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Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of a-ketoglutarate (a-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. Although mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown. To address this question, we exposed immortalized (p53/pRb deficient), untransformed human astrocytes to the mutant IDH1 inhibitor AGI-5198 prior to, concomitant with, or at intervals after, introduction of transforming mutant IDH1, then measured effects on 2-HG levels, histone methylation (H3K4me3, H3K9me2, H3K9me3, or H3K27me3), and growth in soft agar. Addition of AGI-5198 prior to, or concomitant with, introduction of mutant IDH1 blocked all mutant IDH1 driven changes, including cellular transformation. Addition at time intervals as short as 4 days following introduction of mutant IDH1 also suppressed 2-HG levels, but had minimal effects on histone methylation, and lost the ability to suppress clonogenicity in a time-dependent manner. Furthermore, in two different models of mutant IDH1-driven gliomagenesis, AGI-5198 exposures that abolished production of 2-HG also failed to decrease histone methylation, adherent cell growth, or anchorage-independent growth in soft agar over a prolonged period. These studies show although mutant IDH1 expression drives gliomagenesis, mutant IDH1 itself rapidly converts from driver to passenger. Implications: Agents that target mutant IDH may be effective for a narrow time and may require further optimization or additional therapeutics in glioma. (C) 2016 AACR.

BACKGROUND: Although meningiomas are usually attached to the dura matter, intraparenchymal and subcortical meningiomas do not show dural attachment. METHODS: A total of 39 cases of intraparenchymal meningiomas including subcortical meningiomas were reviewed. RESULTS: Compared with ordinary meningiomas, intraparenchymal meningiomas occurred more frequently in males and at younger ages. Unusual magnetic resonance imaging findings such as heterogeneous enhancement and cystic components were frequently recognized. Histologic analysis revealed half of the intraparenchymal meningiomas to be of the fibrous type, and approximately 20% of the tumors were diagnosed as World Health Organization grade II-III disease. Compared with sylvian fissure meningiomas, which also lack dural attachment, patients with intraparenchymal meningiomas were younger than those with sylvian fissure meningiomas. Gross total resection was performed more frequently for intraparenchymal meningiomas than for sylvian fissure meningiomas. More patients with intraparenchymal meningiomas than those with sylvian fissure meningiomas showed malignant phenotypes, and fibrous phenotypes were twice as common among intraparenchymal meningiomas as among sylvian meningiomas. CONCLUSIONS: Because of the unique features described earlier, which contrast with those of ordinary meningiomas, there is a possibility that intraparenchymal meningiomas are not precisely diagnosed. Collectively, the information collected from the study cases may facilitate the appropriate management of these rare tumors.

Recent investigations revealed genetic analysis provides important information in management of gliomas, and we previously reported grade II-III gliomas could be classified into clinically relevant subgroups based on the DNA copy number aberrations (CNAs). To develop more precise genetic subgrouping, we investigated the correlation between CNAs and mutational status of the gene encoding isocitrate dehydrogenase (IDH) of those tumors. We analyzed the IDH status and CNAs of 174 adult supratentorial gliomas of astrocytic or oligodendroglial origin by PCR-based direct sequencing and comparative genomic hybridization, respectively. We analyzed the relationship between genetic subclassification and clinical features. We found the most frequent aberrations in IDH mutant tumors were the combined whole arm-loss of 1p and 19q (1p/19q codeletion) followed by gain on chromosome arm 7q (+7q). The gain of whole chromosome 7 (+7) and loss of 10q (-10q) were detected in IDH wild-type tumors. Kaplan-Meier estimates for progression-free survival showed that the tumors with mutant IDH, -1p/19q, or +7q (in the absence of +7p) survived longer than tumors with wild-type IDH, +7, or -10q. As tumors with +7 (IDH wild-type) showed a more aggressive clinical nature, they are probably not a subtype that developed from the slowly progressive tumors with +7q (IDH mutant). Thus, tumors with a gain on chromosome 7 (mostly astrocytic) comprise multiple lineages, and such differences in their biological nature should be taken into consideration during their clinical management.

The M2 isoform of pyruvate kinase (PK) is upregulated in most cancers including glioblastoma. Although PKM2 has been reported to use dual kinase activities to regulate cell growth, it also interacts with phosphotyrosine (pY)-containing peptides independently of its kinase activity. The potential for PKM2 to use the binding of pY-containing proteins to control tumor growth has not been fully examined. We here describe a novel mechanism by which PKM2 interacts in the nucleus with the RNA binding protein HuR to regulate HuR sub-cellular localization, p27 levels, cell cycle progression and glioma cell growth. Suppression of PKM2 in U87, T98G and LN319 glioma cells resulted in increased p27 levels, defects in entry into mitosis, increased centrosome number, and decreased cell growth. These effects could be reversed by shRNA targeting p27. The increased levels of p27 in PKM2 knock-down cells were caused by a loss of the nuclear interaction between PKM2 and HuR, and a subsequent cytoplasmic re-distribution of HuR, which in turn led to increased cap-independent p27 mRNA translation. Consistent with these results, the alterations in p27 mRNA translation, cell cycle progression and cell growth caused by PKM2 suppression could be reversed in vitro and in vivo by suppression of HuR or p27 levels, or by introduction of forms of PKM2 that could bind pY, regardless of their kinase activity. These results define a novel mechanism by which PKM2 regulates glioma cell growth, and also define a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway. What's new? Pyruvate kinase M2 (PKM2) is overexpressed in many tumors, where it facilitates glycolysis and promotes tumor growth through interactions with phosphotyrosine (pY)-containing peptides. Its exact contributions to tumor cell growth, however, are not fully understood. Here, PKM2 is shown to leverage its pY-binding ability to interact in the nucleus with the RNA-binding protein HuR, thereby promoting glioma cell growth. Disruption of the interaction resulted in cytoplasmic redistribution of HuR, increased cap-independent p27 mRNA translation, and cell cycle arrest. The work defines a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway.

Mutations of the isocitrate dehydrogenase (IDH) genes are considered an important event that occurs at an early stage during gliomagenesis. The mutations often occur in grade 2 or 3 gliomas and secondary glioblastomas. Most IDH mutations are associated with codon 132 and 172 in IDH1 and IDH2 in gliomas, respectively. While IDH1 and IDH2 catalyze the oxidative decarboxylation of isocitrate to form alpha-ketoglutarate (alpha-KG), IDH1 and IDH2 mutations convert alpha-KG to 2-hydroxyglutarate (2-HG). The accumulation of oncometabolite 2-HG is believed to lead progenitor cells into gliomas, inhibiting several alpha-KG-dependent enzymes, including ten-eleven translocation enzymes, histone demethylases, and prolyl hydroxylases, although the mechanisms have not been fully revealed. Herein, we review the contribution of IDH1 and IDH2 mutations to gliomagenesis.

Glioblastomas are the most aggressive of all gliomas and have the worst prognosis, with 5-year survival rates of less than 10%. Temozolomide (TMZ) is a DNA-methylating agent. Now that TMZ is available, the standard treatment is maximal safe resection, followed by treatment with radiation and TMZ. TMZ has also been used for maintenance therapy. Recently, bevacizumab, which is a monoclonal antibody to vascular endothelial growth factor, has been used for the initial treatment of glioblastomas and for the treatment of recurrent glioblastomas. A 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafer can also be placed on the surface of the cavity after near-complete tumor resection. These are currently the three drugs that are most often used to treat glioblastomas. In the near future, other therapeutic options such as immunotherapy may be used to treat glioblastomas.

Isocitrate dehydrogenase 1 (IDH1) mutations occur in most lower grade glioma and not only drive gliomagenesis but are also associated with longer patient survival and improved response to temozolomide. To investigate the possible causative relationship between these events, we introduced wild-type (WT) or mutant IDH1 into immortalized, untransformed human astrocytes, then monitored transformation status and temozolomide response. Temozolomide-sensitive parental cells exhibited DNA damage (gamma-H2AX foci) and a prolonged G(2) cell-cycle arrest beginning three days after temozolomide (100 mu mol/L, 3 hours) exposure and persisting for more than four days. The same cells transformed by expression of mutant IDH1 exhibited a comparable degree of DNA damage and cell-cycle arrest, but both events resolved significantly faster in association with increased, rather than decreased, clonogenic survival. The increases in DNA damage processing, cell-cycle progression, and clonogenicity were unique to cells transformed by mutant IDH1, and were not noted in cells transformed by WT IDH1 or an oncogenic form (V12H) of Ras. Similarly, these effects were not noted following introduction of mutant IDH1 into Ras-transformed cells or established glioma cells. They were, however, associated with increased homologous recombination (HR) and could be reversed by the genetic or pharmacologic suppression of the HR DNA repair protein RAD51. These results show that mutant IDH1 drives a unique set of transformative events that indirectly enhance HR and facilitate repair of temozolomide-induced DNA damage and temozolomide resistance. The results also suggest that inhibitors of HR may be a viable means to enhance temozolomide response in IDH1-mutant glioma. (C) 2014 AACR.

Temozolomide (TMZ) is a DNA methylating agent used to treat brain cancer. TMZ-induced O6-methylguanine adducts, in the absence of repair by O6-methylguanine DNA methyltransferase (MGMT), mispair during DNA replication and trigger cycles of futile mismatch repair (MMR). Futile MMR in turn leads to the formation of DNA single and double strand breaks, Chk1 and Chk2 phosphorylation/activation, cell cycle arrest, and ultimately cell death. Although both pChk1 and pChk2 are considered to be biomarkers of TMZ-induced DNA damage, cell-cycle arrest, and TMZ induced cytotoxicity, we found that levels of pChk1 (ser345), its downstream target pCdc25C (ser216), and the activity of its upstream activator ATR, were elevated within 3 hours of TMZ exposure, long before the onset of TMZ-induced DNA double strand breaks, Chk2 phosphorylation/activation, and cell cycle arrest. Furthermore, TMZ-induced early phosphorylation of Chk1 was noted in glioma cells regardless of whether they were MGMT-proficient or MGMT-deficient, and regardless of their MMR status. Early Chk1 phosphorylation was not associated with TMZ-induced reactive oxygen species, but was temporally associated with TMZ-induced alkalai-labile DNA damage produced by the non-O6-methylguanine DNA adducts and which, like Chk1 phosphorylation, was transient in MGMT-proficient cells but persistent in MGMT-deficient cells. These results re-define the TMZ-induced DNA damage response, and show that Chk1 phosphorylation is driven by TMZ-induced mismatch repair-independent DNA damage independently of DNA double strand breaks, Chk2 activation, and cell cycle arrest, and as such is a suboptimal biomarker of TMZ-induced drug action.

Chronic subdural hematoma (CSDH) is a common disease in the elderly, and the recurrence rate of CSDH is reported to range from 2.3 to 33 %. We performed a retrospective review of a number of CSDH cases and the potential factors associated with CSDH recurrence. The patient population comprised 112 men and 65 women with a mean age of 74.7 years. We analyzed the following factors: age, sex, antiplatelet and anticoagulant use, hematoma laterality, hematoma thickness, degree of midline shift and internal architecture of the hematoma in the preoperative CT films, use of irrigation, direction of the drainage tube, width of the subdural space, and degree of midline shift and the presence of a massive subdural air collection in the postoperative CT films. Univariate analysis revealed that there was a trend for different rates of recurrence among the different types of hematomas. The presence of a postoperative massive subdural air collection tended to be associated with the recurrence of hematoma. Multivariate analysis revealed that separated hematomas were significantly associated with CSDH recurrence, whereas the presence of postoperative massive subdural air collection tended to be associated with hematoma recurrence. Neither univariate nor multivariate analysis could demonstrate an association between the direction of the drainage tube and the recurrence of CSDH.

The recent progress in chemotherapy for malignant gliomas is attributable to the introduction of the DNA-methylating agent temozolomide (TMZ) however, drug resistance remains a major issue. Previous studies have shown that TMZ induces prolonged arrest of human glioma cells in the G2/M phase of the cell cycle followed by a senescence-like phenomenon or mitotic catastrophe. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. We investigated the effect of a cyclin-dependent kinase (Cdk) inhibitor flavopiridol (FP) that inhibits the action of Cdc2, a key protein in the G2 checkpoint pathway, on TMZ-treated glioma cells. Colony formation efficiency revealed that FP potentiated the cytotoxicity of TMZ in glioma cells in a p53-independent manner. This effect was clearly associated with the suppression of key proteins at the G2-M transition, accumulation of the cells exclusively at the G2 phase, and increase in a double-stranded DNA break marker (seen on performing immunoblotting). TMZ-resistant clones showed activation of the G2 checkpoint in response to TMZ, while FP treatment resensitized these clones to TMZ. FP also enhanced the cytotoxicity of TMZ in U87MG-AktER cells. Moreover, administration of TMZ and/or FP to nude mice with xenografted U87MG cells revealed that FP sensitized xenografted U87MG cells to TMZ in these mice. Our findings suggest that TMZ resistance could be promoted by enhanced DNA repair activity in the G2-M transition and that a Cdk inhibitor could suppress this activity, leading to potentiation of TMZ action on glioma cells. © 2013 Springer Science+Business Media New York.

A 63-year-old man who underwent insertion of a lumboperitoneal shunt developed gait disturbance. He had undergone surgery for gastric cancer 7 years and for ileus 5 years previously. Head computed tomography (CT) revealed enlargement of the ventricles. Abdominal CT revealed a cyst in the abdominal region and the distal segment of the peritoneal shunt tube located within the cyst. Laparotomy revealed the cyst located between the small intestine, colon, and peritoneum. The anterior wall of the cyst was excised. The distal segment of the peritoneal shunt tube was replaced in the rectovesical pouch. Histological examination showed that the cyst wall consisted of inner fibrous tissue and outer fat tissue without epithelial lining, and invasion of lymphocytes. The diagnosis was pseudocyst. Only 29 cases of abdominal cerebrospinal fluid (CSF) pseudocysts have been reported in adults. Although the mechanism underlying the formation of abdominal pseudocyst remains to be clarified, several predisposing factors for cyst formation have been reported including changes in absorption of CSF due to inflammation or infection, peritoneal adhesions due to previous abdominal surgery, and increase in the protein content of the CSF. In our case, the medical history and histological features of the cyst wall indicated that formation of the abdominal pseudocyst was associated with previous surgery or inflammatory reaction.

Intratumoral hemorrhage of hypoglossal schwannoma is very rare. A 37-year-old man was admitted to our hospital with severe headache and gait disturbance. Radiologic examination revealed subarachnoid hemorrhage and a well-circumscribed enhanced lesion compressing the medulla oblongata. Gross total removal of the intracranial tumor was performed. Histopathological examination revealed the characteristic features of a schwannoma. The tumor had several hemorrhagic areas and numerous hyalinized blood vessels. Although the mechanism of hemorrhage from schwannomas is unclear, it is hypothesized that tumor vessels showing focal sinusoidal dilatation and hyaline thickening of the walls lead to spontaneous thrombosis with consequent necrosis, and often hemorrhage.

The co-occurrence of different histological tumors in the nervous system is rare and is mainly associated with phakomatoses or radiation exposure. A 72-year-old man underwent surgery for a frontal convexity meningioma. Four years after the surgery, a new lesion was detected in the attached region where the meningioma had been removed. The second tumor exhibited a high degree of cellularity, atypical mitosis, pseudo-palisading and microvascular proliferation, and was immunohistologically positive for GFAP and was diagnosed as a glioblastoma. Wild-type isocitrate dehydrogenase 1 was found in the second specimen. A genetic analysis using comparative genomic hybridization showed a DNA copy number loss on 1p35, 9pter-21, 10, 11q23, 13q, 14q, 20q, 22q and a gain on 7 in the second specimen. Although the mechanism responsible for the consecutive occurrence of meningioma and glioblastoma has not been elucidated, five hypotheses are feasible: (i) the lesions occurred incidentally; (ii) a low-grade astrocytoma present at the time of the first operation transformed into a high-grade glioma during the next 4 years; (iii) radiation received during the endo-vascular treatment induced glioblastoma; (iv) a brain scar created at the time of the first operation for meningioma led to the occurrence of a glioblastoma; and (v) the previous meningioma affected the surrounding glial cells, causing neoplastic transformation.

A 69-year-old male presented with a rare dural cyst manifesting as numbness and pain in the limbs. Magnetic resonance imaging revealed a mass anterior to the medulla oblongata appearing as low intensity on T(1)-weighted and high intensity on T(2)-weighted imaging, with no enhancement. A cystic lesion ventral to the medulla oblongata was removed via the lateral suboccipital transcondylar approach. Histological examination showed the wall of the cyst consisted of fibrous connective tissue with a dense zone and a loose zone, similar to the structure found in the dura mater. The lesion was diagnosed as dural cyst. Dural cysts can be defined as cyst with the wall consisting of dura mater-like fibrous tissue, and attached to the dura mater. The origin of the present dural cyst was considered to be congenital.

Background: Several malignant tumors and brain abscesses have similar magnetic resonance imaging (MRI) findings. Because the prognosis and treatment strategies differ among these disorders, accurate preoperative diagnosis is very significant. Recently, diffusion-weighted imaging (DWI) and calculation of apparent diffusion coefficients (ADCs) have been reported to be useful to differentiate between the two disorders. Materials and Methods: MRI and DWI were performed in 37 patients: 13 with glioblastomas, 14 with metastatic tumors, 7 with malignant lymphomas, and 3 with brain abscesses. The minimum ADC value (ADC min ) and mean ADC value (ADC mean ) were taken into consideration. Results: Statistically significant differences were found in the enhanced lesions for ADC min and ADC mean between metastatic tumors and malignant lymphomas. The receiver operating characteristic analyses revealed no statistically significant differences among them. There were statistically significant differences in ADC mean in the cores of cystic lesions between brain abscesses and metastatic tumors or glioblastomas. Conclusions: Our results suggest that evaluation using ADC values may facilitate differentiating metastatic tumors from malignant lymphomas, and also metastatic tumors or glioblastomas from brain abscesses.

BACKGROUND: Gliomas are classified into pathologically defined subgroups. However, the tumors in the same entity could show varied 'clinical courses. Recently, various studies revealed that genetic analyses of gliomas can provide clinically relevant information. OBJECTIVE: To investigate the correlation between genetic characterization and clinical information of adult supratentorial grade II-III gliomas to establish a genetic classification of these tumors. METHODS: We analyzed the genetic profile of tumor samples microdissected from formalin-fixed archival tissue sections based on the defined selection criteria of tumor region using a comparative genomic hybridization method. We collected genetic and clinical data from 140 adult supratentorial gliomas of World Health Organization grade II-III and classified the tumors analyzed into subgroups according to chromosomal copy number aberrations. The relationship between histologic or genetic subclassification and clinical features was analyzed. RESULTS: The tumors were classified into subgroups based on the genetic profiles. Tumors with +7q and those with -1p/19q showed long progression-free survival, and loss of 10q in association with gain of 7p (+7/-10q) appeared to predict poor outcome. Most tumors with histologic diagnosis of glioblastoma showed +7/-10q; however, World Health Organization grade II-III gliomas contained a variety of genetic subgroups that correlated well with the clinical course, and this might explain why these tumors do not respond uniformly to therapies. CONCLUSION: Our pilot study suggests that care must be taken in clinical studies of these tumors because, unlike glioblastoma, grade II-III tumors may contain genetically distinct subgroups with different sensitivity to the therapies.

Object. Although gross-total resection (GTR) is a preferable treatment for skull base meningiomas, subtotal resection (STR) with or without radiation therapy can be considered as an alternative treatment for patients at considerable surgical risk. The long-term prognosis of such patients might be related to the biological activity of the tumor. This study examined predictors of progression-free survival (PFS) and sought to determine the optimal treatment strategies, focusing on the pathobiological findings of skull base meningiomas. Methods. This study included 281 patients with skull base meningiomas (mean follow-up period 88.4 months). Risk factors for tumor progression were examined using a multivariate analysis. The PFS and overall survival (OS) rates were evaluated using the Kaplan-Meier method. The functional outcomes of the patients were measured using the Kamofsky Performance Scale (KPS). Results. The 10-year PFS and OS rates were 66.4% and 97.4%, respectively. Overall, 83.3% of patients achieved a favorable outcome, that is, an improved or unchanged KPS score. The extent of resection, additional radiotherapy, histological grade, MIB-1 index, and p53-positive rate were significantly associated with PFS. The PFS of patients undergoing STR without radiation therapy was significantly shorter than that of either those undergoing STR with radiation therapy or GTR, while no statistical difference was observed between the latter 2 groups. Among the patients undergoing STR with pathobiological risk factors (histological grade, MIB-1 index, and p53-positive rate), the PFS of the patients who received radiation therapy was better than that of those who did not receive radiation therapy. Among the patients undergoing STR without such risk factors, the PFS was not significantly different between patients who received radiation therapy and those who did not. Conclusions. For patients with skull base meningiomas, a GTR is desirable and additional radiation therapy after STR may contribute to a longer PFS. Additional radiation therapy should be recommended, especially for patients with pathobiological risk factors, but not necessarily for those without such risks. (DOI: 10.3171/2010.11.JNS10701)

Perimedullary arteriovenous fistulas (AVFs) at the craniocervical junction are uncommon, and are often fed by the anterior spinal artery, with only a few cases fed by the intradural vertebral artery (VA). A 55-year-old man presented with a case of perimedullary AVF fed by the VA at the craniocervical junction manifesting as subarachnoid hemorrhage. Left vertebral angiography demonstrated an AVF supplied by branches from the VA. Three-dimensional computed tomography angiography (3D-CTA) revealed that the feeding arteries originated from the VA at the intradural position. Two feeding arteries were coagulated and dissected, followed by coagulation of a small feeder. The draining veins became discolored and shrank. 3D-CTA performed 2 months after the operation revealed disappearance of the AVF. Open surgery was successfully performed for the almost perimedullary AVF at the craniocervical junction, and is considered to be preferable for the treatment of this disease.

BACKGROUND AND IMPORTANCE: Intracranial clear cell meningioma is very rare. We present 3 cases of intracranial clear cell meningiomas genetically characterized by comparative genomic hybridization with a review of the literature. CLINICAL PRESENTATION: Patient 1 is a 38-year-old woman with a petroclival tumor. Patient 2 is a 60-year-old man with a tumor at the foramen magnum. Patient 3 is a 60-year-old man with a tumor at the posterior clinoid process. Gross total resection was performed in patients 1 and 2. Patient 1 has been free from recurrence for 10 years. Patient 2 had a tumor recurrence at 14 months after the operation. After partial resection, conventional radiotherapy was given, and there was no tumor regrowth at 2 years after radiotherapy. Subtotal resection was performed in patient 3, and no regrowth was detected for 3 months. Histologically, all tumors were composed of cells with clear cytoplasm reactive for periodic acid-Schiff and diagnosed as clear cell meningioma. The MIB-1 and p53 staining indexes were 1.8, 1.7, and 5.6 and 1.1, 1.0, and 5.5, respectively. Comparative genomic hybridization revealed no chromosomal number aberrations in patient 1, numerous losses and gains including loss of chromosome 1 in patient 2, and loss of only 22q in patient 3. Because staining indexes of MIB-1 and p53 were equivalent in 2 patient (patients 1 and 2) with a long follow-up period, the contrary clinical courses are likely associated with genetic characteristics. CONCLUSION: To the best of our knowledge, this is the first report that suggests association between tumor behavior and genetic characteristics in clear cell meningiomas.

Meningiomas in identical twins are extremely rare. To our knowledge, only one previous report of meningiomas in identical twins has been published. We present identical twin sisters with meningiomas. The tumors were located at a similar, but not a common, position (the cerebellopontine angle) in both twins. Histologically, both tumors were diagnosed as meningothelial meningiomas with an angiomatous component. Immunohistochemically, the Ki-67 indices in the two cases were 1.0 and 1.1, and the p53 positive rates were 0.2 and 0.9. The specimens in both cases were reactive to neurofibromin 2 (NF2). A comparative genomic hybridization (CGH) assay revealed an aberration in the long arm of chromosome X, but no aberrations in the long arm of chromosome 22 in either case. These results strongly suggest that genetic aberrations other than NF2 are associated with tumorigenesis in some types of sporadic meningiomas.

Object. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. A considerable number of glioblastoma cases are refractory to TMZ, however, and the development of novel chemotherapeutic regimens is needed. The authors of previous studies have revealed that hsp90 is expressed at higher levels in human neoplastic tissues, including gliomas, than in normal tissues. Heat shock protein 90 is involved in a cytoprotective mechanism against cellular stressors such as DNA damage, and the authors hypothesized that hsp90 inhibitors might act as antitumor agents against gliomas and potentiate the cytotoxicity of DNA-damaging agents. Methods. The authors examined the cytotoxicity of an hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), both alone and in combination with I of 3 DNA-damaging agents (cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, and TMZ) in human glioma cell lines. The cytotoxicity of these agents to glioma cells was measured using a colony formation assay. The cell cycle phase distribution, protein expression, and number of apoptotic cells were measured using a fluorescence-activated cell sorting assay, immunoblot assays, and double staining with annexin V and propidium iodide. In an in vivo experiment, 17-AAG, cisplatin, or 17-AAG and cisplatin were administered intraperitoneally to mice with xenografted U87MG cells, and the resulting tumor volumes were measured. Results. The authors found that 17-AAG reduced the clonogenicity of U87MG cells, and at a low concentration (< 100 nM) potentiated the cytotoxicity of the DNA-crosslinking agents cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea, but not that of the DNA-methylating agent TMZ. This 17-AAG-induced potentiation of DNA crosslinking agent-induced cytotoxicity was a consequence of prolonged G(2)-M arrest accompanied by the suppression of cdc2 and cdc25C and of increased apoptotic cell death accompanied by the degradation of the antiapoptosis proteins Akt and survivin. Similar effects were observed when cells were treated with radicicol, another hsp90 inhibitor. The 17-AAG-induced enhancement of DNA crosslinking agent-induced cytotoxicity was also observed in other cell lines. In addition, 17-AAG sensitized xenografted U87MG cells to cisplatin in nude mice. Conclusions. Heat shock protein 90-targeted therapy may be an effective strategy for potentiating chemotherapy using DNA-crosslinking agents for TMZ-refractory gliomas. (DOI: 10.3171/2009.3.JNS081146)

Previous studies have revealed that p38, a member of the family of stress-activated protein kinases (SAPKs), cooperates with the Chk1-pathway to bring about temozolomide (TMZ)-induced G2 arrest, and that the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity. c-Jun N-terminal kinase (JNK), another SAPK, has been reported to have several roles of cell survival, oncogenesis, growth, differentiation and cell death. To elucidate the functions of JNK in glioma cells treated with TMZ, we analyzed alterations in JNK and the effect of modification of JNK in U87MG human glioma cells treated with TMZ. We found that JNK was phosphorylated 1-2 days after TMZ treatment and that pretreatment (for 24 h) and post-treatment (for 72 h) with a JNK inhibitor SP600125 at a concentration of 200 nM or higher remarkably reduced clonogenicity in the TMZ-treated cells. The phosphorylation of the JNK target protein c-Jun, but not of ATF-2, was inhibited by this concentration of SP600125. Therefore JNK was proved to have a role of survival in glioma cells treated with TMZ, and c-Jun-related responses were suggested to be more important in the JNK-mediated survival of glioma cells with DNA damage. SP600125 amplified the percentage of senescence-like cells and of mitotic catastrophe cells in TMZ-treated U87MG and U87MG-E6 cells, respectively, suggesting that the enhancement of TMZ-induced cytotoxicity by a JNK inhibitor in glioma cells is induced (at least in part) by the potentiation of cell death pathways induced by TMZ alone. Further investigation based on the present data may provide a viable approach for enhancing TMZ-induced cytotoxicity in human gliomas.

A 23-year-old male was admitted after a motor vehicle accident with acute epidural hematoma, diffuse subarachnoid hemorrhage (SAH) in the basal cistern, and fractures at the anterior cranial base. Angiography revealed an aneurysm of the right supraclinoid internal carotid artery (ICA). His consciousness suddenly worsened on the 23rd day. Expansion of the SAH in the basal cistern and two hump aneurysms were detected. He underwent endovascular embolization of these aneurysms and the right ICA with Guglielmi detachable coil. Traumatic aneurysms are difficult to diagnose in the early period after injury and are associated with a high mortality. Endovascular treatments for traumatic aneurysms have lower mortality rate, and can be performed under local anesthesia.

Although some authors have reported the malignant transformation of meningiomas, there has been no previous report describing that a meningothelial meningioma transformed into an atypical meningioma within 1 year. This report documents a 57-year-old woman who presented with right hearing disturbance. Magnetic resonance imaging revealed a right petroclival meningioma. The tumor was subtotally removed and was diagnosed to be a meningothelial meningioma. Seven months after surgery, a recurrence of the tumor was confirmed. The diagnosis of this recurrent tumor was an atypical meningioma. The MIB-1 index and the percent of p53 protein-positive cells in the primary tumor were 4.6% and 35.4%, respectively, whereas those of the recurrent tumor were 34.7% and 33.1%, respectively. A chromosomal DNA copy number loss was observed on 1p, 6q, 10, 14q, and -22q detected in both the primary and the recurrent tumors. These results suggest that the present case had a potentially malignant tumor in the early stage, although it had the histological features of benign meningiomas. An evaluation of the MIB-1 index, as well as the expression of p53 and chromosomal aberrations, may be useful for predicting the malignant transformation of meningiomas.

This 32-year-old woman, 27 weeks pregnant, harbored a cystic mass with a solid component in the left frontal lobe. Histologically, the lesion was hypercellular and contained a diffuse sheet of eosinophilic cells of various sizes. The cells were almost round and had a few prominent, eccentrically placed, hyperchromatic nuclei of various sizes. Immunohistochemically, the tumor was reactive for vimentin, epithelial membrane antigen, cytokeratin AE1/AE3, smooth muscle actin, and BAF47/INI-1, and negative for glial fibrillary acidic protein, neurofilament protein, S100 protein, CK7, CK20, HMB-45, MIC2, and Bcl-2. The Ki 67 labeling index was 4.2%. Comparative genomic hybridization analysis revealed aberrations of the chromosomal copy number of +7 and -10. This tumor could not be categorized according to the present World Health Organization classification. Results of staining with glial fibrillary acidic protein were not consistent with a glioma, and staining with INI-1 was inconsistent with atypical teratoid/rhabdoid tumor. The tumor was therefore designated as a "cerebral tumor with extensive rhabdoid features." (DOI: 10.3171/2008.11.JNS08776)

Supratentorial primitive neuroectodermal tumors (sPNET) occurring in adults are rare. Only 56 such cases have been previously reported. This report documents a 56-year-old male who presented with the chief complaint of right facial palsy. Magnetic resonance imaging (MRI) revealed left frontal and bilateral periventricular lesions. Surgery was performed for the frontal mass, which was histologically diagnosed to be sPNET. An immunohistochemistry assay for CD99, and a fluorescence in situ hybridization (FISH) assay for t(11;22) translocation revealed this PNET to be a central PNET. This case was the first case to detect a central PNET using both immunohistochemistry and the FISH assay in adult sPNET. Though radiation therapy was performed, an MRI performed 2.5 months after the surgery revealed a regrowth of the tumor. The patient died 5 months after surgery. This case report is accompanied by a review of 57 cases of adult sPNET.

We present a case of intracranial lipomatous meningioma in the parietal convexity in a 64-year-old woman. The mass showed low density on computed tomography, was hyper-intense on T1-weighted magnetic resonance images, and had decreased intensity upon imaging with fat-suppressed sequences. Gross total removal of the tumor was performed. Histopathologically, the tumor was a meningioma with mixed transitional and lipomatous patterns. Immunohistochemically, the meningothelial foci were positive for epithelial membrane antigen (EMA) and vimentin, and negative for S-100 protein. The lipomatous foci were positive for EMA, vimentin, and S-100 protein. The Ki-67 index values of the meningothelial and lipomatous foci were 1.0% and 1.8%, respectively. We review previous reports of lipomatous meningioma and discuss its clinical presentations and pathology. (c) 2006 Elsevier Ltd. All rights reserved.

Although second-generation replication-conditional herpes simplex virus type 1 (HSV-1) vectors defective for both ribonucleotide reductase (RR) and the virulence factor gamma(1)34.5 have been proven safe through a number of animal experiments and clinical trials, their therapeutic efficacy was also markedly reduced. To overcome this situation, we concentrated on the use of a tumor-specific promoter in this study, to express ICP34.5 selectively in malignant glioma cells. As a molecular marker for malignant glioma, we focused on the neural RNA-binding protein, Musashi1. On the basis of the results of defective vector dvM345, as reported previously, we created, via homologous recombination, a novel HSV-1 vector termed KeM34.5, which expresses ICP34.5 under the transcriptional control of the musashi1 gene promoter (P/musashi1). Cytotoxicity mediated by KeM34.5 was significantly enhanced in human glioma cell lines (U87MG, U87MG-E6, U251, and T98G), resulting in an approximately 2-log increase in viral yield, compared with its parental vector G207. This virus also showed much higher therapeutic efficacy in the in vivo glioma model, while maintaining the desirable neuroattenuated phenotype. These results suggest that oncolytic HSV-1 expressing ICP34.5 under the transcriptional control of the musashil gene promoter could be a promising therapeutic agent for the treatment of malignant glioma.

OBJECTIVE AND IMPORTANCE: Schwannomas originating from the trochlear nerve without neurofibromatosis are extremely rare. Thirty-four cases have previously been reported in the literature, and only 25 cases were pathologically diagnosed. In addition, intratumoral hemorrhage in intracranial schwannomas is also rare. Approximately 30 cases of intracranial schwannomas with intratumoral hemorrhage have been reported. CLINICAL PRESENTATION: A 42-year-old man presented with left hemiparesis and right trochlear nerve palsy. Magnetic resonance imaging revealed an abnormal cystic lesion beside the brainstem. His symptoms rapidly worsened after enlargement of the mass because of intratumoral hemorrhage. INTERVENTION: Gross total removal of the tumor was performed via the anterior transpetrosal approach. The tip of the trochlear nerve was fanned out and unified with the tumor. The tumor was diagnosed as a schwannoma. CONCLUSION: The patient's hemiparesis improved postoperatively, and he was discharged 1 week after the operation. Magnetic resonance imaging performed 4 months later revealed no regrowth of the tumor. Only right trochlear nerve palsy has persisted. This report is the second case of intratumoral hemorrhage from a trochlear nerve schwannoma. Copyright © Congress of Neurological Surgeons.

A 27-year-old female presented with gait disturbance and left facial paresthesia. She had a history of breast and lung masses not yet identified. Magnetic resonance (MR) imaging revealed a tumor suggesting a petroclival meningioma. Her symptoms worsened rapidly. MR imaging showed enlargement of the tumor. Subtotal removal of the tumor was performed. Histological examination revealed metastatic adenocarcinoma. Examination of the other masses confirmed adenocarcinoma originating from lung carcinoma. Dural metastases can be difficult to preoperatively differentiate from meningioma clinically or radiographically. MR spectroscopy and laboratory examinations such as cytologic and serologic studies are valuable for differential diagnosis. The final diagnosis of the tumor depends on the histological findings. However, careful monitoring of the patient's course is very important to detect rapid growth of metastases.

A 32-year-old woman was brought to the emergency room with hemiplegia on the left and consciousness disturbance. Her prior medical history and the circumstances of the onset were unknown. Brain computed tomography showed intracerebral hemorrhage (ICH) with a midline shift of more than 10 mm in the right parietal lobe. Cerebral angiography failed to show any vascular anomalies. Urine analysis with the triage system, a qualitative screening test for psychotropic drug abuse, showed positive reaction for amphetamines. Subsequent laboratory examination confirmed a highly elevated serum concentration of methamphetamine. The patient underwent evacuation of the hemorrhage via a craniotomy, and was discharged 40 days after admission. Abuse of illegal drugs including amphetamines among young adults is increasing in many developed countries, and the suspicion of possible drug abuse should always be raised in young patients with angiographically negative ICH. A urinalysis screening test for psychotropic agents should be a part of routine emergency room diagnostic procedures for such patients.

A 70-year-old woman, with. systemic lupus erythematosus presented with a brain abscess manifesting as I progressive monoparesis of the right lower extremity over 4 days. She had had no episodes of fever, and did not of complain of headache or exhibit any signs of meningeal irritability. Computed tomograph, the brain showed a round, low-density mass with strong ring enhancement in the left frontal lobe. Laboratory examination found a moderately elevated serum level of CA19-9, a marker of some digestive organ cancers. Together with the absence of febrile episodes, headache, and a rise in leukocyte count, the initial suspicion was metastatic brain tumor rather than brain abscess. However, diffusion-weighted magnetic resonance imaging depicted the mass as a very hyperintense area. The neuroimaging diagnosis was brain abscess. After conservative treatment with intravenous antibiotics for 6 weeks, the brain abscess completely resolved, and the patient was discharged without neurological deficits.

Severe metabolic acidosis develops following prolonged periods of cardiopulmonary arrest (CPA), and excessive hydrogen ions derived from lactate and other noxious acids cause marked hyperkalemia in most CPA patients. This study investigated whether the serum electrolyte imbalance in resuscitated CPA patients is affected by the etiology of the CPA. Between 1999 and 2000, return of spontaneous circulation (ROSC) was achieved and serum electrolyte concentration measurements and blood gas analysis (BGA) were performed in 65 of 270 CPA patients treated. Of the 65 patients, subarachnoid hemorrhage (SAH) was the cause of the CPA in ten, cardiac attack was the cause in 16 and asphyxia was the cause in nine patients. The clinical and laboratory data of these 35 patients were retrospectively compared among the three groups. The SAH group had significantly lower serum potassium concentrations than the other two groups and significantly higher glucose concentrations than the asphyxia group. Massive amounts of catecholamines are released into the systemic circulation of SAH patients and our results may indicate that the amount of catecholamines released in resuscitated SAH patients is greater than in heart attack or asphyxia patients, resulting in a lower serum potassium concentration despite the presence of severe metabolic acidosis. It should be clarified in a prospective study whether the presence of normokalemia and hyperglycemia in resuscitated CPA patients reliably predicts the presence of SAH. (C) 2002 Published by Elsevier Science Ireland Ltd.

A 69-year-old man underwent successful endovascular treatment of a posterior communicating artery aneurysm that had caused a third nerve palsy. Pupil size became normal within 10 days and ptosis and ocular ductions became normal within 3 weeks of the procedure. Based on the reported recovery rates of third nerve palsy after aneurysmal clipping, recovery may occur more rapidly in patients who undergo endovascular treatment. Further data are necessary to substantiate this hypothesis.