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Background Central nervous system (CNS) germ cell tumors account for 15.3% of all CNS tumors in children and adolescents and young adults. Five histologic types and mixed types exist and can be classified into the following clinical risk groups: germinomas, malignant germ cell tumors, and other germ cell tumors. In germinomas, platinum-based chemotherapy and whole ventricle/brain irradiations 23.4 Gy/13 fraction are the standard of care, but late adverse events related to radiation therapy are a problem. In malignant germ cell tumors, chemotherapy with alkylating agents and platinum, craniospinal irradiation (CSI), and local radiation therapy (local dose 50-59.4 Gy/25-33 fractions) have become the standard of care, but the 10-year OS is poor at about 60% and late radiation therapy-related adverse events are an issue. For various reasons, it is not easy to establish a standard of care for mature teratomas and immature teratomas, which constitute the other germ cell tumors, but it is essential to collect knowledge on tumor characteristics and prognosis. Methods and Patients The Japan Children's Cancer Group Brain Tumor Committee has planned a study to validate the classification by histological diagnosis and ancillary tumor markers, a phase III study to test the non-inferiority of radiation dose reduction to standard therapy for germinomas, a phase II study to test the superiority of high-dose chemoradiation with methotrexate intrathecal injection excluding CSI to standard therapy for malignant germ cell tumors, observational studies to elucidate pathogenesis of other germ cell tumors. Discussion If these hypotheses are proven, it is expected to reduce late adverse events and prolong survival with radiotherapy in children and adolescent/young adult generation patients.

Background Adjuvant treatment with Gliadel wafers may prolong overall survival (OS) for malignant glioma patients without increasing toxicity. In Japan, the long-term OS of these patients treated with Gliadel 7.7 mg implants has not been studied. We evaluated OS and prognostic factors that might affect OS in Japanese patients with malignant glioma who received the Gliadel 7.7 mg implant. Methods This observational, long-term, postmarketing surveillance was an extension of a previous surveillance. Data were collected through case report forms at 2 and 3 years after Gliadel implant. Up to 8 Gliadel wafers (61.6 mg of carmustine) were placed over the tumor resection site. Primary endpoints were OS and prognostic factors that may influence OS. Results Among the 506 patients analyzed, 62.6% had newly diagnosed disease, and 37.4% had recurrent disease; 79.1% had glioblastoma histological type and 79.6% had World Health Organization Grade IV disease. Patients received a median of 8 wafers. The median OS was 18.0 months; OS rates were 39.8% and 31.5% at 2 and 3 years, respectively. Age ≥65 years (hazard ratio [HR]: 1.456; P = .002), lower resection rate (HR: 1.206; P Conclusions This study confirmed the 2- and 3-year OS of Japanese malignant glioma patients with varied backgrounds after Gliadel implant. With a careful interpretation of indirect comparisons with previously reported data, the results suggest that prognosis could be improved with Gliadel implants. Clinical Trial Registration NCT02300506

BackgroundThalamic high-grade gliomas (HGGs) are rare tumors with a dismal prognosis. H3K27M and telomerase reverse transcriptase promoter (TERTp) mutations reportedly contribute to poor prognoses in HGG cases. We investigated the outcomes of surgically treated adult thalamic HGGs to evaluate the prognostic significance of H3K27M and TERTp mutations.MethodsWe retrospectively analyzed 25 adult patients with thalamic HGG who underwent maximum surgical resection from January 1997 to March 2020. The histological and molecular characteristics, progression-free survival (PFS), and overall survival (OS) of the patients were compared. For molecular characteristics, target sequencing was used to determine the H3F3A, HIST1H3B, and TERTp mutations.ResultsH3K27M mutations were detected in 12/25 (48.0%) patients. TERTp mutations were not detected in H3K27M-mutant gliomas but were detected in 8/13 (61.5%) of H3 wild-type gliomas. Although it was not significant, H3K27M-mutant gliomas tended to have a shorter PFS (6.7 vs 13.1 months; P = .2928) and OS (22.8 vs 24.4 months; P = .2875) than H3 wild-type gliomas. Moreover, the prognosis of TERTp-mutant gliomas was as poor as that of H3K27M-mutant gliomas. Contrary, 5 gliomas harboring both H3 and TERTp wild-type showed a better median PFS (59.2 vs 6.4 months; P = .0456) and OS (71.8 vs 24.4 months; P = .1168) than those harboring H3K27M or TERTp mutations.ConclusionsTERTp-mutant gliomas included in the H3 wild-type glioma group limited patient survival as they exhibited an aggressive course similar to H3K27M-mutant gliomas. Comprehensive molecular work-up for the H3 wild-type cases may further confirm this finding.

Background Treatment options for patients suffering brainstem gliomas are quite limited as surgery is not an option against intrinsic tumors at brainstem and chemotherapy generally failed to demonstrate its efficacy. Intracerebral convection-enhanced delivery (CED) is a novel approach for administering chemotherapy to patients with brain tumors. We present the results of phase I trial of CED of nimustine hydrochloride (ACNU), designed to determine the maximum tolerable concentration of ACNU, for patients with recurrent brainstem gliomas. Methods Sixteen patients, aged 3–81 years old, suffering from recurrent brainstem gliomas, including diffuse intrinsic pontine glioma patients as well as patients with recurrent gliomas that originated from non-brainstem sites, were enrolled in this trial between February 2011 and April 2016. The dose/concentration escalation trial included 3 dose/concentration groups (0.25, 0.5, and 0.75 mg/mL, all at 7 mL) to determine the safety and tolerability of CED of ACNU. Real-time monitoring of drug distribution was performed by mixing gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) in the infusion solution. CED of ACNU was given in combination with oral or intravenous temozolomide chemotherapy. Results CED of ACNU demonstrated antitumor activity, as assessed by radiographic changes and prolonged overall survival. The recommended dosage was 0.75 mg/mL. Drug-associated toxicity was minimal. Conclusions Intracerebral CED of ACNU under real-time monitoring of drug distribution, in combination with systemic temozolomide, was well tolerated among patients with recurrent brainstem gliomas. The safety and efficacy observed suggest the clinical benefits of this strategy against this devastating disease. Based on this phase I study, further clinical development of ACNU is warranted.

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 The treatment strategies for recurrence has not been established. PURPOSE To clarify the tumor control and complications of salvage craniospinal irradiation (CSI) for recurrent germinoma. METHODS We retrospectively reviewed the medical record. Among 153 germinomas treated in Tohoku University Hospital since 1983, 22 had recurrence of germinoma. At first recurrence, 7 cases received CSI, whereas 15 cases did chemotherapy and/or radiation therapy other than craniospinal field (non- CSI). CSI was performed at 24 Gy/ 12 fractions or 30 Gy/ 25 fractions. RESULTS CSI had statistically significant better recurrence-free survival rate after recurrence than non-CSI (100% vs 33%, p CONCLUSION Low dose CSI for the first recurrence of germinoma is effective and safe in the cases treated by chemotherapy and low dose irradiation to whole ventricle only.

Background Brain radiation necrosis (BRN) can be a complication of radiotherapy for primary and secondary brain tumors, as well as head and neck tumors. Since vascular endothelial growth factor (VEGF) is also a vascular permeability factor in the brain, bevacizumab, a humanized antibody that inhibits VEGF, would be expected to reduce perilesional edema that often accompanies BRN. Methods Patients with surgically untreatable, symptomatic BRN refractory to conventional medical treatments (eg, corticosteroid, anticoagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilesional edema with a lesion-to-normal brain ratio ≤1.8 on 11C-methionine or ≤2.5 on 18F-boronophenylalanine PET was BRN, not tumor recurrence, and 6 cycles of biweekly bevacizumab (5 mg/kg) were administered. The primary endpoint was a ≥30% reduction from the patients' registration for perilesional edema continuing for ≥1 month. Results Of the 41 patients enrolled, 38 were fully eligible for the response assessment. The primary endpoint was achieved in 30 of the 38 (78.9%) patients at 3.0 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of their Karnofsy Performance Score. Corticosteroid use could be reduced in 29 patients (76.3%). Adverse events at grade ≥3 occurred in 10 patients (24.4%). Conclusions Bevacizumab treatment offers certain clinical benefits for patients with surgically untreatable, symptomatic BRN. The determination of BRN using amino-acid PET, not biopsy, is adequate and less invasive for determining eligibility to receive bevacizumab.

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

The carmustine (BCNU) wafer, a biodegradable polymer, currently is the only drug that is able to be placed at the surgical site to treat malignant tumors. Biomaterials to treat cancers hold therapeutic potential; however, how they behave inside the tumor microenvironment requires further study. We previously investigated the tumor microenvironment after BCNU wafer implantation, and found that CD68-positive macrophage was significantly introduced around the wafer (Shibahara et al. J Neurooncol 2018). Recent studies demonstrated the importance of tumor-associated macrophage (TAM). However, we could not clarify whether the increased macrophage around the wafer was pro-tumor or anti-tumor phenotype. In the present study, we immunohistochemically examined expressions of CD68, IBA1, CD163, TMEM119, BIN1, CD31, and VEGF to investigate TAM after the wafer implantation. Quantitative evaluation revealed that CD68+ cells were significantly increased (P = 0.0009), whereas TMEM119+ cells were significantly decreased (P = 0.0081) after wafer implantation compared to tissue from cases without wafer implantation. CD163, a known marker of poor prognosis in glioblastoma, did not differ with and without wafer implantation. Among factor analyzed, BCNU wafer did not induce protumor TAM, but reduced microglial marker, TMEM 119. In addition to the aspect of chemotherapy, BCNU wafer may have potential to modify the tumor microenvironment such as TAM.

Anaplastic gliomas and glioblastomas are aggressive brain tumors with median survival times ranging from 72.1 to 82.6 months in anaplastic gliomas and 14.6 months in glioblastomas.1,2 One of the main causes of the poor prognosis is chemo- and radioresistance. Thus, elucidation of mechanisms underlying this resistance is urgent to improve the treatment outcomes of malignant gliomas. The system involving Kelch-like ECH (erythroid cell-derived protein with cap'n'collar homology)-associated protein 1 (KEAP1) and nuclear factor erythroid 2–related factor 2 (NRF2) plays pivotal roles in protecting normal and neoplastic cells from oxidative and electrophilic insults by activating cytoprotective genes. These gene products are involved in glutathione synthesis (eg, glutamate cysteine ligase of catalytic [GCLC] and of modifier subunit [GCLM] genes), reactive oxygen species (ROS) elimination, xenobiotic metabolism (eg, NAD(P)H:quinone oxidoreductase gene [NQO1]), and crossmembrane transport, often resulting in multidrug resistance.3 Under normal conditions, KEAP1 ubiquitinates NRF2, and NRF2 is degraded by the proteosome. In the presence of electrophiles or ROS, KEAP1 is inactivated, and NRF2 is stabilized, binds to antioxidant response elements (AREs), and induces the cytoprotective genes. Recently, constitutive activation of NRF2 was found in various cancers. Multiple causes of the constitutive activation of NRF2 have been described, including somatic mutations of KEAP1 or NRF2, reduced expression of KEAP1, and accumulation of p62.4 Increased NRF2 activity confers cell growth advantage and resistance to chemo- and radiotherapy on lung, prostate, gallbladder, and ovarian cancers5–9 and leads to poor prognosis in lung, esophagus, gallbladder, and breast cancers.10–14 Although similar impacts of NRF2 activation on glioblastoma cell lines and a small cohort of glioblastoma patients have been reported,15,16 the prognostic significance of NRF2 activation in malignant gliomas remains to be elucidated. Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene or IDH2 gene have been identified in adult gliomas.17–19 These mutations occur at a very early stage of gliomatogenesis and confer genetic and prognostic differences on anaplastic gliomas and glioblastomas.17–19 Malignant gliomas with IDH1/2 mutations had better prognoses than those with wild-type IDH1/2.17–19 Although the hypermethylated phenotype is frequently found in World Health Organization grades II and III gliomas with IDH1/2 mutations, underlying mechanisms for better prognosis remain unclear. Recently, IDH1 mutations have been shown to sensitize glioma cells to bis-chloroethylnitrosourea (BCNU)–induced oxidative stress by decreasing the amount of the reduced form of glutathione.20 Because the synthesis and reduction of glutathione is often heavily dependent on NRF2 activity,4 we hypothesized that the NRF2 pathway was suppressed in the presence of mutated IDH1, leading to the better prognosis of malignant gliomas with IDH1/2 mutations. To test this hypothesis, we characterized the prevalence, possible causes, and prognostic value of the NRF2 activation in anaplastic gliomas with mutated or wild-type IDH1/2 and glioblastomas. We also evaluated the association between IDH1/2 mutations and NRF2 activity by analyzing the expression of NRF2 and its target genes in surgical specimens, and confirmed the effect of IDH1 mutation on NRF2 activity, using IDH1 mutant-expressing cells.

Background. Bevacizumab, an anti–vascular endothelial growth factor antibody, has been used for the treatment of radiation necrosis. Thus far, however, there has been no definitive report on its use for the treatment of symptomatic pseudoprogression. Here we report 2 cases of successful treatment with bevacizumab for symptomatic pseudoprogression after boron neutron capture therapy (BNCT) was applied for recurrent malignant gliomas. Methods. Two recurrent malignant gliomas received BNCT. Both cases were treated with intravenous administration of bevacizumab at the deterioration that seemed to be symptomatic pseudoprogression. Results. The first case was recurrent glioblastoma multiforme and the second was recurrent anaplastic oligoastrocytoma. Both cases recurred after standard chemoradiotherapy and were referred to our institute for BNCT, which is tumor-selective particle radiation. Just prior to neutron irradiation, PET with an amino acid tracer was applied in each case to confirm tumor recurrence. Both cases showed deterioration in symptoms, as well as on MRI, at intervals of 4 months and 2 months, respectively, after BNCT. For the first case, a second PET was applied in order to confirm no increase in tracer uptake. We diagnosed both cases as symptomatic pseudoprogression and started the intravenous administration of 5 mg/kg bevacizumab biweekly with 6 cycles. Both cases responded well to this, showing rapid and dramatic improvement in neuroimaging and clinical symptoms. No tumor progression was observed 8 months after BNCT. Conclusions. Bevacizumab showed marked effects on symptomatic pseudoprogression after BNCT. BNCT combined with bevacizumab may prolong the survival of patients with recurrent malignant gliomas.

Immunotherapy trials for glioblastoma (GBM) have some effects but the efficacy was limited, some because of the low immunogenicity and diverse antigens for GBMs. Personalized selection of suitable peptides for patients is one way to conquer this problem. We conducted serial series of clinical trials with 14 kinds of vaccine candidates (ITK-1) in patients with advanced cancers. Here we report our phase I results of ITK-1 in GBM and also introduce the trial design of phase III in GBM which is on-going. (Phase I) Twelve HLA-A-24 positive patients were enrolled from 8 Japanese hospitals. The dose escalation trial was conducted to determine safety and tolerability of ITK-1 peptides (at 1mg, 3mg, 5mg), however because of a dose limiting toxicity (injection site skin reaction) in another ITK-1 phase I trial for advanced prostate cancer, patients with 5mg dose was skipped or discontinued. No serious adverse drug reactions were observed. By analysis of intention to treat, two patients displayed PR, 5 SD and 5 PD by WHO criteria. The PFS rate at 6 months was 16.7%. Median OS from registration was 10.6 months. (Phase III) Based on the phase I trial, phase III trial is on-going. GBM patients refractory or recurrence after standard initial TMZ-radiation treatment were enrolled. The multi-institutional trial are conducting under IRB approval of each institutes and written informed consents from the patients and/or responsible relatives. HLA-A24 positive patients receive peptide vaccine (3mg/1.5ml) or placebo with selected 2 to 4 subcutaneous injection once weekly in total 12 times at the first course. At the second to twenty course, peptide vaccine or placebo is administered biweekly. Patients were randomly assigned (2: 1) to receive relevant peptides or placebo and both arms were under best supportive care. No other chemotherapy, immunotherapy nor radiotherapy are allowed. The primary endpoint is OS and secondary endpoints includes survival rates at 12 month, objective tumor response, immune responses and PFS. A total of 90 cases were registered and the results will be open by June 2017. So far we do not experience serious side effects, excluding one case of pulmonary embolus. Overall survival of all cases (both vaccine and placebo arms together) from registration is 8.4 months.

We have reported that germinomas could be diagnosed from clinical evaluations and radiological imagings, however the specificity was below 100% [J Clin Neurosci. 2014]. In order to precisely diagnose the patients with germinomas, we recently perform advanced MR imaging studies including MR spectroscopy (MRS) and minimum apparent diffusion coefficiency (minADC) study, and evaluation of serum tumor markers, i.e. HCG, beta HCG, HCG-CTP. This retrospective study was carried out to search the possibility of preoperative diagnosis with increased specificity in patients with germinoma-like tumors. Thirty consecutive patients with germinoma-like tumor underwent initial treatment from May 2007 to January 2015. Both minADC value and lipid peak on proton MRS were evaluated in 22 patients, minADC only in 5, and MRS only in 1 patient. Serum level of HCG, beta-HCG, and HCG-CTP were evaluated in 22 cases, HCG and beta-HCG in 5, and only beta-HCG in 1 case. With or without histological verifications, all of these patients received three courses of chemotherapy using ifosfamide, cisplatin, and etoposide or carboplatin and etoposide, and then received 24Gy whole ventricle irradiation. All patient drastically responded to the treatment and are alive with only one events of recurrence. Both low (

PURPOSE: Our hospital introduced an intraoperative computed tomography (CT) for reasons such as its broad utility, safety and economy, despite an increase in intraoperative magnetic resonance imaging (MRI). We would like to verify existence value of our intraoperative CT system for neurosurgical procedures. MATERIALS AND METHODS: We performed intraoperative CT scans for the patients with 16 gliomas and 1 anterior cerebral artery partially thrombosed large aneurysm, which was treated by A2 side to side anastomosis and proximal occlusion, using a CT with 900mm opening size, radiolucent skull clamp and three types of pin made by stainless, titan, and sapphire, respectively. We assessed the residual tumors with plain and enhanced CT scans. In the cases of non-contrast tumors, small titan clips were applied on the wall of resection cavity to clarify the residual tumors. We also use 3-dementional CT angiography (3DCTA) for evaluating the hemodynamics. The time from the preparation to take images to restarting operation, image quality including the amount of halation caused by pins, and incidence during these procedures, were evaluated. RESULT: We could obtain CT scans all of these cases, regardless of the patients' position. All the surgical instruments were just put on the table below the breast. The amount of halation with sapphire pins was minimum, however even with them, it was difficult to evaluate the detailed residual tumors just beneath the location of pins. CTA was useful, especially for demonstrating the hemodynamics after resection of insulo-opercular gliomas and bypass/clipping. Total time to take CT scans was 15–40 (mean, 27) minutes. There had occurred no incidence including anesthesia. CONCLUSION: MRI is better than CT at the point of spatial resolution, but CT can be defined as an useful system in its easy-to-use, safety, and vascular evaluation.