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Epithelioid glioblastomas are one of the rarest histological variants of glioblastomas, which are not formally recognized by the World Health Organization (WHO) classification. Epithelioid glioblastomas usually occur as primary lesions, but there have been several reports of secondary epithelioid glioblastomas or epithelioid glioblastomas with pre- or co-existing lesions to date. The serine/threonine-protein kinase B-Raf (BRAF) V600E mutation has been found at a high frequency of 54% in epithelioid glioblastomas. We present a case of a 26-year-old female patient with an epithelioid glioblastoma with the BRAF V600E mutation in her right frontal lobe. In the present case, a low-grade diffuse astrocytoma component had colocalized with the epithelioid glioblastoma. The component presented prominent calcification on neuroimages as well as by histology, and low-grade diffuse astrocytoma was considered to be a precursor lesion of an epithelioid glioblastoma. However, the BRAF V600E mutation was detected only in epithelioid glioblastoma but not in low-grade diffuse astrocytoma. To the best of our knowledge, this is the first report demonstrating a discrepancy in the BRAF V600E mutation states between epithelioid glioblastoma and colocalized low-grade astrocytoma., (© 2015 Japanese Society of Neuropathology.)

Object: To avoid disorientation during endoscopic endonasal transsphenoidal surgery (ETSS), the confirmation of anatomical landmarks is essential. Neuronavigation systems can be pointed at exact sites, but their spatial resolution power is too low for the detection of vessels that cannot be seen on MR images. On Doppler ultrasonography the shape of concealed arteries and veins cannot be visualized. To address these problems, the authors evaluated the clinical usefulness of the indocyanine green (ICG) endoscope., Methods: The authors included 38 patients with pituitary adenomas (n = 26), tuberculum sellae meningiomas (n = 4), craniopharyngiomas (n = 3), chordomas (n = 2), Rathke's cleft cyst (n = 1), dermoid cyst (n = 1), or fibrous dysplasia (n = 1). After opening the sphenoid sinus and placing the ICG endoscope, the authors injected 12.5 mg of ICG into a peripheral vein as a bolus and observed the internal carotid arteries (ICAs), cavernous sinus, intercavernous sinus, and pituitary., Results: The ICA was clearly identified by a strong fluorescence signal through the dura mater and the covering thin bone. The intercavernous and cavernous sinuses were visualized a few seconds later. In patients with tuberculum sellae meningiomas, the abnormal tumor arteries in the dura were seen and the vague outline of the attachment was identified. At the final inspection after tumor removal, perforators to the brain, optic nerves, chiasm, and pituitary stalk were visualized. ICG fluorescence signals from the hypophyseal arteries were strong enough to see and spread to the area of perfusion with the passage of time., Conclusions: The ICA and the patent cavernous sinus were detected with the ICG endoscope in real time and at high resolution. The ICG endoscope is very useful during ETSS. The authors suggest that the real-time observation of the blood supply to the optic nerves and pituitary helps to predict the preservation of their function.

Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor, and which harbors not only rapidly dividing cells but also small populations of slowly dividing and dormant cells with tumorigenesity-, self-renewal-, and multi-lineage differentiation capabilities. GBM stem cells (GSCs), which are resistant to conventional chemo -radiotherapy and may be a cause of local recurrence and dissemination. Additionally, heterogeneity of GSCs in the same tumor had been shown by the innovation of microarray and sequencing technology. However, outcome in patients with GBM remains unsatisfactory. Accumulation of the clinical evidence and basic research findings targeting for GSCs and their specific microenvironments (GSC niches) raise the possibility of new treatments to overcome GBM.

Cylindromatosis (CYLD) is a tumor suppressor that regulates signaling pathways by acting as a deubiquitinating enzyme. CYLDdown-regulation occurred in several malignancies, with tumor-promoting effects. Although we found loss of CYLD expression in hypoxic regions of human glioblastoma multiforme (GBM), the most aggressive brain tumor, biological roles of CYLD in GBM remain unknown. This study aimed to determine the biological significance of CYLD down-regulation to GBM progression and therapy. CYLD mRNA transcription was dramatically down-regulated in hypoxic GBM cells, consistent with our clinical observations of human GBM tissues. Hypoxia enhanced both basal and tumor necrosis factor-α-induced expression of various proinflammatory cytokines, whereas CYLD overexpression strongly counteracted these responses. In addition, chronic anti-angiogenic therapy with bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, with enhanced hypoxia produced responses similar to these CYLD-regulated proinflammatory responses in a xenograft mouse model. Histologically, CYLD clearly prevented massive immune cell infiltration surrounding necrotic regions, and pseudopalisades appeared in bevacizumab-treated control tumors. Furthermore, CYLD overexpression, which had no impact on survival by itself, significantly improved the prosurvival effect of bevacizumab. These data suggest that CYLD down-regulation is crucial for hypoxia-mediated inflammation in GBM, which may affect the long-term efficacy of anti-VEGF therapy.

Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

The complete resection of intracavernous sinus dermoid cysts is very difficult due to tumor tissue adherence to important anatomical structures such as the internal carotid artery (ICA), cavernous sinus, and cranial nerves. As residual dermoid cyst tissue sometimes induces symptoms and repeat surgery may be required after cyst recurrence, minimal invasiveness is an important consideration when selecting the surgical approach to the lesion. We addressed a recurrent intracavernous sinus dermoid cyst by the endoscopic endonasal transsphenoidal approach assisted by neuronavigation and indocyanine green (ICG) endoscopy to confirm the ICA and patency of the cavernous sinus. The ICG endoscope detected the fluorescence signal from the ICA and cavernous sinus; its intensity changed with the passage of time. The ICG endoscope was very useful for real-time imaging, and its high spatial resolution facilitated the detection of the ICA and the patent cavernous sinus. We found it to be of great value for successful endonasal transsphenoidal surgery.

Background: In patients with brain lesions, the appropriate management of epileptic seizures is important because recurrent seizures have a negative effect on the clinical course and quality of life. Acute symptomatic seizures are known to be one of the risk factors to develop epilepsy that cause recurrent unprovoked seizures in the later stage. To obtain background information, we performed a retrospective study in which we investigated the incidence of seizures as one of the presenting symptoms in neurosurgical patients admitted to our department during the past 43 years., Methods: We extracted 4537 consecutive patients from 11,675 records in our inpatient database to calculate the seizure incidence in patients with 19 most common diagnoses. We also studied whether the location of cortical lesions have relation to the seizure incidence., Results: Among 2342 patients with brain tumors, 9 of 18 (50%) ganglioglioma-, 40 of 87 (46%) oligodendroglioma-, 69 of 207 (33%) low-grade astrocytoma-, 172 of 804 (21%) high-grade astrocytoma- or anaplastic oligodendroglioma-, 84 of 598 (14%) meningioma-, 38 of 313 (12%) metastatic brain tumor-, 7 of 67 (10%) malignant meningioma-, 7 of 79 (9%) ependymoma-, and 11 of 169 (7%) malignant lymphoma patients suffered seizures. There were 1626 patients with vascular lesions, 20 of 80 (25%) with cavernous malformation, 61 of 281 (22%) with arteriovenous malformation, 50 of 666 (8%) with subarachnoid hemorrhage, 26 of 457 (6%) with brain infarcts, and 5 of 142 (4%) with hypertensive brain hemorrhage had seizures. Of the 569 patients with traumatic brain injury, 33 of 168 (20%) with traumatic intracranial hemorrhage, 6 of 31 (19%) with brain concussion, 18 of 96 (19%) with brain contusion, 15 of 244 (6%) with chronic subdural hematoma, and 1 of 30 (3%) with minor head injury suffered seizures. We found that these seizure incidences were significantly higher when the cortical lesion was located in the frontal lobe (p<0.01, chi square test) but not in parietal, occipital, nor temporal lobes., Conclusion: We investigated the prevalence rate of seizures at the time of admission in a large number of patients who had been treated in our institution. Our results suggest that seizures are a common feature in patients with slow-growing and frontal intra-parenchymal lesions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

As the histologic features of reactive glial proliferation seen in many non-neoplastic lesions and of diffusely infiltrating gliomas overlap, tumor-specific diagnostic markers are needed. A mutation in isocitrate dehydrogenase 1 (IDH1), the enzyme involved in lipid metabolism and glucose sensing, has been identified in a variety of diffuse gliomas. The expression of fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, has been examined in several types of tumors including high-grade meningiomas, but not or less examined in normal tissues and benign tumors. We analyzed the expression of mutant IDH1 and FAS proteins in 10 non-neoplastic and 52 neoplastic lesions. Paraffin-embedded samples were immunostained with anti-IDH1R132H and -FAS antibodies. Staining of mutant IDH1 was positive in nine neoplastic lesions (3 diffuse astrocytomas, 2 anaplastic astrocytomas, and 1 oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, and glioblastoma); it was negative in all ten non-neoplastic lesions. Moreover, FAS expression was increased in glioblastomas (83.3%), anaplastic oligodendrogliomas and oligoastrocytomas (80%), and anaplastic astrocytomas (78.9%) compared with non-neoplastic lesions (20%). Immunostaining with mutant IDH1R132H-specific and FAS antibodies may be helpful to differentiate reactive from neoplastic cells in diffuse infiltrative or highly proliferative gliomas.

Glioma initiating cells (GICs) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC maintenance/differentiation, we established GIC clones having the potential to differentiate into malignant gliomas, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart. Gene Ontology analysis revealed that the expression of cell adhesion molecules, including integrin subfamilies, such as α2 and αV, and extracellular matrices (ECMs), such as collagen IV (COL4), laminin α2 (LAMA2), and fibronectin 1 (FN), was significantly upregulated during serum-induced GIC differentiation. This differentiation process, accompanied by the upregulation of MAPK as well as glioma specific proteins in GICs, was dramatically accelerated in these ECM (especially FN)-coated dishes. Integrin αV blocking antibody and RGD peptide significantly suppressed early events in GIC differentiation, suggesting that the coupling of ECMs to integrin αV is necessary for GIC differentiation. In addition, the expression of integrin αV and its strong ligand FN was prominently increased in glioblastomas developed from mouse intracranial GIC xenografts. Interestingly, during the initial phase of GIC differentiation, the RGD treatment significantly inhibited GIC proliferation and raised their sensitivity against anti-cancer drug temozolomide (TMZ). We also found that combination treatments of TMZ and RGD inhibit glioma progression and lead the longer survival of mouse intracranial GIC xenograft model. These results indicate that GICs induce/secrete ECMs to develop microenvironments with serum factors, namely differentiation niches that further stimulate GIC differentiation and proliferation via the integrin recognition motif RGD. A combination of RGD treatment with TMZ could have the higher inhibitory potential against the glioma recurrence that may be regulated by the GICs in the differentiation niche. This study provides a new perspective for developing therapeutic strategies against the early onset of GIC-associated glioma.

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA)., Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108., Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events., Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

Glioblastoma multiforme (GBM) harbors are not only rapidly dividing cells but also small populations of slowly dividing and dormant cells with tumorigenesity, self-renewal, and multi-lineage differentiation capabilities. Known as glioblastoma stem cells (GSCs), they are resistant to conventional chemo- and radiotherapy and may be a causative factor in recurrence. The treatment outcome in patients with GBM remains unsatisfactory and their mean survival time has not improved sufficiently. We studied clinical evidence and basic research findings to assess the possibility of new treatment strategies that target GSCs and their specific microenvironments (GBM niches) and raise the possibility of adding new treatments to eradicate GSCs and GBM niches.

Background/aims: Central nervous system germ cell tumors (CNS-GCTs) are relatively rare. While their incidence was thought to be higher in East Asia than the USA, recent evidence suggests the difference between Japan and the USA is not statistically significant. The aim of this study was to determine the rate of pediatric primary CNS-GCTs in Kumamoto prefecture, Japan., Methods: We surveyed 6,615 new cases of primary intracranial tumors diagnosed in Kumamoto prefecture between 1989 and 2011. Among these, 251 (3.8%) occurred in patients younger than 15 years. The age-adjusted incidence rates were calculated by the direct method using 5-year age groupings; the incidence in the total Japanese population in the year 2000 was the standard., Results: During the 23-year period, 70 cases of primary GCT were diagnosed. Of these tumors, 31 (44.3%) arose in patients aged between 0 and 14 years (22 boys, 9 girls). Their tumor location was pineal in 45.2%; the other sites were nonpineal. There were more germinomas (64.5%) than nongerminomas (35.5%) in this group. The age-adjusted annual incidence rate was 0.45 cases (boys: 0.64, girls: 0.28) per 10(5) children. At 2.29, the ratio of CNS-GCTs was higher in these boys than girls. Our data showed higher rates than data from CBTRUS 2012 (0.18/10(5)), SEER 2008 (0.15/10(5)) and Germany (0.10/10(5))., Conclusions: Our survey showed that the incidence of primary CNS-GCTs in children was higher in Kumamoto prefecture than in the USA and other Western countries, suggesting that racial backgrounds play a role.

Background: A substantial number of patients with brain tumors develop recurrent seizures, known as tumor-associated epilepsy. It is important to identify specific subgroups of brain tumor patients with higher incidences of epilepsy because a meta-analysis failed to certify the effectiveness of prophylactic anti-epileptic drugs (AEDs) to abort tumor-associated epilepsy as a whole., Methods: To investigate the relationship between tumor location and incidence of epilepsy, we performed voxel-wise comparison between 3D MRI scans obtained from patients with meningioma-associated epilepsy and those from control patients using spatial normalization techniques on neuroimaging data. Variables such as age, tumor size, the degree of edema, and pathological diagnosis were also compared between the two groups., Results: Our results showed the highest incidence of epilepsy when the tumor was located on the premotor cortex in the frontal lobe (Z-scores >2.0, Liebermeister's quasi-exact test). The stepwise multiple regression analysis on the clinical data revealed that the tumor diameter (p < 0.001) and the patient's age (p = 0.024) were positive and negative predictors, respectively, for the onset of epilepsy., Conclusions: The incidence of epilepsy was higher in meningiomas located on the premotor cortex than on the other cortex. Larger volume also contributed to the onset of epilepsy. We suggest that variations of epilepsy incidence dependent on tumor characteristics can be considered when treating tumor-associated epilepsy.

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.

Background: The increased use of neuro-imaging techniques, as well as various environmental factors, has been changing the incidence and the proportions of types of intracranial tumors. However, no accurate population-based epidemiological study of intracranial tumors in Japan has been reported. We evaluated recent trends in the occurrence of primary intracranial tumors among residents of Kumamoto prefecture, Japan., Methods and Results: We surveyed 5,448 new cases of primary intracranial tumors that were diagnosed in Kumamoto prefecture between 1989 and 2008. The overall age-adjusted incidence rate was 14.09 (11.59 for males, 16.38 for females) per 100,000 population per year. The most common tumors were meningiomas (36.8%), followed by gliomas (19.5%), adenomas (17.8%), schwannomas (9.9%), and malignant lymphomas (3.6%). The number of cases of primary brain tumors, especially meningiomas and malignant gliomas, among the elderly has steadily increased and the incidence of asymptomatic intracranial tumors also increased. The number of asymptomatic meningiomas diagnosed per year was higher than that of symptomatic meningiomas in the years between 1997 and 2008. Furthermore, the incidence rate of brain lymphoma in Kumamoto prefecture is approaching that recorded in Western countries. On the other hand, the incidence rate of germ cell tumors is on the decline, approaching that recorded for children in Western countries., Conclusion: Even though we adjusted the population in Kumamoto prefecture based on the Japanese population, increasing rates of several types of intracranial tumors were observed. These incidence rates are approaching those in Western countries.

The genetic and clinical features of glioblastoma with an oligodendroglial component (GBMO), pathologically defined as anaplastic oligo-astrocytoma with necrosis, remain unclear. We investigated the correlation between genetic alterations and clinical outcomes in 19 GBMO patients we have encountered since 1997. Using single nucleotide polymorphism oligonucleotide genomic (SNP) microarrays, we analyzed gene amplification, loss of heterozygosity (LOH), and homozygous deletions in their whole genome. We also analyzed their overall survival (OS). Pathological studies revealed the presence of calcification in 11 and of a cyst in 9 of the 19 patients. Whole-genome analysis using SNP microarrays revealed LOH of chromosome 10 in 11, EGFR amplification in 8, 9p21 (INK4 locus) deletion in 12, PDGFR amplification in 2, and LOH of 1p19q in 2 patients. Median OS was 14 months (average 22.8 months). The pattern of genetic alterations was similar in GBMO and glioblastoma multiforme (GBM) patients, and the clinical outcomes were similar in GBMO and GBM patients.

Recent findings have demonstrated that malignant tumors, including glioblastoma multiforme, contain cancer-initiating cells (also known as cancer stem cells), which self-renew and are malignant, with features of tissue-specific stem cells. As these cells are resistant to irradiation and anti-cancer drugs, it is important to characterize them and find targeting therapies. In this study, we established two primary human glioma cell lines from anaplastic oligodendroglioma and glioblastoma multiforme. These lines were enriched in glioma-initiating cells, as just 10 cells formed malignant glioma when injected into mouse brain. We used these cell lines to examine the roles of the Notch, Hedgehog and Wnt signaling pathways, which are involved in stem-cell maintenance and tumorigenesis, to determine which of these pathways are crucial to glioma-initiating cells and their regulation. Here we show that the Hedgehog pathway is indispensable for glioma-initiating cell proliferation and tumorigenesis; the Hedgehog signaling inhibitors prevented glioma-initiating cell proliferation, while signaling inhibitors for Notch or Wnt did not. Overexpression of Gli2ΔC, a C-terminal-truncated form of Gli2 that antagonizes Gli transcription factor functions, blocked glioma-initiating cell proliferation in culture and tumorigenesis in vivo. Knockdown of the Gli downstream factor Cdc2 also prevented glioma-initiating cell proliferation. Taken together, these results show that the Hedgehog→ Gli→Cdc2 signaling cascade plays a role in the proliferation and malignancy of glioma-initiating cells., (© 2011 Japanese Cancer Association.)

Objective: It is sometimes difficult to distinguish between primary central nervous system lymphomas (PCNSL) and glioblastoma multiforme (GBM). The aim of this study was to investigate whether the addition of (18)F-2-fluoro-2-deoxy-D: -glucose positron emission tomography ([(18)F]FDG-PET) and apparent diffusion coefficients (ADC) to conventional MRI improves diagnostic accuracy for distinguishing between PCNSL and GBM with similar MRI findings., Methods: We used conventional- and diffusion-weighted MRI and FDG-PET scans of 21 patients with histologically confirmed brain tumors exhibiting similar MRI findings (PCNSL, n = 14, GBM, n = 7) in our observer performance study that consisted of 3 interpretation sessions. ADC and maximum standard uptake values (SUV(max)) of the tumors were calculated. Three radiologists first interpreted conventional MRI (1st session), then they read images to which the ADC value had been added (2nd session), and finally they interpreted images supplemented with SUV(max) (3rd session). Observer performance was evaluated using κ statistic and receiver operating characteristics analyses., Results: The addition of ADC values to conventional MRI failed to improve the differentiation between PCNSL and GBM. The addition of SUV(max) at the third session improved the diagnostic accuracy of all 3 readers and resulted in higher interobserver agreement; mean accuracy was 95% (range 93-100%). In one observer the accuracy of tumor differentiation was significantly improved at the third compared to the second session (p = 0.017)., Conclusions: In a selected group of PCNSL and GBM with similar MRI findings, the addition of quantitative FDG-PET to MRI may improve their differentiation. ADC measurement did not allow further discrimination.

Object: The authors evaluated the effectiveness of a neoadjuvant therapy (NAT) consisting of combined chemo and radiotherapy followed by complete resection of the residual tumor in patients with nongerminomatous malignant germ cell tumors (NGMGCTs)., Methods: The authors treated 14 consecutive patients in whom NGMGCTs were diagnosed based on elevated levels of the tumor markers α-fetoprotein, human chorionic gonadotropin, and the β-subunit of human chorionic gonadotropin (β-HCG). Chemotherapy and radiotherapy were performed, and after the serum tumor markers level was in the normal or near-normal range, the residual tumors were completely resected., Results: Residual tumors were confirmed in 11 of the 14 patients after NAT, and total removal was successful in 10 of the 11 patients. In the other patient the residual tumor could not be completely excised because it was attached to a deep vein. The follow-up duration ranged from 1.2 to 22.2 years. The 5-year event-free and total survival rates were 86% and 93%, respectively. Although 3 patients died, 2 of tumor recurrence and 1 of a radiation-induced secondary tumor (glioblastoma), the other 11 are alive and without evidence of tumor recurrence., Conclusions: The authors consider their NAT protocol for NGMGCT to be highly effective in relation to survival for the patients with NGMGCT, but there are several quality of life issues that need to be resolved.

Glioblastoma (GBM) is the most aggressive and destructive form of brain cancer. Animal models that can unravel the mechanisms underlying its progression are needed to develop rational and effective molecular therapeutic approaches. In this study, we report the development of mouse models for spontaneous gliomas representing distinct progressive stages of disease that are governed by defined genetic alterations. Neural stem/progenitor cell (NPC)-specific constitutive Ras activation in vivo plus p53 deficiency led to development of primarily anaplastic astrocytoma (grade III), whereas combined loss of p53 plus p16(Ink4a)/p19(Arf) led to development of GBM (grade IV) at 100% penetrance within 6 weeks. These glioma models showed enhanced stem cell properties (stemness) accompanied by malignant progression. Notably, we determined that, in our models and in human specimens, downregulation of the homeodomain transcription factor NKX2.2, which is essential for oligodendroglial differentiation, was correlated with increased tumor malignancy. NKX2.2 overexpression by GBM-derived glioma-initiating cells (GIC) induced oligodendroglial differentiation and suppressed self-renewal capacity. By contrast, Nkx2.2 downregulation in mouse NPCs accelerated GBM formation. Importantly, the inhibitory effects of NXK2.2 on GIC self-renewal were conserved in human cells. Thus, our mouse models offer pathobiologically significant advantages to investigate the nature of brain tumors, with improved opportunities to develop novel mechanism-based therapeutic approaches.

Objective: Environmental factors present around the time of birth may induce the development of childhood cancer. Some studies suggested an excess of brain tumors in children born during the winter months. The aim of this study was to look for evidence of the seasonality of birth in children who were younger than 15 years at the time of brain tumor diagnosis in the Kumamoto Prefecture, Japan., Methods: We surveyed 115 patients younger than 15 years who were diagnosed with primary intracranial tumors. All patients were born between 1989 and 2003., Results: We found a statistically significant difference between the season of their birth and the expected distribution of birth dates in the Kumamoto Prefecture (p = 0.028). Among the different diagnostic groups there was a statistically significant winter peak in the birth of patients with germ cell tumor (p = 0.001). No statistically significant seasonal patterns were detected in the birth season of patients with astrocytoma, malignant glioma, and medulloblastoma., Conclusions: Although our data provide modest support for a winter peak in the birth of children with brain tumors, we posit that there may be yet unknown, complex biological mechanisms that account for these putative seasonal patterns.

Object: Brain tumors are the most common solid tumors in children and their prognosis is poor. Epidemiologic data from a population-based cancer registry provide the information necessary to determine the incidence rate of pediatric brain tumors. The aim of this study was to determine the epidemiology of childhood primary intracranial tumors in Kumamoto Prefecture, Japan., Methods: We surveyed 210 patients younger than 15 years who were diagnosed with primary intracranial tumors between 1989 and 2008; 159 (75.7%) of the tumors were confirmed microscopically., Results: The age-adjusted annual incidence rate was 36.1 cases per million children. The boys/girls ratio was 1.31. The age-specific annual incidence rate was 28.5-, 40.9-, and 38.4 cases per million for the 0- to 4-, 5- to 9-, and 10- to 14-year age group, respectively. The incidence was highest in 10- to 14-year-old boys (53.6 per million) and lowest in 10- to 14-year-old girls (22.6 per million). The most common tumor was astrocytoma (35.7%) with an annual incidence rate of 13.2 per million, followed by germ cell tumor (14.3%, 5.0 per million), craniopharyngioma (10.5%, 3.8 per million), medulloblastoma (10.0%, 3.7 per million), and ependymoma (4.8%, 1.5 per million). The distribution of the tumor type varied with the patient age and gender. Although there were no germ cell tumors in 0- to 4-year-old boys, they were the second-most common tumor in 10- to 14-year-old boys. Conversely, while there were no medulloblastomas in 10- to 14-year-old girls, their incidence was high in 0- to 4-year-old girls., Conclusions: In this Kumamoto survey, the incidence rate of primary intracranial tumors in children was similar to that in Western countries. However, the incidence and relative frequency of particular histological types of childhood brain tumors such as germ cell tumors and craniopharyngiomas were different between Japan and Western countries.

Purpose: To clarify the effect of bevacizumab on NK012 therapy in mice bearing U87MG glioblastoma orthotopic xenografts in comparison with the combination therapy of irinotecan hydrochloride (CPT-11) with bevacizumab., Experimental Design: NK012 at 7-ethyl-10-hydroxycamptothecin (SN-38) equivalent dose of 30 mg/kg was administered intravenously three times every 4 days with or without bevacizumab. CPT-11 at 66.7 mg/kg was administered intravenously three times every 4 days or CPT-11 at 40 mg/kg/d over 5 consecutive days with or without bevacizumab. Bevacizumab was administered intraperitoneally six times every 4 days in each experiment. In vivo antitumor effects were evaluated by bioluminescence imaging, histopathologic evaluation, and immunohistochemistry. To evaluate interaction with bevacizumab, free SN-38 concentration in tumor tissues was examined by high-performance liquid chromatography., Results: CPT-11 in combination with bevacizumab showed significantly more potent antitumor activity and longer survival than CPT-11 monotherapy (P < 0.05). However, there was no difference between NK012 monotherapy and NK012 in combination with bevacizumab. Concentration of free SN-38 released from NK012 in tumor tissue decreased in combination with bevacizumab (P = 0.027). NK012 monotherapy or NK012 with bevacizumab showed potent antitumor activity and longer survival than any dosing method of CPT-11 in combination with bevacizumab (P < 0.05). Orthotopic tumors treated with NK012 showed decreased tumor cellularity and lower Ki-67 index (P < 0.001) relative to those treated with CPT-11/bevacizumab., Conclusions: The present study using orthotopic glioblastoma model in mice may warrant further preclinical evaluation of NK012 before conducting the clinical trial of the drug, because the antitumor activity of NK012 monotherapy was superior to the combination therapy of CPT-11 with bevacizumab.

Malignant glioma (MG) is highly proliferative and invasive, with the malignant characteristics associated with aneuploidy and chromosomal instability (CIN). Here, we found that the level of germinal center-associated nuclear protein (GANP), a mammalian homologue of yeast Sac3, was markedly decreased in MGs with a poor prognosis; and thus we explored the effect of its decrease on cell-cycle progression of MG cell lines. Glioblastomas showed a significantly lower level of ganp mRNA than anaplastic astrocytomas, as measured by real-time reverse transcription-PCR, in 101 cases of adult MG. MGs of ganp(Low) expression displayed more malignant characteristics, with loss of heterozygosity on chromosome 10, epidermal growth factor receptor gene amplification, and significantly poorer prognosis than the ganp(High) group. Human diploid fibroblasts depleted of ganp mRNA by the RNA interference (RNAi) method showed a decreased percentage of S-phase cells and a cellular-senescence phenotype. MG cell lines harboring abnormalities of various cell-cycle checkpoint molecules displayed slippage of mitotic checkpoints and an increased proportion of hyperploid cells after ganp RNAi-treatment. These results suggest that GANP protects cells from cellular senescence caused by DNA damage and that a significant decrease in GANP expression leads to malignancy by generating hyperploidy and CIN.

Recent findings have shown that malignant tumors contain cancer-initiating cells (CIC), which self-renew and are tumorigenic. However, CICs have not been characterized properly due to lack of specific markers. We recently established a mouse glioma cell line, NSCL61, by overexpressing an oncogenic HRas(L61) in p53-deficient neural stem cells. Using limiting dilution assays, we show that only 2 of 24 NSCL61 clones retained their tumorigenicity in vivo, although the others also expressed oncogenic HRas(L61) and could proliferate in culture. A comparison of the gene expression profiles of tumorigenic and nontumorigenic clones showed that the tumorigenic clones had lost Sox11 expression. We show that overexpression of sox11 prevented tumorigenesis of NSCL61s by inducing their neuronal differentiation accompanied with decreased levels of plagl1. We also show that overexpression of plagl1 abolished neuronal commitment of nontumorigenic cells and induced them to become tumorigenic. Moreover, we show that human glioma-initiating cells lost sox11 expression, and overexpression of sox11 prevented their tumorigenesis in vivo. Together with the clinical evidence showing that downregulation of sox11 mRNA correlates with a significant decrease in survival, these findings suggest that Sox11 prevents gliomagenesis by blocking the expression of oncogenic plagl1.

The study of cancer stem cells (CSCs) is on the cutting edge of cancer research. Following the discovery of neural stem cells (NSCs), extensive studies on their characteristics led to the discovery of cancer stem cells (CSCs) in brain tumors: these cells are termed brain tumor stem cells (BTSCs). The study of NSCs provided insights into mechanisms underlying the maintenance of NSCs, and more recently, BTSCs. Adult NSCs exist in the subventricular zone (SVZ) of the lateral ventricle and in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Specific genes referred to as "stemness genes," combined with a specific microenvironment called the "stem cell niche" are important in maintaining NSC characteristics. Glioblastoma multiforme (GBM) is one of the most malignant forms of human cancer. Regardless of intensive treatment regimens, the mean survival time for GBM patients is approximately 12 months. Early cancer therapies for GBM primarily targeted the rapidly-dividing cells and not the slowly-dividing cells, which were minor populations of cells containing BTSCs. Identification of BTSCs yielded new insights regarding the chemo- and radio-resistant properties that facilitate their selective survival and ability to initiate tumor recurrence. Recent studies have focused on BTSCs as treatment targets for GBM. These investigations showed that inhibiting the pathway for stemness genes decreased the number of BTSCs in vitro and improved survival times of xenografted mice. Moreover, treatment with drugs that affect the stem cell niche in brain tumor-bearing mice prolonged their survival. We expect that the continued study of BTSCs, combined with the findings of past studies, will contribute to breakthroughs that will lead to novel treatments to cure GBM patients. In this review, we discuss recent progress in basic research on BTSCs as treatment targets.

Purpose: To assess the utility of both minimum apparent diffusion coefficients (ADCs) and ADC difference values for grading astrocytic tumors at magnetic resonance imaging., Materials and Methods: The hospital's institutional review board approved this retrospective study and waived informed consent. Fifty patients (23 male patients, 27 female patients; median age, 53 years) with newly diagnosed astrocytic tumors were evaluated. Two observers blinded to clinical information independently measured the ADCs by manually placing three to five regions of interest (40-60 mm(2)) within the solid tumor either with or without contrast material-enhanced components and calculated the average ADC. Minimum and maximum ADCs were selected, and the difference between them was recorded as the ADC difference value. These ADC values were used as the parameters for tumor grading and were compared by using the Kruskal-Wallis test and receiver operating characteristic (ROC) curve analysis., Results: According to ROC analyses for distinguishing tumor grade, minimum ADCs showed the largest areas under the ROC curve. Minimum ADCs optimally helped distinguish grade 1 from higher-grade tumors at a cutoff value of 1.47 x 10(-3) mm(2)/sec and grade 4 from lower-grade tumors at a cutoff value of 1.01 x 10(-3) mm(2)/sec (P < .001 for both). ADC difference values helped distinguish grade 2 from grade 3 tumors at a cutoff value of 0.31 x 10(-3) mm(2)/sec (P < .001). When tumors were graded by using the combined minimum ADC and ADC difference cutoff values mentioned above (the two-parameter method), the following positive predictive values were obtained: grade 1 tumors, 73% (eight of 11); grade 2 tumors, 100% (five of five); grade 3 tumors, 67% (eight of 12); and grade 4 tumors, 91% (20 of 22)., Conclusion: Using a combination of minimum ADCs and ADC difference values (the two-parameter method) facilitates the accurate grading of astrocytic tumors.

Background: A good performance status at diagnosis is a prognostic factor in patients with malignant glioma whose median survival is 24 months. As early diagnosis may improve their poor prognosis, we looked for currently unknown initial symptoms among patients in good performance status., Methods: We chose 17 consecutive patients with malignant glioma in the left frontal and/or temporal lobe whose Karnofsky Performance Status was more than 80. At preoperative evaluation, we administered the Japanese version of the Western Aphasia Battery., Results: The chief complaint was difficulty in speech (n = 6), headache/nausea (n = 4), seizures (n = 5), and uncinate fits (n = 1); one patient was symptom-free. Of the 17 patients, 14 exhibited no motor deficits. In 15 patients, the aphasia quotient exceeded 80, indicating that the overall language deficits were mild. However, in the reading section, their scores on the "spelled kanji (Japanese ideogram) recognition" test (full score = 10) were selectively low (5.3 +/- 1.6 for right-handed individuals with frontal lesions, 6.1 +/- 1.0 for right-handed patients with temporal lesions, 7.2 +/- 2.0 for left-handed/bimanual individuals with frontal/temporal lesions). Their scores on the "spelling kanji" test were 3.0 +/- 1.6, 4.8 +/- 1.2, and 9.4 +/- 0.6, respectively., Conclusions: Our findings point to the importance of recognizing spelling deficits as an initial symptom of left hemisphere glioma in efforts to identify patients in good performance status whose prognosis may be improved. It would be important to determine if the spelling of alphabetic words is also impaired early in the clinical course of left hemisphere glioma.

Background: The treatment of intracranial NGMGCTs is generally based on chemotherapy and radiotherapy. To avoid the potential of tumor recurrence, we normally have the residual mass lesion removed after adjuvant therapy. However, since 1988 we have treated 15 patients with NGMGCT and pathologically evaluated 12 such patients after adjuvant therapy by a new method we have developed and found viable tumor cells in 4 (33%) of 12 patients. Based on our experience, therefore, we feel we have been able to develop a reliable diagnostic tool for confirming the presence or absence of viable tumor cells in residual mass after adjuvant therapy for patients with NGMGCT., Case Description: We describe here 2 patients with NGMGCTs who underwent MET-PET. Patient 1 was an 11-year-old boy with immature teratoma. On gadolinium (Gd)-enhanced magnetic resonance imaging (MRI), a high-intensity area was found in his right cerebellar hemisphere and a high uptake in MET-PET was confirmed in the same region. We judged it as the recurrence of the tumor. Finally, he died and was autopsied. Patient 2 was a 16-year-old girl with an NGMGCT who received combined chemo- and radiotherapy that led to a reduction in the volume of the tumor. Her serum beta-HCG and HCG levels also returned to the reference range. However, the mass did not disappear and another MRI scan disclosed a residual Gd-enhanced lesion. To assess whether there were residual viable tumor cells, MET-PET was performed, and it demonstrated no hyper-uptake region in the residual mass. We, therefore, did not surgically remove the mass and kept the patient under observation. There has not been any tumor recurrence in this patient for more than 2 years., Conclusion: In these 2 cases, the increased MET uptake was more specific of tumor tissue and more accurate than MR Gd enhancement. MET-PET may be a useful diagnostic tool for predicting viable tumor cells after adjuvant therapy in patients with NGMGCT, thus allowing further surgical intervention.

We report a boy who in 1994, at the age of 11, presented with headache and vomiting. The fi nal diagnosis was papillary tumor of the pineal region (PTPR). Magnetic resonance imaging (MRI) revealed a heterogeneous mass. Hydrocephalus was addressed by immediate ventricle drainage; subsequently, we attempted tumor removal. As the intraoperative diagnosis of the hemorrhagic tumor was primitive neuroectodermal tumor (PNET), we did not proceed to total removal. After the delivery of radiotherapy (50.4 Gy) and one course of Nimustine hydrochloride (ACNU) chemotherapy, the residual tumor was completely resected. The diagnosis at that time (1994) was papillary pineocytoma. He was followed on an outpatient basis for 15 years and remained free of recurrence. This type of tumor was later proposed to represent a new distinct tumor subtype, papillary tumor of the pineal region (PTPR). Our data indicate that our patient's tumor should be included in this category.

The purpose of this study was to determine whether apparent diffusion coefficient (ADC) value and T2 signal intensity (SI) in primary brain lymphomas affect their SI on diffusion-weighted images (DWI). On DWI of 16 brain lesions of 16 patients, 9 (56.2%) were hyperintense (grade-3), 4 (25%) partially hyperintense (grade-2) and 3 (18.8%) isointense (grade-1). The mean ADC value of grade-3 lesions was significantly lower than of grade-1 lesions (p=0.028). The grade-1 lesions had ADC values of more than 0.8 and contrast-to-noise ratios of less than 18 on T2-weighted images. Their ADC value and T2 signal intensity affect their SI on DWI.

Within tumours, many non-neoplastic cells such as fibroblasts, endothelial cells, and macrophages assist tumour growth by producing various growth factors and pro-angiogenic cytokines. Various tumour-derived molecules drive tumour-associated macrophages towards an anti-inflammatory phenotype (M2) and thus promoting tumour growth. Here we investigated microglia/macrophage differentiation in glioma tissues by means of immunostaining of paraffin-embedded glioma samples. The number of microglia/macrophages with positive staining for CD163 and CD204, which are believed to be markers for M2 macrophages, was correlated with the histological grade of the gliomas. The ratio of M2 macrophages in the tumour-associated microglia/macrophages was also associated with the histological grade. Culture supernatant from the glioma cell line can stimulate macrophages to develop into the M2 phenotype in vitro. Macrophage colony-stimulating factor (M-CSF), which strongly induces M2 polarization of macrophages, was significantly correlated with histological malignancy and with the proportion of M2 microglia/macrophages in vivo. In addition, the proportion of M2 microglia/macrophages and M-CSF expression in tumour cells correlated well with proliferation of glioblastoma cells. These results suggest that tumour-derived M-CSF induces a shift of microglia/macrophages towards the M2 phenotype, which influences tumour growth. Evaluation of the proportion of M2 microglia/macrophages and M-CSF expression in tumour tissue would be useful for assessment of microglia/macrophage proliferative activity and the prognosis of patients with gliomas.

Glioblastoma multiforme (GBM) is one of the most malignant forms of human cancer. Despite intensive treatment, the mean survival of GBM patients remains about 1 year. Recent cancer studies revealed that cancer tissues are pathologically heterogeneous and only a small population of cells has the specific ability to reinitiate cancer. This small cell population is called cancer stem cells (CSCs); in brain tumors these are known as brain tumor stem cells (BTSCs). The identification of BTSCs yielded new insights into chemo-and radioresistance, by which BTSCs can survive selectively and initiate recurrence. Research focused on BTSCs as treatment targets may contribute to the discovery of new therapeutic strategies.

An 80-year-old woman presented with primary central nervous system (CNS) lymphoma manifesting as progressive disorientation and loss of activity. She received three cycles of high-dose methotrexate. The tumor shrank after two cycles and her mental status improved, but she suffered tumor recurrence. The second-line treatment consisted of four cycles of rituximab but the tumor enlarged. She was then treated with three cycles of temozolomide. Magnetic resonance imaging revealed no evidence of disease. Her mental status and performance status improved, and she suffered no toxicity. She is able to pursue her daily life without recurrence after 16 cycles of temozolomide. Temozolomide may be effective against relapsed primary CNS lymphoma without causing neurotoxicity in the elderly.

Murin-double-minute 2 (MDM2) is an important negative regulator of the p53 tumor suppressor, and affects the p53 protein level and transcriptional activity. The genotype of the single nucleotide polymorphism in the promoter region of MDM2 (single nucleotide polymorphism [SNP] 309) is associated with the MDM2 protein expression level and the onset age of several types of cancer. The SNP309 genotype was investigated in 254 Japanese patients with glioma and 50 healthy subjects. The genotype frequency of SNP309 was T/T homozygous in 62 patients (24%), T/G heterozygous in 126 (50%), and G/G homozygous in 66 (26%) of the glioma patients, and was similar in the healthy subjects. The G/G ratio was higher in our Japanese subjects than in Western populations. Immunohistochemical study of glioma tissues showed that the G/G genotype was associated with higher expression of MDM2 protein compared to the T/T genotype, suggesting that SNP309 attenuates MDM2 protein expression in vivo. However, no association was found between the SNP309 genotype and the histological grade of glioma, age at disease onset, or p53 gene mutation rate. In our study population, SNP309 affected MDM2 protein level, but had no significant involvement in glioma tumorigenesis.

Introduction: Although radiation therapy plays an important role in the management of children with brain tumors, radiation-induced brain damage sometimes occurs after radiation therapy. In some pediatric patients who had undergone cranial radiation therapy, we noticed cystic changes in the brain on follow-up MRI. The purpose of this study was to determine the frequency, latency, relationship with patient age, radiation dose, and serial change in the cystic changes in children after cranial irradiation., Methods: We retrospectively studied MRI in 33 children who had undergone cranial irradiation for their primary brain tumors. Postirradiation cystic change in the brain on follow-up MRI was defined as a well-demarcated, oval-shaped, CSF-like signal intensity area, and no contrast enhancement., Results: Of the 33 patients, 6 (18.2%) had one or more cystic lesions. The latency of the cystic changes ranged from 1.5 to 7 years (mean 2.6 years). Cystic changes were found in the subcortical, periventricular and other deep white matter and the basal ganglia. The size of the lesions ranged from 1 to 10 mm at their first appearance; eight cystic lesions increased in size. None the cystic lesions reduced in size or resolved with time and none required intervention. All patients with cystic changes had received irradiation when they were 6 years of age or younger. The cystic changes occurred within the radiation field in patients treated with a radiation dose of 36 Gy or more., Conclusion: Asymptomatic brain parenchymal cystic changes appear to occur in children who have undergone cranial irradiation at 6 years of age or younger.

We report a patient with recurrent glioblastoma, in whom serial magnetic resonance angiography (MRA) demonstrated gradual enlargement of an artery feeding the tumor and the development of an intratumoral aneurysm that led to intratumoral hemorrhage. The literature contains no previous reports that clinically document intratumoral aneurysms arising from these vessels. This is a rare case of glioblastoma in which the association of an intratumoral feeding-artery aneurysm, whose rupture led to intratumoral bleeding, was documented by serial MRA imaging and follow-up.

Objective: Germ cell tumors are the tumors sensitive for adjuvant therapy such as radiotherapy and chemotherapy. We evaluated the pathological findings of these heterogeneous tumors to determine the persistence of residual viable tumor cells after adjuvant therapy., Patients and Methods: Between 1988 and 2005, we treated 31 patients with germinoma or germinoma with syncytiotrophoblastic giant cells (STGC) and 15 patients with non-germinomatous malignant germ cell tumors (NGMGCTs). All 46 patients received a combination of chemo- and radiotherapy. A second-look operation was performed in 3 of 31 patients with germinomas or germinomas with STGC and 12 of 15 patients with NGMGCTs. The follow-up period was 2-139 months (median 95) in patients with germinomas or germinomas with STGC (group 1) and 10-202 months (median 65) in NGMGCT patients (group 2)., Results: Post-treatment, 3 group 1 and 12 group 2 patients manifested residual tumors. The pathological diagnosis in group 1 patients was mature teratoma, pineal cyst, and fibrous tissue with calcification; in group 2 it was yolk sac tumor (n = 1), immature teratoma (n = 3), mature teratoma (n = 4), and necrosis or fibrous tissue (n = 4). While no group 1 patients manifested tumor cells, MIB-1-positive viable tumor cells were present in resected tissues from one-third of the group 2 patients (3 immature teratomas and 1 yolk sac tumor)., Conclusion: The absence of viable tumor cells in residual tissue indicates that the combination of cisplatin-based chemo- and radiotherapy was effective in our germinoma patients. On the other hand, in patients with NGMGCTs, these cells persisted despite this combination therapy., (Copyright (c) 2007 S. Karger AG, Basel.)

A 17-year-old male presented with morning headache and double vision. Neuroimaging revealed a lobulated enhanced mass lesion with a blurred margin and remarkable peritumoral edema, and high uptake of methionine. The gray, soft, well-circumscribed mass was grossly totally resected. Histological examination showed the tumor cells were well differentiated with the perivascular pseudorosette pattern with broad, non-tapering processes radiating towards a central vessel without anaplastic features such as necrosis and endothelial proliferation. The histological diagnosis was low-grade astroblastoma. Follow-up magnetic resonance imaging demonstrated local recurrence 5 months later. Second surgery was followed by adjuvant radiotherapy and combination chemotherapy. Histological examination disclosed wide invasion by tumor cells into the subpial and perivascular space of the surrounding brain tissue. Follow-up magnetic resonance imaging demonstrated further recurrence around the tumor cavity. Surgical removal followed by six courses of combination chemotherapy (ifosfamide, cisplatin, and etoposide) resulted in complete remission of the tumor. Although gross total resection of astroblastoma usually results in long-term survival, some of these yet unfamiliar tumors may develop a more malignant character.

Between 1975 and 2005, we treated 52 newly diagnosed germinoma patients. Until 1991, patients with pure germinomas or germinomas with syncytiotrophoblastic giant cells (STGCs) received whole-brain radiotherapy only. Of the 52 patients, 30 were treated with a reduced radiation volume and combined chemotherapy; seven of these received local irradiation with 24 Gy, two received whole-brain (30 Gy) plus local irradiation (20 Gy), 16 received extended local irradiation delivered to the whole ventricles (30 Gy) plus local (20 Gy) irradiation, and five received extended local irradiation (24 Gy). Of the 30 patients treated with a reduced radiation volume and combined chemotherapy, four experienced tumor recurrence; three patients had been treated with 24 Gy of local radiotherapy and one had received extended local (30 Gy) plus local (20 Gy) irradiation in addition to chemotherapy. In these patients, the delivered radiotherapy was inadequate and the origin of the recurrent tumors was outside the radiation field. None of the patients who had received at least 24 Gy of whole ventricle radiotherapy combined with chemotherapy experienced tumor recurrence. In combination with chemotherapy, the delivery of irradiation covering the ventricles effectively reduced the incidence of tumor recurrence in patients with germinomas or germinomas with STGCs.

Background: Hydrocephalus associated with intracranial germ cell tumors or disseminated medulloblastoma has been treated with ventriculoperitoneal shunt. However, this procedure has a potential risk of intraperitoneal metastasis of these brain tumors. To prevent this potential risk and to minimize the risk of infection, we developed a percutaneous long-tunneled ventricular drainage (PLTVD). To confirm the effectiveness, we retrospectively analyzed the results of this procedure., Methods: From 1979 to 2003, we have treated 96 patients with germ cell tumors and medulloblastoma in our hospital. Of 96 patients, 59 (germ cell tumor, 31; medulloblastoma, 28) had hydrocephalus and 13 needed long-term cerebrospinal fluid drainage to manage the obstructive hydrocephalus due to persistent tumor or communicating hydrocephalus due to dissemination. We performed PLTVD for these cases using a flow-controlled shunt device and percutaneous long-tunneled shunt tube (peritoneal catheter) exiting at the upper abdomen and connecting to a closed drainage system. The occurrence of extraneural metastasis and the incidence of infection were evaluated., Results: The average duration of drainage was 74 days (range, 34-115 days). All 13 cases received full-dose chemotherapy and radiotherapy without infectious complications or extraneural metastasis., Conclusions: Percutaneous long-tunneled ventricular drainage was an effective method to manage long-lasting obstructive or communicating hydrocephalus with germ cell tumors and medulloblastoma.

In our immunohistochemical study of 25 human primary intracranial germinomas and germinomas with syncytiotrophoblastic giant cells (STGC), we stained the same sections for c-kit and placental alkaline phosphatase (PLAP). Immunohistochemical expression was graded using a semi-quantitative scoring system where 3+ =51-75%, and 4+ =76-100%. Of the 25 cases, 7 (28%) were graded 3+ and 18 (72%) 4+ for c-kit; 8 (32%) were 3+ or 4+ for PLAP. All 3 cases negative for PLAP-staining were strongly positive and all embryonal carcinomas, immature teratomas, and yolk sac tumors were negative for c-kit staining. The soluble isoform of c-kit (s-kit) is reportedly detectable in cerebral spinal fluid of patients with germinomas and germinomas with STGC. C-kit and s-kit may be powerful tumor markers for germinomas with or without STGC.

The effectiveness of ramosetron tablets and granisetron injection was compared for reducing the frequency of nausea, vomiting, and anorexia in patients with malignant glioma undergoing ACNU chemotherapy. Patients with malignant glioma to be treated with ACNU chemotherapy were randomly assigned to receive oral ramosetron (20 patients) or intravenous granisetron (19 patients) prior to ACNU injection. Gastrointestinal toxicity within 48 hours of ACNU injection was compared to that in patients who had received ACNU chemotherapy with dopamine D2 receptor-blocker as a historical control group. Within 24 hours of the administration of ACNU, 15 of the 20 patients treated with ramosetron and 16 of the 19 treated with granisetron were nausea-free, and 14 of the former and 14 of the latter regained their normal appetite. There was no significant difference in the anti-emetic effects. Ten of the 17 controls experienced no vomiting within 6 hours of the injection of ACNU, five were nausea-free within 24 hours, and two retained their normal appetite within 24 hours. Oral ramosetron has the same anti-anorectic and anti-emetic effects as intravenous granisetron. Ramosetron tablets are less expensive and are easy to take, so should be on the list of first-choice anti-emetic drugs for patients treated with ACNU chemotherapy.

Regarding glioblastoma, there has been controversy over whether a large number of infiltrating macrophages act as anti-tumor effectors or not. It has been exhibited that intratumoral lipid environments have a possible influence on anti-tumor immunity. Necrosis of glioblastoma and non-necrotic tissues of astrocytic tumors were analyzed to compare the amount of free docosahexaenoic acid (DHA) content. The apoptosis inducible effects of DHA on macrophages derived from peripheral blood monocytes and cultured glioma cells were evaluated by flow cytometry. The influence of DHA on the anti-tumor effects of macrophages was assessed at 0, 30, 60, and 90 mM of DHA by (51)Cr releasing assay and MTT assay. The mean concentration of free DHA in necrotic tissues (757.6 mmol/kg) was 5 times higher than that in non-necrotic tissues (147.2 mmol/kg). The DHA concentration of 30 mM induced apoptosis in macrophages, however, glioma cells were not affected even at a DHA concentration of 60 mM. Macrophages pre-exposed to DHA for 24 h decreased the cytotoxicity to U251MG cells as shown by (51)Cr releasing assay. Total viability of co-cultured macrophages and U251MG cells showed an increase at high concentrations of DHA (60 and 90 mM) according to 24 h MTT assay, although each separate culture did not. The DHA concentration in necrosis of glioblastoma was sufficient for macrophages to cause apoptosis and suppress their anti-tumor effects. The results suggest that liberated DHA in necrosis can induce apoptosis in macrophages and inhibit their functions.

Objective and Importance: Desmoplastic infantile gangliogliomas (DIGs) are extremely rare tumors that respond well to treatment. However, their biological behavior remains to be clarified. We describe two patients whose DIGs spontaneously regressed after surgery, without adjuvant therapy., Clinical Presentation: A 9-month-old girl presented with left hemiparesis, and a 6-month-old boy presented with increasing head circumference. For both patients, neuroimaging demonstrated a huge cystic tumor that included a solid portion and was widely attached to the dura. Gadolinium-diethylenetriamine penta-acetic acid produced strong enhancement., Intervention: One patient underwent partial and the other subtotal tumor removal. Histologically, both tumors were diagnosed as DIGs. Postoperatively, the residual tumors were monitored without adjuvant therapy, and both regressed in several months., Conclusion: Our experience suggests that DIGs may include a subgroup of tumors with a tendency for spontaneous regression, possibly attributable to the induction of apoptosis.

A 28-year-old man presented with progressive mental deterioration. Thirteen years earlier he had undergone radiation therapy for a pineal germinoma. Neuroimaging showed a homogeneously enhanced mass lesion along the ventricular wall. The cerebrospinal fluid (CSF) level of human chorionic gonadotropin (HCG) was high. Endoscopic biopsy revealed that the tumor was a two-cell pattern germinoma. The diagnosis was germinoma with syncytiotrophoblastic giant cells (STGC). He first received three cycles of chemotherapy with carboplatin and etoposide and then two cycles with ifosfamide, cisplatin, and etoposide. Subsequently, the tumor size decreased markedly and the CSF level of HCG returned to normal. However, he died 22 months after the recurrence. Histological verification and measurement of tumor markers are necessary for the optimum treatment of germ cell tumors. Adequate initial chemotherapy and long-term follow up are essential for patients with germinoma with STGC.