Publications by authors named "Tomoo Matsutani"

33 Publications

CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy.

Cancer Immunol Immunother 2021 May 31;70(5):1239-1254. Epub 2020 Oct 31.

Department of Medical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cell-mediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients.
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http://dx.doi.org/10.1007/s00262-020-02742-1DOI Listing
May 2021

Association between serum anti‑ASXL2 antibody levels and acute ischemic stroke, acute myocardial infarction, diabetes mellitus, chronic kidney disease and digestive organ cancer, and their possible association with atherosclerosis and hypertension.

Int J Mol Med 2020 Oct 29;46(4):1274-1288. Epub 2020 Jul 29.

Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan.

The aim of the present study was to identify novel antibody markers for the early diagnosis of atherosclerosis in order to improve the prognosis of patients at risk for acute ischemic stroke (AIS) and acute myocardial infarction (AMI). A first screening involved the serological identification of antigens by recombinant cDNA expression cloning and identified additional sex combs‑like 2 (ASXL2) as a target antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. Antigens, including the recombinant glutathione S‑transferase‑fused ASXL2 protein and its synthetic peptide were then prepared to examine serum antibody levels. Amplified luminescence proximity homogeneous assay‑linked immunosorbent assay, which incorporates glutathione‑donor beads and anti‑human‑IgG‑acceptor beads, revealed significantly higher serum antibody levels against the ASXL2 protein and its peptide in the patients with AIS, diabetes mellitus, AMI, chronic kidney disease, esophageal squamous cell carcinoma, or colorectal carcinoma compared with those in healthy donors. The ASXL2 antibody levels were well associated with hypertension complication, but not with sex, body mass index, habitual smoking, or alcohol intake. These results suggest that the serum ASXL2 antibody marker can discriminate between hypertension‑induced atherosclerotic AIS and AMI, as well as a number of digestive organ cancers.
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http://dx.doi.org/10.3892/ijmm.2020.4690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447314PMC
October 2020

Serum anti-LRPAP1 is a common biomarker for digestive organ cancers and atherosclerotic diseases.

Cancer Sci 2020 Dec 4;111(12):4453-4464. Epub 2020 Oct 4.

Department of Gastroenterological Surgery and Clinical Oncology, Toho University Graduate School of Medicine, Tokyo, Japan.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti-human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S-transferase-fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis-related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well-known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking.
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http://dx.doi.org/10.1111/cas.14652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734161PMC
December 2020

Elevated levels of autoantibodies against DNAJC2 in sera of patients with atherosclerotic diseases.

Heliyon 2020 Aug 19;6(8):e04661. Epub 2020 Aug 19.

Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Background: Serum antibody markers have been increasingly identified not only for cancer and autoimmune diseases but also for atherosclerosis-related diseases such as acute ischemic stroke (AIS), acute myocardial infarction (AMI), diabetes mellitus (DM), and chronic kidney disease (CKD). Biomarkers for transient ischemic attack (TIA) and non-ST segment elevation acute coronary syndrome (NSTEACS) are potentially useful for detection of early phase of atherosclerotic changes against AIS and AMI, respectively.

Methods: We utilized serological identification of antigens by recombinant cDNA expression cloning (SEREX) using a human aortic endothelial cell cDNA phage library and sera from patients with TIA or NSTEACS. Serum antibody levels were measured by amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using purified recombinant antigens.

Results: Screening of sera from patients with TIA identified DnaJ heat shock protein family (Hsp40) member C2 (DNAJC2) as a candidate antigen, which was also isolated by SEREX screening using sera of patients with NSTEACS. The validation cohort revealed significantly higher DNAJC2 antibody (DNAJC2-Ab) levels in the sera of patients with TIA or AIS than those in healthy donors (HDs). Multivariate logistic regression analysis indicated that the predictive odds ratios (OR) of DNAJC2-Ab levels for TIA and AIS were 2.54 (95% confidence interval [CI]: 1.36-4.74, = 0.0034) and 2.14 (95% CI: 1.39-3.30, = 0.0005), respectively. Serum DNAJC2-Ab levels were also higher in patients with AMI, DM, and CKD than those in HDs.

Conclusion: Serum DNAJC2-Ab level may be useful for early detection of atherosclerotic lesions, which lead to AIS and AMI.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452465PMC
August 2020

Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

Breast Cancer Res Treat 2020 Nov 1;184(1):149-159. Epub 2020 Aug 1.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Introduction: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy.

Methods: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis.

Results: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03).

Conclusions: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.
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http://dx.doi.org/10.1007/s10549-020-05835-8DOI Listing
November 2020

Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients.

Neurooncol Pract 2020 Jan 3;7(1):111-117. Epub 2019 Dec 3.

Department of Neurosurgery, Keio University School of Medicine, Japan.

Background: The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients.

Methods: Seven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated.

Results: The histopathological diagnoses were isocitrate dehydrogenase () wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and -mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m) followed by adjuvant 5-day TMZ (150 mg/m) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan.

Conclusions: Decreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.
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http://dx.doi.org/10.1093/nop/npz034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993037PMC
January 2020

Eighty percent survival rate at 15 years for 1p/19q co-deleted oligodendroglioma treated with upfront chemotherapy irrespective of tumor grade.

J Neurooncol 2019 Jan 18;141(1):205-211. Epub 2018 Dec 18.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Chiba, Japan.

Introduction: Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification. Although treatment for oligodendroglioma is controversial, upfront chemotherapy is regarded as one of the treatment option for low-grade tumor. We have treated all the 1p/19q co-deleted oligodendrogliomas, both grades II and III, with upfront chemotherapy without conventional radiotherapy for 20 years. The clinical experience from this trial may be suggestive for understanding of the biological features of oligodendroglioma with 1p/19q co-deletion toward precision medicine.

Methods: This is a long-term retrospective data of the non-selected patients with 1p/19q co-deleted oligodendrogliomas uniformly treated with up-front chemotherapy. Seventy consecutive patients (48 with grade II and 22 with grade III tumors) were included.

Results: The median follow-up period was 13 years. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 85.7%, 54.8%, and 31.5%, respectively, and the median PFS was 146 months. In most cases, tumor recurrence was remained local and could be controlled by salvage surgery and/or chemotherapy. The 5-, 10-, and 15-year overall survival (OS) rates were 96.8%, 88.7%, and 80.0%, respectively, and the median OS was not reached. These survival data compared favorably with previous large clinical studies employing radiotherapy. Tumor grades based on World Health Organization classification, extent of surgery, and age affected neither PFS nor OS. Most patients were able to return to their premorbid social life.

Conclusions: The long-term results drawn from 20-years of single institution experience show that the patients with 1p/19q co-deleted oligodendrogliomas can be successfully treated with up-front chemotherapy alone without compromising OS.
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http://dx.doi.org/10.1007/s11060-018-03027-5DOI Listing
January 2019

Real-time methylation-specific PCR for the evaluation of methylation status of MGMT gene in glioblastoma.

Oncotarget 2018 Jun 12;9(45):27728-27735. Epub 2018 Jun 12.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene is a strong predictor for the efficacy of temozolomide chemotherapy and survival periods. However, the correlation between the extent of methylation and the difference in survival times has not been fully clarified. Simple and quantitative evaluations of the methylation status in the promotor region of the MGMT gene are expected to be worldwide standardized diagnostics. We applied real-time semi-quantitative methylation-specific polymerase chain reaction (SQ-MSP) of the MGMT gene promoter region to 84 glioblastoma patients. The SQ-MSP result showed that the ΔCt value, which represents the difference between uCt and mCt (uCt value - mCt value), is inversely correlated with overall survival. With adequate cutoff setting, this assay showed that those patients suffering from a tumor with low ΔCt (methylated) survived significantly longer than those having tumors with high ΔCt (un-methylated). The most significant difference was observed when the cutoff was set at a ΔCt of 2. Using this cutoff point, the result of MGMT immunohistochemical analysis was also significantly correlated with the methylation status examined with real-time SQ-MSP. These results collectively show that MGMT promoter methylation status actually affects patients' survival and protein expression depending on its methylation level, and the extent of methylated CpGs would be better assessed with real-time SQ-MSP than with the standard gel-based MSP. This method is cost- and labor-saving compared with pyrosequencing, and significantly contributes to the accurate and objective prediction of patient survival.
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http://dx.doi.org/10.18632/oncotarget.25543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021237PMC
June 2018

Hammock Middle Cerebral Artery and Delayed Infarction in Lenticulostriate Artery After Staged Resection of Giant Insular Glioma.

World Neurosurg 2018 Sep 7;117:80-83. Epub 2018 Jun 7.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chuo-ku, Chiba-city, Chiba, Japan.

Background: Delayed infarction in the lenticulostriate artery (LSA) area after insular glioma resection is not common, and its pathophysiology remains unknown.

Case Description: A 32-year-old right-handed man with a giant insular low-grade glioma with frontal and temporal extension underwent awake craniotomy with an intentional staged surgery strategy. Preoperative radiologic images demonstrated a diagonally elevated middle cerebral artery (MCA) by the temporal tumor and a significantly compressed striatum. With intraoperative subcortical direct electrical stimulation, the resection was finalized in the temporal part of the tumor due to the semantic paraphasia induced in the temporal stem, fatigue, and loss of concentration. The immediate postoperative clinical course was uneventful. However, on postoperative day 20, he suddenly experienced right hemiparesis. Repeated images revealed infarction in the LSA area. The previously compressed striatum was then relieved and relocated to its original position in just 20 days, and the M1 segment of the MCA was remarkably downward, in which the MCA resembled a hammock. Angiography confirmed the hammock-shaped MCA and significantly stretched LSA, suggesting the combination of freed striatum from the compression and loss of temporal structure by the tumor resection as the key mechanism of severe dislocation of the MCA and delayed ischemia.

Conclusions: In a staged resection of giant insular glioma, attention should be paid to a possible severe dislocation of the MCA in a delayed postoperative period, which may lead to LSA stretching and delayed infarction.
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http://dx.doi.org/10.1016/j.wneu.2018.05.226DOI Listing
September 2018

Association of serum levels of antibodies against MMP1, CBX1, and CBX5 with transient ischemic attack and cerebral infarction.

Oncotarget 2018 Jan 31;9(5):5600-5613. Epub 2017 Dec 31.

Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.

Transient ischemic attack (TIA) is a predictor for cerebral infarction (CI), and early diagnosis of TIA is extremely important for the prevention of CI. We set out to identify novel antibody biomarkers for TIA and CI, and detected matrix metalloproteinase 1 (MMP1), chromobox homolog 1 (CBX1), and chromobox homolog 5 (CBX5) as candidate antigens using serological identification of antigens by recombinant cDNA expression cloning (SEREX) and Western blotting to confirm the presence of serum antibodies against the antigens. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) revealed that serum antibody levels were significantly higher in patients with TIA or acute-phase CI (aCI) compared with healthy donors ( < 0.01). Spearman's correlation analysis and multivariate logistic regression analysis demonstrated that levels of anti-MMP1, anti-CBX1, and anti-CBX5 antibodies were associated with age, cigarette-smoking habits, and blood pressure. Thus, serum levels of antibodies against MMP1, CBX1, and CBX5 could potentially serve as useful tools for diagnosing TIA and predicting the onset of aCI.
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http://dx.doi.org/10.18632/oncotarget.23789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814161PMC
January 2018

The Pluripotent Stem-Cell Marker Alkaline Phosphatase is Highly Expressed in Refractory Glioblastoma with DNA Hypomethylation.

Neurosurgery 2017 02;80(2):248-256

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Hypomethylation of genomic DNA induces stem-cell properties in cancer cells and contributes to the treatment resistance of various malignancies.

Objective: To examine the correlation between the methylation status of stem-cell-related genes and the treatment outcomes in patients with glioblastoma (GBM).

Methods: The genome-wide DNA methylation status was determined using HumanMethylation450 BeadChips, and the methylation status was compared between a group of patients with good prognosis (survival > 4 yr) and a group with poor prognosis (survival < 1 yr). Immunohistochemistry for proteins translated from hypomethylated genes, including alkaline phosphatase (ALPL), CD133, and CD44, was performed in 70 GBMs and 60 oligodendroglial tumors.

Results: The genomic DNA in refractory GBM was more hypomethylated than in GBM from patients with relatively long survival (P = .0111). Stem-cell-related genes including ALPL, CD133, and CD44 were also significantly hypomethylated. A validation study using immunohistochemistry showed that DNA hypomethylation was strongly correlated with high protein expression of ALPL, CD133, and CD44. GBM patients with short survival showed high expression of these stem-cell markers. Multivariate analysis confirmed that co-expression of ALPL + CD133 or ALPL + CD44 was a strong predictor of short survival. Anaplastic oligodendroglial tumors without isocitrate dehydrogenase 1 mutation were significantly correlated with high ALPL expression and poor survival.

Conclusion: Accumulation of stem-cell properties due to aberrant DNA hypomethylation is associated with the refractory nature of GBM.
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http://dx.doi.org/10.1093/neuros/nyw026DOI Listing
February 2017

Transforming growth factor-β and stem cell markers are highly expressed around necrotic areas in glioblastoma.

J Neurooncol 2016 08 18;129(1):101-7. Epub 2016 May 18.

Department of Neurological Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-2870, Japan.

Invasion into surrounding normal brain and resistance to genotoxic therapies are the main devastating aspects of glioblastoma (GBM). These biological features may be associated with the stem cell phenotype, which can be induced through a dedifferentiation process known as epithelial-mesenchymal transition (EMT). We show here that tumor cells around pseudopalisading necrotic areas in human GBM tissues highly express the most important EMT inducer, transforming growth factor (TGF-β), concurrently with the EMT-related transcriptional factor, TWIST. In addition, the stem cell markers CD133 and alkaline phosphatase (ALPL) were also highly expressed around necrotic foci in GBM tissues. The high expression of TGF-β around necrotic regions was significantly correlated with shorter progression-free survival and overall survival in patients with GBM. High expression of stem cell markers, ALPL, CD133, and CD44 was also correlated with poor outcomes. These results collectively support the hypothesis that tissue hypoxia induces the stem cell phenotype through TGF-β-related EMT and contributes to the poor outcome of GBM patients.
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http://dx.doi.org/10.1007/s11060-016-2145-6DOI Listing
August 2016

Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma.

Cancer Cell 2016 Apr;29(4):563-573

Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.

Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.
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http://dx.doi.org/10.1016/j.ccell.2016.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831071PMC
April 2016

Molecular imaging of 1p/19q deletion in oligodendroglial tumours with 11C-methionine positron emission tomography.

J Neurol Neurosurg Psychiatry 2016 Sep 4;87(9):1016-21. Epub 2016 Feb 4.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Objective: Chromosome 1p/19q deletion is an established prognostic and predictive marker in the WHO grade III oligodendroglial tumours (OT). To estimate the genetic status preoperatively, the authors investigated the correlation between the uptake of (11)C-methionine in positron emission tomography (PET) and the 1p/19q status in grades II and III OT.

Methods: We retrospectively reviewed 144 patients with gliomas who received (11)C-methionine PET. 66 cases with grades II-III oligodendrogliomas or oligoastrocytomas underwent fluorescence in situ hybridisation to determine the 1p/19q status. The tissue uptake of (11)C-methionine was expressed as the ratio of the maximum standardised uptake value (SUVmax) in tumour areas to the mean SUV (SUVmean) in the contralateral normal brain (tumour-to-normal tissue (T/N) ratio).

Results: The T/N ratio in (11)C-methionine PET was significantly higher in grade III OT than in grade II tumours. The mean T/N ratio of the grade II tumours without 1p/19q deletion was significantly higher than that of the grade II tumours with 1p/19q deletion (mean 2.67 vs 1.94, respectively; p=0.0457). In grade III tumours, the mean T/N ratio of the tumours without 1p/19q deletion was also significantly higher than that of the tumours with 1p/19q deletion (mean 4.83 vs 3.49, respectively; p=0.0261). The rate of IDH1 mutation was lower and the rate of contrast enhancement on MRIs was higher in the 1p/19q non-deleted OT than those with 1p/19q deletion, which may contribute to the high T/N ratio.

Conclusions: Among suspected OT, (11)C-methionine PET may help us preoperatively discriminate tumours with and without 1p/19q deletion.
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http://dx.doi.org/10.1136/jnnp-2015-311516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013113PMC
September 2016

Intrinsic protective mechanisms of the neuron-glia network against glioma invasion.

J Clin Neurosci 2016 Apr 4;26:19-25. Epub 2016 Jan 4.

Department of Neurological Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.

Gliomas arising in the brain parenchyma infiltrate into the surrounding brain and break down established complex neuron-glia networks. However, mounting evidence suggests that initially the network microenvironment of the adult central nervous system (CNS) is innately non-permissive to glioma cell invasion. The main players are inhibitory molecules in CNS myelin, as well as proteoglycans associated with astrocytes. Neural stem cells, and neurons themselves, possess inhibitory functions against neighboring tumor cells. These mechanisms have evolved to protect the established neuron-glia network, which is necessary for brain function. Greater insight into the interaction between glioma cells and the surrounding neuron-glia network is crucial for developing new therapies for treating these devastating tumors while preserving the important and complex neural functions of patients.
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http://dx.doi.org/10.1016/j.jocn.2015.07.024DOI Listing
April 2016

IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy.

J Neurooncol 2015 Sep 5;124(3):493-500. Epub 2015 Aug 5.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan.

Despite accumulating knowledge regarding molecular backgrounds, the optimal management strategy for low-grade gliomas remains controversial. One reason is the marked heterogeneity in the clinical course. To establish an accurate subclassification of low-grade gliomas, we retrospectively evaluated isocitrate dehydrogenase-1 (IDH1) mutation in clinical specimens of diffuse astrocytomas (DA) and oligodendroglial tumors separately. No patients were treated with early radiotherapy, and modified PCV chemotherapy was used for postoperative residual tumors or recurrence in oligodendroglial tumors. Immunohistochemical evaluation of IDH status, p53 status, O(6)-methylguanine methyltransferase expression, and the MIB-1 index were performed. The 1p and 19q status was analyzed with fluorescence in situ hybridization. Ninety-four patients were followed for a median period of 8.5 years. For DAs, p53 was prognostic for progression- free survival (PFS) and IDH1 was significant for overall survival (OS) with multivariate analysis. In contrast, for oligodendroglial tumors, none of the parameters was significant for PFS or OS. Thus, the significance of IDH1 mutation is not clear in oligodendroglial tumors that are homogeneously indolent and chemosensitive. In contrast, DAs are heterogeneous tumors including some potentially malignant tumors that can be predicted by examining the IDH1 mutation status.
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http://dx.doi.org/10.1007/s11060-015-1863-5DOI Listing
September 2015

A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.

Cancer 2015 Oct 15;121(19):3481-90. Epub 2015 Jul 15.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.

Background: The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC-223 in patients with advanced cancer.

Methods: Patients with advanced solid tumors or multiple myeloma received an initial dose of 7.5-60 mg of CC-223, followed by oral daily dosing in 28-day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy.

Results: Twenty-eight patients were enrolled and received ≥1 dose of CC-223. The most common treatment-related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose-limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg/d was determined to be the MTD. The pharmacokinetics of CC-223 demonstrated a mean terminal half-life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng/mL in patients who received CC-223 ≥45 mg/d. Phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells was inhibited by CC-223 ≥30 mg/d with an exposure-response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30-mg/d cohort), stable disease (8 patients across ≥15 mg/d cohorts; response duration range, 36-168 days), and progressive disease (12 patients). The disease control rate was 32%.

Conclusions: CC-223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed.
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http://dx.doi.org/10.1002/cncr.29422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832308PMC
October 2015

Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas.

BMC Cancer 2014 Jun 18;14:452. Epub 2014 Jun 18.

Department of Neurological Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.

Background: Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers.

Methods: We searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas.

Results: FLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients' sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC.

Conclusions: The present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study.
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http://dx.doi.org/10.1186/1471-2407-14-452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094678PMC
June 2014

Direct application of MALDI-TOF mass spectrometry to cerebrospinal fluid for rapid pathogen identification in a patient with bacterial meningitis.

Clin Chim Acta 2014 Aug 4;435:59-61. Epub 2014 May 4.

Division of Laboratory Medicine, Clinical Genetics and Proteomics, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Background: Bacterial meningitis is a neurological emergency. Early diagnosis and rapid initiation of antimicrobial therapy are vital.

Methods: Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is increasingly used as a rapid and accurate microbial diagnostic method for species identification of pathogens. Although this technology requires a growth step to obtain bacterial colonies for the acquisition of substantial spectra in most cases, it can also be used to analyze clinical specimens such as urine and cerebrospinal fluid for direct bacterial identification. There are very few reports describing the use of MALDI-TOF MS for the direct detection of microorganisms causing bacterial meningitis.

Results: We describe a case of bacterial meningitis caused by Klebsiella pneumoniae in which MALDI-TOF MS provided a rapid bacteriological diagnosis, thus enabling early and appropriate treatment.

Conclusions: Identification of microbes based on MALDI-TOF MS is now an important technology in clinical microbiology laboratories that are required to provide a rapid diagnosis of bacterial meningitis.
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http://dx.doi.org/10.1016/j.cca.2014.04.024DOI Listing
August 2014

Non-deep-seated primary CNS lymphoma: therapeutic responses and a molecular signature.

J Neurooncol 2014 Apr 1;117(2):261-8. Epub 2014 Feb 1.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan,

The survival of patients with primary CNS lymphoma (PCNSL) has been improved by high-dose methotrexate (HD-MTX). Since the combination therapy of HD-MTX and whole-brain radiotherapy (WBRT) carries a significant risk for delayed neurotoxicity, it is important to know the therapeutic potential and prognostic factors for HD-MTX without WBRT. We retrospectively reviewed 46 consecutive patients with PCNSL treated with a HD-MTX (3.5 g/m(2)) and deferred WBRT. Patients who achieved complete response or partial response after three courses of HD-MTX were cautiously followed-up without additional treatment. Patients who had either stable disease, progressive disease, or disease relapse were offered salvage therapy. The median progression-free survival period was 10 months and the median overall survival period was 52 months, with a 5-year survival rate of 39 %. Nineteen patients (49 % of the evaluable patients) achieved a complete response at the initial response assessment. Involvement of deep structures of the brain (corpus callosum, basal ganglia and brainstem) was significantly associated with the worse progression-free survivals (p = 0.0058) and overall survivals (p = 0.0177). Gene expression profiling analysis by microarray was compared in eight patients between PCNSLs located in the deep structures of the brain and non-deep-seated tumors. The result showed that up-regulation of signal transduction-related genes and down-regulation of catalytic activity-related genes in the non-deep-seated PCNSL compared with the deep-seated tumors. The present study shows that PCNSL located in non-deep structures of the brain responds better to HD-MTX alone than those involved deep-structures.
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http://dx.doi.org/10.1007/s11060-014-1379-4DOI Listing
April 2014

mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc.

Cell Metab 2013 Nov 17;18(5):726-39. Epub 2013 Oct 17.

Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.

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.
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http://dx.doi.org/10.1016/j.cmet.2013.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840163PMC
November 2013

The mTOR kinase inhibitors, CC214-1 and CC214-2, preferentially block the growth of EGFRvIII-activated glioblastomas.

Clin Cancer Res 2013 Oct 12;19(20):5722-32. Epub 2013 Sep 12.

Authors' Affiliations: Laboratory of Molecular Pathology, Ludwig Institute for Cancer Research; Moores Cancer Center; University of California San Diego, La Jolla; Celgene Corporation, San Diego; Department of Neurological Surgery and Brain Tumor Research Center, University of California at San Francisco, San Francisco; California Institute of Technology, Pasadena; Henry Singleton Brain Tumor Program; Jonsson Comprehensive Cancer Center; Department of Neurology, David Geffen UCLA School of Medicine; Department of Molecular and Medical Pharmacology; UCLA Medical Scientist Training Program, University of California, Los Angeles, Los Angeles, California; Celgene Corporation, Summit, New Jersey; Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center and Arthur G. James Cancer Hospital, Columbus, Ohio; Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Verona, Italy; INSERM; Metabolomics Platform, Institut Gustave Roussy, Villejuif; Université Paris Descartes/Sorbonne Paris Cité; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers; and Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France.

Purpose: mTOR pathway hyperactivation occurs in approximately 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 pharmacologic strategy to overcome it.

Experimental Design: We conducted 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 glioblastoma growth and a novel single-cell technology-DNA Encoded Antibody Libraries-was used to identify mechanisms of resistance.

Results: Here, we show 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 glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2-induced cell death.

Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815450PMC
October 2013

PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.

Proc Natl Acad Sci U S A 2013 Mar 25;110(11):4339-44. Epub 2013 Feb 25.

Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.

Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.
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http://dx.doi.org/10.1073/pnas.1217602110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600508PMC
March 2013

Autologous antibody to src-homology 3-domain GRB2-like 1 specifically increases in the sera of patients with low-grade gliomas.

J Exp Clin Cancer Res 2012 Oct 11;31:85. Epub 2012 Oct 11.

Departments of Neurological Surgery, Chiba University, Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.

Background: Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable in spite of various therapeutic approaches. Clarification of the oncogenic process in its early stage is important for the diagnosis and effective therapy.

Methods: In the present study, we used the serological identification of antigens by recombinant cDNA expression cloning (SEREX) to explore the subtle changes of the protein expression in low-grade glioma. The levels of serum autoantibodies to the SEREX-identified glioma-related antigens were analyzed by ELISA, and the epitope site was identified using deletion mutants and overlap peptide array. Changes in the serum autoantibody levels were examined in the rat glioma model using C6 and 9 L glioma cell lines.

Results: We identified 31 glioma-related antigens by SEREX. Among them, the serum level of autoantibody to src-homology 3-domain GRB2-like 1 (SH3GL1) was significantly higher in patients with low-grade glioma than healthy volunteers or high-grade gliomas. The 10 amino-acids at the C-terminal were identified as the epitope site by the overlap peptide array and the ELISA using deletion mutants. The tissue expression of SH3GL1 protein increased in proportion to glioma progression. The rat glioma models confirmed the increase of anti-SH3GL1 autoantibody level in the early stage and the suppression in the late stage.

Conclusion: SH3GL1 may be involved in the oncogenic process of gliomas and effectively elicit an autologous antibody response in low-grade gliomas. The immunological reaction to SH3GL1 would contribute to the establishment of a novel diagnostic and therapeutic target for gliomas.
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http://dx.doi.org/10.1186/1756-9966-31-85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548755PMC
October 2012

mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma.

Sci Transl Med 2012 Jun 25;4(139):139ra84. Epub 2012 Apr 25.

Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH 45215, USA.

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.
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http://dx.doi.org/10.1126/scitranslmed.3003923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703151PMC
June 2012

Anaplastic oligodendroglial tumors harboring 1p/19q deletion can be successfully treated without radiotherapy.

Anticancer Res 2011 Dec;31(12):4475-9

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan.

Although anaplastic oligodendroglial tumors are known to be chemosensitive, patients under this diagnosis have been traditionally treated with radiotherapy. To avoid possible neurotoxicity, we prospectively treated patients with anaplastic oligodendroglial tumors harboring 1p/19q deletion, with exclusive procarbazine, ACNU, and vincristine chemotherapy without radiotherapy. Twenty-five patients were enrolled in the study (12 with 1p/19q co-deletion, 2 with 1p mono-deletion, 2 with 19q mono-deletion, and 9 without 1p/19q deletion). The median progression-free survival (PFS) was 50 months for all the patients, and those with tumors harboring 1p/19q deletion were progression free for a significantly longer period than those without the deletion (p=0.0391). The median overall survival (OS) time was not reached in both patient groups with and without 1p/19q deletion (p=0.230), and the 5-year OS rate was 62.2% for all patients. The excellent treatment results warrant a large-scale clinical study to confirm the efficacy of upfront chemotherapy omitting radiotherapy as initial therapy for anaplastic oligodendroglial tumors with 1p/19q deletion.
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December 2011

Metabolic state of glioma stem cells and nontumorigenic cells.

Proc Natl Acad Sci U S A 2011 Sep 7;108(38):16062-7. Epub 2011 Sep 7.

Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.

Gliomas contain a small number of treatment-resistant glioma stem cells (GSCs), and it is thought that tumor regrowth originates from GSCs, thus rendering GSCs an attractive target for novel treatment approaches. Cancer cells rely more on glycolysis than on oxidative phosphorylation for glucose metabolism, a phenomenon used in 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography imaging of solid cancers, and targeting metabolic pathways in cancer cells has become a topic of considerable interest. However, if GSCs are indeed important for tumor control, knowledge of the metabolic state of GSCs is needed. We hypothesized that the metabolism of GSCs differs from that of their progeny. Using a unique imaging system for GSCs, we assessed the oxygen consumption rate, extracellular acidification rate, intracellular ATP levels, glucose uptake, lactate production, PKM1 and PKM2 expression, radiation sensitivity, and cell cycle duration of GSCs and their progeny in a panel of glioma cell lines. We found GSCs and progenitor cells to be less glycolytic than differentiated glioma cells. GSCs consumed less glucose and produced less lactate while maintaining higher ATP levels than their differentiated progeny. Compared with differentiated cells, GSCs were radioresistant, and this correlated with a higher mitochondrial reserve capacity. Glioma cells expressed both isoforms of pyruvate kinase, and inhibition of either glycolysis or oxidative phosphorylation had minimal effect on energy production in GSCs and progenitor cells. We conclude that GSCs rely mainly on oxidative phosphorylation. However, if challenged, they can use additional metabolic pathways. Therefore, targeting glycolysis in glioma may spare GSCs.
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http://dx.doi.org/10.1073/pnas.1106704108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179043PMC
September 2011

Discrimination between low-grade oligodendrogliomas and diffuse astrocytoma with the aid of 11C-methionine positron emission tomography.

J Neurosurg 2011 Jun 7;114(6):1640-7. Epub 2011 Jan 7.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Japan.

Object: The diagnostic usefulness of (11)C-methionine PET scans in gliomas is still controversial. The authors investigated the clinical significance of (11)C-methionine PET findings in preoperative diagnosis of histological type and grade.

Methods: The tissue uptake of (11)C-methionine was assessed using PET in 70 patients with histologically confirmed intracerebral gliomas. The ratio of maximum standard uptake values in tumor areas to the mean standard uptake values in the contralateral normal brain tissue (tumor/normal tissue [T/N] ratio) was calculated and correlated with tumor type, histological grade, contrast enhancement on MR imaging, Ki 67 labeling index, and 1p/19q status.

Results: The T/N ratio was significantly increased as tumor grade advanced in astrocytic tumors (WHO Grade II vs Grade III, p = 0.0011; Grade III vs Grade IV, p = 0.0007). Among Grade II gliomas, the mean T/N ratio was significantly higher in oligodendroglial tumors than in diffuse astrocytomas (DAs) (p < 0.0001). All T/N ratios for oligodendroglial tumors were ≥ 1.46, and those for DA were consistently < 1.46, with the exception of 2 cases of gemistocytic astrocytoma. The Ki 67 labeling index significantly correlated with T/N ratio in astrocytic tumors, but not in oligodendrogliomas. Oligodendroglial tumors without 1p/19q deletion had a significantly higher T/N ratio than those with the codeletion. In combination with Gd-enhanced MR imaging, 67% of nonenhanced tumors with a T/N ratio of ≥ 1.46 were proved to be Grade II oligodendrogliomas.

Conclusions: These results clearly show that (11)C-methionine PET T/N ratios in Grade II oligodendrogliomas were higher than those in DAs independently of their proliferative activity. This information contributes to preoperative differential diagnoses of histological type, especially in suspected low-grade gliomas.
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http://dx.doi.org/10.3171/2010.11.JNS10553DOI Listing
June 2011

Favorable long-term outcome of low-grade oligodendrogliomas irrespective of 1p/19q status when treated without radiotherapy.

J Neurooncol 2011 May 19;102(3):443-9. Epub 2010 Aug 19.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Despite the accumulating evidences of high chemosensitivity especially in anaplastic oligodendrogliomas with loss of chromosomes 1p and 19q, the optimal management strategy for low-grade tumors using the 1p/19q information remains controversial. We have treated all low-grade oligodendrogliomas by a chemotherapy-preceding strategy without radiotherapy, and here we analyzed the survival outcomes of 36 consecutive patients in relation to 1p/19q status. The treatment protocol was as follows: (1) simple observation after gross total resection, and (2) modified PCV chemotherapy for postoperative residual tumors or recurrence after total resection. The 1p and 19q status were analyzed by fluorescence in situ hybridization. The median follow-up period was 7.5 years and no patient was lost during the follow-up periods. 1p/19q co-deletion was observed in 72% of the patients, and there was no significant association between 1p/19q co-deletion and chemotherapy response rate. The 5- and 10-year progression-free survival (PFS) rate was 75.1 and 46.9%, respectively, and the median PFS was 121 months for 1p/19q-deleted tumors and 101 months for non-deleted tumors (log-rank test: P = 0.894). Extent of surgery did not affect PFS (P = 0.685). In contrast, the elder patients (>50) had significantly shorter PFS (P = 0.0458). Recurrent tumors were well controlled by chemotherapy irrespective of 1p/19q status, and 35 out of 36 patients survived without receiving radiotherapy. The 5- and 10-year overall survival rates were 100 and 93.8%, respectively. Two of the patients in their sixties (29%) suffered from severe cognitive dysfunctions and marked brain atrophy following chemotherapy alone. These results show that low-grade oligodendrogliomas could be successfully treated by surgical resection and nitrosourea-based chemotherapy alone without radiotherapy irrespective of 1p/19q status.
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http://dx.doi.org/10.1007/s11060-010-0340-4DOI Listing
May 2011

Selection of chemotherapy for glioblastoma expressing O(6)-methylguanine-DNA methyltransferase.

Exp Ther Med 2010 Jan 1;1(1):53-57. Epub 2010 Jan 1.

Departments of Neurological Surgery, and.

The therapeutic benefit of nitrosoureas or temozolomide for glioblastoma is limited mainly by O(6)-methylguanine-DNA methyltransferase (MGMT) expression. The aim of this study was to evaluate the effectiveness of various anticancer drugs for MGMT-positive glioblastoma. Seventy-four glioblastoma patients were administered various anticancer drugs according to drug sensitivity testing. For the individualization, drug-induced apoptosis was quantified by flow cytometry in the primary culture of surgically resected tumor cells. The MGMT protein expression was analyzed by immunohistochemistry. The median survival of the patients receiving the individualized chemotherapy was 19.4 months (95% CI, 15.9-22.1). The patients with negative MGMT immunostaining had significantly longer survival than those with positive MGMT immunostaining [median survival, 22.3 months (95% CI, 17.6-27.0) vs. 15.1 months (95% CI, 13.4-16.8); p=0.0188]. For MGMT-positive tumors, the platinum agents and the taxanes were more frequently selected for administration than the other categories of anticancer agents. The patient survival period of MGMT-positive glioblastomas treated with the platinum agents or the taxanes [median survival, 20.1 months (95% CI, 18.0-22.7)] was significantly longer than that of MGMT-positive tumors treated with nitrosoureas (p=0.0026), and was equivalent to that of MGMT-negative glioblastomas (p=0.3047). These results suggest that the platinum agents and the taxanes offer the best probability to be effective against immunohistochemically MGMT-positive glioblastomas.
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http://dx.doi.org/10.3892/etm_00000009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490398PMC
January 2010