Kazuhiro Tanaka

Ludwig Institute for Cancer Research, La Jolla, California, United States

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Publications (25)140.78 Total impact

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    ABSTRACT: Here, we describe an extremely rare case of angiosarcoma arising in schwannoma of the cerebellopontine angle and later associating with meningioma in a patient with neurofibromatosis type 2. A 33-year-old disabled Japanese man with right drop foot after surgery for an unspecified tumor demonstrated multiple tumors, suspected to be schwannoma, in the bilateral cerebellopontine angles, the cervical and lumbar spinal cord, and on the right nuchal skin. Also present were several tumors in the medulla and thoracic spinal cord suspected to be ependymoma or astrocytoma. The patient was diagnosed with neurofibromatosis type 2 according to the diagnostic criteria by the U.S. National Institutes of Health. The bilateral tumors in the cerebellopontine angle were resected to reduce symptoms and brain stem compression. Histopathological analysis revealed angiosarcoma arising in schwannoma of the bilateral tumors, and angiosarcoma was proportionally larger in the right tumor than in the left. At age 36, the patient underwent a second resection of the regrown tumor in the left cerebellopontine angle, and histopathology demonstrated mixed angiosarcoma and meningioma. That angiosarcoma arises in schwannoma is a pathogenesis within the realm of conjecture, especially that the phenomenon of mixed meningioma and angiosarcoma has not been reported to date.
    Brain Tumor Pathology 03/2014; · 1.58 Impact Factor
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    ABSTRACT: BackgroundMRI group analysis is a powerful tool for elucidating pathological conditions in the brain that are challenging to reveal from single subject analysis. This research aimed to elucidate special distribution characteristics of primary central nervous system lymphoma (PCNSL) within the brain with respect to molecular marker expression patterns.MethodsMR images from 100 treatment-naive PCNSL patients were collected and registered onto averaged standard anatomical MRI (MNI152). Gadolinium-enhanced lesions were extracted, and a lesion frequency map was created. Lymphoma subtypes were classified as germinal center B (GCB) or non-GCB by immunohistochemistry in 90 patients.ResultsA PCNSL frequency map showed that these tumors tended to occur around the lateral, third and fourth ventricles. Moreover, GCB (27 cases) and non-GCB (63 cases) PCNSL frequency maps showed GCB lymphomas located at the upper tegmentum and cerebellum around the fourth ventricle, while non-GCB lymphomas tended to occupy the anterior fornix. These differences were significant and confirmed by the existence of voxels with P values <.05 (random permutation analysis with voxel-wise Fisher' exact test). This is the very first report to address phenotypical and spatial distributional differences between GCB and non-GCB PCNSL using an MR group analytical method.
    Neuro-Oncology 02/2014; · 6.18 Impact Factor
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    ABSTRACT: Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
    Cell metabolism 10/2013; · 17.35 Impact Factor
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    ABSTRACT: mTOR pathway hyperactivation occurs in nearly 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacological strategy to overcome it. We performed in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin resistant signaling and blocking GBM growth and a novel single cell technology, DNA Encoded Antibody Libraries, was used to identify mechanisms of resistance. Here we demonstrate that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling; block mTORC2 signaling and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes GBM cells and orthotopic xenografts to CC214-1 and CC214-2 induced cell death. These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in GBM and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. This study also demonstrates a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacological strategy for overcoming it.
    Clinical Cancer Research 09/2013; · 7.84 Impact Factor
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    ABSTRACT: Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.
    Cell metabolism 05/2013; · 17.35 Impact Factor
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    ABSTRACT: Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. Multiple genetic mechanisms of acquired TKI resistance have been identified in several types of human cancer. However, the possibility that cancer cells may also evade treatment by co-opting physiologically regulated receptors has not been addressed. Here we demonstrate the first example of this alternate mechanism in brain tumors by showing that EGFR-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing PDGFRβ. Mechanistic studies demonstrate that EGFRvIII signaling actively suppresses PDGFRβ transcription in an mTORC1 and ERK-dependent manner. Genetic or pharmacologic inhibition of oncogenic EGFR renders GBMs dependent on the consequently de-repressed PDGFRβ signaling for growth and survival. Importantly, combined inhibition of EGFR and PDGFRβ signaling potently suppresses tumor growth in vivo. These data identify a novel, non-genetic TKI resistance mechanism in brain tumors and provide compelling rationale for combination therapy.
    Cancer Discovery 03/2013; · 10.14 Impact Factor
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    ABSTRACT: Metabolomics has recently undergone rapid development; however, metabolomic analysis in cerebrospinal fluid (CSF) is not a common practice. We analyzed the metabolite profiles of preoperative CSF samples from 32 patients with histologically confirmed glioma using gas chromatography/mass spectrometry (GC/MS). We assessed how alterations in the metabolite levels were related to the World Health Organization (WHO) tumor grades, tumor location, gadolinium enhancement on magnetic resonance imaging (MRI), and the isocitrate dehydrogenase (IDH) mutation status. Sixty-one metabolites were identified in the CSF from glioma patients using targeted, quantitative and non-targeted, semi-quantitative analysis. The citric and isocitric acid levels were significantly higher in the glioblastoma (GBM) samples than in the grades I-II and grade III glioma samples. In addition, the lactic and 2-aminopimelic acid levels were relatively higher in the GBM samples than in the grades I-II glioma samples. The CSF levels of the citric, isocitric, and lactic acids were significantly higher in grade I-III gliomas with mutant IDH than in those with wild-type IDH. The tumor location and enhancement obtained using MRI did not significantly affect the metabolite profiles. Higher CSF levels of lactic acid were statistically associated with a poorer prognosis in grades III-IV malignant gliomas. Our study suggests that the metabolomic analysis of CSF from glioma patients may be useful for predicting the glioma grade, metabolic state, and prognosis of gliomas.
    Journal of Neuro-Oncology 03/2013; · 3.12 Impact Factor
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    ABSTRACT: INTRODUCTION: Preoperative knowledge of the position of the facial nerve relative to a vestibular schwannoma would be very helpful to decide for an adapted therapeutic strategy. The aim of this study is to assess the feasibility of predicting the course of the facial nerve in vestibular schwannoma patients using 3 T high-resolution magnetic resonance cisternography in a large consecutive series. METHODS: The study was prospectively conducted in 82 patients operated for vestibular schwannoma. All patients underwent preoperative gadolinium (Gd)-enhanced, balanced fast-field echo (bFFE) imaging. The course of the facial nerve was estimated preoperatively and the results were verified with the intraoperative findings. RESULTS: The facial nerve could be identified by preoperative MRI in 38 cases (46.3 %). In 28 cases (34.1 % of total patients, 73.7 % of identified patients), the course of the MRI-identified facial nerve was completely congruent with the intraoperative findings. In the patient group with MRI-identified facial nerves, tumor size was smaller and the number of solid type was larger. There were 23 cases where the tumor was solid and smaller than 20 mm. Nineteen (82.6 %) of those cases could estimate the facial nerve preoperatively and 16 cases (69.6 %) have complete congruency. CONCLUSION: Gd-enhanced bFFE at 3 T is capable of demonstrating the location of the facial nerve in vestibular schwannoma patients prior to surgery. Slices that were perpendicular to the internal auditory canal were useful besides axial images. In small, solid-type tumors, facial nerve was more easily identified than other types of tumors.
    Neuroradiology 02/2013; · 2.70 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and contribute to cell proliferation, differentiation and metabolism. Our previous study revealed the extensive modulation of a set of miRs in malignant glioma. In that study, miR microarray analysis demonstrated the upregulation of microRNA-183 (miR-183) in glioblastomas. Therefore, we examined the expression levels of miR-183 in various types of gliomas and the association of miR-183 with isocitrate dehydrogenase 2 (IDH2), which has complementary sequences to miR-183 in its 3'-untranslated region (3'UTR). In present study, we used real-time PCR analysis to demonstrate that miR-183 is upregulated in the majority of high-grade gliomas and glioma cell lines compared with peripheral, non-tumorous brain tissue. The mRNA and protein expression levels of IDH2 are downregulated via the overexpression of miR-183 mimic RNA in glioma cells. Additionally, IDH2 mRNA expression is upregulated in glioma cells expressing anti-miR-183. We verified that miR-183 directly affects IDH2 mRNA levels in glioma cells using luciferase assays. In malignant glioma specimens, the expression levels of IDH2 were lower in tumors than in the peripheral, non-tumorous brain tissues. HIF-1α levels were upregulated in glioma cells following transfection with miR-183 mimic RNA or IDH2 siRNA. Moreover, vascular endothelial growth factor and glucose transporter 1, which are downstream molecules of HIF-1α, were upregulated in cells transfected with miR-183 mimic RNA. These results suggest that miR-183 upregulation in malignant gliomas induces HIF-1α expression by targeting IDH2 and may play a role in glioma biology.
    Journal of Neuro-Oncology 12/2012; · 3.12 Impact Factor
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    ABSTRACT: We treated a 56-year-old woman who had a right temporal lobe tumor found by chance after a traffic accident. MRI confirmed a heterogeneously enhanced tumor in the temporal lobe with large peritumoral edema extending to the superior parietal lobe. The patient underwent tumor resection. The tumor consisted largely of distinct cells with discrete borders and granular cytoplasm. In granular cells, the accumulation of PAS-positive granules was observed. Immunohistochemical analysis demonstrated positive staining for GFAP, S-100, and oligodendrocyte transcription factor 2 and negative staining for synaptophysin. CD68 was negative in granular cells, but positive in stromal cells. Ki-67 labeling index was quite low. The tumor was diagnosed as a granular cell astrocytoma (GCA). Postoperative radiotherapy combined with temozolomide was administered. One month after chemoradiotherapy, the tumor occurred in the parietal lobe, and a tumorectomy was performed. The tumor was composed of poorly differentiated astrocytic tumor cells with prominent microvascular proliferation and necrosis. A small number of granular cells were locally observed and the tumor was diagnosed as a glioblastoma. O6-methylguanine-DNA methyltransferase promoter methylation was detected in the GCA but not in the glioblastoma. Isocitrate dehydrogenase mutations were not detected in either tumor. Comparative genomic hybridization analysis demonstrated that no chromosomal abnormality was found in the GCA; however, a gain of chromosomes 7 and 19 and a loss of chromosomes 10 and 9p21 (CDKN2A) were found in the glioblastoma. p53 was strongly expressed in both the GCA and glioblastoma. The tumor progressed despite extensive chemotherapy, and the patient died 1 year after the initial treatment. Our immunohistochemical, genetic and chromosomal analyses indicate that the glioblastoma was transformed from the GCA.
    Neuropathology 09/2012; · 1.91 Impact Factor
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.
    Proceedings of the National Academy of Sciences 08/2012; 109(35):14164-9. · 9.74 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Because mammalian target of rapamycin (mTOR) signaling is up-regulated in 50% of HCCs, we compared the effects of the U.S. Food and Drug Administration-approved mTOR-allosteric inhibitor, RAD001, with a new-generation phosphatidylinositol 3-kinase/mTOR adenosine triphosphate-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) dephosphorylation, which is implicated in the suppression of tumor cell proliferation. In a mouse model approximating human HCC, the drugs in combination, but not singly, induced a marked regression in tumor burden. However, in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggests that additional target(s) may also be involved. Microarray analyses revealed a large number of genes that reverted to normal liver tissue expression in mice treated with both drugs, but not either drug alone. These analyses also revealed the down-regulation of autophagy genes in tumors compared to normal liver. Moreover, in HCC patients, altered expression of autophagy genes was associated with poor prognosis. Consistent with these findings, the drug combination had a profound effect on UNC51-like kinase 1 (ULK1) dephosphorylation and autophagy in culture, independent of 4E-BP1, and in parallel induced tumor mitophagy, a tumor suppressor process in liver. These observations have led to an investigator-initiated phase 1B-2 dose escalation trial with RAD001 combined with BEZ235 in patients with HCC and other advanced solid tumors.
    Science translational medicine 04/2012; 4(139):139ra84. · 10.76 Impact Factor
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    ABSTRACT: Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer. SIGNIFICANCE: This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.
    Cancer Discovery 11/2011; 1(6):524-38. · 10.14 Impact Factor
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    ABSTRACT: Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)-dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1-dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.
    Cancer Discovery 09/2011; 1(5):442-56. · 10.14 Impact Factor
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    ABSTRACT: The phosphatase and tensin homolog (PTEN) is a tumor suppressor that is inactivated in many human cancers. PTEN loss has been associated with resistance to inhibitors of the epidermal growth factor receptor (EGFR), but the molecular basis of this resistance is unclear. It is believed that unopposed phosphatidylinositol-3-kinase (PI3K) activation through multiple receptor tyrosine kinases (RTKs) can relieve PTEN-deficient cancers from their "dependence" on EGFR or any other single RTK for survival. Here we report a distinct resistance mechanism whereby PTEN inactivation specifically raises EGFR activity by impairing the ligand-induced ubiquitylation and degradation of the activated receptor through destabilization of newly formed ubiquitin ligase Cbl complexes. PTEN-associated resistance to EGFR kinase inhibitors is phenocopied by expression of dominant negative Cbl and can be overcome by more complete EGFR kinase inhibition. PTEN inactivation does not confer resistance to inhibitors of the MET or PDGFRA kinase. Our study identifies a critical role for PTEN in EGFR signal termination and suggests that more potent EGFR inhibition should overcome resistance caused by PI3K pathway activation.
    Proceedings of the National Academy of Sciences 03/2010; 107(14):6459-64. · 9.74 Impact Factor
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    ABSTRACT: A 54-year-old man with Klinefelter syndrome presented with glioblastoma multiforme manifesting as a 2-week history of motor weakness of the bilateral extremities. Magnetic resonance imaging showed multiple heterogeneously enhanced tumors in the bilateral frontal lobes. Angiography showed no tumor stain or arteriovenous shunt. The tumor was partially removed through a right craniotomy. The histological diagnosis was glioblastoma. Immunohistochemical examination showed no O(6)-methylguanine-deoxyribonucleic acid methyltransferase protein expression. Postoperative local radiotherapy (60 Gy/30 fractions) combined with temozolomide (75 mg/m(2) x 42 days) and interferon-beta (3,000,000 U, 3 times/week) was performed. The patient's clinical status rapidly deteriorated during chemoradiotherapy, and he died of tumor progression 3.5 months after the surgery. Postmortem examination revealed widespread glioblastoma infiltrating the basal ganglia and thalamus. Klinefelter syndrome is associated with increased cancer predisposition, especially for male breast cancer and germ cell tumors, but glioma is extremely rare. The abnormal genetic constitution of this patient may have been directly responsible for the poor outcome.
    Neurologia medico-chirurgica 11/2009; 49(11):532-5. · 0.49 Impact Factor
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    ABSTRACT: A 49-year-old man was admitted suffering from headache persisting for a month. He had a history of primary spinal intramedullary malignant melanoma at the T6 level 18 years previously, which had remained stable for 18 years. Magnetic resonance imaging revealed central nervous system (CNS) dissemination of malignant melanoma. Whole brain radiation therapy (30 Gy), local radiation therapy (15 Gy), and routine intrathecal injection of interferon beta were performed. The progression of CNS dissemination of malignant melanoma was controlled without neurological deterioration for 38 months. The prognosis for primary CNS malignant melanomas better than that for cutaneous melanoma. However, the clinical course is still unknown, and CNS dissemination is regarded fatal. The unusually long survival in the present case indicates the effectiveness of the combined radiotherapy and interferon therapy.
    Neurologia medico-chirurgica 11/2009; 49(11):546-8. · 0.49 Impact Factor
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    ABSTRACT: Choroid plexus papilloma usually occurs in the lateral or the fourth ventricle. Primary choroid plexus papilloma of the cerebellopontine angle, as described here, is an uncommon lesion. A 42-year-old man presented with a 1-month history of dysphagia and gait unsteadiness. CT scans and MRI showed a large extra-axial tumor in the right cerebellopontine angle. Pathological study revealed that the lesion was choroid plexus papilloma. Repeat imaging conducted 1 year after the operation showed that the tumor had recurred with distinct cystic features. Pathological examination again revealed increased mitotic activity and supported a diagnosis of atypical choroid plexus papilloma.
    Journal of Clinical Neuroscience 12/2008; 16(1):121-4. · 1.25 Impact Factor
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    ABSTRACT: Various radiation-induced tumors, including meningioma, glioma, and sarcoma, have been reported; however, metachronous intracranial double tumors induced by radiation therapy are extremely rare. A 1-year-old boy had undergone tumor removal and craniospinal radiation therapy (30 Gy) for cerebellar medulloblastoma. At 24 years old, parasagittal meningioma developed in the left parietal region and was totally removed. Six years later, an infiltrative tumor was newly found in the right fronto-temporal white matter. The patient underwent stereotactic biopsy, and the tumor was found to be an anaplastic astrocytoma. Chromosomal analysis by fluorescence in situ hybridization (FISH) revealed loss of heterozygosity (LOH) of 1p. As the patient had previously had craniospinal irradiation, no additional radiation therapy was delivered. He underwent chemotherapy with temozolomide and the disease is now stable. Since both secondary tumors were located within the area of previous radiation and the patient did not have any genetic disease predisposing him to tumors, radiation therapy was considered to be responsible for their tumorigenesis. To our knowledge, this case is the fourth case of radiation-induced double CNS tumors arising after radiotherapy to be described in the literature. Whenever radiation is administered to children or young adults, careful serial screening studies are needed.
    Journal of Neuro-Oncology 08/2008; 88(3):315-20. · 3.12 Impact Factor
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    ABSTRACT: Chalcones are considered the precursors of flavonoids and have been identified as interesting compounds with antitumor properties. Boronic-chalcone derivatives are more toxic to breast cancer cells compared to normal breast cells. Here, we studied the antitumor activities of trans-4-lodo,4'-boranyl-chalcone (TLBC), which is a boronic-chalcone derivative, in several glioma cell lines. TLBC showed a dose-dependent inhibition with inhibitory concentration 50% value in the muM range (5.5-25.5 microM) in various glioma cell lines. Flow cytometric and western blot assay demonstrated that TLBC induced apoptosis independent of changes to the tumor suppressor p53. This cytotoxic effect was the caspase-dependent manner. Also, TLBC lowered levels of anti-apoptotic Bcl-2 and/or Bcl-X(L) protein in several of the cell lines. To examine the antitumor effect of TLBC in vivo, we used a malignant glioma xenograft model. This result showed that in the mice treated with TLBC at 20 mg/kg, mean tumor volume was reduced by 43.9% (P < 0.01) in comparison with the control group. Immunohistochemical and western blot analysis showed that Bcl-2 protein levels were decreased and Bax protein levels were slightly increased in the tumors injected with 20 mg/kg TLBC compared with the control tumors. Therefore, we conclude that TLBC may be a potential chemotherapeutic agent for human glioma.
    Journal of Neuro-Oncology 11/2007; 85(2):123-32. · 3.12 Impact Factor

Publication Stats

188 Citations
140.78 Total Impact Points

Institutions

  • 2013
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 2006–2013
    • Kobe University
      • Division of Neurosurgery
      Kōbe, Hyōgo, Japan
  • 2011–2012
    • University of California, Los Angeles
      • Department of Pathology and Laboratory Medicine
      Los Angeles, California, United States
    • The Ohio State University
      • Department of Radiation Oncology
      Columbus, OH, United States
  • 2008
    • Hyogo Brain and Heart Center
      Himezi, Hyōgo, Japan
  • 2005
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan