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Background: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001., Methods: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method., Results: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples., Conclusions: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: Due to the effectiveness of growth hormone therapy (GHT), the number of cancer survivors receiving GHT has increased. Previous studies had indicated that GHT was not associated with the increasing risks of tumor recurrence and development with second neoplasm (SN) in cancer survivors. However, to date, research on those risks in germinoma survivors is still limited. The aim of this study is to evaluate the impact of GHT in relation to tumor recurrence and development with SN in pure germinoma survivors., Methods: This retrospective cohort study was approved by the Ethical Committee for Epidemiology of our institution. Seventy-three consecutive patients who underwent a biopsy of the lesion and were diagnosed with pure germinoma were retrospectively studied. They (median age, 15.0 years) were followed up more than 1 year after biopsy (median follow-up period, 14.3 years). The following data was obtained from the medical records of the patients: age, sex, preoperative magnetic resonance imaging findings, hormonal replacement, and events including tumor recurrence and/or SN., Results: In our patient series, 16 patients (21.9%) who were more likely to have neurohypophysial lesion and receive multiple hormonal therapies had received GHT. No significant differences in the rates of tumor recurrence and development with SN were observed between the patients who had and had not received GHT. Moreover, the recurrence-free survival and overall survival rates were not different between the patients who had and had not received GHT., Conclusions: GHT did not increase the risks of tumor recurrence and development with SN in pure germinoma survivors., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The so-called radiation-induced glioma (RIG, a secondary glioma after cranial irradiation), is a serious late effect after cranial radiation therapy. The clinical characteristics of and ideal treatment for these tumors are unclear. We analyzed our case series and conducted a comprehensive literature review to reveal the precise characteristics of RIGs., Methods: We analyzed the cases of six patients with RIGs treated at our institution and 354 patients with RIGs from the literature. The latency period from irradiation to the development of each RIG and the median overall survival of the patients were subjected to Kaplan-Meier analyses. Spearman's correlation test was used to determine the relationship between age at irradiation and the latency period., Results: The mean age of the 360 patients at the development of RIG was 27.42 ± 17.87 years. The mean latency period was 11.35 ± 8.58 years. Multiple gliomas were observed in 28.4%. WHO grade 3 and 4 RIGs accounted for 93.3%. The latency periods were significant shorter in the higher WHO grade group (p = 0.0366) and the concomitant systemic chemotherapy group (p < 0.0001). Age at irradiation was negatively associated with the latency period (r =- 0.2287, p = 0.0219). The patients treated with radiotherapy achieved significantly longer survival compared to those treated without radiotherapy (p = 0.0011)., Conclusions: Development in younger age, multiplicity, and high incidence of grade 3 and 4 are the clinical characteristics of RIGs. Cranial irradiation at older ages and concomitant chemotherapy were associated with shorter latency for the development of RIG. Radiation therapy may be the feasible treatment option despite radiation-induced gliomas., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs., Methods: Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH)., Results: A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs., Conclusions: 12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Astroblastoma is an extremely rare primary brain tumor accounting for 0.45 to 2.8% of all neuroglial tumors and usually occurs in pediatrics and young adults. The natural history of astroblastoma still remains unknown. In the World Health Organization (WHO) classification of tumors of the central nervous system, astroblastoma is classified as other neuroepithelial tumors and standard treatment other than surgery has not been established. As molecular and genetic diagnosis becomes more important in the latest WHO classification of brain tumors, the development of therapeutic options based on the information of molecular genetics are expected. Here we report a case of astroblastoma in a 49-year-old male. Small tumor was discovered by coincidence during his check-up following traffic accident, but three months later, tumor bleeding with cystic enlargement resulted in disturbance of consciousness. Initial diagnosis of low grade astroblastoma with BRAF V600E mutation was made. After 1 year, local tumor recurrence was observed. The histological diagnosis at recurrence was high grade astroblastoma. We here, discuss about diagnosis, treatment and the possibility of usefulness of molecular genetic analysis for astroblastoma with some literature review. (Received 10 August, 2021; Accepted 15 December, 2021; Published 1 April, 2022).

Background: Endoscopic third ventriculostomy (ETV) for obstructive hydrocephalus and endoscopic biopsy (EB) for intraventricular and paraventricular tumors are standard therapies because they are minimally invasive procedures. Although EB-associated hemorrhagic risk has been well documented, there have been only a few reports on hemorrhagic risk associated with ETV. We conducted a single-institution retrospective study on the incidence of hemorrhage secondary to EB and/or ETV., Methods: We retrospectively reviewed patient characteristics, procedure, pathological findings, and complications including hemorrhage of 100 patients with intraventricular and paraventricular tumors who underwent EB and/or ETV at our institution from 2000 to 2020., Results: EB/ETV combined surgery (combined group), EB-alone surgery (EB-alone group), and ETV-alone surgery (ETV-alone group) were performed in 44 (44%), 24 (24%), and 32 (32%) patients, respectively, and all procedures were successful. The rates of definitive and suggestive diagnoses in EB were 76.5% and 23.5%, respectively. Adverse events were observed in 6 patients. In the combined group, acute obstruction of the ETV stoma was observed in 1 patient and transient double vision was observed in 1 patient. Transient aqueductal stenosis/obstruction was observed in 2 patients in the EB-alone group. In the ETV-alone group, hemorrhage was observed in 2 patients; these patients developed intratumoral hemorrhage despite ETV-alone surgery. Subsequently, these 2 patients underwent tumor removal, and the histopathological diagnosis was atypical teratoid/rhabdoid tumor in both., Conclusions: For obstructive hydrocephalus with atypical teratoid/rhabdoid tumor, physicians must be aware of the risk of postoperative intratumoral hemorrhage after performing ETV., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There is no clinical evidence supporting the effectiveness of trastuzumab deruxtecan (T-DXd) for treating advanced gastric cancer (AGC) with brain metastasis., Case Report: This is a case of a 65-year-old man with human epidermal growth factor-2 (HER2)-positive AGC. He was initially treated with capecitabine, cisplatin, and trastuzumab, followed by paclitaxel and ramucirumab, nivolumab, trifluridine and tipiracil, and irinotecan regimens in addition to radiation therapy for brain metastasis. The patient exhibited refractoriness to the standard regimen used for AGC and developed relapse of the brain metastasis after radiation accompanied by headache, nausea, and dizziness. In August 2020, following the approval of T-DXd for HER2-positive AGC, he received T-DXd therapy. After 5 cycles of T-DXd, contrast-enhanced computed tomography and magnetic resonance imaging demonstrated significant tumor shrinkage and improvement of symptoms., Conclusion: T-DXd demonstrated effectiveness for the treatment of brain metastasis arising from HER2-positive AGC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Differentiating between germinoma and non-germinomatous germ cell tumor (NGGCT) is important because sensitivity to chemotherapy and/or radiotherapy is quite different between these two subgroups. In this study, we evaluated whether the arterial spin labeling (ASL) based perfusion-weighted imaging (PWI) could provide additional information for the differential diagnosis between germinoma and NGGCT., Method: Between 2011 and 2018, 20 patients with central nervous system (CNS) germ cell tumor (GCT) who underwent preoperative MR imaging including ASL-PWI were enrolled in this study. Relative tumor blood flow (rTBF) was evaluated on ASL-PWI by manually placing regions of interest at gadolinium enhanced part of the tumors and normal subcortical white matter. Presence of intratumoral T1 hyperintense foci and apparent diffusion coefficient (ADC) were also evaluated. The final diagnosis was made by the combination of tumor markers and the histological diagnosis., Results: Among 20 patients of CNS-GCT, 11 were diagnosed as germinoma and 9 were diagnosed as NGGCT. In the germinoma subgroup, the rTBF ranged from 0.90 to 1.71 (mean 1.21, median 1.09), while it ranged from 1.14 to 5.75 (mean 3.91, median 3.31) in NGGCT subgroup. The receiver operating characteristic (ROC) curve showed that calculating rTBF is useful for differentiating between germinoma and NGGCT (area under the curve (AUC) 0.929, P = 0.0012) compared to intratumoral T1 hyperintense foci (AUC 0.788, P = 0.0304) and ADC (AUC 0.919, P = 0.0016)., Conclusions: High rTBF obtained by ASL-PWI implied the presence of NGGCT component. This information might help in deciding the chemotherapy/radiotherapy intensity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The current status and future prospects of glioblastoma treatment were explained through the understanding of the pivotal and important papers from the brain tumor guideline.

Purpose: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonβ (IFNβ) plus temozolomide (TMZ) with that of TMZ alone., Experimental: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations., Results: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNβ + Radiotherapy (RT) group were found., Conclusion: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNβ addition were identified.

Purpose: T2-FLAIR mismatch sign was reported as specific imaging marker in non-enhancing diffuse astrocytoma, IDH-mutant & 1p/19q non-codeleted. However, most of the previous studies for T2-FLAIR mismatch sign were confirmed only among lower grade glioma. The aim of this study is to assess the T2-FLAIR mismatch sign in dysembryoplastic neuroepithelial tumor (DNET) and unveil the exception rules of the sign., Method: Eleven patients with histopathologically confirmed DNET were included in this study. The MR images were evaluated by 2 independent reviewers to assess (i) the presence or absence of T2-FLAIR mismatch sign and (ii) the presence or absence of gadolinium enhancement. CT was also performed to evaluate calcification and localized thinning of the skull bone. Inter-reviewer agreement with Cohen's kappa (κ) was calculated., Results: The T2-FLAIR mismatch sign was present in 8 cases (72.7 %) and absent in 3 cases (27.3 %). None of them showed contrast enhancement on initial MR images. The inter-reviewer agreement for T2-FLAIR mismatch and CT characteristics was excellent (κ = 1.00). All of the DNET without T2-FLAIR mismatch presented with calcification on CT. All of the DNET adjacent to skull vault (5 cases) presented with localized bone thinning overlying the tumor., Conclusions: The T2-FLAIR mismatch sign was observed in more than half of the DNET and the sign is not specific for diffuse astrocytoma, IDH-mutant & 1p19q non-codeleted. The localized skull bone thinning overlying the tumor might help for diagnosis of DNET in some cases., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown., Methods: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases., Results: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%)., Conclusions: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies., (© 2019 British Neuropathological Society.)

Background: The term "growing teratoma syndrome (GTS)" has been used as follows: patients with germ cell tumor (GCT) who present with enlarging original/metastatic masses during or after appropriate systemic chemotherapy despite normalized serum markers. In other words, the definition of the term GTS is not fully established. We analyzed and reviewed our case series regarding GTS that developed after the treatment of central nervous system (CNS) nongerminoatous germ cell tumors (NGGCTs)., Methods: Our institutional review board approved this retrospective study. Between 2003 and 2018, we treated 16 patients (16 males; age ranging from 5.4 to 51.9 years, median 13.8) with CNS-NGGCT at our institution. We reviewed those patients and also reviewed the literature about GTS of CNS. We defined primary GTS (p-GTS) as the enlargement of cyst size and/or solid tumor occurred during treatment in the absence of marker elevation, and recurrent GTS (r-GTS) as the enlargement of teratoma after complete response of initial tumors., Results: Among 16 patients with CNS-NGGCT, we surgically confirmed mature/immature teratoma components in 15 patients. Two patients underwent surgical removal of tumor before neoadjuvant therapy, and among the rest 14 patients, 6 developed p-GTS, and 2 patients underwent salvage surgery during chemo-/chemoradiotherapy. Those with histologic diagnosis of immature teratoma during salvage surgery had a shorter interval from the initiation of chemoradiotherapy compared with mature teratoma (P < 0.05). One patient developed r-GTS. In the literature review, most of the p-GTS consisted of enlargement with the multicystic component. Histologic diagnosis of immature teratoma during salvage surgery was observed in earlier stages of chemoradiotherapy (P < 0.05, log-rank test). Previous history of p-GTS might be a risk factor of r-GTS., Conclusions: The incidence of p-GTS, enlargement of the cystic component during treatment, is not rare. Physicians need to be aware of this important phenomenon., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: H3.3 G34R/V mutation is predominantly identified in the supratentorial nonmidline tumors. However, this tumor is not yet categorized as an entity in 2016 WHO CNS classification. More information is necessary to further determine the characteristics of this tumor., Case Presentation: Three cases of adolescent hemispheric glioma were treated in our institution. All tumors showed the characteristics of huge tumor size with mild peritumoral edema on T2WI/FLAIR, hyperintense on DWI, and slight partial enhancement by gadolinium. The single-voxel proton MR spectroscopy revealed characteristics of high choline peak, marked decrease in N-acetyl aspartate peak, and small lactate peak. The histopathological diagnosis, based on 2007 WHO CNS classification, was high-grade glioma in 2 cases and a PNET. Immuno-staining revealed that the tumor cells were positive against H3.3 G34R, H3K27me3, and p53 antibodies and negative against H3K27M, IDH1-R132H, ATRX, and Olig2 antibodies. Pyrosequencing analysis confirmed H3.3 G34R mutation, IDH-wildtype, and BRAF-wildtype., Conclusion: Radiological and immunostaining findings are characteristic in our 3 cases of H3.3 G34-mutant glioma. It is essential to consider H3.3 G34-mutant glioma as a differential diagnosis particularly in pediatric and adolescents and young adult hemispheric tumors., (© 2020 S. Karger AG, Basel.)

Background: Bevacizumab improves symptoms via reducing the peritumoral edema and/or normalizing blood brain barrier, and occasionally via reducing the tumor size. However, the effect against active cystic components has not been documented yet., Materials and Methods: Between 2008 and 2018, 139 patients with primary or metastatic brain tumors were treated with bevacizumab (BEV) in our institution. The images and symptoms before and after administration of BEV were examined, and changes in size of cysts were evaluated as follows: CR (complete disappearance), PR (reduction by ≥50%), MR (reduction by ≥25%), SD (size change <25%), PD (increase by ≥25%). The effect of BEV on tumor itself was determined according to Response Assessment in Neuro-Oncology criteria., Results: Of the 139 patients, 21 (15.1%) had cystic components. The best responses of cysts to BEV treatment were as follows: CR 6, PR 7, MR 4, SD 4. The group of patients with progressively increasing cysts prior to BEV treatment had significant cyst size reduction compared to stable cyst size groups, at initial imaging after BEV (mean 62.6% vs 22.5%, P = .0055) and at best response timing (mean 76.3% vs 32.8%, P = .0050). Patients with cysts showed significant improvement in symptoms after the treatment with BEV compared to patients without cysts (P = .0033). However, response rate was not different between patients with or without cysts. Overall survival after starting BEV was not different between glioblastoma patients with or without cysts., Conclusion: Bevacizumab is effective against progressively increasing cysts. Although cysts reduction effect and tumor response and/or overall survival are independent, BEV may be effective in patients who are symptomatic due to cyst enlargement., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Several intracranial pathologies present as a ring-enhancing lesion on conventional magnetic resonance imaging (MRI), creating diagnostic difficulty. We studied the characteristics of the anatomical border of gadolinium enhancement on T1-weighted imaging (WI) and hypointensity on T2WI to employ a simple technique of histogram-profile analysis of MRI for differentiation of various ring-enhancing intracranial lesions., Methods: After approval from the institutional review board, preoperative MRI (T2WI, postcontrast T1WI) scans were analyzed retrospectively in 18 patients with histologically confirmed brain abscess, 66 glioblastomas, 46 brain-metastases, and 16 tumefactive multiple sclerosis (MS). T2WI and postcontrast T1WI were overlapped, and histogram-profile analysis was performed with in-house image-fusion software. The pattern of differential-peaks in histogram-profile was assessed visually. Kaplan-Meier survival analysis incorporating histogram-profile patterns was performed in patients with glioblastoma., Results: The histogram-profile study revealed 4 distinct patterns. Pattern 1 showed no differential T2-hypointensity trough, pattern 2 had T2-hypointensity trough inside, whereas pattern 3 had T2-hypointensity trough overlapping the enhanced margin. Pattern 4 had T2-hypointensity trough immediately external to the enhanced margin. Pattern 1 was specific for tumefactive MS (93.3%), whereas pattern 4 was specific for glioblastoma (40.7%). Pattern 4 glioblastoma was subdivided into rim (T2-hypointensity ≥50% of circumference of contrast-enhanced tumor) and arc (T2-hypointensity <50% of circumference of contrast-enhanced tumor). Pattern 4 glioblastoma was further subdivided into group A (edema: T2-hyperintensity ≥50% of circumference of contrast-enhanced tumor) and group B (less edema: T2-hyperintensity <50% of circumference of contrast-enhanced tumor). Patients with pattern 3 glioblastoma (37.6%) had better survival compared with others (P = 0.0341) and pattern 4B had decreased survival compared with pattern 4A (P = 0.0001) and others (P = 0.0003)., Conclusions: Tumefactive MS and a subset of glioblastomas show specific patterns in histogram-profile analysis. The difference in anatomical border also determines difference in survival in glioblastoma. Histogram-profile analysis is a simple and efficient technique to differentiate these pathologies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The interaction of K27M mutation in histone H3 (H3K27M mutation) with polycomb repressive complex 2 (PRC2) is facilitated by the enhancer of zeste homolog 2 (EZH2). Subsequently, this interaction leads to the global reduction level of H3K27me3. We analyzed the EZH2 expression level in H3K27M mutation-positive tumors and revealed the association of high EZH2 expression with poor survival., Methods: Our study included 12 patients, with an age range of 6-56 years and treated between 2007 and 2016. All patients underwent MRI study for nonenhanced T1, T2, diffusion, gadolinium-enhanced T1-weighted imaging, and fluid-attenuated inversion recovery (FLAIR). Immunohistochemical staining was performed against H3K27M, H3K27me3, EZH2, EED, mutant isocitrate dehydrogenase 1 (IDH1), α-thalassemia X-linked intellectual disability (ATRX), p53, O6-methylguanine-DNA methyltransferase (MGMT), and Ki-67 antibodies., Results: All patients were negative for IDH1R132H and H3K27me3, but H3K27M-positive. Staining against EZH2 was negative in all histological features of grade II cases (3/12) and positive in grade III and IV cases; EZH2 positivity is associated with poor prognosis (p = 0.0082). EZH2 positivity was not associated with EED positivity. Retained ATRX staining was found mostly in grade III and IV cases (6/12). P53 was predominantly positive in cases of astrocytoma and glioblastoma (8/12). The labeling index of Ki-67 was 1.2-31.4% for grade II and III histological features and 11.2-24.8% for grade IV., Conclusion: We suggest that the expression of EZH2 is not associated with the PRC2 pathway and increases in patients with H3K27M-mutant diffuse midline glioma and a poor prognosis. Further studies are necessary to understand the mechanism involved., (© 2019 S. Karger AG, Basel.)

Background: Some childhood cancer survivors experience employment difficulties. This study aimed to describe pediatric brain-tumor survivors' employment status., Methods: A cross-sectional, observational study was conducted, with questionnaires distributed to 101 pediatric brain-tumor survivors (aged 15 years or older) and their attending physicians from nine institutions in Japan. We compared category and time-series histories for participants' first-time employment using national census information. Factors related to delayed employment or early employment termination were examined using survival-time analyses., Results: Excluding students and homemakers, 38 brain-tumor survivors (median age 27 years, with 15 years since diagnosis) were of working age. Of these, 12 (32%) were unemployed and 9 (24%) had never been employed. First-time employment occurred later for brain-tumor survivors than the general population, particularly in those with lower educational levels. The number of brain-tumor survivors whose first job was terminated within the first year was higher than that for the general population, particularly in male survivors and germ cell-tumor survivors. Brain-tumor survivors described their working patterns (irregular), job types (specialist or professional), reasons for early termination (unsuitable job), and thoughts about working (they wished to serve their communities but lacked confidence)., Conclusion: Brain-tumor survivors are associated with high unemployment rates and multiple unemployment-related factors. Education and welfare systems should identify individual methods of social participation for this group.

Astroblastoma is a rare, enigmatic tumor of the central nervous system (CNS) which shares some clinicopathologic aspects with other CNS tumors, especially ependymoma. To further clarify the nature of astroblastoma, we performed clinicopathologic and molecular genetic studies on eight cases of astroblastoma. The median age of the patients was 14.5 years, ranging from 5 to 60 years, and seven of the patients were female. All tumors arose in the cerebral hemisphere and radiologically appeared to be well-bordered, nodular tumors often associated with cystic areas and contrast-enhancement. Six of the seven patients with prognosis data survived without recurrences during the follow-up periods ranging from six to 76 months. One patient had multiple recurrences and died six years later. All tumors exhibited salient microscopic features, such as being well demarcated from the surrounding brain tissue, perivascular arrangement of epithelioid tumor cells (represented by "astroblastic" pseudorosettes, trabecular alignment, and pseudopapillary patterns), and hyalinized blood vessels. Immunoreactivity for GFAP, S-100 protein, Olig2, and EMA was variably demonstrated in all tumors, and IDH1 R132H and L1CAM were negative. Array comparative genomic hybridization revealed numerous heterozygous deletions on chromosome X in the four tumors studied, and break-apart fluorescence in situ hybridization demonstrated rearrangement of MN1 in five tumors with successful testing. The characteristic clinicopathologic and genetic findings support the idea that astroblastoma is distinct from other CNS tumors, in particular, ependymoma. In addition, MN1 rearrangement and aberrations of chromosome X may partly be involved in the pathogenesis of astroblastoma., (© 2017 International Society of Neuropathology.)

Purpose: This study explored the superiority of temozolomide (TMZ) + interferonβ (IFNβ) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design., Experimental Design: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m 2 , daily) followed by TMZ maintenance (100-200 mg/m 2 /day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNβ + RT arm intravenously received IFNβ (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8)., Results: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNβ + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNβ + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%., Conclusions: TMZ + IFNβ + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

Purpose: It is often difficult to distinguish between embryonal and ependymal tumors using conventional MR imaging. The apparent diffusion coefficient (ADC) calculated from diffusion-weighted images (DWI) has been widely used for diagnosis, but its usefulness for differential diagnosis between embryonal and ependymal tumors has not been determined yet. Both DWI properties and ADC values of these two types of tumor at regular and high b-values on a 3 T MR scanner were retrospectively reviewed., Materials and Methods: DWI at 3 T was acquired for 16 patients with embryonal tumors (including medulloblastoma, CNS embryonal tumors (NOS), and atypical teratoid/rhabdoid tumor), and 7 patients with ependymal tumors (including ependymoma and anaplastic ependymoma). ADC was measured by manually placing multiple regions of interest (ROIs) on ADC maps corresponding to enhancing lesions on contrast-enhanced T1-weighted images, both on standard (b-1000) and high (b-4000) b-value DWI. The minimum ADC (ADC-MIN) was calculated from several ROIs placed on each tumor. The relationship between tumor cell density and ADC-MIN was also investigated., Results: Both at b-1000 and b-4000, ADC-MIN was significantly lower in embryonal tumors than in ependymal tumors. Embryonal tumors could be completely discriminated from ependymal tumors using both b-values, but ADC-MIN at b-4000 (t-value = -8.312, p < 0.001) was better than ADC-MIN at b-1000. There was a stronger negative correlation between cell density and ADC-MIN at b-4000 (r 2  = 0.50, p < 0.001) than with ADC-MIN at b-1000 (r 2  = 0.41, p < 0.001)., Conclusion: Evaluating ADC-MIN at b-4000 would be a useful tool for distinguishing embryonal from ependymal tumors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Standard treatment for patients with primary glioblastoma (GBM) includes surgery, radiotherapy, and concomitant and adjuvant temozolomide (TMZ). Recent reports have demonstrated that TMZ-induced myelosuppression correlates with survival in patients with GBM. However, those results were evaluated before the 2016 revision of the World Health Organization classification. This study examined whether myelosuppression during concomitant TMZ phase correlates with prognosis in GBM, IDH-wildtype patients. We examined circulating blood cell counts in 50 patients with GBM, IDH-wildtype who received the standard treatment protocol between August 2005 and November 2015. We assessed relationships between rates of decrease in blood cells (white blood cells (WBC), neutrophils, lymphocytes, red blood cells, and platelets) during the concomitant TMZ phase and overall survival (OS) using univariate and multivariate analyses including other clinicopathological factors (age, sex, Karnofsky Performance Status (KPS), extent of resection, O 6 -methylguanine-DNA methyltransferase (MGMT) status). Log-rank testing revealed that age, KPS, extent of resection, MGMT status, and decrease rates of WBC, neutrophils, and platelets correlated significantly with OS. On multivariate analysis, age, MGMT status, and decrease rate of neutrophils correlated significantly with OS. Patients with a ≥ 40% decrease in neutrophils showed significantly longer OS than those with < 40% (hazard ratio = 2.815; 95% confidence interval = 1.177-7.038; P = 0.0196). A decrease of ≥ 40% in neutrophils represents a predictor of good prognosis for GBM, IDH-wildtype. Blood cell counts during the concomitant TMZ phase can help predict OS in patients with GBM, IDH-wildtype receiving the standard treatment protocol.

OBJECTIVE Glioblastoma differentials include intracranial tumors, like malignant lymphomas and metastatic brain tumors with indiscernible radiological characteristics. The purpose of this study was to identify a distinct radiological feature for the preoperative differentiation of glioblastoma from its differentials, which include malignant lymphomas and metastatic brain tumors. METHODS Preoperative MR images, including diffusion-weighted imaging (DWI) studies (b = 1000 and 4000 sec/mm 2 ), obtained in patients with newly diagnosed malignant tumor, were analyzed retrospectively after receiving approval from the institutional review board. Sixty-four patients with histologically confirmed glioblastoma, 32 patients with malignant lymphoma, and 46 patients with brain metastases were included. The presence of a nonenhancing peritumoral DWI high lesion (NePDHL, i.e., hyperintense lesion in a nonenhancing peritumoral area on DWI) was confirmed in both DWI sequences. Gray matter lesions were excluded. Lesions were termed "definite" if present within 3 cm of the hyperintense tumor border with a signal intensity ratio ≥ 30% when compared with the contralateral normal white matter in both sequences. Discriminant analysis between the histological diagnosis and the presence of Definite-NePDHL was performed, as well as Kaplan-Meier survival analysis incorporating the existence of Definite-NePDHL. RESULTS In 25% of glioblastoma patients, Definite-NePDHL was present, while it was conspicuously absent in patients with malignant lymphoma and metastatic brain tumors. The specificity and positive predictive value were 100%. In the glioblastoma subset, a higher preoperative Karnofsky Performance Scale score (p = 0.0028), high recursive partitioning analysis class (p = 0.0006), and total surgical removal (p = 0.0012) were associated with better median overall survival. Patients with Definite-NePDHL had significantly early local (p = 0.0467) and distant/dissemination recurrence (p < 0.0001) and poor prognosis (p = 0.0007). CONCLUSIONS The presence of Definite-NePDHL is very specific for glioblastoma and indicates poor prognosis. Definite-NePDHL is a significant indicator of early local and distant/dissemination recurrence in patients with glioblastoma. Studying peritumoral DWI and high-b-value DWI is useful for tumor differentiation.

OBJECTIVE Currently, the standard treatment protocol for patients with newly diagnosed glioblastoma (GBM) includes surgery, radiotherapy, and concomitant and adjuvant temozolomide (TMZ). Various prognostic biomarkers for GBM have been described, including survivin expression. The aim of this study was to determine whether the subcellular localization of survivin correlates with GBM prognosis in patients who received the standard treatment protocol. METHODS The authors retrospectively examined the subcellular localization of survivin (nuclear, cytoplasmic, or both) using immunohistochemistry in 50 patients with GBM who had received the standard treatment. The relationship between survivin localization and overall survival (OS) was assessed with uni- and multivariate analyses including other clinicopathological factors (age, sex, Karnofsky Performance Scale [KPS] score, extent of resection, the use of second-line bevacizumab, O 6 -methylguanine-DNA methyltransferase [MGMT] status, and MIB-1 labeling index). RESULTS Log-rank tests revealed that patient age, KPS score, extent of resection, MGMT status, and survivin localization (p < 0.0001) significantly correlated with OS. Multivariate analysis indicated that patient age, MGMT status, and survivin localization significantly correlated with OS. Patients with nuclear localization of survivin had a significantly shorter OS than those in whom survivin expression was exclusively cytoplasmic (median OS 19.5 vs 31.7 months, respectively, HR 5.690, 95% CI 2.068-17.612, p = 0.0006). There was no significant difference in OS between patents whose survivin expression was exclusively nuclear or nuclear/cytoplasmic. CONCLUSIONS Nuclear expression of survivin is a factor for a poor prognosis in GBM patients. Subcellular localization of survivin can help to predict OS in GBM patients treated with the standard protocol.

Background: Earlier studies proposed phosphatase and tensin homolog (PTEN) acts as a 3'-specific phosphatidylinositol phosphatase and inhibits the PI3K pathway. Recent reports show that PTEN mRNA expression is significantly downregulated in brain metastases compared to primary breast cancer. We focused on the differential expression of nuclear and cytoplasmic PTEN between primary tumors and brain metastases., Materials and Methods: We retrospectively studied 30 patients with histologically confirmed primary tumors and brain metastases. PTEN and PDK1 expression levels were examined by immunohistochemical staining and categorized as negative, positive, or strong positive expression. The difference in PTEN expression levels were compared, and the values with P<0.05 were considered statistically significant., Results: Expression of cytoplasmic PTEN was 100% at primary site, and 70% at brain metastases. Expression of nuclear PTEN was 87% at primary site, and 20% at brain metastases. Study results demonstrated that PTEN expression levels in brain metastases are lower compared with that of primary tumors. Especially, nuclear PTEN expression was significantly downregulated in various brain metastases. Higher PDK1 expression at brain metastases also confirmed the down regulation of PTEN function., Conclusions: Our findings indicate that decreased PTEN function by loss of nuclear PTEN expression may be associated with brain metastases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Glioblastoma (GBM) relapses locally or in a disseminated pattern and is highly resistant to chemoradiotherapy. Although dissemination is associated with poor prognosis for patients with GBM, the clinicopathologic factors that promote dissemination have not been elucidated. Glypican-1 (GPC-1) is a heparin sulfate proteoglycan that is attached to the extracytoplasmic surface of the cell membrane and regulates cell motility. The aim of this study was to determine whether GPC-1 expression correlated with GBM dissemination and patient prognosis., Methods: GPC-1 expression was examined by immunohistochemistry in 53 patients with GBM who received radiotherapy and temozolomide treatment. We assessed the relationship between dissemination and clinicopathologic factors, including GPC-1 expression. We also evaluated the relationship between GPC-1 expression and overall survival (OS) by uni- and multivariate analyses of a range of clinicopathologic factors, including age, Karnofsky Performance Status, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) status., Results: Logistic regression analysis revealed that GPC-1 expression correlated with dissemination (P = 0.0116). Log-rank tests revealed that age, Karnofsky Performance Status, extent of resection, MGMT status, dissemination (P = 0.0008) and GPC-1 expression (P = 0.0011) were significantly correlated with OS. Multivariate analysis indicated that age, MGMT status, and GPC-1 expression were significantly correlated with OS. GPC-1 expression had the highest hazard ratio (2.392) among all regressors., Conclusions: GPC-1 expression significantly correlated with OS in patients with GBM who received radiotherapy and temozolomide treatment. GPC-1 expression can help predict the occurrence of dissemination and shorter OS in patients with GBM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study is to investigate the incidence of cystic malacia in long-term survivors of pediatric brain tumors treated with high-dose cranial irradiation., Materials and Methods: Between 1997 and 2015, we treated 41 pediatric patients (26 males, 15 females; age ranging from 3.3 to 15.7 years, median 9-year-old) of pediatric brain tumors [17 medulloblastomas, 7 primitive neuroectodermal tumors (PNET), 3 pineoblastomas, 6 non-germinomatous germ cell tumors (NGGCT), 8 gliomas (including 4 ependymomas, 1 anaplastic astrocytoma, 1 oligodendroglioma, 1 pilocytic astrocytoma, 1 astroblastoma)] with high-dose craniospinal irradiation. Follow-up ranged from 14.0 to 189.2 months (median 86.0 months, mean 81.5 months), the irradiation dose to the whole neural axis ranged from 18 to 41.4 Gy, and the total local dose from 43.2 to 60.4 Gy. All patients underwent follow-up magnetic resonance imaging (MRI) studies at least once a year. Diagnosis of cystic malacia was based solely on MRI findings. Of the 41 patients, 31 were censored during their follow-up due to recurrence of the primary disease (n = 5), detection of secondary leukemia after development of cystic malacia (n = 1), or the absence of cystic malacia on the last follow-up MRI study (n = 25). We also evaluated the development of post-irradiation cavernous angioma and white matter changes., Results: Following irradiation treatment, 11 patients developed 19 cystic malacia during a median course of 30.8 months (range 14.9 to 59.3 months). The site of predilection for cystic malacia was white matter around trigone of lateral ventricles with an incidence of 47.4% (9 of 19 lesions, 7 in 11 patients). Patients with supratentorial tumors developed cystic malacia statistically earlier than the patients with infratentorial tumors (P = 0.0178, log-rank test). Among the same patient group, incidence of post-irradiation cavernous angioma increased progressively, while the incidence of post-irradiation cystic malacia did not increase after 5 years. White matter degeneration developed earlier than cystic malacia or cavernous angioma, and these three clinical entities developed mutually exclusive of each other., Conclusion: We attribute the higher incidence of post-irradiation cystic malacia, in our long-term follow-up study, to the cranial irradiation for pediatric brain tumors, particularly supratentorial brain tumors, and recommend a regular, long-term follow-up of brain tumor patients treated with cranial irradiation.

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.

Objective: The current standard treatment protocol for patients with newly diagnosed glioblastoma (GBM) includes surgery, radiotherapy, and concomitant and adjuvant temozolomide (TMZ). We hypothesized that the permeability surface area product (PS) from a perfusion computed tomography (PCT) study is associated with sensitivity to TMZ. The aim of this study was to determine whether PS values were correlated with prognosis of GBM patients who received the standard treatment protocol., Methods: This study included 36 patients with GBM that were newly diagnosed between October 2005 and September 2014 and who underwent preoperative PCT study and the standard treatment protocol. We measured the maximum value of relative cerebral blood volume (rCBVmax) and the maximum PS value (PSmax). We statistically examined the relationship between PSmax and prognosis using survival analysis, including other clinicopathologic factors (age, Karnofsky performance status [KPS], extent of resection, O6-methylguanine-DNA methyltransferase [MGMT] status, second-line use of bevacizumab, and rCBVmax)., Results: Log-rank tests revealed that age, KPS, MGMT status, and PSmax were significantly correlated with overall survival. Multivariate analysis using the Cox regression model showed that PSmax was the most significant prognostic factor. Receiver operating characteristic curve analysis showed that PSmax had the highest accuracy in differentiating longtime survivors (LTSs) (surviving more than 2 years) from non-LTSs. At a cutoff point of 8.26 mL/100 g/min, sensitivity and specificity were 90% and 70%, respectively., Conclusions: PSmax from PCT study can help predict survival time in patients with GBM receiving the standard treatment protocol. Survival may be related to sensitivity to TMZ., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Multicentric gliomas are very rare. Due to differences in their tumor types they remain enigmatic. We focused on the pathogenesis of multicentric gliomas and compared their immunoprofile with that of solitary gliomas. This retrospective study included 6 males and 8 females with multicentric glioma (8 glioblastomas, 2 anaplastic astrocytomas, 4 diffuse astrocytomas). Their age ranged from 27 to 75 years and all were treated between 2004 and June 2015. The expression of mutant isocitrate dehydrogenase 1 (IDH1), α-thalassemia X-linked intellectual disability (ATRX), p53, phosphatase and tensin homolog (PTEN), and epidermal growth factor receptor (EGFR) was examined immunohistochemically; for 1p19q analysis we used fluorescence in situ hybridization (FISH). In all patients, immunohistochemical staining was negative for mutant IDH1 and cytoplasmic PTEN; only 1 patient (7.1%) manifested nuclear PTEN positivity. FISH for 1p19q codeletion was negative in all 9 examined samples; 5 of 14 specimens (35.7%) were p53-positive, 9 (64.3%) were EGFR-positive, and 4 (28.6%) were ATRX-negative. The MIB-1 labeling index was 0.9-15.6% for grades II and III, and ranged between 17.3 and 52.4% for glioblastoma. Our results suggest that the pathogenesis of multicentric gliomas is different from the mutant IDH1-R132H pathogenesis of lower-grade glioma and secondary glioblastomas. More studies are needed to confirm the molecular mechanisms underlying the pathogenesis of multicentric glioma., (© 2016 S. Karger AG, Basel.)

OBJECTIVE Patients with symptomatic Rathke's cleft cysts (RCCs) managed by surgical treatment often experience recurrence. The authors attempted to clarify the outcome of surgically treated RCCs over a long-term follow-up period. METHODS Ninety-one consecutive RCC patients with a follow-up period of more than 12 months (mean 80.2 months, range 12-297 months) were retrospectively studied. The authors examined the clinical features and postoperative course of patients who experienced a reaccumulation of cyst contents visible on MRI after the initial surgery, and they investigated data from the patients who underwent reoperation for symptomatic recurrent RCCs. RESULTS Reaccumulation of cyst contents occurred in 36 patients (39.6%). In 34 of these patients, a reaccumulation occurred in the first 5 years after surgery. The initial cysts in these patients were most often large, with squamous metaplasia in the cyst walls. Thirteen patients (14.3%) with recurrent symptoms underwent a reoperation, and 10 of the 13 patients had a reaccumulation of RCCs within the 1st year after surgery. The reoperations were performed in the 1st year (61.5%) or several years later (23.1%). Patients were likely to initially have had a visual disturbance and the cyst walls likely included squamous metaplasia. However, no association was observed between the incidence of reaccumulation/reoperation of RCCs and the surgical procedure for RCCs. CONCLUSIONS The reaccumulation rate of RCC is high in the long-term period, and it is associated with the histological findings but not with the surgical procedure. Long-term monitoring, for a period of at least 5 years, should therefore be conducted to identify and assess any RCC reaccumulation.

The apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) plays an important role in diagnosing intracranial tumors and predicting the histopathological grade of the tumor. However, the differences in the ADC values between craniopharyngiomas and germ cell tumors (GCTs) have not been clarified. We therefore evaluated the DWI and ADC values at b = 1000 and b = 4000 s/mm(2) on 3T magnetic resonance (MR) imaging and assessed the possibility of differentiating between craniopharyngiomas and GCTs. We retrospectively reviewed 19 patients with craniopharyngioma and 24 patients with GCT who underwent surgery and received a histopathological diagnosis. Thirty-four patients underwent DWI with b = 1000 and b = 4000 s/mm(2) and nine patients underwent periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) DWI with b = 1000 s/mm(2). The ADC was determined by manually placing regions of interests (ROIs) in the respective tumor regions on the ADC maps and is expressed as the minimum (ADC(MIN)), mean (ADC(MEAN)), and maximum (ADC(MAX)) absolute values. The craniopharyngiomas showed lower intensity on DWI at b = 1000 and b = 4000 s/mm(2) than the GCTs. Furthermore, the craniopharyngiomas demonstrated significantly high ADC values (ADC(MIN), ADC(MEAN), and ADC(MAX)) in comparison with the GCTs on DWI at b = 1000 and b = 4000 s/mm(2). The logistic discriminant analysis clarified the advantage of ADC(MIN) at b = 4000 s/mm(2) in differentiating between craniopharyngiomas and GCTs compared with the other ADC values. DWI and the ADC values may help clinicians to differentiate between craniopharyngiomas and GCTs. The ADC(MIN) at b = 4000 s/mm(2) is particularly useful for differentiation.

Purpose: While cavernous angioma (CVA) after cranial irradiation has been documented, its development after high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has not. We present a patient with desmoplastic/nodular medulloblastoma (DNMB) associated with anhidrotic ectodermal dysplasia (AED) who developed CVA 2 years after high-dose chemotherapy and PBSCT., Methods: A 1-year-old boy with ingravescent vomiting was admitted to our institute. He presented with a large head, a depressed nasal bridge, low-set ears, thick lips with peg-shaped teeth, hypohidrosis, sparse hair, thin atrophic skin, scaly dermatitis with frontal bossing, and a bulging anterior fontanel. Neuroradiological examination revealed multiple cerebellar masses with heterogeneous enhancement and speckled calcifications and severe obstructive hydrocephalus. The histological diagnosis of surgical specimens was DNMB, and he underwent postoperative multiple-drug chemotherapy with autologous PBSCT. The outcome was favorable and he did not undergo radiotherapy., Results: After 2 years, intracranial hemorrhage was detected at his regular radiological check-up and he again underwent surgery. The histological diagnosis was CVA., Conclusions: To our knowledge, this is the first report of AED-associated DNMB and CVA.

Human chorionic gonadotropin (hCG) production has been utilized as a diagnostic marker for germinoma with syncytiotrophoblastic giant cells (STGC) and choriocarcinoma. Elevated hCG in germinoma is considered to predict less favorable prognosis, and an intensive treatment strategy may accordingly be applied. However, there is some evidence that any germinoma may produce hCG to varying extent. We investigated mRNA expression of the hCG β subunit (hCGβ) using real time quantitative polymerase chain reaction in 94 germ cell tumors (GCTs). Most (93.3 %) GCTs showed higher expression levels compared with that of normal brain tissue (1.09 × 10(0)-1.40 × 10(5) fold). The expression was the highest in GCTs which harbor choriocarcinoma or STGC components. The expression level of hCGβ in germinoma was highly variable (1.09 × 10(0)-5.88 × 10(4) fold) in linear but not bimodal distribution. hCG concentrations in serum and CSF correlated with gene expression, especially when GCTs with single histological component were analyzed separately. The expression was not significantly associated with recurrence in pure germinoma. These results suggest that the serum/CSF hCG levels may need to be interpreted with caution as most GCTs appear to have the capacity of producing hCG irrespective of their histology. The clinical significance of ubiquitous hCG expression in GCTs needs further investigation.

Object: The differentiation of malignant lymphomas from gliomas or malignant gliomas by conventional MRI can be difficult. The authors studied Gd-enhanced MR images to obtain a differential diagnosis between malignant lymphomas and gliomas without central necrosis or cystic changes and investigated the diagnostic value of single-voxel proton MR spectroscopy ((1)H-MRS) using different parameters, including lipid levels., Methods: This was a retrospective study of patients with primary malignant CNS lymphoma (n = 17) and glioma (n = 122 [Grades I, II, III, and IV in 10, 30, 33, and 49 patients, respectively]) who were treated between 2007 and 2013. The authors focused on 15 patients with homogeneously enhanced primary malignant CNS lymphomas and 7 homogeneously enhanced gliomas. Images of all the included tumors were acquired with (1)H-MRS at 3 T, and the diagnoses were histologically confirmed., Results: Using a short echo time (1)H-MRS, large lipid peaks were observed in all 17 patients with a malignant lymphoma, in 39 patients (79.6%) with a Grade IV glioma, and in 10 patients (30.3%) with a Grade III glioma. A focus on homogeneously enhanced tumors revealed large lipid peaks in 15 malignant lymphomas that were free of central necrosis on Gd-enhanced T1-weighted images. Conversely, in the 7 homogeneously enhanced gliomas (glioblastoma and anaplastic astrocytoma, n = 2 each; anaplastic oligodendroglioma, diffuse astrocytoma, and pilomyxoid astrocytoma, n = 1 each), lipid peaks were small or absent., Conclusions: Large lipid peaks on (1)H-MRS images of tumors without central necrosis were characteristic of malignant lymphomas. Conversely, small or absent lipid peaks in intraaxial tumors without central necrosis were strongly suggestive of glioma.

Purpose: To evaluate the efficacy of sequential chemoradiotherapy (CRT) for intracranial germinoma by long-term follow-up., Materials and Methods: We retrospectively evaluated 23 consecutive intracranial germinoma patients without spinal dissemination, who had been treated by sequential CRT. All patients except for one were biopsied or surgically resected before treatment and all patients received both cranial and spinal magnetic resonance imaging. Three cycles of induction chemotherapy composed of etoposide and platinum agents were administered. The prescription of radiotherapy was 24 Gy per 12 fractions. No patients received spinal irradiation., Results: All patients accomplished CRT and achieved complete remission. No severe acute and late toxicities were observed. Median follow-up time was 11.8 years. The 5- and 10-year overall survival rates were 100 and 100 %, and relapse-free survival rates were 96 and 89 %, respectively. Three patients developed intracranial recurrence and all of them were successfully salvaged by additional CRT. All patients were alive without disease at final follow-up., Conclusion: Treatment of 24 Gy of sequential CRT for intracranial germinoma might be promising as an alternative to radiotherapy alone. Spinal irradiation may not be necessary for patients who had no spinal dissemination and who were treated with CRT.

Glioblastoma is a highly proliferative and invasive tumor. Despite extensive efforts to develop treatments for glioblastoma, the currently available therapies have only limited effects. To develop novel strategies for glioblastoma treatment, it is crucial to elucidate the molecular mechanisms that promote the invasive properties of glioblastoma. In the present study, we showed that the paired related homeobox 1 (PRRX1) is associated with glioblastoma cell invasion. The depletion of PRRX1 suppressed the invasion and neurosphere formation of glioblastoma cells. Conversely, the exogenous expression of PRRX1 promoted invasion. The Notch signaling pathway, which is an evolutionarily conserved pathway that is essential for developmental processes, plays an important role in the tumorigenesis of glioblastoma. The expression of PRRX1 induced the activation of Notch signaling, and the inhibition of Notch signaling suppressed PRRX1-mediated cell invasion. Our results indicate that activation of Notch signaling by PRRX1 is associated with the promotion of glioblastoma cell invasion.

Background: Survivors of pediatric brain tumors are often affected by late effects, such as motility disturbance of limb(s), seizure, ocular/visual impairment, endocrine abnormality, and higher brain dysfunction, resulting from the disease and its treatment. Appropriate provision of supportive care will require understanding the effects of these experiences on survivors' health-related quality of life (HRQOL)., Objective: The aim of this study was to identify the relationships between late effects and specific aspects of the HRQOL of pediatric brain tumor survivors., Methods: We distributed questionnaires for measuring HRQOL to 138 survivors and their parents at 8 hospitals and 1 clinic in Japan and simultaneously surveyed late effects using information provided by the survivors' attending physicians. We compared the HRQOL of survivors with and survivors without specific late effects., Results: A total of 106 survivors and their parents returned the questionnaires to the researchers. The HRQOL of survivors 18 years or older was negatively affected by all 5 late effects, indicating that their higher impairment was associated with diminished HRQOL. The HRQOL of survivors aged 12 to 17 years was negatively affected by 2 late effects (ocular/visual impairment and motility disturbance of the limbs). A part of the HRQOL subdomain (motor and cognitive functioning) of survivors aged 12 to 17 years was positively related to ocular/visual impairment., Conclusions: Five late effects influenced the HRQOL of pediatric brain tumor survivors., Implications for Practice: Nurses and other health professionals should provide specific care designed to support aspects of HRQOL affected by late effects. For example, survivors with ocular/visual impairment may be expected to require additional emotional support, and those with seizures or endocrine abnormalities may be expected to require additional support for sleep disorders.

Objectives: The objective in the present study was to evaluate the usefulness of cortico-cortical evoked potentials (CCEP) monitoring for the intraoperative assessment of speech function during resection of brain tumors., Methods: Intraoperative monitoring of CCEP was applied in 13 patients (mean age 34 ± 14 years) during the removal of neoplasms located within or close to language-related structures in the dominant cerebral hemisphere. For this purpose strip electrodes were positioned above the frontal language area (FLA) and temporal language area (TLA), which were identified with direct cortical stimulation and/or preliminary mapping with the use of implanted chronic subdural grid electrodes. The CCEP response was defined as the highest observed negative peak in either direction of stimulation. In 12 cases the tumor was resected during awake craniotomy., Results: An intraoperative CCEP response was not obtained in one case because of technical problems. In the other patients it was identified from the FLA during stimulation of the TLA (7 cases) and from the TLA during stimulation of the FLA (5 cases), with a mean peak latency of 83 ± 15 msec. During tumor resection the CCEP response was unchanged in 5 cases, decreased in 4, and disappeared in 3. Postoperatively, all 7 patients with a decreased or absent CCEP response after lesion removal experienced deterioration in speech function. In contrast, in 5 cases with an unchanged intraoperative CCEP response, speaking abilities after surgery were preserved at the preoperative level, except in one patient who experienced not dysphasia, but dysarthria due to pyramidal tract injury. This difference was statistically significant (p < 0.01). The time required to recover speech function was also significantly associated with the type of intraoperative change in CCEP recordings (p < 0.01) and was, on average, 1.8 ± 1.0, 5.5 ± 1.0, and 11.0 ± 3.6 months, respectively, if the response was unchanged, was decreased, or had disappeared., Conclusions: Monitoring CCEP is feasible during the resection of brain tumors affecting language-related cerebral structures. In the intraoperative evaluation of speech function, it can be a helpful adjunct or can be used in its direct assessment with cortical and subcortical mapping during awake craniotomy. It can also be used to predict the prognosis of language disorders after surgery and decide on the optimal resection of a neoplasm.

Purpose: To understand the influence of disease and treatment on the health-related quality of life (HRQOL) of children with brain tumors, compared to the HRQOL of children with other cancers, from the viewpoints of children and parents., Methods: A total of 133 children aged 5-18 years and 165 parents of children aged 2-18 completed questionnaires of the Pediatric Quality of Life Inventory Cancer Module (Pain and Hurt, Nausea, Procedural Anxiety, Treatment Anxiety, Worry, Cognitive Problems, Perceived Physical Appearance, and Communication scales); higher scores indicate a better HRQOL. The Cancer Module scores, weighted by age and treatment status, were compared to those obtained in a previous study of children with other cancers (mostly leukemia)., Results: The weighted mean scores for Pain and Hurt (effect size d = 0.26) and Nausea (d = 0.23) from child reports and the scores for Nausea (d = 0.28) from parent reports were higher for children with brain tumors than scores for children with other cancers. The scores for Procedural Anxiety (d = -0.22) and Treatment Anxiety (d = -0.32) from parent reports were lower for parents of children with brain tumors than the scores for parents of children with other cancers. The child-reported Pain and Hurt score of the Cancer Module was higher (d = 0.29) and in less agreement (intraclass correlation coefficient = 0.43) with scores from the Brain Tumor Module, indicating that assessments completed with the Cancer Module misesteem pain and hurt problems in children with brain tumors., Conclusions: The profiles of cancer-specific HRQOL in children with brain tumors differ from those of children with other cancers; we therefore suggest that these children receive specific psychological support.

Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.

A 61-year-old woman had an intracranial tumour that was located on the falx. Meningioma was suspected and the tumour rapidly grew over 1 year. It showed nearly equal density with spinal fluid showing almost no enhancement on radiographic images, like microcystic meningioma. Successful removal of the tumour was achieved. Histopathologically, the tumour was diagnosed as low-grade meningioma. The meningioma had variable sized microcysts and the appearance of solid area was meningothelial meningioma. This is a rare radiographic image for meningothelial meningioma.

Purpose: Health-related quality of life (HRQOL) is not only a degree of health but also reflects patient perceptions and expectations of health. For children with brain tumors, better understanding of HRQOL requires the use of complementary reports from parents and interviewer-administered reports for children. Here, we aimed to test whether or not the trait anxiety of children and the psychological distress of their parents influence children's and parents' responses to HRQOL questionnaires, and whether or not the report-administration method for children influences children's responses to HRQOL questionnaires., Methods: One hundred and thirty-four children aged 5-18 with brain tumors and one of their parents completed the Pediatric Quality of Life Inventory(™) (PedsQL(™)) Brain Tumor Module questionnaires. In addition, the children also completed the State-Trait Anxiety Inventory for Children (STAIC), and the parents also completed the Kessler-10 (K10) and health and sociodemographic characteristics questionnaires. The child questionnaires were administered either by the child (self-administered) or an interviewer. Rater-dependent perceptions about HRQOL were derived from the subscales scores of the PedsQL(™) Brain Tumor Module using structural equation modeling based on a multitrait-multimethod model. The STAIC trait-anxiety score, K10 score, report-administration method, and other health and sociodemographic factors related to each child's or parent's perceptions were identified through multiple linear regression analyses of the questionnaire responses. We used a path analysis to estimate the change in a PedsQL(™) child-reported score that occurs when interviewer-administration changes the child's perception about HRQOL., Results: Surveys for 89 children were self-administered while those for 45 were interviewer-administered. The perceptions of the children and parents were calculated by fitting data to the model (chi-squared P = 0.087, normed fit index = 0.932, comparative fit index = 0.978, standardized root mean squared residual = 0.053, and root mean square error of approximation = 0.054). The children's perception of HRQOL was affected by their STAIC trait-anxiety score (b = -0.43, 95% CI [-0.60, -0.25]). The parent's perception was affected by their child's treatment status (b = 0.26, 95% CI [0.09, 0.43]), the parent's K10 score (b = -0.21, 95% CI [-0.37, -0.04]), and by education level (b = 0.17, 95% CI [0.00, 0.34]). The change in the child-reported PedsQL(™) score in relation to the method of administration ranged from -1.1 (95% CI: -3.5, 1.3) on the procedural anxiety subscale to -2.5 (95% CI: -7.6, 2.6) on the movement and balance subscale., Conclusion: Child-reporting of HRQOL is little influenced by the method of administration. Children's perception about HRQOL tended to be influenced by their trait anxiety, while parents' perception was influenced by their psychological distress, academic background, and their child's treatment status.

Based on intracranial-video electroencephalography (EEG), histopathological features, and postoperative seizure outcome, we elucidated the epileptogenicity in patients with dysembryoplastic neuroepithelial tumor (DNT). Five patients (P1-P5) pathologically diagnosed with DNT underwent intracranial-video EEG to identify the ictal onset zone and irritative zone. We evaluated the correlations of ictal onset zone and irritative zone with the magnetic resonance imaging-visible lesion (MRI-lesion) and their histopathological features. Intracranial-video EEG located the ictal onset zone adjacent to the MRI-lesion margin in four patients with complex/simple forms of DNT subcategory, and on the MRI-lesion in P3 with a nonspecific DNT form. The irritative zone extended to surrounding regions of the ictal onset zone in all patients. Histopathologically, MRI-lesions were characterized by specific glioneuronal elements, whereas the ictal onset zone and irritative zone were represented with dysplastic cortex accompanying oligodendroglia-like cells in four (P1, P2, P4, and P5) of five patients. Cortical dysplasia was identified with typical histopathologic features in the irritative zone remote from the MRI-lesion in P5. P3, with a nonspecific form, indicated prominent component of dysplastic cortex with oligodendroglia-like cells scattered in the MRI-lesion. Lesionectomy of MRI-lesion with additional cortical resections (including the ictal onset zone and irritative zone) yielded postoperative seizure freedom (Engel Class I) in P3, P4, and P5, while P1 and P2 (with only lesionectomy) experienced postoperative residual seizure (Class II and III in each patient). Our results suggest the intrinsic epileptogenicity of DNT. The topographical correlation indicated that the dysplastic cortex accompanying oligodendroglia-like cells was more epileptogenic than the specific glioneuronal elements itself. Meticulous intracranial-video EEG analysis delineating the MRI nonvisible ictal onset zone and the irritative zone may yield better seizure outcome.

Background: The diagnosis of pseudo-responses after bevacizumab treatment is difficult. Because diffusion-weighted imaging (DWI) is associated with cell density, it may facilitate the differentiation between true- and pseudo-responses. Furthermore, as high b-value DWI is even more sensitive to diffusion, it has been reported to be diagnostically useful in various clinical settings., Materials and Methods: Between September 2008 and May 2011, 10 patients (5 males, 5 females; age range 6-65 years) with recurrent glioma were treated with bevacizumab. All underwent pre- and post-treatment MRI including T2- or FLAIR imaging, post-gadolinium contrast T1-weighted imaging, and DWI with b-1000 and b-4000. Response rates were evaluated by MacDonald- and by response assessment in neuro-oncology working group (RANO) criteria. We also assessed the response rate by calculating the size of high intensity areas using high b-value diffusion-weighted criteria. Prognostic factors were evaluated using Kaplan-Meier survival curves (log-rank test)., Results: It was easier to identify pseudo-responses with RANO- than MacDonald criteria, however the reduction of edema by bevacizumab rendered the early diagnosis of tumor progression difficult by RANO criteria. In some patients with recurrent glioma treated with bevacizumab, high b-value diffusion-weighted criteria did, while MacDonald- and RANO criteria did not identify pseudo-responses at an early point after the start of therapy., Discussion and Conclusion: High b-value DWI reflects cell density more accurately than regular b-value DWI. Our findings suggest that in patients with recurrent glioma, high b-value diffusion-weighted criteria are useful for the differentiation between pseudo- and true responses to treatment with bevacizumab., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: This single-arm, open-label, Phase II study evaluated the efficacy and safety of single-agent bevacizumab, a monoclonal antibody against vascular endothelial growth factor, in Japanese patients with recurrent malignant glioma., Methods: Patients with histologically confirmed, measurable glioblastoma or World Health Organization Grade III glioma, previously treated with temozolomide plus radiotherapy, received 10 mg/kg bevacizumab intravenous infusion every 2 weeks. The primary endpoint was 6-month progression-free survival in the patients with recurrent glioblastoma., Results: Of the 31 patients enrolled, 29 (93.5%) had glioblastoma and 2 (6.5%) had Grade III glioma. Eleven (35.5%) patients were receiving corticosteroids at baseline; 17 (54.8%) and 14 (45.2%) patients had experienced one or two relapses, respectively. The 6-month progression-free survival rate in the 29 patients with recurrent glioblastoma was 33.9% (90% confidence interval, 19.2-48.5) and the median progression-free survival was 3.3 months. The 1-year survival rate was 34.5% with a median overall survival of 10.5 months. There were eight responders (all partial responses) giving an objective response rate of 27.6%. The disease control rate was 79.3%. Eight of the 11 patients taking corticosteroids at baseline reduced their dose or discontinued corticosteroids during the study. Bevacizumab was well-tolerated and Grade ≥3 adverse events of special interest to bevacizumab were as follows: hypertension [3 (9.7%) patients], congestive heart failure [1 (3.2%) patient] and venous thromboembolism [1 (3.2%) patient]. One asymptomatic Grade 1 cerebral hemorrhage was observed, which resolved without treatment., Conclusion: Single-agent bevacizumab provides clinical benefit for Japanese patients with recurrent glioblastoma.

Objective: The differentiation of oligodendroglial tumors from astrocytic tumors is important clinically, because oligodendroglial tumors are more chemosensitive than astrocytic tumors. This study was designed to clarify the usefulness of 3T MR perfusion imaging (PWI) in the histopathological differentiation between astrocytic and oligodendroglial tumors. This is because there is a growing interest in the diagnostic performance of 3T MR imaging, which has the advantages of a higher signal-to-noise ratio (SNR) and greater spatial and temporal resolution., Materials and Methods: This study retrospectively included 24 consecutive patients with supratentorial, WHO grade II and III astrocytic and oligodendroglial tumors (7 astrocytic, 10 oligoastrocytic, and 7 oligodendroglial tumors) that were newly diagnosed and resected between November 2006 and December 2009 at Hiroshima University Hospital. These patients underwent dynamic susceptibility contrast-enhanced (DSC) PWI relative cerebral blood volume (rCBV) measurements before treatment. Astrocytic tumors were designated as the astrocytic group, and oligoastrocytic and oligodendroglial tumors as the oligodendroglial group. The regions of interest with the maximum rCBV values within the tumors were normalized relative to the contra-lateral white matter (rCBVmax)., Results: The average rCBVmax of astrocytic tumors (2.01±0.68) was significantly lower than that of the oligoastrocytic (4.60±1.05) and oligodendroglial tumors (6.17±0.867) (P<0.0001). A cut-off value of 3.0 allowed to differentiate the oligodendroglial group from the astrocytic group at 100% sensitivity and 87.5% specificity., Conclusion: The rCBVmax values obtained from 3T MR PWI may be useful as an adjunct to the postoperative histopathological diagnosis of glioma patients., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objectives: In the absence of guidelines on the use of corticosteroids in children with cancer and brain tumors, neurosurgeons (neurosurgical oncologists) and pediatricians administer these drugs based on their own experience. We surveyed Japanese neurosurgeons and pediatricians with regard to their policies for the use of corticosteroids in pediatric patients., Methods: This survey was performed in November, 2010. Questionnaires designed for neurosurgeons and pediatricians were mailed to institutions registered with the Japanese Society of Pediatric Hematology (pediatricians) and to departments and hospitals providing training under the auspices of the Japan Neurosurgical Society (neurosurgeons)., Results: The questionnaire focused on identifying the adverse effects of corticosteroids delivered for longer than 3 months to pediatric patients. Members of both specialties considered it important to avoid the development of infection, gastrointestinal ulcer, moon face/obesity, and abnormal glucose tolerance. Pediatricians but not neurosurgeons cited osteoporosis, aseptic bone necrosis, hypertension, and glaucoma as adverse effects that concerned them with respect to the prolonged administration of corticosteroids. Physicians working in high-volume centers tended to differentiate between adverse effects elicited in patients under palliative care and those receiving long-term corticosteroid treatment for other reasons; clinicians who encountered fewer patients did not., Conclusions: As their experience of treating children with cancer increased, clinicians began to focus on quality-of-life issues raised by the administration of corticosteroids rather than the avoidance of adverse effects. This survey may help to develop guidelines regarding the use of corticosteroids in pediatric patients, especially those needing palliative care.