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Simple Summary The molecular machineries regulating resistance against photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) in glioblastomas (GBM)s and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. Herein, we established an in vitro NPe6-mediated PDT model using human GBM cell lines. NPe6-PDT induced both caspase-dependent and -independent GBM cell death in a NPe6 dose-dependent manner. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was revealed resistance to re-NPe6-PDT, migration, and invasion of GBM cells that survived following NPe6-PDT (NPe6-PDT-R cells) were enhanced. Immunoblotting of NPe6-PDT-R revealed that only ERK1/2 activation exhibited the same trend as migration. Importantly, treatment with the MEK1/2 inhibitor trametinib reversed resistance against re-NPe6-PDT and suppressed the enhanced migration and invasion of NPe6-PDT-R cells. Overall, enhanced ERK1/2 activation is suggested as a key regulator of elevated malignant phenotypes of GBM cells surviving NPe6-PDT. Abstract To manage refractory and invasive glioblastomas (GBM)s, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) was recently approved in clinical practice. However, the molecular machineries regulating resistance against NPe6-PDT in GBMs and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. Herein, we established an in vitro NPe6-mediated PDT model using human GBM cell lines. NPe6-PDT induced GBM cell death in a NPe6 dose-dependent manner. However, this NPe6-PDT-induced GBM cell death was not completely blocked by the pan-caspase inhibitor, suggesting NPe6-PDT induces both caspase-dependent and -independent cell death. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was also revealed resistance to re-NPe6-PDT of GBM cells and GBM stem cells survived following NPe6-PDT (NPe6-PDT-R cells), as well as migration and invasion of NPe6-PDT-R cells were enhanced. Immunoblotting of NPe6-PDT-R cells to assess the behavior of the proteins that are known to be stress-induced revealed that only ERK1/2 activation exhibited the same trend as migration. Importantly, treatment with the MEK1/2 inhibitor trametinib reversed resistance against re-NPe6-PDT and suppressed the enhanced migration and invasion of NPe6-PDT-R cells. Overall, enhanced ERK1/2 activation is suggested as a key regulator of elevated malignant phenotypes of GBM cells surviving NPe6-PDT and is therefore considered as a potential therapeutic target against GBM.

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90–100%) were associated with favorable prognosis (p TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.

In traditional craniofacial resection of tumors invading the anterior skull base, the bilateral olfactory apparatus is resected. Recently, transnasal endoscopy has been used for olfactory preservation in resections of unilateral low-grade malignancies. However, for tumors that invade the orbita or for high-grade malignancies, the transnasal endoscopic skull base surgery has been controversial. This video demonstrates the surgical techniques of olfactory preservation during craniofacial resection of a high-grade malignancy invading the hemianterior skull base and orbita.We present the case of a 32-year-old woman with osteosarcoma in the right ethmoid sinus. The tumor invaded the ipsilateral cribriform plate, dura menta, and orbital periosteum; however, the nasal septum and crista galli were intact (Fig. 1A, B). Because the tumor was a high-grade malignancy and the orbita had been invaded, we performed craniofacial resection instead of endoscopic resection (Fig. C2A). We drilled into the right side of the crista galli, midline of the cribriform plate, and perpendicular plate of the ethmoid bone via craniotomy. As a result, we accessed the nasal cavity directly (Fig. 2B). To preserve the nasal septum, we detached the remaining right septal mucosa through the transfacial approach (Fig. 2C). Because of the high risk of cerebrospinal fluid leakage as a result of previous irradiation, we performed vascularized free flap reconstruction of the skull base instead of pericranial flap.Postoperative computed tomography revealed no evidence of tumor (Fig. 1C, D). The patient's sense of smell returned after 1 postoperative day, and she was discharged on the postoperative day 14.The link to the video can be found at: https://youtu.be/XzPABYwzkjs.

The Japan Neurosurgical Database (JND) is a prospective observational study registry established in 2017 by the Japan Neurosurgical Society (JNS) to visualize real-world clinical practice, promote science, and improve the quality of care and neurosurgery board certification in Japan. We summarize JND's aims and methods, and describes the 2018 survey results. The JND registered in-hospital patients' clinical data mainly from JNS training institutions in 2018. Caseload, patient demographics, and in-hospital outcomes of the overall cohort and a neurosurgical subgroup were examined according to major classifications of main diagnosis. Neurosurgical caseload per neurosurgeon in training in core hospitals in 2018 was calculated as an indicator of neurosurgical training. Of 523,283 cases (male 55.3%) registered from 1360 participating institutions, the neurosurgical subgroup comprised of 33.9%. Among the major classifications, cerebrovascular diseases comprised the largest proportion overall and in the neurosurgical subgroup (53.1%, 41.0%, respectively), followed by neurotrauma (19.1%, 25.5%), and brain tumor (10.4%, 12.8%). Functional neurosurgery (6.4%, 3.7%), spinal and peripheral nerve disorders (5.1%, 10.1%), hydrocephalus/developmental anomalies (2.9%, 5.3%), and encephalitis/infection/inflammatory and miscellaneous diseases (2.9%, 1.6%) comprised smaller proportions. Most patients were aged 70-79 years in the overall cohort and neurosurgical subgroup (27.8%, 29.4%). Neurotrauma and cerebrovascular diseases in the neurosurgical subgroup comprised a higher and lower proportion, respectively, than in the overall cohort in elderly patients (e.g. 80 years, 46.9% vs. 33.5%, 26.8% vs. 54.4%). The 2018 median neurosurgical caseload per neurosurgeon in training was 80.7 (25-75th percentile 51.5-117.5). These initial results from 2018 reveal unique aspects of neurosurgical practice in Japan.

Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2—and 3 if caused only by neurologic deficits—and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.

The radiological features of lower-grade gliomas (LGGs) classified according to isocitrate dehydrogenase (IDH) mutations and codeletion of chromosomal arms 1p and 19q (1p/19q codeletion) remain unclear. We aimed to systematically characterize the radiological features of molecularly classified LGGs using IDH and 1p/19q codeletion statuses. One hundred and one LGGs were re-classified into 36 tumors with IDH mutations (IDH-Mut), 35 tumors with IDH-Mut and 1p/19q codeletion (IDH-Mut/Codel), and 30 tumors with wildtype IDH (IDH-Wt). Calcification, heterogeneous signal intensity in T2-weighted images, and cortical invasion were significantly more frequent in IDH-Mut/Codel than in IDH-Mut and IDH-Wt tumors (calcification: 48.6 vs 5.6 and 6.7%, heterogeneity: 94.3 vs 33.3 and 50%, and cortical invasion: 94.3 vs 55.6 and 40.0%, respectively). A frontal location was significantly more frequent for IDH-Mut and IDH-Mut/Codel than for IDH-Wt tumors (52.8 and 71.4 vs 12.1%, respectively), and dense contrast-enhancement was significantly more frequent in IDH-Wt than in IDH-Mut and IDH-Mut/Codel tumors (50.0 vs 2.8 and 2.9%, respectively). In conclusion, IDH-Mut/Codel tumors were characterized by calcification, frontal location, heterogeneous signal intensity, and cortical invasion; IDH-Mut tumors differed from IDH-Wt tumors according to predominant frontal lobe location and less frequent dense enhancement patterns.

An amendment to this paper has been published and can be accessed via the original article.

Background: Based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646), tirabrutinib (TIR), a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL). We have previously reported overall response rate of 63.6% and manageable safety profile results of this study (Narita et al. Neuro Oncol. 2021;23(1):122-133). Further, one-year follow-up data after the last patient had enrolled showed that the effects of TIR persisted in r/r PCNSL patients (Mishima et al. Poster presented at the Society for Neuro-Oncology virtual conference; November 19-21, 2020). Here, based on this one-year follow-up data, we describe the Quality of Life (QoL) and Karnofsky Performance Status (KPS) in r/r PCNSL patients treated with TIR. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with TIR once daily (QD) at a dose of 320 mg, 480 mg, or 480 mg upon fasting (480 mg fasted QD). TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely QLQ-C30 (EORTC QLQ-C30), EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L). The QoL survey was conducted during the screening period, on Day 28 of Cycle 1, after every 2 cycles (i.e., after Day 1 of Cycle 3), after every 4 cycles (i.e., after Day 1 of Cycle 25), and at the end of treatment. KPS was measured during the screening period, on days 1, 8, 15, and 28 of Cycle 1, on day 1 of every cycle after Cycle 3, and at the end of treatment. Results: Forty-four patients were prospectively enrolled, and 20, 7, and 17 patients were treated with TIR at 320 mg QD, 480 mg QD, and 480 mg fasted QD, respectively. Median patient age was 60 years (range 29-86). Median follow-up period was 14.9 months (range, 1.4-27.7) for the entire cohort but was 19.1 months, 23.5 months, and 12.0 months for the 320 mg QD, 480 mg QD, and 480 mg fasted QD groups, respectively. At the time of data cutoff (February 25, 2020), 11 patients (25%) remained on treatment. Mean (SD) score for the global health status/QoL section of the EORTC QLQ-C30 was 50.9 (23.7) at baseline and remained relatively constant during treatment (Figure 1). This trend was also observed for emotional function, cognitive function, and fatigue sections of the EORTC QLQ-C30, for motor dysfunction, communication deficit, weakness of legs, and bladder control sections of the EORTC QLQ-BN20, and in items pertaining to self-care, usual activities, and anxiety/depression in the EQ-5D-3L. Median KPS was 80.0 (range, 70-100) at baseline, which remained unchanged during TIR treatment (Figure 2). Conclusion: QoL and KPS scores in r/r PCNSL patients were maintained during TIR administration, a new treatment option for r/r PCNSL, which does not lead to the deterioration of QoL and KPS. Figure 1 Figure 1. Disclosures Terui: Ono Pharmaceutical: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Esai: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Celgene: Speakers Bureau; AbbVie: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Narita: Ono Pharmaceutical co.: Honoraria, Research Funding; Dainippon-Sumitomo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Research Funding; Ohara: Research Funding; Chugai Pharmaceutical co.: Honoraria; Novocure: Honoraria. Nagane: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Astellas: Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Shionogi: Research Funding; Otsuka: Research Funding; Ono Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novocure: Honoraria; Sumitomo Dainippon Pharma: Honoraria; RIEMSER: Membership on an entity's Board of Directors or advisory committees. Mishima: Ono Pharmaceutical Co: Research Funding; Astellas: Research Funding; HOYA Technosurgical Co.: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Research Funding; Medical U and A: Research Funding; Teijin Pharma: Research Funding; Eisai: Research Funding; MSD: Research Funding; Chugai: Research Funding. Arakawa: Sanofi: Research Funding; Carl Zeiss: Honoraria, Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Philips: Research Funding; Siemens: Research Funding; Tanabe Mitsubishi: Research Funding; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Stryker: Research Funding; Astellas Pharma: Research Funding; Taiho Pharma: Research Funding; Nippon Kayaku: Honoraria; Novocure: Honoraria; UCB Japan: Honoraria; Integra Japan: Honoraria; Otsuka: Honoraria; Abbvie: Honoraria. Yonezawa: Eisai: Speakers Bureau; Ono Pharmaceutical co.: Speakers Bureau; Chugai Pharmaceutical co.: Speakers Bureau. Fukuhara: Celgene: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; HUYA Bioscience International: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; Bayer: Research Funding; AbbVie: Honoraria. Sugiyama: Daichi Sankyo Inc.: Consultancy; Ono Pharmaceutical Inc: Honoraria. Aoi: Ono Pharma USA, Inc.: Current Employment. Nishikawa: Novocure: Consultancy; Chugai: Honoraria, Research Funding; MSD: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria; Nihon-Kayaku: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

Objective: To investigate the efficacy and safety of pazopanib for recurrent or metastatic solitary fibrous tumor (SFT) in first- and second-line settings. Methods: Patients histologically diagnosed with SFT at our hospital who received pazopanib monotherapy for inoperable disease between January 2013 and November 2016 were eligible. We retrospectively investigated treatment outcomes according to the treatment lines and assessed adverse events. Results: Nine patients were eligible. The median age was 67 years (range 42–81), and 6 patients (66.7%) were male. Four patients (50%) received pazopanib as second-line treatment. According to the RECIST and Choi criteria, the respective response rates were 0 and 50%, while the respective disease control rates were 88.9 and 75%. The median progression-free survival (PFS) was 6.2 months (95% confidence interval 3.2–8.8). Treatment line and high frequency of mitosis were not predictive of PFS (p = 0.67, 0.92). Two patients (22.2%) experienced elevated liver enzymes of grade 3 or higher. Conclusion: Pazopanib is an effective treatment option for recurrent or metastatic SFT in first- and second-line settings. Liver injury is a major adverse event and adequate treatment withdrawal and dose reduction should be considered when necessary.

Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1α in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), to address the need for additional treatment for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors. Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM accumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. To evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64Cu-ATSM in mice bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and multiple dosages (37 MBq × 4) of 64Cu-ATSM was investigated. Single administration of 64Cu-ATSM in high-dose groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse events. Multiple dosages of 64Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the dose of 64Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of 64Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for treating this fatal disease.

Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the “RTK I (PDGFRA)” group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1771-1) contains supplementary material, which is available to authorized users.

Background The prevalence of brain metastases (BM) from uterine cancer has recently increased because of the improvement of overall survival (OS) of patients with uterine cancer due to its early detection and improved local control as a result of new effective treatments. However, little information is available regarding their clinical characteristics and prognosis, because oncologists have encountered BM from uterine cancer on rare occasions. Methods Records from 81 patients with uterine BM were collected from 10 institutes in Japan. These were used in a multi-institutional study to identify prognostic factors and develop a graded prognostic assessment (GPA) for patients with BM from uterine cancer. Results Median OS after the development of BM was 7 months (95% confidence interval, 4 to 10 months). Multivariate analysis revealed that there were survival differences according to the existence of extracranial metastases and number of BM. In the present uterine-GPA, a score of 0 was assigned to those patients with ≥5 BM and extracranial metastasis, a score of 2 was assigned to those patients with one to four BM or without extracranial metastasis, and a score of 4 was assigned to those patients with one to four BM and without extracranial metastasis. The median OS for patients with a uterine-GPA scores of 0, 2, and 4 was 3, 7, and 22 months, respectively. A survival analysis confirmed the presence of statistically significant differences between these groups (p

Population-based cancer registry data in Japan for 2009–2011 revealed predominant cancers to change dramatically from childhood to young adulthood., Little is known about cancer incidence among children and youths in Japan. We aimed to describe cancer incidence in Japan focusing on childhood, adolescence and young adulthood (AYA). Cancer incidence data were obtained from the Monitoring of Cancer Incidence in Japan project. For the 2009–2011 incidence, the data were collected from 40 prefectures, of which data from 27 prefectures meeting quality standards were analyzed (population coverage: 38.6%). Cancers diagnosed in 0–39 years of age were classified according to the International Classification of Childhood Cancer (version 3). Crude incidence rates of cancer (including benign or behavior-unknown brain tumors) were 122.7, 142.2, 310.7, and 910.6 for the 0–14, 15–19, 20–29, and 30–39 age groups, respectively (per million population). Using the sex- and age-specific incidence rates, the national estimates of cancer incidence were 2055 for 0–14 years (1118 males and 937 females), 864 for 15–19 years (450 males and 414 females), 4246 for 20–29 years (1699 males and 2547 females), and 16 295 for 30–39 years of age (5101 males and 11 194 females). The five leading cancers were leukemia, cancer of the central nervous system (CNS), lymphoma, malignant germ cell and other gonadal tumors, and neuroblastoma in childhood cases (0–14 years old); leukemia, malignant germ cell and other gonadal tumors, lymphoma, CNS, and malignant bone tumors in adolescence (15–19 years old). The leading cancer in 20–29 years of age was malignant germ cell other gonadal tumors (mainly testis and ovary), whereas female breast cancer was most frequent in 30–39 years of age. These results provide an overall picture of childhood and AYA cancer in Japan.

Glioblastoma multiforme is the most malignant primary intrinsic brain tumor. Glioma stem cells (GSCs) are associated with chemoradiotherapy resistance and the recurrence of glioblastomas after conventional therapy. The targeting of GSCs is potentially an effective treatment for the long-term survival of glioblastoma patients. Licochalcone A, a natural chalconoid from licorice root, exerts anticancer effects; however, its effect on GSCs remains unknown. We found that Licochalcone A induced massive caspase-dependent death in GSCs but not in differentiated GSCs nor normal somatic and neural stem cells. Prior to cell death, Licochalcone A caused mitochondrial fragmentation and reduced the membrane potential and ATP production in GSCs. Thus, Licochalcone A induces mitochondrial dysfunction and shows promise as an anticancer stem cell drug.

The development of gliomas subsequent to therapeutic cranial irradiation is a rare but serious complication. The purpose of this study is to understand the clinical characteristics and outcome of patients with radiation-induced glioma (RIG). Between 2001 and 2018, we identified 10 patients with RIG, which satisfied the Cahan’s criteria in our data base. There was no sex predominance (M: 5, F: 5), and the median age of the primary diseased was 13.5 years (range: 1–39). The primary diseases included 2 germinoma, 2 acute lymphoblastic lymphoma, 2 medulloblastoma, 1 diffuse astrocytoma, 1 pilocytic astrocytoma, 1 pituitary adenoma and 1 metastatic tumor from lung cancer. All the patients received cranial radiation (range: 12–60 Gy). The median latency time between primary disease and RIG was 16 years (range: 9–30 years), which was not correlated with age at the time of primary disease (r2= 0.014, p=0.74). Radiation-induced gliomas included 8 glioblastoma and 2 grade III glioma based on histological diagnosis. After surgical removal or biopsy of the RIG, 4 patients underwent chemotherapy alone (nimustine, temozolomide (TMZ), carboplatin and etoposide), and 6 received chemotherapy (nimustine, TMZ, bevacizumab) combined with radiotherapy (range: 40-66Gy). The median progression free survival and survival time from RIG were 10.1 and 27.5 months, respectively. In summary, RIG may occur many years after successful initial treatment using radiotherapy, and the outcome of our patients with RIG supports the use of radiotherapy and/or chemotherapy after surgical resection.

BACKGROUND Central nervous system germ cell tumor (CNSGCT) is a rare pediatric brain tumor. However, they are found at a relatively high incidence in East Asia. Germinoma is sensitive toward radiotherapy and chemotherapy; however, non-germinoma GCTs (NGGCT) often show poor response. Some cases are a mixture of germinoma and NGGCT (mixed GCT), and they sometimes change histological subtypes at recurrence. Previous report demonstrated that a germinoma and NGGCT component within the same mixed GCT tissue shared the same gene mutation, whereas the genome-wide methylation profiles were distinct from each other. The methylation profiles of germinoma was similar to the primordial germ cells (PGC) at the migration phase, supporting a model that PGC is the cell of origin for CNSGCT. However, tumor heterogeneity hinder information of the mixed bulk RNA-sequence data, causing difficulty in elucidating the mechanism of tumor development. The purpose of this study was to investigate the tumor cells subpopulations at the resolution of individual cells by single-cell RNA-seq. RESULTS Fresh surgical tumor tissue was immediately dissociated mechanically and enzymatically. Tumor cells are separated from CD45-labelled lymphocytes by FACS, and libraries were generated by Chromium Single cell 3’ Reagent Kit. Total of 11 tumor samples were collected and sequenced. Unsupervised Clustering showed individual clusters. One of the clusters had high expression of Oct-4, which is a marker of germinoma. The other clusters showed different subtypes of cells representing the heterogeneity of CNSGCT. Further analysis including a pseudo-time course analysis is underway to identify the lineage of tumor cell development.

Germ cell tumors (GCTs) are unique neoplasms in that they arise from the migrated cells which were supposed to be directed to gonads. They occur in the central nervous system (CNS), as well as gonadal organs such as testis and ovary. Our genomic analysis revealed that they are characterized by mutations in MAPK and PI3K pathways, chromosomal instability and global hypomethylation in germinoma. However, there were plenty of cases which lacked driver alterations and their pathogenesis is yet to be fully unraveled. Here we aimed to uncover CNSGCT’s pathogenesis from a transcriptomic perspective. Genome-wide transcriptional analysis was performed for 58 CNS and 3 testicular GCTs. This demonstrated that germinoma had a transcriptional profile characteristic to primordial germ cells (PGCs) at early embryogenesis, whereas non-germinomatous germ cell tumors (NGGCTs) showed that with differentiation into various tissues. Integration of transcriptome and methylome corroborated the above finding that pluripotency/meiosis-genes were unmethylated and highly expressed in germinoma compared with NGGCT. Co-analysis with transcriptome of various developmental stages of embryonic cells revealed germinoma and NGGCT had similarities in expression to PGC and embryonic stem cells, respectively. Multi-omics analysis with testicular GCTs (n=134) from TCGA showed shared genomic backgrounds between germinoma-seminoma and NGGCT-nonseminomatous GCT (NSGCT) in mutation and methylation profiles, and contrast in the chromosomal instability, which was more highlighted in testicular GCTs. These new insights into molecular profiles of GCTs lead to a better understanding of the complex pathogenesis of GCTs, and will hopefully provide a clue to future development of new treatments.

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.

Primary central nervous system lymphoma (PCNSL) is known as one of the incurable brain tumors. In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (rrPCNSL) based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646). In this study, 44 Japanese patients with rrPCNSL 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 on June 13, 2019 (Nagane et al., the 61st American Society of Hematology Annual Meeting and Exposition in 2019). 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 (32%), neutropenia (23%), leukopenia (18%), and lymphopenia (16%), 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 25, 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for OS, duration of response, and time to onset of AEs will also be presented.

A 71-year-old Japanese man with travel history to the Vancouver Island, Canada was diagnosed the pulmonary and central nervous system infections caused by Cryptococcus gattii genotype VGIIa. This is the first imported case of Cryptococcus gattii genotype VGIIa infection from endemic area of North America to Japan. He was recovery with no residual neurological dysfunction by early resection of brain mass and antifungal therapy. Early surgical resection of cerebellar cryptococcoma may shorten the length of induction therapy with antifungal drugs.

Identification of genotypes is crucial for treatment of glioma. Here, we developed a method to predict tumor genotypes using a pretrained convolutional neural network (CNN) from magnetic resonance (MR) images and compared the accuracy to that of a diagnosis based on conventional radiomic features and patient age. Multisite preoperative MR images of 164 patients with grade II/III glioma were grouped by IDH and TERT promoter (pTERT) mutations as follows: (1) IDH wild type, (2) IDH and pTERT co-mutations, (3) IDH mutant and pTERT wild type. We applied a CNN (AlexNet) to four types of MR sequence and obtained the CNN texture features to classify the groups with a linear support vector machine. The classification was also performed using conventional radiomic features and/or patient age. Using all features, we succeeded in classifying patients with an accuracy of 63.1%, which was significantly higher than the accuracy obtained from using either the radiomic features or patient age alone. In particular, prediction of the pTERT mutation was significantly improved by the CNN texture features. In conclusion, the pretrained CNN texture features capture the information of IDH and TERT genotypes in grade II/III gliomas better than the conventional radiomic features.

Background: Small bowel adenocarcinoma (SBA) accounts for et al. reported 1 case of brain metastasis out of 217 SBA cases, but details of the clinical course of the case were unclear. Our case might be the first report covering the full clinical course, pathological findings, and genetic data. Here, we report a very rare case of brain metastasis from poorly differentiated SBA. Case Description: A 54-year-old man who suffered from abdominal pain and melena visited a nearby hospital. This patient had no risk factors for SBA. He underwent partial resection of the jejunum with regional lymphadenectomy and combined resection of the transverse colon. Pathological diagnosis was poorly differentiated adenocarcinoma, pT4N2M0 Stage IIIB (UICC-TNM: 8th edition). One month after curative surgery, liver metastasis was detected by a computed tomography (CT) scan, and then, palliative chemotherapy was started. During the third-line chemotherapy, a brain tumor on the left cerebellum was detected by the CT scan. Tumor resection was performed, and the histopathological features coincided with the primary jejunum tumor. Based on surgical, radiological, pathological, and genetic findings, this brain tumor was comprehensively diagnosed as a metastasis from poorly differentiated SBA. Conclusion: Here, we experienced a very rare case of brain metastasis from poorly differentiated SBA.

Background and purpose The purpose of this study was to evaluate the outcomes of elderly patients (aged ≥75 years) with newly diagnosed glioblastoma (GBM), who were treated with hypofractionated radiotherapy comprising 45 Gy in 15 fractions combined with temozolomide (TMZ) or TMZ and bevacizumab (TMZ/Bev). Materials and methods Between October 2007 and August 2018, 30 patients with GBM aged ≥75 years were treated with hypofractionated radiotherapy consisting of 45 Gy in 15 fractions. Twenty patients received TMZ and 10 received TMZ/Bev as upfront chemotherapy. O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed by pyrosequencing. The cutoff value of the mean level of methylation at the 16 CpG sites was 16%. Results Median overall survival (OS) and progression-free survival (PFS) were 12.9 months and 9.9 months, respectively. The 1-year OS and PFS rates were 64.7 and 34.7%, respectively. Median OS and PFS did not differ significantly between patients with MGMT promoter hypermethylation (N = 11) and those with hypomethylation (N = 16) (17.4 vs. 11.8 months, p = 0.32; and 13.1 vs. 7.3 months, p = 0.11, respectively). The median OS and PFS were not significantly different between TMZ (N = 20) and TMZ/Bev (N = 10) chemotherapy (median OS: TMZ 12.9 months vs. TMZ/Bev 14.6 months, p = 0.93, median PFS: TMZ 8.5 months vs TMZ/Bev 10.0 months, p = 0.64, respectively). The median time until Karnofsky performance status (KPS) score decreasing below 60 points was 7.9 months. The best radiological responses included 11 patients with a partial response (36.7%). Grade 3/4 toxicities included leukopenia in 15 patients (50%), anorexia in 4 (13.3%), and hyponatremia during concomitant chemotherapy in 3 (10%). Conclusion Our hypofractionated radiotherapy regimen combined with TMZ or TMZ/Bev showed benefits in terms of OS, PFS, and KPS maintenance with acceptable toxicities in elderly patients with GBM aged ≥75 years.

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.

TERT promoter mutation is associated with 1p/19q codeletion and favorable prognosis in IDH-mutated gliomas. Prognostic and diagnostic significance of TERT promoter mutation is well-recognized in IDH-wildtype glioblastomas, but not in IDH-mutated gliomas. We investigated prognostic efficacy of TERT mutation in a cohort of 560 Japanese IDH-mutated adult gliomas. The molecular status of IDH, TERT and 1p/19q and patient clinical data including Karnofsky performance status (KPS) were collected in all cases. TERT mutations and 1p/19q codeletions were found in 303 and 285 cases, respectively. The patient cohort was divided into four groups by a combination of the 1p/19q and TERT status. The characteristics of 1p/19q intact-TERT mutated group (Astro-TERT group, n=24) were compared with those of 1p/19q intact-TERT wild (Astro-group, n=251) or 1p/19q codeleted-TERT mutated (Oligo-group, n=279) cases. Astro-TERT group with any grade showed intermediate overall survival between the Oligo-group and Astro-group although the survival differences were not statistically significant (median overall survival (OS) not reached (NR) versus NR, and 106 months, respectively. p >0.05). We further conducted subgroup analysis by adjusting KPS and WHO grade as Cox regression analysis for survival indicated the unfavorable survival impact of KPS < 90 and WHO grade IV. In the subgroup with favorable KPS (90–100) and grade II-III (n=438), The OS of Astro-TERT group (median NR) was significantly longer survival than that of Astro-group (median 120.2 months, p=0.032), and was comparable with that of the Oligo-group (median NR, p >0.05). On the other hand, OS of none of the molecular groups significantly differ in poorer KPS subgroups (p >0.05). In grade IV tumors, the OS of the Astro-TERT group (NR) was comparable with that of Astro-group (29 months, p=0.19) rather than Oligo-group (NR, p=0.051). Thus, TERT promoter status provides a valuable prognostic information for IDH-mutated grade II-III gliomas in the current molecular diagnostic system.

Background Primary central nervous system lymphoma (PCNSL) responds relatively quickly to chemotherapy or radiotherapy. However, determination of a complete response after treatment is often difficult because of extremely light residual contrast enhancement on magnetic resonance images due to the effects of microhemorrhages and scar tissue formation. These small enhancing lesions define an unconfirmed complete response. The aim of this study was to investigate the usefulness of carbon-11-labeled methionine (11C-Met) positron-emission tomography (PET) for determining the treatment response of PCNSL. Methods Data for 36 patients who were treated for PCNSL between 2011 and 2015 and underwent magnetic resonance imaging and 11C-Met PET were reviewed. Magnetic resonance imaging findings were classified as complete response, unconfirmed complete response, and tumor mass (a composite of partial response, stable disease and progressive disease). PET images were evaluated, standardized uptake values were quantified, and the tumor-to-normal tissue count ratio (TNR) was calculated. Receiver operating characteristic curves were generated to determine the optimal cutoff TNRs. Results The optimal TNRs for differentiating complete response and unconfirmed complete response from tumor mass were 1.83 (area under the curve, 0.951) and 1.80 (area under the curve, 0.932), respectively. The corresponding sensitivity and specificity values for the diagnosis of tumor mass were 82.4 and 100%, respectively, in the complete response group and 85.3 and 85%, respectively, in the unconfirmed complete response group. Conclusions A TNR of ≥1.80 can aid in the detection of active PCNSL using 11C-Met PET. Thus, 11C-Met-PET may be a useful tool for accurate evaluation of the treatment efficacy in PCNSL.

Background: Little information is available about the feasibility and prognostic assessment of surgical resection of brain metastasis (BM) from sarcomas. We aimed to analyze functional and survival outcomes, and develop a preoperative graded prognostic assessment (GPA) for patients with BM from sarcomas to predict survival time after local resection surgery. Methods: This study involved a multi-institutional retrospective analysis of 22 patients with BM from sarcomas who underwent resection at six institutes in Japan between September 2002 and September 2018.Overall survival (OS) after resection of BM was calculated by the Kaplan–Meier method. Prognostic factors were analyzed to develop a GPA using the log-rank test and Cox regression analysis. P < 0.05 was considered to indicate statistical significance. For GPA validation, we collected data on 100 patients from 48 published reports. Results: Postoperative Karnofsky Performance Status (KPS) was improved in 50% (11/22) of patients. Median OS was 21 months. Univariate analysis of OS showed that age (≥ 30 years old), gross total resection, and alveolar soft part sarcoma (ASPS) were significant positive prognostic factors (P

Background We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. Methods Data from the Intracranial Germ Cell Tumor Genome Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews. Results All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. Conclusions The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.

Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world. EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody–drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography. EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P

A randomized phase III trial in Japan commenced in June 2019. The present standard treatment for newly diagnosed glioblastoma is maximal resection followed by chemoradiotherapy with temozolomide. The purpose of this study is to confirm the superiority of maximal resection with carmustine wafer implantation followed by chemoradiotherapy with temozolomide over the standard maximal resection followed by chemoradiotherapy with temozolomide in terms of overall survival for newly diagnosed glioblastoma. A total of 250 patients will be accrued from 35 Japanese institutions in 5.5 years. Patients with >90% surgical resection will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, loco-regional progression-free survival and incidence of adverse events. This trial has been registered in the Japan Registry of Clinical Trial, as jRCT1031190035 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031190035].

OBJECTIVECentral nervous system (CNS) germ cell tumors (GCTs) are rare malignant neoplasms that arise predominantly in adolescents and young adults. CNS GCTs demonstrate characteristic trends in national associations, with implications for both tumor incidence and genetics. Although the incidence of CNS GCTs is markedly higher in East Asia than Western countries, direct comparative analyses between these CNS GCT populations are limited.METHODSIn Japan, to facilitate the genomic analyses of CNS GCTs, the Intracranial Germ Cell Tumor Genome Analysis Consortium was established in 2011, and more than 200 cases of GCTs are available for both tumor tissue and clinical data, which is organized by the National Cancer Center (NCC) Japan. At the Mayo Clinic, there have been 98 cases of intracranial GCTs treated by the Department of Neurologic Surgery since 1988. In this paper, the authors compared the epidemiology, clinical presentation including location and histology, and prognosis between cases treated in the US and Japan.RESULTSThere was no significant difference in age and sex distributions between the databases. However, there was a significant difference in the tumor locations; specifically, the frequency of basal ganglia was higher in the NCC database compared with the Mayo Clinic (8.4% vs 0%, p = 0.008), and bifocal location (neurohypophysis and pineal gland) was higher at the Mayo Clinic than at the NCC (18.8% vs 5.8%, p = 0.002). There was no difference in histological subdivisions between the databases. There was no difference in progression-free survival (PFS) and overall survival (OS) of germinoma cases and OS of nongerminomatous GCT (NGGCT) cases treated with chemotherapy and radiation therapy covering whole ventricles. However, PFS of NGGCTs differed significantly, and was better in the NCC cohorts (p = 0.04).CONCLUSIONSThere appears to be a differential distribution of GCTs by neuroanatomical location between major geographic and national groups. Further study is warranted to better characterize any underlying genomic, epigenetic, or environmental factors that may be driving the phenotypic differences.

To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

2038 Background: TAS0313 is a cancer vaccine cocktail comprising three long peptides with a total of 12 cytotoxic T lymphocyte (CTL) epitope peptides. These peptides were derived from eight cancer-associated antigens (EGFR, KUA, LCK, MRP3, PTHRP, SART2, SART3, and WHSC2) that are overexpressed in various cancer types including glioblastoma (GBM). We performed a single-arm, multicenter efficacy confirmatory cohort study as part of the TAS0313 Phase I/II study in patients with recurrent GBM. Methods: The enrolled patients with histologically or cytologically confirmed grade IV GBM (including gliosarcoma, giant cell glioblastoma, and epithelioid glioblastoma) had at least one of the following HLA types: HLA-A*02:01, -A*02:06, -A*02:07, -A*11:01, -A*24:02, -A*31:01, or -A*33:03. Eligible patients were those who received standard radiotherapy and temozolomide, had a confirmed first or second recurrence, or progression with measurable disease outcomes with good performance status (Karnofsky Performance Status score > 70). TAS0313 (27mg) was subcutaneously administered on days 1, 8, and 15 of cycles 1 and 2 and day 1 of cycle 3 or later in 21-day cycles until disease progression or unacceptable toxicity occurred. Tumor response was evaluated using The Response Assessment in Neuro-Oncology criteria. The antigen-specific CTL and immunoglobulin G (IgG) were analyzed by ELISPOT assay and Luminex assay, respectively, before and after treatment. The primary objective was to evaluate the efficacy of TAS0313. Secondary and exploratory methods were used to evaluate the safety and immune response of TAS0313. Results: As of 10th September 2020, 10 patients have been treated with TAS0313 (eight with GBM and two with gliosarcoma). The median age of participants was 56.5 [range, 33–69 years], and methylation status of the MGMT promoter was methylated in four patients, unmethylated in four, and unknown in two. The best overall response was partial response 1/10 (10.0%) and stable disease 4/10 (40.0%). One case showed 69.1% tumor shrinkage. The treatment of two patients was ongoing for over 7 months. The 6-month progression-free survival (PFS) rate was 25.0%, and the median PFS was 2.3 months. The most common adverse drug reactions (ADRs) were grade 1–2 injection site reactions and pyrexia. There were no grade 4 or 5 ADRs. In some patients, TAS0313 treatment was confirmed to increase CTL and IgG levels compared with pre-treatment samples. Conclusions: TAS0313 showed promising efficacy with expected immune responses and favorable safety and tolerability in patients with recurrent GBM. Further investigation of TAS0313 is warranted to validate our findings. Clinical trial information: JapicCTI-183824.

Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell.

Few prospective studies have investigated the etiology of brain tumor, especially among Asian populations. Both coffee and green tea are popular beverages, but their relation with brain tumor risk, particularly with glioma, has been inconsistent in epidemiological studies. In this study, we evaluated the association between coffee and greed tea intake and brain tumor risk in a Japanese population. We evaluated a cohort of 106,324 subjects (50,438 men and 55,886 women) in the Japan Public Health Center-Based Prospective Study (JPHC Study). Subjects were followed from 1990 for Cohort I and 1993 for Cohort II until December 31, 2012. One hundred and fifty-seven (70 men and 87 women) newly diagnosed cases of brain tumor were identified during the study period. Hazard ratio (HR) and 95% confidence intervals (95%CIs) for the association between coffee or green tea consumption and brain tumor risk were assessed using a Cox proportional hazards regression model. We found a significant inverse association between coffee consumption and brain tumor risk in both total subjects (≥3 cups/day; HR = 0.47, 95%CI = 0.22–0.98) and in women (≥3 cups/day; HR = 0.24, 95%CI = 0.06–0.99), although the number of cases in the highest category was small. Furthermore, glioma risk tended to decrease with higher coffee consumption (≥3 cups/day; HR = 0.54, 95%CI = 0.16–1.80). No association was seen between green tea and brain tumor risk. In conclusion, our study suggested that coffee consumption might reduce the risk of brain tumor, including that of glioma, in the Japanese population.

Chemoradiotherapy for primary central nervous system lymphoma (PCNSL) is associated with a considerable risk of long-term neurotoxicity. The present study aimed to assess the health-related quality of life (HRQOL) of outpatients with PCNSL who have received radiotherapy and high-dose methotrexate (HDMTX) chemotherapy, and to determine the factors that cause a decline in HRQOL and interfere with home living. A total of 37 patients were surveyed 0.9–14.2 years after their initial diagnosis and treatment. Each patient completed a multi-part HRQOL questionnaire that was used to examine the associations of HRQOL scores with leukoencephalopathy, Karnofsky performance status (KPS) scores, age, history of recurrence and HDMTX-based chemoradiotherapy. The results demonstrated that the history of recurrence, number of cycles of MTX chemotherapy and age affected the development of leukoencephalopathy. Reductions in KPS score were associated with a history of recurrence (P=0.03), but not with leukoencephalopathy (P=0.8). KPS score, leukoencephalopathy and age were significantly associated with a decline in HRQOL score. A decline in the HRQOL associated with a reduction in KPS score was also observed by multivariate analyses. Deterioration of the HRQOL among outpatients with PCNSL post-chemoradiotherapy was significantly associated with older age (≥66 years) and decreased KPS score. Older patients with a history of recurrence had a higher risk for deteriorated QOL due to development of leukoencephalopathy. Therefore, it is recommended that clinicians monitor the KPS score among outpatients with PCNSL. QOL examination for older patients with a lower KPS score was found to be particularly important for identifying any obstacles for home living.

A highly enhanced cap attached to the surface of metastatic tumors in the brain parenchyma is occasionally encountered on magnetic resonance (MR) images. This atypical enhanced cap tends to occur in severe peritumoral edema and may produce the characteristic bulge of a metastatic mass lesion termed the "comet tail sign" (CTS). The purpose of this study was to demonstrate the features of the CTS using MR imaging and pathological findings, and to clarify its clinical relevance. We selected 21 consecutive cases of newly diagnosed metastases from MR imaging studies that demonstrated the CTS; all had diffuse peritumoral edema. The MR T2-weighted images showed similarly homogenous and high intensity signals in both the tail and peritumoral edema. Fourteen of the 21 patients underwent surgical resection of their tumors, and 12 tails were separately removed for pathological examination, no tumor cells which revealed. We speculate that the CTS does not contain neoplastic tissues but is observed as a result of the leakage of contrast medium from the tumor body into the interstitial space of the white matter. Although CTS is a peculiar and uncommon enhancement pattern, it has clinical significance in determining the extent of the margin for invasive local treatments, such as surgical resection or stereotactic radiotherapy; this is particularly true in and near the eloquent areas.

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.

PURPOSE The current research tested the hypothesis that TI shorter than 2400 ms under 3T for FLAIR can improve the diagnostic accuracy of the T2-FLAIR mismatch sign for identifying IDHmt, non-CODEL astrocytomas. EXPERIMENTAL DESIGN We prepared three different cohorts; 94 MRI from 76 IDHmt, non-CODEL LrGGs, 33 MRI from 31 LrGG under the restriction of FLAIR being acquired with TI < 2400 ms for 3T or 2016 ms for 1.5T, and 103 MRI from 103 patients from the TCIA/TCGA dataset for LrGG. The presence or absence of the “T2-FLAIR mismatch sign” was evaluated, and we compared diagnostic accuracies according to TI used for FLAIR acquisition. RESULTS The T2-FLAIR mismatch sign was more frequently positive when TI was shorter than 2400 ms under 3T for FLAIR acquisition (p = 0.0009, Fisher’s exact test). The T2-FLAIR mismatch sign was positive only for IDHmt, non-CODEL astrocytomas even if we confined the cohort with FLAIR acquired with shorter TI (p = 0.0001, Fisher’s exact test). TCIA/TCGA dataset validated that the sensitivity, specificity, PPV, and NPV of the T2-FLAIR mismatch sign to identify IDHmt, non-CODEL astrocytomas improved from 31%, 90%, 79%, and 51% to 67%, 94%, 92%, and 74%, respectively if we acquired FLAIR with TI shorter than 2400 ms. CONCLUSIONS We revealed that TI for FLAIR impacts diagnostic accuracy of the T2-FLAIR mismatch sign and that FLAIR scanned with TI < 2400 ms in 3T is necessary for LrGG imaging.

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.

Qualitative imaging, primarily focusing on brain tumors’ genetic alterations, has gained traction since the introduction of molecular-based diagnosis of gliomas. This trend started with fine-tuning MRS for detecting intracellular 2HG in IDH-mutant astrocytomas and further expanded into a novel research field named “radiomics”. Along with the explosive development of machine learning algorithms, radiomics became one of the most competitive research fields in neuro-oncology. However, one should be cautious in interpreting research achievements produced by radiomics as there is no “standard” set in this novel research field. For example, the method used for image feature extraction is different from research to research, and some utilize machine learning for image feature extraction while others do not. Furthermore, the types of images used for input vary among various research. Some restrict data input only for conventional anatomical MRI, while others could include diffusion-weighted or even perfusion-weighted images. Taken together, however, previous reports seem to support the conclusion that IDH mutation status can be predicted with 80 to 90% accuracy for lower-grade gliomas. In contrast, the prediction of MGMT promoter methylation status for glioblastoma is exceptionally challenging. Although we can see sound improvements in radiomics, there is still no clue when the daily clinical practice can incorporate this novel technology. Difficulty in generalizing the acquired prediction model to the external cohort is the major challenge in radiomics. This problem may derive from the fact that radiomics requires normalization of qualitative MR images to semi-quantitative images. Introducing “true” quantitative MR images to radiomics may be a key solution to this inherent problem.

2536 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 mentioned 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 which was decided by preceding phase I trial. Primary endpoint was 1-year survival rate and secondary ones were median overall survival (mOS), median progression free survival (mPFS) and so on. 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) (data cutoff = 20 Jun 2019) 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. 21 out of 27 cases were 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 with bevacizumab. Clinical trial information: JapicCTI-194742 . [Table: see text]