bluuebunny/crossref_metadata_2025 huggingface dataset:
ET-1 Translational research platform for malignant brain tumors
Authors: Tateishi Kensuke , Miyake Yohei , Nakamura Taishi , Sasame Jo , Hayashi Takahiro , Oshima Akito , Honma Hirokuni , Ikegaya Naoki , Yamamoto Tetsuya
Published: December 2021

Introduction: The standard therapy for malignant brain tumors includes surgery and combination therapy with radiation and chemotherapy, but to provide individualized treatment based on the biological and molecular genetic background of the tumor, integrate genetic information with various functional data are required. In this study, we present an overview of our integrated approaches for translational research and clinical management. Methods: In glioma, pre-and intra-operative clinical information, including intraoperative genetic diagnosis, and intraoperative rapid immunohistochemistry is obtained, then a multidisciplinary treatment approach is started based on these integrated data. Specimens collected intraoperatively are cryopreserved for future analysis, and primary cultured cells are routinely collected. The cultured cells are transplanted into the brain of immunodeficient mice to establish patient-derived xenograft model (PDX). Genetic screening, such as IDH, TERT, BRAF, H3F3A mutation and MGMT methylation analysis are routinely assessed within a few days after surgery and used as information for integrated diagnosis. In case of PDX establishment or recurrence, we perform whole exon sequencing or comprehensive genomic assessment to identify genetic abnormalities. If genomic alterations for possible molecular targeted therapy are identified, we assess drug sensitivity test in vitro and in vivo, which are utilized for research to develop optimal molecular targeted therapy. The results, such as the therapeutic effects of molecular targeted drugs, are used for clinical applications. Results: Since the platform was established, we have treated a total of 286 patients, including 189 gliomas and 37 central nervous system lymphomas based on the integrated information. We are currently collecting clinical data to examine if this integrated approach could provide clinical benefit.Conclusion: The translational research system for malignant brain tumors plays an important role in the promotion of clinical and basic research.
ET-8 Integrated diagnostic approach to predict prognosis for malignant gliomas
Authors: Isoda Masataka , Tateishi Kensuke , Sasame Jo , Hayashi Takahiro , Miyake Youhei , Oshima Akito , Honma Hirokuni , Yamamoto Tetsuya
Published: December 2021

Previous studies indicated that MGMT promoter methylation status with IDH and TERT promotor mutation are major prognostic factors in glioma. In addition to these molecular features, we have been assessing drug sensitivity against several chemotherapeutic agents, including temozolomide (TMZ). Here, we examined if this combined information could strongly predict drug sensitivity and the prognosis in glioma patients. One hundred and twenty-five IDH wild-type gliomas (WHO grade III and grade IV) were included in this study and retrospectively analyzed. Among them, we focused on 37 patients with partial surgical resection and biopsy to assess radiological difference on MRI. The primary cultured tumor cells were exposed with several compounds for 72 hours, then ATP based cell viability assay was performed. The favorable radiological therapeutic effect was found in 6 out of 8 (75%) with MGMT promoter methylated cases, while unfavorable in 23 of 29 (79.3%) with MGMT promoter unmethylated cases (p=0.008). The drug screening assay demonstrated that 7 of 10 cases with favorable TMZ sensitivity in vitro showed response on MRI, whereas 22 of 27 (81.5%) cases with TMZ resistance in vitro indicated tumor progression (p=0.006). Of note, all 5 cases with sensitive to TMZ and methylated MGMT promoter demonstrated favorable radiological response (p=0.002). These 5 cases tended to survive longer (median survival time, 697 days) as compared to others (median survival time, 391 days, p=0.13). These data indicate that integrated approach with genomic assessment and drug screening test may predict therapeutic response to chemotherapy and contribute selecting optimal therapy in glioma patients.
TB-2 Patient-derived meningioma organoid model demonstrates FOXM1 dependent tumor proliferation
Authors: Yamazaki Shintaro , Ohka Fumiharu , Hirano Masaki , Shiraki Yukihiro , Motomura Kazuya , Tanahashi Kuniaki , Tsujiuchi Takashi , Motomura Ayako , Aoki Kosuke , Shinjo Keiko , Murofushi Yoshiteru , Kitano Yotaro , Maeda Sachi , Kato Akira , Shimizu Hiroyuki , Yamaguchi J Unya , Adilijiang Alimu , Wakabayashi Toshihiko , Saito Ryuta , Enomoto Atsushi , Kondo Yutaka , Natsume Atsushi
Published: December 2021

Recent comprehensive studies have revealed several molecular alterations that are frequently found in meningiomas. However, effective treatment reagents targeting specific molecular alterations have not yet been identified because of the limited number of representative research models of meningiomas.

We established 18 organoid models comprising of two malignant meningioma cells (HKBMM and IOMM-Lee), 10 benign meningiomas, four malignant meningiomas, and two solitary fibrous tumors (SFTs). Using immunohistochemistry and molecular analyses consisting of whole exome sequencing, RNA-seq, and DNA methylation analyses, we compared the histological findings and molecular profiling of organoid models with those of parental tumors. The organoids exhibited consistent histological features and molecular profiles with those of the parental tumors. Using a public database of meningioma, we identified that upregulated forkhead box M1 (FOXM1) was correlated with increased tumor proliferation. Overexpression of FOXM1 in benign meningioma organoids increased organoid proliferation; depletion of FOXM1 in malignant organoids decreased proliferation. Additionally, thiostrepton, a FOXM1 inhibitor combined with radiation therapy, significantly inhibited proliferation of malignant meningioma organoid models (P<0.01).

An organoid model for meningioma enabled us to elucidate the tumor biology of meningioma along with potent treatment targets for meningioma.
TB-3 miR-33a depletion accelerate medulloblastoma generation and invasion
Authors: Mineharu Yohei , Matsui Yasuzumi , Oichi Yuki , Kamata Takahiko , Morimoto Takaaki , Nakao Tetsushi , Horie Takahiro , Ono Koh , Terada Yokinori , Tanji Masahiro , Arakawa Yoshiki , Miyamoto Susumu
Published: December 2021

Background and purposes: Lipid metabolism have been shown to be associated with tumorigenicity in various malignancies. The purpose of this study was to investigate the association of miR-33, a key regulator of lipid metabolism, in tumorigenicity and progression of medulloblastoma. Methods: Incidence of medulloblastoma and histopathological findings were compared between ptch1+/- mice and ptch1+/- miR-33a-/- mice. Tumors extracted from these mice were transplanted subcutaneously in nude mice (n=14 for ptch1+/-, n=19 for ptch1+/- miR-33a-/-) and in C57BL/6 mice (n=12 for each). Gene expression profile was compared between tumors from ptch1+/- mice and those from ptch1+/- miR-33a-/- mice. Results: Knockout of miR-33a in ptch1+/- transgenic mouse model increased the incidence of spontaneous generation of medulloblastoma from 34.5% to 84.0% (p< 0.001) at 12 months. Histopathological analysis showed infiltrative tumor borders in ptch1+/- miR-33a-/- tumors as compared with ptch1+/- ones. Tumor formation was observed in 21.4% for ptch1+/- tumors and 68.4% for ptch1+/- miR-33a-/- tumors in nude mice (p= 0.008). It was observed in 0% and 16.7% in immune competent mice. RNA sequencing detected that SCD1 and SREBF1 was upregulated in tumors from miR-33a knockout mice. Discussion: Our results demonstrated that depletion of miR-33a accelerated medulloblastoma generation and invasion. miR-33a may also be important for immune evasion. SCD1, which is reported to play a role in tumor stem cell maintenance and metastasis, can be a potential therapeutic target for medulloblastoma.
ACT-5 Prognosis of IDH-mut lower-grade gliomas in Hokkaido University Hospital
Authors: Yamaguchi Shigeru , Ishi Yukitomo , Okamoto Michinari , Sawaya Ryousuke , Motegi Hiroaki , Kobayashi Hiroyuki , Terasaka Shunsuke , Fujimura Miki
Published: December 2021

Background: WHO grade 2 and 3 adult gliomas are nowadays getting together as lower-grade gliomas (LrGGs), but we had been recognized grade 3 (G3) tumors as high-grade and grade 2 (G2) tumors as low-grade. In this report, we investigate the treatment and prognosis of the patients with LrGG harboring IDH mutations in our institutions. Methods:We retrospectively review primary treatments and their prognosis for LrGG patients with IDH mutation since 2003. They categorized as astrocytomas and oligodendrogliomas according to 1p/19q loss-of-heterozygosity status. Prognosis were evaluated by overall survival. Postoperative primary treatments applied chemo-radiotherapy (CRT), radiotherapy only (RT), chemotherapy only (CT), and observation (Ob). Results: 36 astrocytomas and 60 oligodendrogliomas were identified. In astrocytomas, the patients with G3 (N=16) were treated by CRT (N=14) or CT (N=2), and the patients with G2 (N=20) were treated by CRT (N=2), RT (N=3), CT (N=3), or Ob (N=12). In oligodendrogliomas, the patients with G3 (N=34) were treated by CRT (N=32) or CT (N=2), and the patients with G2 (N=26) were treated by CRT (N=3), RT (N=1), CT (N=5), or Ob (N=17). 10-year survival rate (10yOS) of astrocytomas and oligodendrogliomas are 54% and 90%, respectively (p=0.002). According to histological malignancy, 10yOS of G3 and G2 astrocytomas were 54% and 54%, respectively (p=0.97) and that of G3 and G2 oligodendrogliomas were 86% and 100%, respectively (p=0.64). In both group, there are no different of prognosis according to histological malignancy. Discussion: There was no prognostic different between G2 and G3 astrocytomas in our institution. Since the treatment intensity for G2 and G3 astrocytomas were clearly different, the primary treatment for G2 astrocytomas might be insufficient. On the other hand, there were no prognostic different between G2 and G3 oligodendrogliomas in our institution, as with recent reports, so the primary treatment intensity for oligodendrogliomas should be appropriate.
STMO-6 Impact of the extent of resection on the survival of patients with lower grade gliomas using awake brain mapping
Authors: Motomura Kazuya , Chalise Lushun , Ohka Fumiharu , Aoki Kosuke , Nishikawa Tomohide , Yamaguchi Junya , Shimizu Hiroyuki , Kibe Yuji , Natsume Atsushi , Wakabayashi Toshihiko , Saito Ryuta
Published: December 2021

Purpose: The aim of this study was to assess the effect of the extent of resection (EOR) of tumors on survival in a series of patients with lower-grade gliomas (LGGs) who underwent awake brain mapping.

Methods: We retrospectively analyzed 126 patients with LGGs in the dominant and non-dominant hemisphere who underwent awake brain surgery at the same institution between December 2012 and May 2020.

Results: The median progression-free survival (PFS) rate of patients with LGGs in the group with an EOR >100 %, including supratotal resection (n = 47; median survival [MS], not reached), was significantly higher than that in the group with an EOR <100% (n = 79; MS, 43.1 months; 95% CI: 37.8–48.4 months; p = 0.04). In patients with diffuse astrocytomas and anaplastic astrocytomas, the group with EOR >100 %, including supratotal resection (n = 25; MS, not reached), demonstrated a significantly better PFS rate than did the group with an EOR <100% (n = 45; MS, 35.8 months; 95% CI: 19.9–51.6 months; p = 0.03). Supratotal or gross total resection was correlated with better PFS in IDH-mutant type of diffuse astrocytomas and anaplastic astrocytomas (n = 19; MS, not reached vs. n = 35; MS, 40.6 months; 95% CI: 22.3–59.0 months; p = 0.02). By contrast, supratotal or gross total resection was not associated with longer PFS rates in patients with IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas.

Conclusions: It is noteworthy that supratotal or gross total resection significantly correlated with better PFS in IDH-mutant type of WHO grade II and III astrocytic tumors. In light of our finding that EOR did not correlate with PFS in patients with aggressive IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas, we suggest treatments that are more intensive will be needed for the control of these tumors.
STMO-17 Treatment outcome of photodynamic therapy using talaporfin sodium for recurrent high-grade glioma
Authors: Ohno Makoto , Kawauchi Daisuke , Hayashi Yoshiharu , Satomi Kaishi , Miyakita Yasuji , Takahashi Masamichi , Yanagisawa Shunsuke , Tamura Yukie , Kikuchi Miyu , Hamada Akinobu , Narita Yoshitaka
Published: December 2021

Objective: Photodynamic therapy (PDT) using Talaporfin Sodium (TS) is a novel therapeutic strategy to improve local tumor control in high-grade glioma. TS is a photosensitizer that accumulates in tumor cells and produces highly toxic free radicals by intraoperative irradiation of laser with a 664nm wavelength. However, little is known about the treatment outcomes of PDT in recurrent high-grade gliomas (rHGG). In this study, we investigated the treatment outcome of PDT in rHGG and evaluated the correlation between intratumoral TS accumulation and outcomes. Methods: We included 21 patients with rHGG and 22 tumors, who were treated by PDT between June 2016 and March 2021. TS was transvenously administered 22–26 hours before PDT. Intratumoral TS concentrations were measured by liquid chromatography using frozen tissue. Results: The rHGGs included 10 glioblastoma, IDH1/2-wildtype (GBM, IDH1/2-WT: 45.5%), 3 GBM, IDH1/2-mutant (GBM, IDH1/2-Mut: 13.6%), 7 anaplastic oligodendroglioma, IDH1/2-Mut/codel (AO, IDH1/2-Mut/codel: 31.8%), 1 anaplastic astrocytoma, IDH1/2-WT (AA, IDH1/2-WT: 4.5%), 1 high-grade astrocytoma, IDH1/2-WT (4.5%). The median local progression free survival (PFS) time after PDT was 3.6 months and the median survival time from PDT was 19.4 months. The intratumoral TS concentrations of 7 tumors (TS(-): 31.8%) were below the limit of quantification, and the intratumoral TS concentrations of the remaining 15 tumors (TS(+)) were 43.5 ng/mg-protein (14.7–132 ng/mg-protein). The intratumoral TS concentrations were not significantly associated with IDH1/2 mutation status, cellularity, tumor grade, and pattern of enhancement. The median PFS from PDT tended to be longer in TS(+) than in TS(-) (TS(+): 6.3 vs TS(-): 1.4 months, p = 0.054). Conclusions: We found that the intratumoral TS concentrations were heterogeneous and 31.8% were below the limit of quantification. TS(+) tended to have better local tumor control than TS(-), suggesting the intratumoral TS accumulation have an impact of treatment outcomes of PDT.
STMO-19 Impact of aggressive resection for glioblastoma of the thalamus with histone H3-K27M mutation
Authors: Nonaka Masahiro , Hashiba Tetsuo , Asai Akio
Published: December 2021

Glioblastoma of the thalamus occurs predominantly in childhood and young adulthood, and cases with histone mutations are thought to have a particularly poor prognosis. We studied tumor resection rate, age, type of adjuvant therapy, and histone gene mutations on progression-free survival (PFS) and overall survival (OS) in patients who underwent aggressive removal. Eight cases of thalamic glioblastoma were included in the study. The mean age at surgery was 36.1 years (10–74 years, 3 cases under 18 years). Tumor removal was performed from the parieto-occipital lobe to the thalamus via the lateral ventricles in all cases. In all cases, more than 90% of the contrast-enhancing lesions were removed. Postoperatively, one patient had sensory disturbance of the left upper limb, and the other had incomplete paralysis of the left upper and lower limbs, but both were able to walk with a cane. In the case of the patient with postoperative complications, the tumor was located in the vicinity of the internal capsule. All patients were treated with radiation therapy and temozolomide, and bevacizumab and Novo-TTF were used in cases after approval. All patients were able to return home and return to school or work after initial treatment. The mean progression-free survival (PFS) was 0.87 years, and overall survival (OS) was 1.95 years. Five patients had histone H3-K27M mutations, and three patients had no mutations. PFS and OS were 1.02 years and 0.62 years, respectively, and 2.53 years and 1.20 years, respectively, both of which were longer in patients with mutations (PFS; p=0.16, OS; p=0.23).Aggressive removal of glioblastoma of the thalamus may improve prognosis, especially in patients with histone H3-K27M mutations. In patients with tumors extending to the vicinity of the internal capsule, total removal may cause paralysis and sensory disturbance.
MPC-5 Characteristics of H3 G34-mutant gliomas
Authors: Kibe Yuji , Ohka Fumiharu , Motomura Kazuya , Aoki Kosuke , Maeda Sachi , Hirano Masaki , Nishikawa Tomohide , Yamaguchi Junya , Yamazaki Shintaro , Natsume Atsushi , Saito Ryuta
Published: December 2021

Introduction: Diffuse hemispheric gliomas, H3 G34-mutant (DHG H3G34-mutant) are newly recognized infiltrating gliomas of the cerebral hemispheres of pediatric and young adult patients. We experienced 6 DHG H3G34-mutant cases. In this study, we describe the clinical, radiological and pathological characteristics of these cases.

Result: Mean age at diagnosis was 16.8 years (range:10–26). Three patients were male. Among six cases, tumors located in cerebral cortex in five cases and multiple sites including basal ganglia and cortex in a case. All tumors showed no or only a faint contrast-enhancement and harbored restriction of diffusion. One patient underwent total resection, four underwent partial resection and one underwent biopsy. Pathological diagnosis were CNS embryonal tumors (n=3/6), glioblastoma, IDH-wildtype (n=2/6) and anaplastic astrocytoma, IDH-wildtype (n=1/5). All cases were negative for Olig2 and positive for GFAP in immunohistochemistry. Mean Ki-67 index was 38% (range: 10–60%). All cases revealed at least one of mitosis, necrosis or microvascular proliferation. Especially, mitosis was the most frequently found (n=5/6). The H3F3A mutations were G34R mutations in all cases. One case revealed a characteristic mutation pattern, therefore now we are performing further examination. Adjuvant chemoradiotherapies were performed for all cases. Mean progression free survival was 10.1 months (range: 1.6–33.1).

Discussion: As published literatures reported, all cases exhibited restriction of diffusion and negative for Olig2. For a cerebral hemispheric tumor of pediatric or young adult patient which shows restriction of diffusion and no contrast-enhancement, and of which pathological findings is malignant and olig2 is negative, genetic analysis of H3F3A gene might be essential.
MPC-10 Prognostic analysis in IDH mutant astrocytoma patient with CDKN2A/B homozygous deletion
Authors: Yanagisawa Shunsuke , Satomi Kaishi , Miyakita Yasuji , Ohno Makoto , Takahashi Masamichi , Tamura Yukie , Kawachi Daisuke , Kikuchi Miyu , Kitahara Mai , Matushita Yuko , Yoshida Akihiko , Ichimura Koichi , Narita Yoshitaka
Published: December 2021

background: IDH mutant astrocytoma has good prognosis compared with IDH wildtype one. In IDH mutant astrocytoma, However, patients with CDKN2A/B homozygous deletion (HD) are worse prognosis than non CDKN2A/B HD. Here we analyzed the prognosis of glioma patients identified with CDKN2A/B HD in our hospital. method: There were 62 cases, and female was 26. Mean age of all cases was 41.2 and median age was 38. In IDH gene status, R132H was 59 cases (95.2%), R172K 2 (3.2%) and R132S 1 (1.6%). All 62 cases were TERT wildtype. CDKN2A/B HD were 12 cases (19.4%). In log-rank test, the group of CDKN2A/B HD was poor prognosis than non HD. In astrocytoma grade 3, CDKN2A/B HD had significantly poor prognosis (p=0.002). In Cox proportional hazard model analysis, CDKN2A/B HD was effective predictive prognostic factor as well as age and grading (p=0.03). discussion/conclusion: We showed that CDKN2A/B HD was good predictive prognostic factor in IDH mutant astrocytoma.
NI-2 Use of neurite orientation dispersion and density imaging(NODDI)for early distinction between infiltrating tumor and vasogenic edema in non-enhancing lesions with glioblastoma patients
Authors: Okita Yoshiko , Takano Koji , Tateishi Soichiro , Hayashi Motohisa , Sakai Mio , Kinoshita Manabu , Kishima Haruhiko , Nakanishi Katsuyuki
Published: December 2021

Background: Glioblastoma is a highly infiltrative tumor. In the non-enhancing T2-weighted hyperintense area, differentiating between non-enhancing tumors (NETs) and vasogenic edema is challenging. Neurite orientation dispersion and density imaging (NODDI) is a new diffusion MRI technique that reveals the inhomogeneity of the brain microstructure. The aim of this study is to differentiate between NETs and edema in glioblastomas using NODDI. Methods: Data were collected from 20 patients with glioblastoma as well as three patients with metastasis and two with meningioma (control), who underwent MRI as part of pre-surgical examination. The MRI data included T2- and T1-weighted contrast-enhanced images and NODDI images. Three neurosurgeons manually placed the volume of interest (VOI) on the NETs and edema based on the previous reports. ICVF, ODI, ISOVF, FA, and ADC were calculated for each VOI. Results: Fifteen and 13 VOIs were placed on NETs and edema, respectively. Each parameter was measured and the unpaired t-test revealed a significant difference between NETs and edema (p <0.0001). The ROC curve analysis revealed a large difference in the ADC, FA, and ISOVF between NETs and edema compared to ICVF and ODI. Principal component analysis of the five parameters showed that ADC, ISOVF, and FA contributed to the differentiation between NETs and edema. Multiple logistic regression analysis was performed with the three aforementioned parameters. A predictive formula could be created to discriminate between NETs and edema, following the use of which, the ROC curve revealed an AUC value of 0.8891. Furthermore, this formula was applied to the edematous regions of the images of the negative control group, and the prediction degree of the tumor was well below 0.5, thus enabling differentiation as edema.Conclusions: NODDI may prove to be a useful tool to discriminate between NETs and edema in the non-contrast T2 hyperintensity region of glioblastoma.
NI-11 Usefulness of the magnetic resonance imaging arterial spin labeling method for diagnosing posterior fossa hemangioblastoma
Authors: Hiu Takeshi , Ishiyama Ayano , Morikawa Minoru , Baba Shiro , Ujifuku Kenta , Yoshida Koichi , Izumo Tsuyoshi , Matsuo Takayuki
Published: December 2021

Purpose: It is sometimes challenging to diagnose hemangioblastoma by MRI when the tumor is a solid mass in the posterior fossa. We therefore evaluated perfusion images and diffusion-weighted images to diagnose hemangioblastoma in order to obtain the most useful quantitative features. Methods: Thirty-one posterior fossa tumors whose pathological diagnosis was confirmed by surgery were included in groups A (12 hemangioblastomas) and B (non-hemangioblastoma 19 cases: metastatic tumor 6 cases, pilocytic astrocytoma 3 cases, malignant lymphoma 3 cases, glioblastoma 2 cases, medulloblastoma 2 cases, and other 3 cases). All cases were imaged by 3.0-Tesla MRI, with the apparent diffusion coefficient (ADC) on diffusion-weighted imaging as the parameter, arterial spin labeling (ASL) as the relative value from the CBF map to the region of interest (ROI) in the contralateral hemisphere as perfusion image, dynamic susceptibility contrast (DSC) as rCBF, rCBV, corrected CBV, and K2. The ROI was set to match the contrast-enhanced part, and the two groups were compared and examined. Results: The relative ASL value of group A and the corrected CBV in DSC were significantly higher than group B (p<0.001). In contrast, the ADC showed no marked difference between the two groups. In the distinction between the two groups, the receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of the relative ASL value was significantly higher than the other parameters (AUC 0.995, cut-off value 2.34, sensitivity 100%, specificity 99.5%). Discussion/Conclusion: The non-contrast ASL method was extremely useful for diagnosing hemangioblastoma in posterior fossa tumors. The ASL method has been reported helpful for the follow-up of residual tumors or recurrence after surgery. Contrast-enhanced DSC is not always essential for diagnosing posterior fossa hemangioblastoma. It should be noted that measuring the ROI by ASL is difficult when the size of the mural nodule is small.
ML-4 A case of primary CNS lymphoma diagnosed 5 years after stereotactic radiosurgery
Authors: Tabei Yusuke , Nakazato Ichirou , Ooyama Kenichi , Kawashima Masatou , Matsuno Akira , Nomura Ryutarou
Published: December 2021

Central nervous system primary malignant lymphoma (PCNSL) is rarely diagnosed as multiple metastatic brain tumors. Almost tumors recure early after receiving stereotactic radiosurgery (SRS). Regardless of the fact, the following case report displays PCNSL, diagnosed five years after the initial treatment with SRS as brain metastases of unknown primary origin. This extraordinal case suggests long-term follow-up regarding PCNCL. The case was a 55-year-old woman with a history of a total hysterectomy for cervical cancer. She developed left paralysis. Brain MRI confirmed a 27 mm contrast-enhanced lesion in the right frontal lobe and three other lesions. SRS was performed as a diagnosis of multiple brain metastases for urgent symptom relief. No extra-cranial cancerous lesions were found. Unknown primary cancer was a probable diagnosis at that time. Two years after SRS, local regrowth of tumor of the right frontal primary motor area was discovered. Re-irradiation was performed. Cerebral edema, contrast enhancement, and left paralysis progressed following five months, taking an oral corticosteroid. Craniotomy and debulk. The pathological diagnosis was brain radiation necrosis due to no viable tumor cells. New lesions in the left temporal lobe and basal ganglia appeared three years after surgery. Awake craniotomy was performed for the left temporal lobe lesion. Histopathology showed diffuse growth of tumor cells with a high nucleo-cytoplasmic ratio and irregular nuclear shape. Immunohistochemistry revealed positive CD10, CD20, CD45 (LCA), MUM1, and negative CD3, CD5. The Ki- 67 labeling rate was as high as almost 100% to diagnose diffuse large B-cell lymphoma, PCNSL. Multidrug chemotherapy consisting of rituximab, high-dose methotrexate, procarbazine, and vincristine were performed. Complete remission was obtained without any serious adverse events. Considering the residual radiation necrosis, whole-brain irradiation was avoided. Moreover, consolidation therapy was performed only with high-dose cytarabine therapy.
ML-7 Liquid biopsy for MYD88 mutation in cerebrospinal fluid in patients with suspected primary CNS lymphoma
Authors: Yuki Yamagishi , Sasaki Nobuyoshi , Matsushita Yuko , Shimizu Saki , Matsumoto Yoshie , Saito Kuniaki , Kobayashi Keiichi , Nakatomi Hirofumi , Shiokawa Yoshiaki , Ichimura Koichi , Nagane Motoo
Published: December 2021

Background: Treatment intervention for central nervous system lymphoma (CNSL) requires pathological diagnosis by surgical biopsy. However, there are some cases in which the risk of surgery is high due to age, comorbidities, localization of lesions, etc. We are developing a CNSL diagnostic method based on the detection of MYD88 L265P mutation by digital PCR (dPCR) using CSF-DNA, and a high accuracy with a sensitivity of 92.9% and a specificity of 100% has been reported. Here, we report two cases with suspected brain stem CNSL, whose treatment strategy was determined by integrated clinico-laboratory information including neurological presentations, imaging, and the result of liquid biopsy. Result: Case 1. A 63-year-old woman visited our hospital with a complaint of right hemiplegia, which deteriorated in two months. MR images revealed a contrast-enhancing lesion in the left midbrain-ventral pons, suggesting CNSL. Biopsy was not considered because of its location, while dPCR using CSF-DNA showed a cluster of MYD88 mutation signals. Based on these work-ups, she was treated with high-dose methotrexate-based chemotherapy, resulting in a complete response with marked improvement of symptoms. Case 2. An 83-year-old man was referred for a history of diplopia and ataxic gait lasting for a month. MR images revealed an invasive lesion on his right midbrain-dorsal pons. Biopsy was declined due to the location, and liquid biopsy using CSF-DNA was performed to assist the diagnosis. In the first test, the CSF-DNA yield was too insufficient to determine the mutation signal by dPCR. The second dPCR using sufficient amount of CSF-DNA resulted in the Target/Total value of 0.049% which was lower than the threshold, suggesting the absence of MYD88 mutation. The patient underwent radiation therapy accordingly.Conclusions: CSF MYD88 mutation analysis by dPCR may have clinical utility and requires sufficient amount of CSF-DNA for exclusion of noise signals.
ML-10 Tirabrutinib, a second-generation BTK inhibitor in relapsed and refractory primary CNS lymphoma: A single institute study
Authors: Mishima Kazuhiko , Mitsuaki Shirahata , Adachi Junichi , Suzuki Tomonari , Uchida Eita , Nishikawa Ryo
Published: December 2021

BACKGROUND: The prognosis of relapsed and refractory (r/r) primary CNS lymphoma (PCNSL) is poor, and the development of new therapeutic agents is desirable. Comprehensive genetic analysis of PCNSL has shown that MYD88 and CD79B are frequently mutated and are oncogenic drivers, suggesting that Bruton’s tyrosine kinase (BTK), which is located downstream of MYD88 and CD79B, may be a reasonable therapeutic target. Tirabrutinib is a second-generation oral BTK inhibitor recently approved in Japan for the treatment of r/r PCNSL. In this study, we evaluated the efficacy and safety of tiraburtinib treatment of r/r PCNSL at Saitama Medical University. MATERIAL AND METHODS: Eighteen patients with r/r PCNSL to HD-MTX-based regimens were treated with 480 mg tiraburtinib daily under fasting conditions until disease progression. RESULTS: The median age was 63.5 years, and the median KPS was 70. Nine patients (50%) achieved a CR, 2 (11%) had a partial response, 3 (17%) had stable disease, and 4 (22%) had progressive disease. After a median follow-up of 17.3 months, the median progression-free survival was 7.9 months, and the median overall survival was 23.6 months. There were four cases of long-term treatment lasting more than one year. Grade 3 or higher adverse events were observed in 1 case of maculopapular rash, 1 case of cardiac failure, 1 case of neutropenia, and 1 case of lymphopenia. CONCLUSION: Tiraburtinib can be administered relatively safely to patients with relapsed or refractory PCNSL, and a certain degree of efficacy can be expected. Which patients can be treated with tiraburtinib over the long term, when can stop tirabrutinib treatment for patients with long-term CR, and the mechanism of tiraburtinib resistance needs to be determined.
ML-12 Clinical impact and management of skin-related disorders during treatment of relapsed PCNSL by tirabrutinib
Authors: Sasaki Nobuyoshi , Kobayashi Keiichi , Saito Kuniaki , Onoda Ryo , Seiya Yosuke , Suzuki Saki , Yamagishi Yuki , Nakatomi Hirofumi , Shiokawa Yoshiaki , Nagane Motoo
Published: December 2021

BACKGROUNDS: Tirabrutinib is a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, approved by the Japanese Pharmaceutical and Medical Devices Agency (PMDA) for relapsed and refractory PCNSL in March 2020. Skin-related disorder (SRD)s are the most prevalent adverse events in tirabrutinib, which accounted for 54.5% in a phase I/II trial. While the use of tirabrutinib is increasingly considered in clinical practice, the prevalence and clinical impact of tirabrutinib-related SRDs in real-world practice remains unclear. METHODS: Relapsed PCNSL patients treated with tirabrutinib at the author’s institution were identified, and divided into those with SRDs (SRD group), and without SRDs (non-SRD group). Response rate and progression-free survival (PFS) were retrospectively analyzed and compared between the two groups. RESULTS: Eleven patients were identified (median age: 73 [range: 50–83], median KPS: 70 [range: 40–90]), which included six (54.5%) from the SRD group and five (45.5%) from the non-SRD group. Response rate was 100% in the SRD group and 60% in the non-SRD group. Median PFS was 2.8 months in the SRD group and 36.3 months in the non-SRD group, which yielded no significant difference (p=0.446). While antihistamine prophylaxis using fexofenadine was performed in seven patients, among them SRDs were observed in three (27.3%). SRDs lead to tirabrutinib interruption (for seven days or more) in two (18.2%), dose reduction in three (27.3%), and discontinuation in two (18.2%) patients. Four patients in whom tirabrutinib was interrupted or discontinued due to SRDs had shorter PFS, compared with the two patients from the SRD group in whom tirabrutinib was continued (median PFS: 2.3 and 29.6 months, respectively) (p=0.049). CONCLUSIONS: SRDs substantially lead to tirabrutinib interruption or discontinuation, which could result in early PD. Since fexofenadine prophylaxis seems ineffective for preventing SRDs, other antihistamines should be considered. Establishment of the optimal management of tirabrutinib-related SRDs is warranted.
ML-17 Clinical usefulness of Tirabrutinib in recurrent PCNSL: single institute experience
Authors: Matsuura Jin , Kuroda Jun-Ichiro , Takezaki Tatsuya , Shinojima Naoki , Mukasa Akitake
Published: December 2021

Background: Primary central nervous system lymphoma (PCNSL) is a lymphoma whose primary lesion is localized in the brain and spinal cord. Treatment is a combination of high-dose methotrexate-based chemotherapy and whole-brain irradiation, often leading to recurrence. Pathologically, non-GCB type diffuse large B-cell lymphoma (DLBCL) predominates. In DLBCL, constitutive activation of B cell receptor signal (BCR) is the tumor mechanism of tumor development and growth. Tirabrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) located downstream of BCR. In a phase I / II study, an overall response rate was 64%. Currently, Tirabrutinib is used to treat relapsed or refractory PCNSL. Purpose: Tirabrutinib is a drug that has just been approved, and there are few reports of its use in clinical practice. We report on our experience with Tirabrutinib with a review of the literature. Methods: We retrospectively examined the clinical course of 11 recurrent PCNSL patients treated with Tirabrutinib at our institution. Results: The average age of the subjects was 68.7 years, and 7 cases were male. Tirabrutinib 480 mg was administered in all cases. The response rate was 60% (6/10 cases). The median progression-free survival was 4.3 months. The adverse events were Grade 3 neutropenia in 1 patient and Grade 2 skin disorder in 4 patients. Treatment was discontinued in 5 of the 11 patients due to the progression of the disease. Due to the eruption, Tirabrutinib was reduced to 320 mg in 1 patient and discontinued in 1 patient. Treatment was discontinued at the request of the patient in 1 case, and four patients are still on medication. Summary: According to the results we obtained, the response rate was the same as that in the phase I / II study, and the progression-free survival was slightly longer.
BT-1 An autopsy case of multicentric malignant glioma, H3K27M mutant
Authors: Hayashi Nobuhide , Enomoto Hiroki , Kubo Kenji , Nakanishi Yuta , Ishii Kenji , Kawaguchi Takumi , Okada Hideo , Kuwata Toshikazu , Tsubota Yukari , Kanemura Yonehiro
Published: December 2021

Introduction: In 2016, the World Health Organization (WHO) defined diffuse midline glioma, H3K27M mutant (WHO Grade 4) as a tumor with K27M mutation in histone H3.3 (H3F3A) or H3.1 (HIST1H3B/C) that develops mainly in the midline regions of the central nervous system. Here, we report a rare case of the abovementioned disease with remote multiple lesions in addition to the midline regions that was diagnosed on the initial visit. Case: The 52-year-old man, suffered from dysarthria, dysphagia, gait disturbance, and headache that gradually worsened over several months. Non-contrast-enhanced lesions were noted in the pons(swelling and involvement of the basilar artery trunk), cerebellum, thalamus, fornix, periventricular area, hippocampus, medial aspect of bilateral frontal lobes, and distally in the right frontal cortex and apical region of the left temporal lobe. The open biopsy was performed for left cerebellar surface lesion, and the pathological and genetic diagnosis was diffuse midline glioma, H3K27M mutant. Extended focal radiation at 50Gy/25fr and corpus callosal/cerebellar boost at 10Gy/5fr were performed. The lesions were markedly reduced, and neurological symptoms were also alleviated. However, 20 months after the initial visit, neurological symptoms had worsened and cerebrospinal fluid dissemination occurred, after that died at 29 months. An autopsy revealed tumor invasion mainly in the midline regions of the cerebrum and in the cerebellum, brain stem, pituitary gland, entire spinal cord, and cauda equina. Immunostaining of the distally cerebral cortex lesions showed that with a negative result for H3G34V. Discussion/Conclusion: It was suggested that caution is required for primary differential diagnosis may be presented at multiple lesions such as remote cerebral cortex of diffuse midline glioma, H3K27M-mutant.
BT-4 The treatment history of long-term survivors of Optic Pathway Glioma in Kobe Children’s Hospital
Authors: Kawamura Atsufumi , Koyama Junji , Akutsu Nobuyuki , Higashino Masashi , Fujita Kenji
Published: December 2021

Optic pathway glioma(OPG) is almost recognized in childhood and about 0.01–0.02% of whole brain tumor in Japan. Because of the rare tumor, there are few reports about results of its treatment. In 2021, Guideline of Optic pathway/hypothalamic glioma is indicated from The japan Society for Neuro-Oncology. We retrospectively study 9 cases history of OPG who have treated for more than 5 years from January 2005 to March 2021 in Kobe Children’s Hospital. Cases are 4 boys and 5 girls. Average age at diagnosis is 3.8 years old and average follow up term is 11 years 10 months. They are 4 Pilocytic astrocytoma, 3 Pilomyxoid astrocytoma, and 1 Fibrillary astrocytoma. Al l cases have survived. There are only 2 cases who could be controlled with single series of surgical treatment and chemotherapy. Most cases need several times of resection and chemotherapy and uncontrollable 5 cases required radiological treatment. 2 cases are still under treatment for over 10 years. For OPG, partial resection to control hydrocephalus is recommended and several trial of chemotherapy must be carried out. There exist a few cases who need continuous treatment for long term. The other side, a few cases are uncontrollable those need radiotherapy to manage tumor volume. Because the history of OPG would be long term, we should adjust the treatment plan to environment of patients.
BT-7 Long-term outcome and late adverse effects of intracranial primary germ cell tumor
Authors: Hanihara Mitsuto , Kawataki Tomoyuki , Saito Ryu , Ogiwara Masakazu , Kinouchi Hiroyuki
Published: December 2021

Background: Current standard of care for intracranial germ cell tumor (IGCT) have favorable cure rates. However, long-term treatment-related adverse event data are limited. The present study examined the long-term outcome of IGCT.Methods: The data from 27 patients with IGCT treated at our institutes from 1993 to 2020 were retrospectively analyzed. The patients were divided into two groups: group A; who received whole-ventricle RT (30 Gy) or focal RT (40-50Gy) from 1993 to 2012, group B; who received whole-ventricle RT (23.4 Gy) from 2013 to 2020. Complications and physical-activity level after treatment were retrospectively analyzed.Results: Pathological diagnosis was germinoma in all cases, and chemotherapy was CARE in 19 cases and ICE in 2 cases. Radiation therapy was performed in 15 cases in group A and 6 cases in group B. The follow-up period was 8–19 years (mean 11.3 years) in group A and 0.4–7 years (mean 3.6 years) in group B. Radiological cure was obtained in all cases, there was no recurrence. Hypopituitarism requiring hormone replacement therapy was observed in 53% of patients in group A and 50% of patients in group B. Late complications were cerebral hemorrhage from venous malformation (4 years after treatment), symptomatic cerebral atrophy in 2 cases (3 years / 6 years after treatment), radiation induced malignant glioma (19 years after treatment) in group A. The rate of good physical-activity was 71% of group A and 100% of group B.Discussion/Conclusions: CARE + whole-ventricle radiation therapy is appropriate as a standard treatment for ICGT. Late complications are directly linked to poor quality of life and may be radiation dose dependent. Optimize radiation therapy to further improve outcomes is required.
CS-1 Cerebellar liponeurocytoma; Report of two cases with detailed metabolic, immunohistochemical, and genetic evaluations
Authors: Shimizu Miyuki , Origuchi Shinichi , Hirono Seiichiro , Matsutani Tomoo , Oota Masayuki , Ikeda Jun-Ichiro , Yokoo Hideaki , Iwadate Yasuo
Published: December 2021

Cerebellar liponeurocytoma (cLNC), World Health Organization grade II neoplasm, is a rare brain tumor characterized by advanced neuronal/neurocytic differentiation and focal lipid accumulation in neuroepithelial tumor cells. However, the expression and genetic profiling of cLNC, as well as metabolic imaging characteristics, have been poorly studied. Two patients with lower vermian tumors were operated on with telovelar approach. Moderate methionine uptake in positron emission tomography was observed in both cases. Histologically, the tumor was composed of small, uniform cells with round nuclei in a sheet-like fashion. Vacuolate cells with displacement of nuclei suggested the lipid accumulation, which was further supported by immunohistochemical staining of S-100. Although the extent of lipidization was relatively low compared with the reported cLNC cases, the immunohistochemical findings confirmed the diagnosis of cLNC. Next-generation sequencing of tumoral DNA in one case detected a splice site mutation of the ATRX gene, which is the first observation in the literature. Neither chemotherapy nor radiotherapy were administered postoperatively in both cases. In one case with spinal dissemination, residual tumor demonstrated progression 7 months after the resection. Long term follow-up data of cLNC cases with detailed expression and genetic profiles are essential for precise diagnosis and better understanding of the oncogenic pathway as well as the natural history of cLNC.
COT-3 Exosomal microRNA expression signature in blood and cerebrospinal fluid of glioblastoma patients
Authors: Yamashita Daisuke , Suehiro Satoshi , Ohtsuka Yoshihiro , Ozaki Saya , Nishikawa Masahiro , Inoue Akihiro , Kohno Shohei , Ohue Shiro , Ohnishi Takanori , Kunieda Takeharu
Published: December 2021

Analysis of exosomes derived from plasma or cerebrospinal fluid (CSF) has emerged as a promising biomarker platform for therapeutic monitoring in glioblastoma patients. However, the contents of the various subpopulations of exosomes in these clinical specimens remain poorly defined. Here we characterize the relative abundance of miRNA species in exosomes derived from the plasma and CSF of glioblastoma patients. To this end, we first employed miRNA arrays to measure the expression of exosomal miRNAs in the plasma from glioblastoma patients (n = 24) and healthy volunteers (n = 7) as control. In addition, we performed global miRNA profiling of exosomal miRNAs in the CSF from glioblastoma patients (n = 5) and non-tumoral patients (n = 3; hydrocephalus patients) as control. In plasma derived exosomes, 80 miRNAs were altered by >2-fold in glioblastoma patients compared to controls. In CSF, 92 miRNAs were altered by >2-fold in glioblastoma patients compared to controls. Combined analysis of plasma and CSF revealed a similar fold difference in eight miRNAs. Next, we measured these eight miRNAs expression in in the plasma from pre- and post-operative glioblastoma patients (n = 9). Among these eight miRNAs, we identified only one miRNA (miR-34b-3p) that was upregulated in exosomes from pre-operative glioblastoma patients. Our results suggest that miR-34b-3p might have a potential as a novel diagnostic marker or a therapeutic tool for glioblastoma patients.
COT-11 Relationship between preoperative liquid biopsy and prognosis of glioblastoma -Next Generation Sequencing of small noncoding RNA-
Authors: Onishi Shumpei , Yamasaki Fumiyuki , Takayasu Takeshi , Takano Motoki , Yonezawa Ushio , Taguchi Akira , Kanda Miyuki , Sugiyama Kazuhiko , Tahara Hidetoshi
Published: December 2021

Background

Non-invasive biomarkers are required in clinical practice of glioblastoma (GBM). We have previously reported the liquid biopsy for differentiating glioblastoma, central nervous system primary lymphoma and healthy control. In this study, we analyzed the relationship between the preoperative serum expression of circulating small non-coding RNAs and the prognosis of GBM patients.

Methods

Preoperative blood samples of GBM, IDH-wildtype patients (N=26) were centrifuged and collected all small RNAs in serum. The expression of small non-coding RNAs were analyzed using a next-generation sequencing system. The small non-coding RNAs that could predict short-term survivals in GBM patients were selected by the stepwise analysis. A diagnostic model was created using the combination of these RNAs and evaluated with ROC curve.

Results

GBM patients treated with adjuvant therapy of temozolomide and radiotherapy were divided into two groups: (1) a short-term survival group (N=11) with a survival time less than 15 months and (2) a long-term survival group (N=15) with a survival time more than 15 months. In the short-term survival group, the preoperative serum expression levels of small RNA-X and small RNA-Y were high, and the expression levels of small RNA-Z and small RNA-W were low. Using these four small non-coding RNAs, a prognostic model was created. The model was able to predict the short-term survival group of GBM patients with a sensitivity of 90.9% and specificity of 93.3% (AUC: 0.969).

Conclusion

The prognostic model developed with preoperative small non-coding RNA in GBM patients may be useful for estimating the survival of GBM patients treated with adjuvant therapy of temozolomide and radiotherapy.