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BackgroundThe safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).MethodsPatients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.ResultsForty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.ConclusionThese data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL.Trial registrationJapicCTI-173646.

BACKGROUND Neurocognitive deficits are common among brain tumour patients, and may impact on patient awareness of deficits in instrumental activities in daily life (IADL). This study aimed to examine differences between patient-reported and proxy-reported assessments of the patient’s performance of IADL, and whether the level of (dis)agreement is associated with neurocognitive deficits. MATERIAL AND METHODS A phase III EORTC questionnaire measuring IADL in brain tumour patients (EORTC IADL-BN32) and six neurocognitive test measures were administered as part of a larger multicentre international study designed to develop a brain tumour specific IADL questionnaire. Bland-Altman plots and Mann-Whitney U tests were used to evaluated patient- and proxy-reported IADL on a group level. Subsequently, Mann-Whitney U tests were performed to compare patient-proxy difference scores (patient IADL score - their proxy IADL score) between patients who were considered clearly neurocognitively impaired (≥2 neurocognitive test measures; ≤2.0 SD below healthy controls) and patients who were not. Furthermore, multinomial logistic regression analyses were performed to examined which sociodemgraphic, clinical, and particularly neurocognitive variables were independently associated with patients and proxies differing in their evaluation of patient’s IADL. RESULTS Patients (N=81) and proxies (N=81), on group level, did not significantly differ on either the IADL individual item or scale scores. However, significant differences were found on patient-proxy difference scores between patients who were (N=37) and were not (N=44) considered clearly neurocognitively impaired for 10/32 individual items and one of the scales (i.e. Scale 4: Administrative tasks), all showing that the proxies of clearly neurocognitively impaired patients reported more problems relative to the patients themselves, compared to proxies of patients not clearly neurocognitively impaired. Furthermore, for each scale, a neurocognitive variable, either impaired information processing speed, cognitive flexibility, verbal fluency or the number of neurocognitive test measures impaired, was found to be independently associated with proxies reporting more problems. For 4/5 scales, a clinical variable was additionally independently associated with proxies reporting more problems. Only one variable was independently associated with patient reporting more problems, namely being in active treatment was found to be associated with patients reporting more problems on Scale 4: Administrative tasks. CONCLUSION Results imply a consistent trend of clearly neurocognitively impaired patients underreporting problems with IADL compared to their proxies. It would therefore be advised to administer both the patient- and proxy-version of the EORTC IADL-BN32, particularly if neurocognitive deficits are presumed.

BACKGROUND In BIOMARK trial, patients with newly diagnosed glioblastoma were treated with standard chemoradiotherapy combined with first-line bevacizumab; a subset of patients continued bevacizumab beyond progression (BBP). Neurocognitive function (NCF), symptom burden, and health-related quality of life (HRQoL) were examined as secondary endpoints. PATIENTS AND METHODS In the primary protocol, newly diagnosed glioblastoma patients aged 20-75 received standard 6-week radiotherapy combined with temozolomide and bevacizumab followed by 4-week cycles of temozolomide plus bevacizumab, and then 2-3-week cycles of bevacizumab monotherapy. Upon recurrence, patients were subjected to the secondary protocol with 2-3-week cycles of bevacizumab monotherapy with or without other chemotherapeutic agents. NCF tests (Hopkins verbal learning test-revised, trail making test, and controlled oral word association), EORTC QLQ-C30/BN20, and MDASI-BT were completed by the patients. Time to deterioration (TTD) was defined as the time from randomization until a pre-specified change from baseline without further improvement or death. The Kaplan-Meier method and the log-rank test were used to assess TTD for each subscale of the above tests. RESULTS Overall, 94 patients were enrolled in the study. Analyses were based on the full analysis set cohort (N=90), excluding non-glioblastoma diagnosis by central review. The median overall survival (OS) and progression-free survival (PFS) were 25.0 and 14.9 months, respectively. Baseline HRQoL and symptom burden subscales (emotional functioning, symptom severity score, affective factor, and focal factor) were significantly associated with PFS. The median TTD was 8.7, 7.5, 8.1 months for global health status/QoL, symptom severity score, interference score, respectively. Among patients who experienced recurrence, disease progression was apparently preceded by deterioration in terms of symptom burden. CONCLUSIONS Detailed analysis of HRQoL and symptom burden may aid care of glioblastoma patients throughout the disease trajectory.

BACKGROUND Boron neutron capture therapy (BNCT) is tumor-selective particle radiation and theoretically efficacious especially for tumors with infiltrative nature, such as glioblastoma (GBM). The aim of this study is to assess safety and efficacy of accelerator-based BNCT (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent malignant gliomas, chiefly GBM. METHODS The multi-institutional open-label, phase II clinical trial for recurrent 27 cases of malignant gliomas (MG) (24 cases were GBM) was conducted with above AB-BNCT system, using 500mg/kg of SPM-011 (study code, JG002). The patients were enrolled from February 2016 to June 2018. The inclusion criteria are bevacizumab-naïve MG, recurrent after standard treatment composed of XRT and chemotherapy with TMZ. Neutron-irradiation time were determined not to exceed to 8.5 Gy-Eq for scalp dose. Primary endpoint was 1-year survival rate and secondary ones were median overall survival (mOS), median progression free survival (mPFS). The results were compared to previous Japanese domestic bevacizumab trial for recurrent GBM (JO22506) which had the similar inclusion criteria with JG002. RESULTS 1-year survival rate and mOS of recurrent GBM cases in JG002 was 79.2% (95% CI:57.0–90.8) and 18.7 months (95% CI:12.9–23.4) respectively, while those of JO22506 was 34.5% (90% CI:20.0–49.0) and 10.5 months (95% CI:8.2–12.4), respectively. Median PFS of JG002 and JO22506 were 0.9 and 3.3 months, respectively. Most important adverse event in JG002 was brain edema. Brain edema in 21 out of 27 cases was treated with bevacizumab after progress disease. CONCLUSIONS AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG chiefly GBM. AB-BNCT might produce brain edema somewhat after the treatment, which might be the unavoidable adverse event of re-irradiation for recurrent MG, however that seemed to be controlled well with bevacizumab.

BACKGROUND Clinical benefit of continuing bevacizumab beyond progression is unknown in glioblastomas. A biomarker analysis of the AVAglio trial suggested that proneural subtype of IDH-wildtype glioblastoma patients may receive an OS benefit from a first-line bevacizumab. This study explored biomarkers that may predict survival of glioblastoma patients treated with concurrent irradiation, temozolomide (TMZ) and bevacizumab (BEV) followed by BEV beyond progression (BBP). METHODS In the primary protocol, newly diagnosed GBM patients aged 20–75 received concurrent TMZ (75 mg/m2, D1-42), irradiation (2 Gy x 5 QW x6) and BEV (10 mg/kg Q2W x 3) followed by ≤12 4-week cycles of TMZ (150–200 mg/m2, D1-5) plus BEV (10 mg/kg, D1 and 15) and then 2 or 3-week cycles of BEV monotherapy (15 or 10 mg/kg). Upon PD/recurrence during the primary protocol, the patients were subjected to the secondary protocol with 2-3-week cycles of BEV monotherapy with or without other chemotherapeutic agents (BBP). The primary endpoint was 2-year survival rate in patients receiving BBP. Fresh-frozen tumor specimen were subjected to genome-wide methylation, copy number, expression and mutation analysis. A subset of the control cohort of the AVAglio study was used as BEV-negative control. RESULTS A total of 94 GBM patients were enrolled at 39 centers between June 2015 and January 2017. Efficacy analyses were based on the full analysis set (FAS) cohort (N=90), excluding non-GBM diagnosis by central review. The median time to PD/recurrence was 453 days in the FAS and 348 days in patients receiving BBP (N=27). The 2-year survival rate (90% CI) was 52.4% (43.3–60.8%) and 28.8% (15.4–43.7%), respectively. The 2-year survival rate in GBM patients receiving BBP was lower than expected (50%). That of proneural and mesenchymal IDH-wt GBM in the biomarker cohort (n=83) were 52.9% (31.7–70.3%) and 56.6% (41.6–69.1%), respectively. A full biomarker analysis will be presented.

To improve clinical outcomes, a less invasive screening test for detection of diffuse glioma is needed. The purpose of this study is to establish models using serum microRNAs (miRNAs) to distinguish between diffuse glioma patients from non-cancer controls (Glioma Index) and between glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic brain tumors (Meta) (3-Tumor Index). A total of 580 patients, including 266 with brain or spinal tumors and 314 non-cancer controls, were analyzed. Non-cancer control samples were collected from the National Cancer Center Biobank and members of the general population undergoing routine health examinations. Expression of serum 2565 miRNAs was assessed in each sample, and the expression profiles were compared between diffuse glioma patients and non-cancer controls, and between GBM, PCNSL, and Meta. Diagnostic models were established using a training set, and diagnostic performance was confirmed in validation and exploratory sets and area under the receiver operating curve (AUC), sensitivity, specificity, and accuracy were used to evaluate their diagnostic performances. The Glioma Index was constructed using three miRNAs. The AUC was 99%, with sensitivity of 95% and specificity of 97% in the validation set. The Glioma Index classified 93% of PCNSL, 89% of Meta, 91% of benign brain tumors, and 0% of spinal tumors as positive in the exploratory set. The 3-Tumor Index was constructed using 48 miRNAs and had an accuracy of 0.80 in the validation set, positively detecting 94.1% of GBM, 80% of Meta, and 50% of PCNSL. In conclusion, we developed novel serum miRNA discriminant models to detect diffuse glioma from non-cancer control and to discriminate tumor histology. These models could serve as less invasive screening tools or complementary diagnostic tools, thereby decreasing neurosurgical risks.

BACKGROUND Despite aggressive treatment with surgery and chemo-radiation therapy, it is difficult to cure patients with glioblastoma (GBM). The end-of-life (EOL) phase of patients with GBM, and related problems, have not yet been adequately studied. Unlike in other countries, most cancer patients died in the hospital (84%) in 2017, but the Japanese government has recommended palliative home care and the number of deaths at home has recently been increasing. This study explores the current situation of EOL care for GBM patients in Japan. METHODS We retrospectively examined the clinical course and EOL phase of 166 consecutive patients who were treated in our hospital between 2010 and 2017. RESULT: In total, 107 patients died; 27 (25.7%) at home, 24 (22.8%) in hospice care, 8 (7.6%) in nursing homes, 46 (43.9%) in hospitals (long-term care hospitals [LTCH; 19.8%], our hospital [13.3%], and other neurosurgical hospitals [10.4%]). According to our previous research, in 2001–2005, 6% of GBM patients died at home, 3% in hospice case, and 91% in the hospital. The KPSof patients who started palliative home care or transferred to another hospital was 50–60. The median survival time and length of EOL phase for patients who died at home were 498 and 76.5 days; 395 and 103 days in hospice care; 533 days and 149 days in LTCH; 374 days and 52 days in our hospital; 338 and 75.5 days in other neurosurgical hospital; and 557 days and 37 days in nursing homes, respectively. CONCLUSION The number of GBM patients who died at home in Japan is increasing, and we must consider the problems of the EOL phase and improve the quality of EOL care.

BACKGROUND Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan. RESULTS Clinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors. DISCUSSION Although the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.

The national cancer registries began in January 2016 and the actual number of cancer patients in 2016 including primary brain tumors in Japan was released as a preliminary report in January 2019. According to the report, 667 incidence of pediatric brain tumors were reported in aged 0–14 years (boy: 382; girl: 285), of them 537 patients underwent surgery, chemotherapy, or radiation therapy (diagnosis: 516, undiagnosed: 21), and 130 patients were followed up without any treatments. The breakdown of tumor types was 279 Neuroepithelial tumors, 73 Embryonal tumors (61 Medulloblastomas), and 63 Germ Cell Tumors (GCTs). The crude rate per 100,000 population in 2016 was 4.23 for all pediatric brain tumors, 1.77 for Neuroepithelial tumor, 0.39 for Medulloblastoma, and 0.40 for GCTs. In comparison, the United States CBTRUS2019 (2012–2016) reported that the age-adjusted incidence rates per 100,000 population in the United States was 5.74 for all pediatric brain tumors, 4.15 for Neuroepithelial tumors, 0.48 for Medulloblastoma, and 0.22 for GCTs. The age-adjusted incidence in Japan based on the US population in 2000 was 4.21 for all pediatric brain tumors, Neuroepithelial tumor 1.77, Medulloblastoma 0.39, and GCTs 0.39, suggesting that the incidence of Neuroepithelial tumor and Medulloblastoma is lower whereas that of GCTs is approximately twice comparing to the US. By taking advantage of the national cancer registry data, which was publicly opened to researchers in 2019, we report the incidence of primary brain tumors and its comparison worldwide based on the re-classification criteria of primary brain tumors including benign tumor.

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.

BACKGROUND: We conducted a phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality. METHODS: We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n = 58) or the placebo (n = 30) at a 2-to-1 ratio. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebos were injected 1×/week for 12 weeks. RESULTS: Our trial met neither the primary (overall survival [OS]) nor secondary endpoints. Unfavorable factors for OS of 58 PPV patients compared with 30 placebo patients were SART2-93 peptide selection (n = 13 vs 8, hazard ratio [HR]: 15.9), ≥70 years old (4 vs 4, 7.87), >70 kg body weight (10 vs 7, 4.11), and performance status (PS)3 (8 vs 2, 2.82), respectively. Consequently, the median OS for PPV patients without SART2-93 selection plus one of these 3 favorable factors (

Mutations in isocitrate dehydrogenase 1 or 2 genes (IDH1/2) frequently occur in lower-grade gliomas and secondary glioblastomas. Mutant IDH1/2 proteins gain a new ability to produce the oncometabolite 2-hydroxyglutarate (2HG). Recently, IDH1/2 mutations were suggested to be related with seizure onset through the structural similarity of 2HG to the excitatory neurotransmitter glutamate. Therefore, we sought to investigate the relationship between seizure onset and IDH1/2 status, tissue 2HG concentration and distribution. We assessed 149 patients with WHO grade II-IV glioma, whose IDH1/2 status were identified and measured serum and tissue 2HG concentrations in 123 and 104 patients by using liquid chromatography-tandem mass spectrometry method. The matrix assisted laser desorption and ionization mass spectrometry imaging (MALDI-MSI) was use to analyze tissue 2HG distribution for 12 tissue samples. Seizure onset was observed in 34 among 56 (60.7%) patients with IDH mutant tumor, whereas in 18 among 93 (19.4%) patients with IDH wild-type tumor (p

BACKGROUND: Depatuxizumab mafodotin (depatux-m, formerly ABT-414) is an EGFR-directed antibody-drug conjugate being developed for treatment of EGFR-amplified glioblastoma (GBM). As therapeutic pressure engenders tumor adaptations, it is important to understand the stability of biomarkers targeted by precision medicine approaches such as depatux-m. Therefore, we assessed EGFR amplification (amp) and expression in longitudinally-sampled GBMs from patients (pts) treated +/- depatux-m to explore biomarker stability. MATERIAL AND METHODS: Formalin-fixed, paraffin embedded GBM tumor tissue was analyzed from 68 patients who underwent at least 2 surgeries; EGFR amp was detected by in situ hybridization (e.g., FISH) or next-generation sequencing in all samples. Fifty-six pts did not receive depatux-m; among 12 pts who did, EGFR expression was also evaluated by RNA sequencing. RESULTS: Of 56 pts who did not receive depatux-m, 31 (55%) had tumors harboring EGFR amp at 1st surgery (initial diagnosis); among those, EGFR amp was maintained at re-operation in 27 (87%), and not maintained in 4 (13%). None of the 25 cases without baseline EGFR amp acquired it at the 2nd surgery. Of 12 pts treated with depatux-m between surgeries, 9 cases harbored EGFR amp at baseline which was maintained in 4 (44%) at the 2(nd) surgery, all 4 of which had the highest levels of EGFR expression at baseline. Of the 3 cases without EGFR amp at baseline, none acquired amplification at the 2(nd) surgery, and all 3 had the lowest levels of EGFR expression at study start. CONCLUSION: The presence of EGFR amp in GBM tissue at baseline was maintained at 2(nd) surgery in 87% of pts who received treatment other than depatux-m, and in 44% following depatux-m exposure. Therefore, depatux-m exposure appears to reduce EGFR amp maintenance (p=0.0159 by Fisher’s exact test); accordingly, the therapeutic approach may influence EGFR status. In no case was EGFR amp acquired at recurrence, regardless of depatux-m therapy. Ongoing analyses of additional tumor samples will increase power and further examine concordance among EGFR amp assays.

Despite of recent intense investigations, no effective molecular targeting therapy has been successfully developed in patients with glioblastomas (GBMs). Approximately 60–80% of GBM harbor mutations in the promoter region of telomerase reverse transcriptase (TERT), which leads to its upregulation. It has been reported recently that TERT has an RNA-dependent RNA polymerase (RdRP) activity and TERT-RdRP activity controls cell cycle and maintains stem cell phenotype, suggesting that TERT can be directly targeted to suppress tumor cell proliferation. We have previously identified eribulin mesylate, which is an FDA-approved drug used to treat breast cancer and liposarcoma, as a specific inhibitor of RdRP activity of TERT and investigated the antitumor efficacy of eribulin using multiple human GBM cell lines in preclinical mouse brain tumor models. All GBM cell lines tested in vitro that harbored TERT promoter mutations were highly sensitive to eribulin with IC50 below 1nM. Intraperitoneal administration of eribulin (0.5 mg/kg), which was equivalent to the dose used in human (1.4 mg/m2), significantly prolonged the survival of multiple mouse brain tumor models established with U87MG or LN229 (p

PURPOSEGenetic alterations found in WHO grade 2 and 3 gliomas include IDH1/2 and TERT promoter mutations and 1p19q co-deletion, which alterations are known to have great impact on the prognosis of the patient. In this research, the authors attempted to test the hypothesis that genetic alterations could contribute to the locations and heterogeneity of the tumor by analyzing 191 WHO grade 2 and 3 gliomas via MR radionomics.METHODS191 WHO grade 2 and 3 gliomas were retrospectively collected and the genomic DNA of the tumor was sequenced for IDH1/2 and TERT promoter mutations. Treatment naive MR images were also collected. T2 weighted, T1 weighted, FLAIR and Gd-enhanced T1 weighted images were collected for analysis. Voxel-based lesion mapping (VLM), and redionomics analysis was performed for all images and were further challenged to construct a model that predicts genetic alterations within the tumor. 126 patients were allocated as training set and 65 for validation set. Patient cohort was divided into the following 3 groups; IDH mt/TERTp wt, IDH mt/TERTp mt and IDH wt. A multi-regression model was constructed using the training set to predict the 3 genetic subgroups and the validation set was used for model validation.RESULTSVLM revealed that IDH mt/TERTp wt gliomas dominated temporal lobe involvement while IDH mt/TERTp mt occupied the frontal lobe. IDH wt tumors, on the other hand, located at much posterior lobes and centered at the deep white matter. 15 radionomic features were identified for model construction to predict 3 genetic subgroups of WHO grade 2 and 3 gliomas. When these 15 texture elements were used to construct a prediction model of the 3 genetic subgroups, AUCs calculated from the training set ranged from 0.7 to 0.75. Accuracy for prediction was 63% for the training set and 60% for the validation set.

BACKGROUND WHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in intratumoral accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier. METHODS In this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and D-2-HG levels. RESULTS Between Jan 2017 and May 2019, DS-1001b (125–1400 mg bid) had administered for 47 pts, and 15 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1–2. Gr 3 AEs were observed in 40% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Of 35 evaluable pts with contrast enhancing gliomas, one, five and 11 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable 12 pts with contrast non-enhancing gliomas, four achieved minor response and eight achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently. CONCLUSIONS DS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. The latest data will be updated. Funding source: This study was funded by Daiichi Sankyo Co., Ltd.

Purpose Genomic medicine is in progress, but the median survival of glioblastoma is 14–16 months. It seems to have the same life prognosis as stage 4 like unresectable pancreatic cancer, lung cancer and colon cancer. Palliative care including Advance care planning (ACP) at first diagnosis of glioblastoma is important We conducted a questionnaire survey to understand the current status of Japanese oncologists. Method In July 2018, a questionnaire of 37 items was sent by e-mail to 767 members of Japanese Society of Neuro Oncology, and in August replies were received from 154 persons (20%). The same 22-item questionnaire in 2012–2013 was compared internationally with a report (Walbert T., et al., 2015) by Society of NeuroOncology and the European Association of NeuroOncology. In addition, we compared domestically with a 30-item questionnaire (Narita et al. 2009) in 2007. The Nonparametric Mann-Whitney’s U test was mainly used. Result 1 Characteristics of Japan in comparison with Western countries(p

BACKGROUND: Although it is recognized that methylation status of MGMT promoter is predictive for the response to temozolomide in newly diagnosed glioblastoma (GBM), at least in elderly patients, there is no study examining the ability of quantitative MGMT methylation status to predict volumetric changes of residual tumor in magnetic resonance images (MRIs) after surgery, radiation and temozolomide therapy. In this study, we performed retrospective volumetric analysis of the residual tumor in glioblastoma patients and investigated the relationship of MGMT status assessed by pyrosequencing. METHOD: Among 160 newly diagnosed GBM patients treated in our institute since 2006, volumetric analysis of the residual tumor was performed retrospectively in patients who were with residual unresected tumors after surgery, treated with standard radiation and temozolomide therapy. Patients who were without residual tumors or treated with bevacizumab were excluded. The MGMT methylation status was quantitatively assessed by averaging methylation at the 16 CpG sites measured by pyrosequencing. Enhanced tumor volume in MRI was measured at four time points of pre-operation, beginning of the treatments, three and six months after the initial treatment. RESULT: Forty four patients were enrolled (M:F = 25:19, median age: 61 y.o., median KPS: 70). The quantitative MGMT methylation data and tumor volume ratio, normalized to pre-treatment volume, were significantly correlated at 3 and 6 months after the initial treatment (p = 0.0002 and 0.0004, respectively). For the response rate, patients with lower MGMT methylation than 10% showed more progressive disease (defined as more than 50% gain in tumor volume) compared to patients with higher MGMT methylation than 10% at 3 and 6 months after initial treatment (3 months: 67.9% vs 18.8%, 6 months: 70.8% vs 15.4%, respectively). CONCLUSION: Quantitative MGMT methylation status analyzed by pyrosequencing may be useful to predict disease progression in glioblastomas treated with partial tumor removal followed by radiation and temozolomide therapy.

BACKGROUND: The Brain Tumor Registry of Japan (BTRJ) was founded to investigate the statistical characteristics of brain tumors in Japan from 1975. The 13th edition of the BTRJ is published in 2014 (Neurologia medico-chirurgica Vol. 54 (2014) Supplement). METHODS: Data on primary or metastatic brain tumor cases that were newly diagnosed from 2001 to 2004 were collected from 2009 until the end of 2012. Approximately 330 neurosurgeons, medical doctors, and staff from 109 institutions collected 16,338 data from clinical records. These institutions included most universities, colleges, and hospitals with Japan Neurosurgical Society-authorized boards. These data were collected via the Internet Data and Information Center for Medical Research. Data, including the birthplace, age, tumor sites, diagnostic method, therapy (surgery, radiation, or chemotherapy), and the outcome of these treatments, according to the World Health Organization (WHO) 2007 brain tumor classification were collected. Survival data were analyzed using the Kaplan-Meier method. RESULTS: 5-year overall survival (OS) and 5-year progression free survival (PFS) of major brain tumors are as follows; grade II diffuse astrocytoma: 75%, 57%, grade II oligodendroglial tumor: 90%, 74.6%, grade III anaplastic astrocytoma: 41.1%, 28.7%, grade III anaplastic oligodendroglial tumor: 68.2%, 54%, glioblastoma: 10.1%, 9.2%, primary CNS lymphoma: 64.4%, 34.7%, null cell pituitary adenoma: 98.3%, 85.1%, neurinoma: 98.8%, 89.5%, grade I meningioma: 97.9%, 90.5%, grade II meningioma: 91.2%, 60.6%, grade III meningioma: 86.6%, 53.4%, chordoma: 89.1%,48.1%. CONCLUSIONS: Trends and problems in the treatment and outcomes of brain tumors of Japan in 2001-2004 will be presented and discussed.

BACKGROUND: (blind field). METHODS: Data on primary or metastatic brain tumor cases that were newly diagnosed from 2001 to 2004 were collected from 2009 until the end of 2012. Approximately 330 neurosurgeons, medical doctors, and staff from 109 institutions collected 16,338 data from clinical records. These institutions included most universities, colleges, and hospitals with Japan Neurosurgical Society-authorized boards. These data were collected via the Internet Data and Information Center for Medical Research. Data, including the birthplace, age, tumor sites, diagnostic method, therapy (surgery, radiation, or chemotherapy), and the outcome of these treatments, according to the World Health Organization (WHO) 2007 brain tumor classification were collected. Survival data were analyzed using the Kaplan-Meier method. RESULTS: Overall survival (OS, months), progression free survival (PFS, months), 5-year OS, 5-year PFS of each grade of gliomas are as follows; pilocytic astrocytoma; NR (not reached), NR, 92.1%, 73.8%, diffuse astrocytoma: NR, 84.1, 75%, 57%, grade II oligodendroglial tumor: NR, NR, 90%, 74.6%, anaplastic astrocytoma: 38, 19, 41.1%, 28.7%, grade III anaplastic oligodendroglial tumor: NR, 71, 68.2%, 54%, glioblastoma: 15, 8.1, 10.1%, 9.2%. CONCLUSIONS: The 5-year OS of grade II and III gliomas improved compared to that in 1997-2000 but that of glioblastoma did not. Based on the data of BTRJ 2001-2004, trends and problems in treatment and outcomes of gliomas will be presented and discussed. SECONDARY CATEGORY: n/a.

Primary central nervous system lymphoma (PCNSL) is confined within the brain, with occasional involvement of the ocular structures.1,2 Previous reports have suggested that this neoplasm tends to arise in deep-seated locations such as the basal ganglia and white matter surrounding the ventricles.1 These investigations, however, have mainly been performed using individual anatomical identification of the lesions. Individual differences in size and shape of the brain hamper cross-patient analysis of lesion location. With the advent of image registration and 3-dimensional structural deformation algorithms, it is now possible to manipulate and register individual brain images onto an averaged standard brain image,3 allowing objective and statistically verifiable cross-patient analyses of lesion location. This technique has the potential to elucidate regions within the brain that are likely to be affected by a disease. Moreover, by incorporating biological information such as gene expression patterns, group analyses of diseases will become possible, thus revealing differences in locations prone to be affected by different subtypes of the disease.4,5 Although PCNSL is reported to arise in specific locations within the brain, as mentioned above,1 no previous studies have attempted such cross-patient analysis of lesion location. In this study, MR images from 100 consecutive treatment-naive PCNSL patients were retrospectively collected and analyzed. In addition, 90 cases were classified as either germinal center B-cell (GCB) or non-GCB lymphoma according to molecular expression patterns based on immunohistochemistry. Lesion locations were then compared between these 2 groups, and statistical analyses were applied to clarify lymphoma subtype-specific patterns of lesion occurrence.

The alkylating agent temozolomide (TMZ) is widely used for the treatment of gliomas. Although reports of treatment-related myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) associated with TMZ are accumulating, it remains unclear whether TMZ has the same leukemogenic potential as other alkylating agents.We performed a single-institution retrospective analysis using a database of 359 glioma patients given nimustine (ACNU)-based therapy, TMZ-based therapy, or combination therapy, who were followed up for a minimum of 2 months, between January 1990 and December 2009, at the National Cancer Center Hospital in Japan.Of the 359 patients, 225 received ACNU alone or ACNU plus other chemotherapeutic drugs (ACNU-based group; median follow-up period, 31.4 mo), 63 patients received ACNU-based therapy followed by TMZ therapy (ACNU-TMZ group; median follow-up period, 19.1 mo), and 71 patients received TMZ alone or TMZ plus other chemotherapeutic drugs (TMZ-based group; median follow-up period, 16.9 mo). Three patients in the ACNU-based group developed MDS/AML (incidence rate: 2.9 cases per 1000 person-years), 2 patients in the ACNU-TMZ group developed MDS/AML (13.0 cases per 1000 person-years), and 1 patient in the TMZ-based group developed ALL (9.9 cases per 1000 person-years).Despite the limitations of this study, published reports and our results suggest that TMZ induces secondary hematological malignancies, particularly ALL, and might shorten the latency period when used in combination with other chemotherapeutic agents.