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Background Tumour-treating fields therapy is a locoregional, anti-cancer treatment. Efficacy and safety of tumour-treating fields therapy in adults with newly diagnosed glioblastoma were demonstrated in the pivotal phase 3 EF-14 study (NCT00916409). Here, we report post-approval data of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma. Methods Unsolicited post-marketing surveillance data from Japanese patients with newly diagnosed glioblastoma treated with tumour-treating fields therapy (December 2016–June 2020) were retrospectively analysed. The primary endpoints were skin, neurological and psychiatric adverse events. The secondary endpoints were 1- and 2-year overall survival rates, and the 6-month progression-free survival. adverse events were analysed using MedDRA v24.0. The overall survival and progression-free survival were assessed using the Kaplan–Meier survival analysis (log-rank testing). The Cox proportional hazard regression analyses were also performed. Results Forty patients with newly diagnosed glioblastoma were enrolled (62.5% male; median age 59 years; median baseline Karnofsky Performance Scale score 90). The most common tumour-treating-fields-therapy-related adverse event was beneath-array local skin reaction (60% of patients). The adverse events were mostly mild to moderate in severity. Neurological disorders were observed in 2.5% patients (one patient reported dysesthesia). No psychiatric disorders were reported. The 1- and 2-year overall survival rates were 77.9% (95% CI 60.6–88.3) and 53.6% (35.5–68.7%), respectively. The 6-month progression-free survival was 77.5% (61.2–87.6%). These survival rates compare favourably with those in the EF-14 trial (1- and 2-year overall survival rates: 73% [69–77%] and 43% [39–48%], respectively; 6-month progression-free survival rate: 56% (51–61%). Conclusion This post-approval, real-world evidence study revealed no new safety signals and suggests the safety and efficacy of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma.

Although adult diffuse gliomas, IDH-wildtype, histologically diagnosed as grade 2-3 have been regarded as clinically equivalents with glioblastomas, the prognosis of this population has scarcely been discussed with further consideration of treatment backgrounds. This retrospective study aimed to investigate the prognosis of adult patients with IDH-wildtype diffuse gliomas histologically diagnosed as WHO grade 2-3 using a cohort with homogenous treatment background. A total of 214 IDH-wildtype cases were extracted from the collected data of the previous study investigating the prognostic significance of molecular markers (Arita, Acta Neuropathol Commun 2016). The inclusion criteria were as follows: supratentorial tumor, pretreatment Karnofsky Performance status of 70 or higher, wildtype-H3.3 status, chemoradiation therapy with temozolomide after the initial surgery. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier methods. The histological diagnosis in this study was made based on the WHO 2016 classification, and the histological criteria is compatible with the current classification (CNS WHO5).The mean age was 62.8, 59.8 and 60.2 years in grade 2 (n=8), 3 (n=45) and 4 (n=161) case, respectively. The higher ratio of biopsy cases was associated lower grades (50% in grade 2, 22% in grade 3 and 9% in grade 4 cases). Grade 2-3 cases showed short survival (OS 24.7 months and PFS 9.7months) despite the intensive treatment of chemoradiation at the time of diagnosis. In details, OS was 41.5, 23.1 and 17.8 months in grade 2, 3 and 4 cases, respectively. PFS was 12.6, 9.7 and 8.2 months in grade 2, 3 and 4 cases, respectively. Our results revealed that IDH-wildtype grade 2-3 cases showed dismal prognosis even after the chemoradiation at the time of diagnosis. Further development of treatments is needed in this population as well as glioblastomas, IDH-wildtype.

Objective The MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) module is a widely used instrument for measuring symptom burden and interference of daily activities in brain tumor patients. This study aims to develop and validate its Japanese version (MDASI-BT-Japanese). Methods Following forward and backward translation of the original MDASI-BT into Japanese, understandability and feasibility were assessed by cognitive debriefing. Subsequently, patients with brain tumors were asked to fill out MDASI-BT-Japanese and European Quality of Life-5 Dimensions (EQ-5D). Feasibility, reliability and validity of MDASI-BT-Japanese were assessed. Results Cognitive debriefing confirmed overall ease of completion and good understandability. The study population composed of 140 patients with brain tumors (most commonly gliomas). The mean symptom severity score and mean interference score were 1.9 ± 1.7 and 2.8 ± 2.7, respectively. The top items included distress and drowsiness for symptom severity and general activity and work for interference. The median time required was 4 minutes (range, 0.5–30), and missing values were seen in 1%. Internal consistency was proven by excellent Cronbach’s coefficient alpha (0.94 for symptom severity, 0.92 for interference). Test–retest reliability was assessed with acceptable intra-class correlation coefficient (mean, 0.76). Correlation efficient ranged between 0.7 and 0.9 for convergent validity. Known-group validity was confirmed by significantly different mean symptom severity score and mean interference score among patients with different performance status. As evidence of concurrent validity, MDASI-BT-Japanese correlated with EQ-5D in the hypothesized magnitude and direction. Conclusions The newly developed MDASI-BT-Japanese has demonstrated feasibility, reliability and validity in evaluation of clinical benefit in Japanese-speaking brain tumor patients.

Background Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results. Methods Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation. Results Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 123 germinomas, 76 intermediate-prognosis-group cases (including 38 germinoma with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year recurrence-free survival (RFS) for germinoma, intermediate and poor-prognosis-groups were 84/79%, 83/76% and 59/59%, respectively, and overall survival (OS) for each were 97/91%, 92/85% and 57/53%, respectively. Prognosis for germinoma with or without STGC was the same. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, and ages were significantly different depending on causes, such as disease-related (14 years on average) and complications (29 years). OS after recurrence at 5/10/20 years were 64/62/48%.Hormonal supplementation was seen in 82% for neurohypophyseal cases and antidiuretic hormone supplementation was most frequent (82%). Among available cases, 20-out-of-155 cases showed neoplastic/vascular complications, among which cavernous malformation was the most (n=9). Median period until complication presentation was 235 months, and the rate at 20 years was 11%. Conclusions Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.

Background Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Here, we report the result of phase I part and the current status of phase II part. Patients and Methods Patients between 20 and 74 years of age with supratentorial GBM histologically diagnosed according to the World Health Organization 2016 classification were eligible. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. Results Between February 2021 and January 2022, the first three patients were treated with 1,500 mg/day MF and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. The median age of the patients was 41 years. Three tumors (42.9 %) were IDH1/2 mutants and 4 (57.1 %) were IDH1/2 wild-types. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2. Only one grade 3 seizure was reported, which was likely related to the tumor. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up. Conclusion MF dose of up to 2,250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to phase II study with 2,250 mg/day MF.

Introduction: Glioblastoma, IDH-wild type (GBM) is the most common malignant brain tumor with a dismal prognosis. Although its coding region is well-analyzed, little is yet known about the landscape of whole-genome in GBM. Here, we analyzed whole-genome sequencing data from large cohorts to completely uncover the genetic aberrations in GBM. Methods: We analyzed 281 whole-genome sequencing data of patients with GBM, of which 152 cases are from our cohort with deep coverage (×120) and 129 cases are from a public database. Results: The median numbers of somatic mutations and structural variants (SVs) per case are 3.0/Mb and 62.5, respectively. While a complex SV is rare in other malignant brain tumors such as IDH-mutant glioma (35% of samples), a large proportion of GBM cases (85%) have complex SV with ≥10 breakpoints. CDKN2A/B homozygous deletions (HDs) are usually comprised of a simple deletion in IDH-mutant glioma whereas about a quarter of CDKN2A/B HDs in GBM are induced by complex SVs. In addition, 30.5% of extrachromosomal DNA (ecDNA) involves multiple chromosomes. Taken together, complex SVs could play a key role in the initiation and progression of GBM. Our deep WGS enables us to delineate a fine view of clonal architecture, where mutational signature varies between clonal and subclonal mutations. The majority of clonal mutations consist of the clock-like signature, whereas subclonal mutations have a relatively low proportion of the clock-like signature. Instead, several other signatures including the APOBEC signature significantly increase in subclones, presuming that various mutational processes along with the clock-like signature contribute to the GBM pathogenesis in its progression phase. Conclusions: GBM evolves through exploiting complex structural variants involving multiple driver genes and the accumulation of genetic mutations caused by distinct mechanisms depending on its developmental stage.

Introduction Recent large-scale sequencing projects for IDH-mutant adult-type diffuse glioma (Astrocytoma, IDH-mutant and Oligodendroglioma, IDH-mutant and 1p/19q-codeleted) have revealed the genetic landscape of coding mutations. However, little is yet known about the non-coding regions and structural variants (SVs). We analyzed deep (> x120) whole-genome sequencing (WGS) to delineate the comprehensive genetic lesions of IDH-mutant gliomas. Methods We investigated WGS of 228 cases with IDH-mutant glioma (204 cases in our cohort along with 24 publically available cases). Results The median tumor mutational burden in astrocytoma and oligodendroglioma was 2.0/Mb and 1.7/Mb, respectively. The median number of SV per case was 15.0 and 4.5, respectively. SV was involved in known driver genes in 7.7% of cases, supporting a model in which accumulation of SV as well as mutation drives tumor initiation and/or progression. The distribution of SV is biased on each chromosome, suggesting that each chromosome has a distinct susceptibility for SV. In IDH-mutant astrocytoma, complex SVs are significantly enriched on chromosome 12 which frequently involves CDK4, suggesting that SVs could lead to tumor evolution. The numbers of SVs and single nucleotide variants (SNVs) per case are correlated, presuming that IDH-mutant glioma can progress by acquiring both SNV and SV in a time-dependent manner. Conclusion SV could contribute to the development of IDH-mutant gliomas as well as mutations. Since WGS has a great resolution for genetic alterations, further analysis would enable us to uncover glioma pathogenesis.

Ependymomas encompass multiple, clinically relevant tumor types based on localization, genetic alterations, and epigenetic and transcriptomic profiles. Tumors belonging to the methylation class of spinal ependymoma (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, molecular data of SP-EPN are scarce, and clear treatment recommendations are lacking. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations. Yet, it remains unclear whether SP-EPN with germline or sporadic NF2 mutations or with NF2 wild type status differ clinically or molecularly. To provide a comprehensive molecular profile of SP-EPN, we integrated epigenetic, genomic, transcriptomic, and histological analyses of up to 237 cases. Clustering of methylation data revealed two distinct molecular SP-EPN subtypes. The distribution of NF2 mutated cases differed significantly across these subtypes (p

Background Cerebrospinal fluid (CSF) cytology and spinal MR imaging are routinely performed for staging before treatment of intracranial germinoma. However, the interpretation of the results of CSF cytology poses 2 unresolved clinical questions: (1) Does positive CSF cytology correlate with the presence of spinal lesion before treatment? and (2) Is craniospinal irradiation (CSI) necessary for patients with positive CSF cytology in the absence of spinal lesion? Methods Multicenter retrospective analyses were performed based on a questionnaire on clinical features, spinal MR imaging finding, results of CSF cytology, treatments, and outcomes which was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Pretreatment frequencies of spinal lesion on MR imaging were compared between the patients with positive and negative cytology. Progression-free survival (PFS) rates were compared between patients with positive CSF cytology without spinal lesion on MR imaging treated with CSI and with whole brain or whole ventricular irradiation (non-CSI). Results A total of 92 germinoma patients from 45 institutes were evaluated by both CSF cytology and spinal MR images, but 26 patients were excluded because of tumor markers, the timing of CSF sampling or incomplete estimation of spinal lesion. Of the remaining 66 germinoma patients, spinal lesions were equally identified in patients with negative CSF cytology and positive cytology (4.9% and 8.0%, respectively). Eleven patients treated with non-CSI had excellent PFS comparable to 11 patients treated with CSI. Conclusion CSI is unnecessary for germinoma patients with positive CSF cytology without spinal lesions on MR imaging.

PURPOSE Fluorescence imaging is an important surgical adjunct in malignant glioma surgery. 5-aminolevulinic acid (5-ALA) has been proven effective for radical tumor resection and extended progression-free survival in a phase III randomized trial and therefore integrated into surgery for malignant glioma. Importantly, however, some limitations still exist in its use, which include false positivity and false negativity as well as inability of re-administration. In this study, we aimed to develop a novel, spray-type fluorescent probe using hydroxymethyl rhodamine green (HMRG) as a fluorescent scaffold. METHODS We have previously established a fluorescent probe library comprised of more than 320 kinds of HMRG probes. They have HMRG as a fluorescent scaffold with various types of dipeptides attached to it. Primary probe screening was performed using the homogenized tumor samples from patients with glioblastoma operated at our institution. Secondary screening followed using the selected probes and fresh tumor samples obtained from patients with glioblastoma operated from 2016 until 2018. Diced electrophoresis gel (DEG) assay, two-dimensional gel electrophoresis followed by a multi-well plate-based fluorometric assay, was performed to identify responsible enzymes for the selected probe. Further experiments with inhibitors, real-time PCR, immunohistochemistry, and western blotting were performed for confirmation. RESULTS Proline-arginine-HMRG (PR-HMRG) was selected as a candidate probe based upon the above two-step screenings. It achieved 79.4% accuracy in receiver operating characteristic curve analysis. Calpain-1 was found to be responsible to cleave PR-HMRG probe by DEG-proteome analysis. Calpain-1 protein was expressed at significantly higher level in tumors that were fluoresced by PR-HMRG than in those that were not. CONCLUSIONS Our innovative screening method was able to find PR-HMRG as a novel fluorescent probe effective for rapid detection of glioblastoma. A preclinical study is planned to assess the efficacy and safety of the selected probe.

BACKGROUND Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases. MATERIALS AND METHODS We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups. RESULTS Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups. CONCLUSION Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.

BACKGROUND Manual segmentation of brain tumor images from a large volume of MR images generated in clinical routines is difficult and time-consuming. Hence, it is imperative to develop a machine learning model for automated segmentation of brain tumor images. PURPOSE Machine learning models for automated MR image segmentation of gliomas may be useful. However, the image differences among facilities cause performance degradation and impede successful automatic segmentation. In this study, we proposed a method to solve this issue. METHODS We used the data from the Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) and the Japanese cohort (JC) datasets collected from 10 facilities. Three models for tumor segmentation were developed. The BraTS model was trained on the BraTS dataset, and the JC model was trained on the JC dataset; whereas, the Fine-tuning model was a fine-tuned BraTS model using the JC dataset. RESULTS MR images of 544 patients were obtained for the JC dataset. Half of the JC dataset was used for independent testing. The Dice coefficient score of the JC model for the JC dataset was 0.779± 0.137, whereas that of the BraTS model was remarkably lower (0.717 ± 0.207). The mean of the Fine-tuning models for the JC dataset was 0.769 ± 0.138. There was a significant difference between the BraTS and JC models (P < 0.0001) and the BraTS and Fine-tuning models (P = 0.002); however, no significant difference was observed between the JC and Fine-tuning models (P = 0.673). CONCLUSIONS Application of the BraTS model to heterogeneous datasets can significantly reduce its performance; however, fine-tuning can solve this issue. Since our fine-tuning method only requires less than 20 cases, this methodology is particularly useful for a facility where there are a few glioma cases.

BACKGROUND convolutional neural network (CNN) model using MRI imaging are likely to be effective for grading glioma. However, interpretation of the judgment basis of CNN is difficult. The purpose of this study is twofold. One is to create a high accuracy machine learning model that grading of glioma (Glioma grade II, between III and IV). The other is to visualize the judgment basis of the model. METHODS We targeted cases that were imaged at our Hospital during the period from August 2014 to January 2018. Five types of MRI are used. The five types are two types of DWI (b1000DWI and b2000DWI, respectively, with a value of 1000 and 2000), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and mean kurtosis (MK). The images were input to CNN wtihout ROI. Seven types of CNN were prepared, and 100 epochs of learning were performed. RESULTS 55 cases were included. There were 14 grade II, 12 grade III, and 29 grade IV). Of these, 44 cases up to July 2017 in chronological order were used as a dataset for learning, and 11 cases from August 2017 to January 2018 were taken as independent test dataset. The best results were obtained using MK as input, with a percentage of correct cases of test data of 0.82. Subsequently, we applied Grad-CAM to the model. Grad-CAM is visualized technique that shows where CNN focused on. The model focused on the tumor part of the image. In addition, in the cases of glioma and meningioma coexisting, grading was performed focusing on the glioma area not on meningioma area. CONCLUSION When grading glioma, it was considered that CNN decide glioma’s grade focusing on tumor part of the image, as well as humans.

INTRODUCTION Neuroendoscopic surgery is useful for intraventricular tumors accompanied by ventriculomegaly. However, it is often challenging for cases with small ventricles. Our institution is actively performing surgeries for pediatric intraventricular tumors without frank ventriculomegaly. METHODS Seven cases of intraventricular tumors without ventriculomegaly (5 cases of subependymal giant cell astrocytoma (SEGA) and 2 cases of germ cell tumors (GCTs)) were analyzed. The age ranged between 3 and 14 years (median 5 years). The sizes of SEGA were between 10-27mm, and all the tumors showed an enlargement around the foramen of Monro, which was the indication for surgery. Biopsy and third ventriculostomy were performed for GCTs. For resection, after making a small craniotomy of 2 x 3 cm, ellipse-cone-like sheath with a diameter of 12mm or 17mm was inserted through it to the lateral ventricle, which enabled a wide surgical view. Under a rigid endoscope of 4mm diameter, 2 types of surgical instruments were employed, making the microsurgical procedure like under a microscope, with a wider view, possible. For the cases of tumor resection, septostomy and placement of a drain in the ventricle were performed at the end of surgery. RESULTS The lesions were safely approached in all the cases. For resection, endoscopic microsurgery was possible, and tumor was totally removed in all the cases. No postoperative complication was observed in any of them. CONCLUSIONS Our experience shows that tumor resection can be safely achieved with the aid of endoscope even for cases without ventriculomegaly.

INTRODUCTION Diffuse midline glioma (DMG) mostly affects young children. The newly-introduced disease entity DMG, H3K27M-mutant uniformly portends poor prognosis, and therefore that in the pons is usually treated based upon radiological diagnosis without histological confirmation. DMG is rarer in adolescents and young adults (AYA), and remains poorly characterized. In this study, we sought to investigate the clinical, pathological, and molecular profiles of DMG in AYA generation. METHODS Patients of age between 16 and 39 undergoing biopsy at the University of Tokyo Hospital between 2003 and 2019 were included in the study. Clinical data and images were retrospectively reviewed. Genetic analyses were performed in cases with abundant tissues. RESULTS Ten patients included 8 brainstem and 2 thalamic DMG. The median age was 25 years (range, 19–38). Pathological diagnosis was DMG, H3K27M-mutant in 3 patients, glioblastoma, IDH-mutant in 1, anaplastic astrocytoma, IDH-wildtype in 4, diffuse astrocytoma, IDH-mutant in 1, and diffuse astrocytoma, IDH-wildtype in 1. Genetic analyses detected H3F3A-K27M mutation in 2, HIST1H3B-K27M mutation in 1, IDH1-R132H mutation in 1, and IDH1-R132S mutation in 1. With a median follow-up of 23 months (range, 2–61), only 3 patients died 29–61 months after diagnosis, and the remaining 7 patients survived for 2–59 months. Neither IDH1 mutation nor H3K27M mutation was associated with survival in this series. CONCLUSION Survival of AYA patients with DMG was seemingly variable with some long survivors. H3K27M mutation was present in a subset of patients. A further study is warranted to correlate molecular profile with clinical pictures including patient survival.

BACKGROUND Ependymomas commonly occur in the fourth ventricle and the spinal cord. Gross total resection, age and WHO grade are known prognostic factors. Ependymomas are currently classified into 9 distinct subgroups by DNA methylation profile analysis. Spinal cord ependymoma is distinct from other subgroups. To investigate heterogeneity within spinal cord ependymoma, we examined DNA methylation profiles. MATERIALS AND METHODS We used Infinium MethylationEPIC array (illumina) to obtain DNA methylation data from frozen specimens of spinal ependymoma resected at the University of Tokyo, Osaka City University, and Tokyo Metropolitan Neurological Hospital. Japan Pediatric Molecular Neuro-Oncology Group provided methylation data for 11 reported cases. Cluster analysis was performed using Cluster3.0. RESULTS We analyzed 34 patients, 21 male and 13 female, aged from 18 to 76 years (median 50.5 years), including 2 cases with neurofibromatosis type 2. WHO grade was grade_3 in 2 cases and grade_2 in others. Clustering of the DNA methylation data showed that WHO grade_3 cases tended to be classified into a subgroup distinct from other cases. CONCLUSION This is the largest DNA methylation profiling study on spinal cord ependymoma to date. The study may suggest a new subgroup correlated with higher WHO grade.

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. To further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior, we compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. By comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas,136 up-regulated genes and 203 down-regulated genes were extracted. Down-regulated genes in the 19q-loss astrocytomas were heavily clustered to 19q and 4p, and up-regulated genes to 4q. It was noted that fibroblast growth factor 1 associated with stem cell maintenance was down-regulated in 19q-loss astrocytomas and genes associated with glioma progression were differentially expressed, these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, 19q-loss astrocytomas did not shift to oligodendrogliomas with 1p/19q codeletion but were a subgroup in astrocytomas. These results indicated that 19q-loss in astrocytomas is more likely to be an acquired event rather than early event in oncogenesis like 1p/19q codeletion in oligodendrogliomas, and the biological and morphological features of 19q-loss astrocytomas were possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

The systems that can objectively predict the future trends of a particular research field are always anticipated while conducting medical research. Such systems also provide a considerable aid to researchers while determining and acquiring appropriate research budgets. This study intended to establish a novel and versatile algorithm that can predict the latest trends in neuro-oncology. Seventy-nine neuro-oncological research fields were selected using computational sorting methods, such as text-mining analyses, along with 30 journals that represent the recent trends in the neuro-oncology field. Further, the annual impact (AI) for each year with respect to each journal and field (number of articles published in the journal × the impact factor of the journal) was calculated as a novel concept. Subsequently, the AI index (AII) for the year was defined as the sum of the AIs for the aforementioned 30 journals. With respect to the aforementioned neuro-oncological research fields, the AII trends from 2008 to 2017 were subjected to machine learning predicting analyses. The prediction accuracy of the latest trends in neuro-oncology was validated using actual data obtained from previous studies. In particular, the linear prediction model achieved a relatively good accuracy. The most notable and latest predicted fields in neuro-oncology included some interesting emerging fields, such as microenvironment and anti-mitosis, as well as the already renowned fields, such as immunology and epigenetics. Furthermore, we retrospectively attempted an analysis of the fields different from neuro-oncology. Interestingly, as of 2008, the future emergence of the CRISPR-Cas9 gene editing system has been predicted using this system. Overall, the presented algorithm displays potential to be an effective and versatile tool for the prediction of future trends in a particular medical field.

PURPOSE Diffusion tensor-based tractography (DTT) is a method to estimate the direction of white matter fibers, but it is difficult to verify the relationship with brain function spatially with high accuracy. We developed a registration method to fuse the real space (brain surface photograph) and preoperative fused 3D image (virtual space) using the landmark method and thin plate spline method. In our previous study, this method was able to achieve highly accurate alignment registration error 0.7±0.1mm (mean±SE) even after brain shift due to craniotomy. In this study, we proposed a method to examine spatial errors of DTT and direct cortical stimulation (DCS) and verify its accuracy. METHODS We included 7 gliomas performed awake surgery. We created the fused three – dimensional image before surgery and acquired the brain surface photograph immediately after craniotomy, then we aligned them using the proposed method. Sites that showed speech arrest by DCS were plotted on the fused image. A circle with a radius of 15 mm centered on the same site was taken as the range over which the current spreads. The surface area of each of the circles was calculated to make it true if there was arcuate fasciculus drawn with DTT in the circle, and false if it did not exist. By using this method, the accuracy of the DTT was verified. RESULT: In 7 cases, speech arrest was shown at 21 DCS plots. The probability of the presence of DTT within the current spread of DCS was 64.4%. CONCLUSION The proposed method indicates that DTT does not necessarily match the DCS results by verification using real space and virtual space. We present some illustrative cases.

OBJECTIVE: Creating a machine learning model using diffusion tensor and kurtosis images are effective for malignancy diagnosing of glioma. However, it is unknown whether an IDH mutation, which is the most important mutation in glioma, can be predicted using diffusion tensor and kurtosis images. The purpose of our research was to predict the IDH mutation by using diffusion tensor and kurtosis images based on a machine learning. METHODS: Between August 2014 and July 2017, 38 consecutive patients with suspected glioma and preoperative MRI including diffusion coefficient (ADC), fractional anisotropy (FA), mean kurtosis (MK), were included in the study. All IDH mutations were identified by Sanger sequencing. A volume of interest (VOI) was created manually and applied to T2-weighted images, diffusion-weighted images (DWI), ADC, FA, MK. 476 per imaging sequence and 2856 features were extracted. RESULTS: 39 datasets were obtained. The number of cases for the IDH mutation and wild-type was 21 cases of the IDH1 mutation (3 diffuse astrocytoma, 8 anaplastic astrocytoma, 4 oligodendroglioma, 3 anaplastic oligodendroglioma, 3 glioblastoma, 18 cases of wild-type(2 anaplastic astrocytoma, 16 glioblastoma). An IDH2 mutation was not observed in our cases. Features were selected by using recursive feature elimination (RFE). The most accurate machine learning model was created using the extracted eight features from ADC, Fa, and MK. The best AUC was 0.95 ± 0.02 in a support vector machine (SVM). Discussion: Imaging sequences useful for the IDH1 mutation identification are ADC, MK, FA, similar to malignancy diagnosing of glioma. However, useful features were different. The machine learning models using diffusion images may be useful for identifying the IDH1 mutations.

BACKGROUND: It has been recognized that symptom burden reported as a patient-reported outcome is valuable in assessment of both disease and treatment-related symptoms and should be incorporated into evaluation of clinical benefit of novel therapies. MDASI-BT is a widely-used instrument for measuring symptom burden in brain tumor patients, and its Japanese version (MDASI-BT-J) has recently been validated linguistically. The purpose of this study is to psychometrically validate MDASI-BT-J. METHODS: Patients with brain tumors who were undergoing oncologic treatments in The University of Tokyo Hospital or National Cancer Center Hospital between 2014 and 2015 were asked to fill out MDASI-BT-J and the Japanese version of European Quality of Life-5 Dimensions (EQ-5D-J). Feasibility, reliability, and validity of MDASI-BT-J were assessed. RESULTS: One-hundred-and-forty patients (72 men) including 63 patients with gliomas participated in the study. The median age was 54 years, and the median Karnofsky Performance Status (KPS) score was 90. The mean symptom severity score (MSS) and mean interference score (MIS) were 1.9 ± 1.7 and 2.8 ± 2.7, respectively. The median amount of time required to complete the form was 4 minutes (range, 0-30), and missing values were seen in 1%. Internal consistency using Cronbach's coefficient alpha was 0.94 and 0.92 for symptom severity and interference, respectively. Test-retest reliability was assessed in 30 patients with acceptable intra-class correlation coefficient (mean, 0.74). Known-group validity confirmed a significant difference in MSS (1.6 versus 2.3, P = 0.007) and MIS (2.0 versus 3.9, P = 0.007) between patients with KPS score >= 90 and those with KPS score

OBJECTIVE: Intracranial ependymoma is a rare brain tumor in adults. The standard treatments comprise of aggressive resection and radiotherapy, although only a few contemporary studies have evaluated their prognostic values. The objective of this study is to analyze clinical data from Brain Tumor Registry of Japan for assessing prognostic factors in adult intracranial ependymoma. MATERIALS AND METHODS: Seventy-six adult patients of intracranial ependymoma treated at 31 hospitals between 2001 and 2004 were included in the study. Subependymoma was excluded. Clinical data collected prospectively were retrospectively analyzed. RESULTS: The median age was 45 years (range,18-85), and the median KPS score was 80 (range,40-90). Infratentorial and multiple tumors were noted in 40 and 4 cases, respectively. Forty-five cases were classified as WHO grade 2 and 29 cases as grade 3. Grade 3 tumors were significantly associated with low KPS score, supratentorial tumor, large tumor diameter, and seizure onset compared to grade 2 tumors. All the grade 3 tumors except one were treated with radiotherapy and/or chemotherapy, while only 18 were treated with radiotherapy among 45 grade 2 tumors. With a median follow-up of 40 months, 5-year overall survival (OS) was 98% for grade 2 and 46% for grade 3; the median OS was not reached for grade 2 and 44 months for grade 3. Five-year progression-free survival (PFS) was 85% for grade 2 and 33% for grade 3; the median PFS was not reached for grade 2 and 21 months for grade 3. Multivariate analyses revealed that WHO grade (P = 0.009), complete resection (P = 0.002), and KPS score (P = 0.02) were associated with OS and that WHO grade (P = 0.02) and complete resection (P = 0.003) with PFS. CONCLUSION: WHO grade 3 ependymoma more often presents as a supratentorial mass provoking seizure than grade 2. WHO grade and complete resection were independent prognostic factors in adult intracranial ependymoma.