side in bilateral cases), and solid or nodular lesions were located on the upper surface of the cerebellum. Cerebellar edema was severe in five cases with hydrocephalus. TAE was performed under local anesthesia in all cases, using a coil alone in two cases and liquid or particle embolization material in five cases. The day before direct surgery, TAE was performed in four cases, one of which underwent emergency decompression due to severe cerebellar edema. Three cases were intentionally embolized on the day of direct surgery. The median blood loss during direct surgery was 100 ml. Although cerebral infarction was observed in all cases, there were no cases of brain stem infarction or hemorrhagic complications. The Modified Rankin Scale at discharge was 0 in 2 cases, 1 in 3 cases, 3 in 1 case, and 4 in 1 case.

Discussion/Conclusion: Preoperative TAE for hemangioblastoma reduced the blood loss for direct surgery. Same-day TAE avoided neurological deficit due to cerebral infarction and cerebellar edema. To prevent severe infarction, guiding the microcatheter to the vicinity of the tumor bed is important.
STMO-07 Adverse events related to the glioblastoma surgery and their perioperative management in our hospital
Authors: Kashiwagi Hideki , Kawabata Shinji , Kimura Seigo , Yagi Ryokichi , Ikeda Naokado , Nonoguchi Naosuke , Furuse Motomasa , Wanibuchi Masahiko
Published: November 2020

Background: The standard treatment for glioblastoma is surgical resection following chemoradiation therapy. The rate of removal or the amount of residual tumor has some impact on the prognosis of patients with glioblastoma, but the highly invasive nature of this tumor makes complete removal limited to the contrast-enhanced lesions difficult due to its localization. Furthermore, when postoperative seizures and venous thrombosis are included in surgery-related complications, these perioperative adverse events can cause delays in the initiation of chemoradiotherapy and delay the return to work and home, such as prolonged hospitalization and rehabilitation time.

Methods: We retrospectively reviewed the perioperative status of the recent 50 consecutive cases with histologically confirmed as glioblastoma at our hospital, the patient background, tumor localization, and perioperative treatment, and so on. Results: The major perioperative complications were ischemic or hemorrhagic complications, epileptic seizures, venous thrombosis, and pneumonia; CTCAE grade 2 or higher, grade 3 or higher, and grade 4 occurred in about 40%, 20%, and 10%, respectively, with some patients having multiple complications. Discussion: Although there was a tendency for ischemic changes around the cavity of the resection as the resection rate increased, most cases were asymptomatic and it seemed to be acceptable if residual brain function could be preserved. Residual tumors tended to show hemorrhagic changes and epileptic seizures because this is thought to be that the tumor was deliberately left in place to preserve function, based on the localization of the tumor. Postoperative FDP levels were useful in predicting the development of deep vein thrombosis and pulmonary artery thromboembolism. Conclusion: Because glioblastoma has short survival time and patient PS before and after surgery varies greatly depending on tumor localization, it is important to consider risk-benefit strategies for each case and to establish a scheme for a seamless transition from perioperative management to the introduction of postoperative therapy and maintenance therapy.
RT-01 Treatment results of salvage gamma knife and bevacizumab (AVAgamma therapy) for recurrent glioblastoma
Authors: Sato Kenichi , Asanome Taku , Ishida Yuuki , Sugio Hironori , Ozaki Yoshimaru , Takanashi Masami , Nakamura Hirohiko
Published: November 2020

Purpose: We report the treatment results of AVAgamma therapy combining gamma knife (GK) and bevacizumab for recurrent glioblastoma. Subjects: From August 2013 to April 2020, 44 patients (88 lesions) with recurrent glioblastoma treated with AVAgamma therapy as salvage therapy at the time of relapse after initial treatment. The average age is 61.5 years, with 26 men and 18 women. The tumor volume is 150 ml or less, and KPS is 40% or more as the indication of AVAgamma therapy. When the irradiation volume of GK is 15 ml or less, a single irradiation with a boundary dose of 20 to 26 Gy was performed, and when the irradiation volume was 15 ml or more, a single irradiation boundary dose was divided into two divided irradiations of 12 to 15 Gy. The mean therapeutic borderline dose was 24 Gy. Bevacizumab was administered 10 mg / kg or 15 mg / kg 1 to 10 times after GK. Methods: Median progression-free survival (mPFS), 6-month progression-free survival (PFS-6m), 6-month survival (OS-6m), median survival (mOS) from treatment with AVAgamma Considered mOS from initial treatment. Results: The mPFS from AVAgamma therapy was 5 months, PFS-6m was 37%, OS-6m was 79%, and mOS was 9 months. The mOS from initial treatment were 25 months. In relapsing glioma RPA classification, NABTT CNC class 5 mOS is 5.6 months, class 6 mOS is 6.4 months, but mOS from AVAgamma therapy is 9 months in class 5, 9 months in class 6. The survival time has been extended. Discussion: By AVAgamma therapy, it was thought that recurrent lesions were locally controlled and life prognosis was prolonged. Conclusion: AVAgamma therapy is thought to prolong the survival of recurrent glioblastoma and play an important role as salvage treatment.
RT-04 Stereotactic irradiation for 2 - 3 cm brain metastases: A multicenter retrospective cohort study
Authors: Hirata Takero , Harada Ken , Shimamoto Shigetoshi , Kawaguchi Hiroki , Igaki Hiroshi , Ito Yusuke , Yamada Kazunari , Kakuhara Hisao , Maebayashi Katsuya , Aoyama Hidefumi
Published: November 2020

Purpose: We retrospectively analyzed the treatment outcomes of Stereotactic irradiation (STI) for large size (2–3 cm) brain metastasis. Materials and methods: One hundred and sixty-nine lesions with 156 patients who underwent STI from January 1, 2013 to December 31, 2015 at 21 institutions participating in the Japanese Radiation Oncology Study Group were included in the study. Patients who had a history of whole-brain irradiation in the past and those who received whole-brain irradiation sequentially with STI were excluded. RANO-BM was used to evaluate the effect on each lesion, and the survival time or time to occurrence of local failure was defined as the number of months from the initial day of STI to the day of the events. Results: The median age was 66 (33–87) years. The median follow-up time was 14 (1–52) months. Male/female = 95/61 cases. The number of brain metastases was 1/2/3/4 or more = 93/35/14/14 cases. The median doses and fraction size were 30 Gy in 3 fractions. The primary site was lung/breast/colon or rectum/others = 95/14/14/33 cases. The median survival time was 16 months. A 1-year overall survival rate was 62% and a 1-year local control rate was 77%. Comparing the 1-year local control rate by the fraction size, single/3 or 4 /5 or more = 66/86/75%, the rate was better in the 3–4 fractions group (Log-rank test, p = 0.069). Cerebral necrosis (Grade 1/2/3/unknown = 9/10/8/3 cases) was observed in 30 lesions (18%), and the median time to diagnosis of brain necrosis was 9 (1–41) months. The incidence of necrosis in the single fraction cases was 29%, which was significantly higher than that in the fractionated irradiation cases (15%) (p = 0.039). Conclusion: Fractionated STI seems to be more favorable than single fraction STI for large brain metastases.
NI-04 Evaluation of post boron neutron capture therapy for recurrent meningioma using fluoride-labeled boronophenylalanine PET
Authors: Takai Satoshi , Matsushita Yoko , Kawabata Shinji , Ono Koji , Isohashi Kayako , Wanibuchi Masahiko , Miyatake Shinichi
Published: November 2020

We have applied boron neutron capture therapy (BNCT) for 46 recurrent high grade meningiomas (HGM). Twelve cases among them, fluoride-labeled boronophenylalanine positron emission tomography (18F-BPA-PET) were utilized before and after BNCT to evaluate the tumor activity. The lesion to normal brain (L/N) ratios of 14 lesions of these 11 cases were investigated. In all cases L/N ratio decreased after BNCT. The L/N ratio of recurrent (HGM) was 3.2±1.5 (mean±SD) before BNCT and 2.1±0.6 after that. In contrast enhanced MRI, 13 out of 14 lesions shrank or unchanged at least 3 months after BNCT, while one lesion transiently increased and then decreased within 3 months, showing pseudoprogression. In addition, 6 of 12 lesions which could be followed on MRI for more than 3 months progressed after 8 months. 4 of them were performed PET at the time of progressing. The L/N ratio of 2 progressing lesion which were diagnosed as recurrence due to continuously increasing were showed increasing. The L/N ratio of the other 2 lesions which were diagnosed radiation necrosis due to unchanged or shrinkage showed decreasing. Moreover, some systemic metastasis detected in PET image. F-BPA-PET seems to be useful for the evaluation of tumor activity.
NI-08 Utility of multiple positron emission tomography tracers in the diagnosis of brain tumors according to the 2016 World Health Organization classification
Authors: Miyake Keisuke , Fujimori Takeshi , Toyota Yasunori , Ogawa Daisuke , Hatakeyama Tetsuhiro , Okauchi Masanobu , Kawanishi Masahiko , Tamiya Takashi
Published: November 2020

Objective: Magnetic resonance imaging alone is not sufficient for the diagnosis and therapy outcomes in brain tumors. We herein examined the utility of positron emission tomography (PET) studies for diagnosis in brain tumors. Methods: Between April 2009 and June 2020, 320 patients with central nervous diseases, including 140, 65, 52, 52, and 11 patients with glioma, metastatic brain tumor, malignant lymphoma, meningioma, and demyelinating disease, respectively, underwent PET studies (FDG, MET, FLT, and FMISO) in our department. Lesion/normal (L/N) ratios for FDG, MET, and FLT and lesion/blood ratio (L/B ratio) for FMISO were compared. The glioma subtypes were compared based on the 2016 World Health Organization classification (IDH-mut, Codel, IDH-wt, GBM), and metastatic brain tumors, malignant lymphomas, meningiomas, and demyelinating diseases were compared with GBM. Results: In glioma, the cutoff MET L/N ratios to distinguish between IDH-mut and Codel, IDH-mut and GBM, Codel and GBM, and IDH-wt and GBM were 3.61, 4.42, 4.92, and 4.33, respectively, and the cutoff FLT L/N ratios to distinguish between IDH-mut and IDH-wt, IDH-mut and GBM, Codel and GBM, and IDH-wt and GBM were 3.43, 6.46, 3.39, and 7.56, respectively. The cutoff FDG and MET L/N ratios between metastatic brain tumors and GBM were 2.27 and 4.89; the cutoff FDG L/N and FMISO L/B ratios between malignant lymphoma and GBM were 4.68 and 2.13; and the cutoff FDG and MET L/N ratios between meningioma and GBM were 1.58 and 4.36. Demyelinating disease and GBM were distinguishable by FDG, MET, and FLT L/N ratios of 2.29, 3.32, and 5.85, and FMISO L/B ratio of 1.68. Conclusion: Four PET tracers were required to differentiate glioma subtypes. FDG and MET are useful for distinguishing GBM from metastatic brain tumor, malignant lymphoma, and meningioma, whereas accumulation was lower for all four PET tracers in demyelinating diseases than in GBM.
NI-10 T2/FLAIR mismatch sign and methionine PET uptake in grade II and III gliomas
Authors: Ebiko Yusuke , Tamura Kaoru , Hara Shoko , Inaji Motoki , Tanaka Yoji , Nariai Tadashi , Ishii Kenji , Maehara Taketoshi
Published: November 2020

Background: Recent study suggests that “T2/FLAIR mismatch” sign is specific MRI finding for isocitrate dehydrogenase mutated (IDH-mut) 1p19q non-codeleted gliomas (Grade II and III astrocytic tumors). T2/FLAIR mismatch sign may be useful for predicting the histological type of glioma before surgery. However, it is not known what this finding reflects. Therefore, we examined the correlation between T2/FLAIR mismatch sign and uptake of methionine with positron emission tomography (MET-PET), and molecular classification of glioma.

Methods: 74 glioma patients (grade II: 30 cases, grade III: 44 cases) with preoperative MRI and MET-PET who underwent surgical resection during 2000–2019 were included in this study. MR scans were evaluated by 3 independent reviewers to assess presence/absence of T2/FLAIR mismatch sign. 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. We examined the relationship between IDH mutation, 1p/19q codeletion, mismatch, and T/N ratio of MET-PET.

Results: Out of the 74 cases, astrocytic tumors (A group: IDH-mutant, 1p19q non-codeleted) were 21 (28%), oligodendroglial tumors (O group: IDH-mutant, 1p19q codeleted) were 19 (26%), and IDH wild tumors (W group) were 34 (46%). The T2/FLAIR mismatch sign was present in 16 cases (22%). The T/N ratio of MET-PET in the tumor with T2/FLAIR mismatch sign was 1.56, which was significantly lower than that in the tumor without mismatch sign (2.01, p=0.016). T2/FLAIR mismatch sign was found in 7 (33%) cases in the A group, 0 (0%) case in the O group and 9 (26%) cases in the W group, and the positive rate was significantly higher in the A group (p=0.013).

Conclusions: “T2/FLAIR mismatch” sign was a specific finding for astrocytic tumor, and the cases with positive “T2/FLAIR mismatch” sign had significantly lower MET-PET uptake than that with negative cases.
NI-11 Clinical significance of intracystic diffusion hyperintensity lesions remaining after treatment of intracranial germ cell tumor
Authors: Takano Motoki , Takayasu Takeshi , Yonezawa Ushio , Taguchi Akira , Sugiyama Kazuhiko , Yamasaki Fumiyuki
Published: November 2020

Background and purpose: About 30% of intracranial germ cell tumors are mixed germ cell tumors and teratomas are often found as those components. Intense chemoradiotherapy is performed according to the malignancy of the histopathology, but high-intensity lesion inside the cystic tumor on diffusion weighted imaging (DWI) sometimes remains after completion of the chemoradiotherapy. In this study, we examined the clinical significance of the DWI high-intensity lesion remaining in the cyst. METHODS: Five patients after initial chemoradiotherapy were resected residual tumor by craniotomy at our hospital from 2009 to 2019. Preoperative gadolinium-enhanced MRI defined the non-contrast-enhanced part of the tumor as intracystic, and DWI intensity was classified by its look as low-intensity, equal-intensity, and high-intensity compared to the cortex of the same slice. DWI signals in the solid area, cyst wall, and cyst were evaluated. Results: All cases were mature teratoma in histopathology, and no other tumor components were observed. On DWI, the cyst wall and solid part were visualized with low signal. High-intensity lesions and equal-intensity lesions in the cyst cavity were found in 3 and 1 cases, respectively. In these cases, pathological findings revealed a keratin-like substance in the cyst. Discussion: The intracystic high and equal intensity lesions on DWI removed after completion of chemoradiotherapy are considered to reflect the keratin-like component of mature teratoma. If DWI- high intensity and equal intensity lesions remain in the cyst of the tumor after the completion of chemoradiotherapy, tumor shrinkage cannot be expected even if the chemotherapy is strengthened. In such cases, we should consider to removing them by surgery. Conclusion: When DWI high and equal intensity lesions are found in the cysts of tumors remaining after chemoradiotherapy for intracranial germ tumors, it is possible that mature teratoma remains.
NI-13 The effectiveness and limitation of survival prediction in primary glioblastoma using machine learning-based texture analysis
Authors: Umehara Toru , Kinoshita Manabu , Sasaki Takahiro , Arita Hideyuki , Yoshioka Ema , Shofuda Tomoko , Kodama Yoshinori , Hirayama Ryuichi , Kijima Noriyuki , Kagawa Naoki , Okita Yoshiko , Takano Koji , Uda Takehiro , Fukai Junya , Sakamoto Daisuke , Mori Kanji , Kanemura Yonehiro
Published: November 2020

Introduction: Clinical application of survival prediction of primary glioblastoma (pGBM) using preoperative images remains challenging due to a lack of robustness and standardization of the method. This research focused on validating a machine learning-based texture analysis model for this purpose using internal and external cohorts. Method: We included all cases of IDH wild-type pGBM available of preoperative MRI (T1WI, T2WI, and Gd-T1WI) from the databases of Kansai Molecular Diagnosis Network for CNS tumors (KN) and The Cancer Genome Atlas (TCGA). Of 242 cases from KN, we assigned 137 cases as a training dataset (D1), and the remaining 105 cases as an internal validation dataset (D2). Furthermore, we extracted 96 cases from TCGA as an external validation dataset (D3). Preoperative MRI scans were semi-quantitatively analyzed, leading to the acquisition of 489 texture features as explanatory variables. Dichotomous overall survival (OS) with a 16.6 months cutoff was regarded as the response variable (short/long OS). We employed Lasso regression for feature selection, and a survival prediction model constructed for D1 via cross-validation (M1) was applied to D2 and D3 to ensure the model robustness. Results: The population of predicted short OS by M1 significantly showed poorer prognosis in D2 (median OS 11.1 vs. 19.4 months; log-rank test, p=0.03), while there was no significant difference in D3 (median OS 14.2 vs. 11.9 months; p=0.61). In the comparative analysis using t-SNE, there was little variation in the feature distribution among three datasets. Conclusion: We were able to validate the prediction model in the internal but not in the external cohort. The presented result supports the use of machine learning-based texture analysis for survival prediction of pGBM in a localized population or country. However, further consideration is required to achieve a universal prediction model for pGBM, irrespective of regional difference.
NI-17 Evaluation of preoperative apparent diffusion coefficient (ADC) of peritumoral FLAIR high lesion and histopathological features in patients with glioblastoma
Authors: Matsuda Kenichiro , Oe Rintaro , Sonoda Yukihiko
Published: November 2020

Objective: In removal of the glioblastoma, maximum and safe removal is desired for recurrence prevention with functional preservation. In recent years, the setting of the removal range has also been studied not only the contrast enhanced lesions, but also the surrounding FLAIR high signal lesion. We are studying the prediction of the site that is likely to occur recurrence in the FLAIR high signal lesion of glioblastoma, and we are focusing on the ADC of pre-operative MRI as an index. The purpose of this study is to evaluate the ADC and the actual pathological tissue image in the FAIR high signal lesion around the contrast enhanced lesion of glioblastoma. Method: We examined the case of removal of the glioblastoma treated in our department. Analysis was performed using a pathological tissue specimen of excised tumors and their surrounding tissues in each case, and the ADC value of pre-operative MRI. Pathological tissue image and ADC values of FAIR high signal lesion were compared. Results: 19 tissue samples which were taken from the FLAIR high signal lesion around the contrast enhanced tumor from 10 cases. For a total of 19 locations, it was compared with the histopathological features of the site. As a result, in the low part of the ADC value in the preoperative MRI relatively had high cell density of atypical cells, it was often exhibited findings that infiltration of tumor cells is suspected. Conclusion: In general, ADC is said to suggest an increase in cell density and thus infiltration of tumor cells. However, the same findings were obtained in the pre-operative MRI examined this time. Since ADC also suggests cell density and tumor infiltration in pre-operative MRI, ADC of pre-operative MRI was considered useful for examination of the removal range and radiation therapy planning in surgery for glioblastoma.
NQPC-02 Long-term survival in patients with primary intracranial germ cell tumors treated with surgery, platinum-based chemotherapy, and radiotherapy: a single-institution study
Authors: Motomura Kazuya , Shimizu Hiroyuki , Ohka Fumiharu , Aoki Kosuke , Tanahashi Kuniaki , Hirano Masaki , Chalise Lushun , Nishikawa Tomohide , Yamaguchi Junya , Yoshida Jun , Natsume Atsushi , Wakabayashi Toshihiko
Published: November 2020

Purpose: In the present study, we performed a retrospective review of patients receiving carboplatin based chemotherapy followed by radiotherapy for newly diagnosed primary intracranial germ cell tumors. In order to identify an optimal germ cell tumor treatment strategy, we evaluated treatment outcomes and toxicity and compliance.

Methodology: This study included 110 consecutive patients with newly diagnosed primary intracranial germ cell tumors. The drug doses and administration schedule of carboplatin-etoposide (CARB-VP) were as follows: carboplatin (300 mg/m2 daily for 1 days), and etoposide (100 mg/m2 on days 1 to 3). Ifosfamide-carboplatin-etoposide (ICE) treatment comprised ifosfamide (1500 mg/m2 daily for 3 days), carboplatin (300 mg/m2 daily for 1 days), and etoposide (100 mg/m2 daily for 3 days). Patients with germinomatous germ cell tumors (pure germinoma or germinoma with STGC) basically receive three cycles of CARB-VP and a total dose of 30Gy whole ventricular radiotherapy. We delivered combination therapy consisting of combined ICE chemotherapy and craniospinal irradiation followed by the complete resection of the residual tumor for nongerminomatous malignant germ cell tumors.

Results: The median follow-up time was 11.0 years (range, 0.5–37.8 years). The 5-year total survival rates of germinomatous and nongerminomatous germ cell tumors were 97.2% and 66.7%, respectively. The 10-year and 20-year total survival rates of germinomatous germ cell tumors were 95.7% and 90.0%, respectively. Adverse events related to carboplatin based chemotherapy are not detected. Furthermore, no treatment-related deaths were observed.

Conclusions: Our treatment with surgery, carboplatin based chemotherapy followed by radiotherapy is effective in treating primary intracranial germ cell tumors, especially in germinomatous group.
ML-01 Pathological characteristics of primary central nervous system lymphoma with atypical radiological finding
Authors: Inukai Madoka , Shibahara Ichiyo , Handa Hajime , Saruta Wakiko , Sato Sumito , Hide Takuichiro , Kumabe Toshihiro
Published: November 2020

Background: If the brain tumor is suspected to be a primary central nervous system lymphoma (PCNSL) on radiological findings, it is general to perform biopsy to obtain the pathological diagnosis. Glioblastomas (GBs) must be distinguished from PCNSLs. In addition to commonly used contrast-enhanced T1-weighted imaging, diffusion-weighted image (DWI), and apparent diffusion coefficient (ADC) value, the following characteristics of PCNSLs were reported to be essential for this purpose: 1) no increase in blood flow on perfusion images obtained by the arterial spin labeling (ASL) method; 2) less microbleeding on T2*-weighted images (T2*). However, we experienced some exceptional cases. Purpose: To clarify the histopathological features of PCNSLs those had atypical radiological findings. Method: 62 consecutive PCNSL cases (40 males, 22 females, mean age 65.4 years, range 35–84) treated in our department from April 2013 to March 2020 were retrospectively analyzed. We compared the following features between 47 biopsy cases showing typical image findings as PCNSLs (Group A) and 15 surgically resected cases with atypical findings (Group B), 1) number of blood vessels per hyper 10 fields, 2) occupying area of blood vessels per unit area, 3) immunoreactivity of vascular endothelial growth factor (VEGF), and 4) germinal center B-cell (GCB) subtype. Results: In Group A, the number of blood vessels in the tumor was 39.3 on average, and the area occupied by blood vessels was 3.8%. In Group B, the former was 133.2, and the latter was 9.9%. There was no significant difference in VEGF expression and GCB subtype. Conclusion: In PCNSLs showing with high blood flow and microbleeds, the blood vessels were rich and partial bleeding was confirmed histologically. We should analyze much more cases to set the threshold both of the ADC value and the absolute value of blood flow calculated by the ASL method to distinguish between PCNSLs and GBs.
ML-05 One-year follow-up data of phase I/II study of tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma
Authors: Mishima Kazuhiko , Narita Yoshitaka , Nagane Motoo , Terui Yasuhito , Arakawa Yoshiki , Yonezawa Hajime , Asai Katsunori , Fukuhara Noriko , Sugiyama Kazuhiko , Shinojima Naoki , Aoi Arata , Nishikawa Ryo
Published: November 2020

In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (r/rPCNSL) based on the results of a phase I/II study in Japan. In this study, 44 Japanese patients with r/rPCNSL were treated with TIR QD at 320 mg, 480 mg, or 480 mg in the fasted condition (480 mg fasted QD). The primary endpoint was overall response rate (ORR) assessed by an independent review committee according to International PCNSL Collaborative Group criteria. We previously reported the results of this study with data cutoff in June 2019 (Narita et al. Neuro Oncol. 2020). In the report, 17 of 44 patients were treated with TIR at 480 mg fasted QD which is an approved dose, and had ORR of 52.9%, median progression-free survival of 5.8 months, and median overall survival of not reached (median follow-up: 3.8 months). In 44 patients, ORR was similar among patients harboring either of the oncogenic mutants CARD11, MYD88, CD79B, or wild type. Throughout the whole patients, most common adverse events (AEs) at any grade were rash (31.8%), neutropenia (22.7%), leukopenia (18.2%), and lymphopenia (15.9%), and grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). We will present one-year follow-up data of this study at the meeting. As of data cutoff (February 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for overall survival, duration of response, and time to onset of AEs will also be presented. TIR is a promising new treatment for r/rPCNSL.
ML-08 Safety and efficacy of consolidation cytarabine for newly-diagnosed primary central nervous system lymphoma
Authors: Sasaki Nobuyoshi , Kobayashi Keiichi , Saito Kuniaki , Sasaki Yuta , Okamura Yuma , Yamagishi Yuki , Shimizu Saki , Shiokawa Yoshiaki , Nagane Motoo
Published: November 2020

Backgrounds: While consolidation therapies which incorporate whole brain radiotherapy (WBRT) and/ or chemotherapies such as high dose (HD)- cytarabine are commonly applied following induction chemotherapies in primary central nervous system lymphoma (PCNSL), the optimal treatment for consolidation therapy has not been established. We aimed to investigate the safety and efficacy of consolidation cytarabine with a dose modification policy in PCNSL. Patients and methods: PCNSL patients initially treated by R-MPV (rituximab, methotrexate, procarbazine and vincristine) and subsequently treated either by WBRT of 24Gy followed by cytarabine (WBRT-AraC group), or cytarabine alone (AraC group) were identified. WBRT was deferred in patients 71 years old or younger who had obtained a complete response (CR) after R-MPV. Cytarabine was dose-modified according to age groups (3 g/m2 in patients 70 years old or younger, 2 g/m2 in patients aged 71–75 years, 1 g/m2 in patients aged 76–80 years). Toxicity profiles, progression-free survival (PFS), overall survival (OS) were analyzed. Results: Twenty-five patients were identified (median age: 69 [range: 34–80], median KPS:70 [range: 40–90]), including 11 patients from the WBRT-AraC group, and 14 patients from the AraC group. Median PFS was unreached in the WBRT-AraC group, and 41.8 months in the AraC group. Median OS was unreached in both groups. The overall rate of grade 3/4 hematologic toxicities was high (92%), but mostly manageable without major complications. Fourteen patients received 3 g/m2, 4 patients received 2 g/m2, 7 patients received 1 g/m2 of cytarabine, and the rate of grade 4 leukopenia/ thrombocytopenia was 64%/57%, 25%/50%, and 29%/29%, respectively. Discussion: HD-cytarabine consolidation therapy with dose modification according to age groups for PCNSL was feasible and well-tolerated in patients 80 years of age or younger. The efficacy of HD-cytarabine was undetermined and further investigation is warranted.