[MR studies of perivascular spaces with main emphasis on space-occupying lesions].
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Animals↗
Biomedical subjects
Yasuo Iwadate
Publications and source records attributed to Yasuo Iwadate.
Cathepsin D is a potential serum marker for poor prognosis in glioma patients.
Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling which can be secreted from cancer cells. To identify a potential serum marker for gliomas, we investigated the gene expression levels of cathepsin D in 87 tissue samples and measured the protein concentrations in sera of glioma patients. The tissue samples consisted of 43 glioblastomas, 13 anaplastic astrocytomas, 22 astrocytomas, and 9 normal brain tissues. The results of real-time quantitative reverse transcription-PCR analysis showed that cathepsin D transcript levels became significantly higher as the glioma grade advanced (P = 0.0466, glioblastoma and anaplastic astrocytoma; P = 0.0008, glioblastoma and astrocytoma; P = 0.0271, glioblastoma and normal brain tissue; unpaired t test). Immunohistochemical analysis with anti-cathepsin D antibody revealed dense and spotty staining in the tumor cells with high transcript levels. The low expression of cathepsin D significantly correlated with long survival of the glioma patients. Furthermore, the glioblastoma patients with high gene expression of cathepsin D lived significantly shorter than those with low expression (P = 0.0104, Cox-Mantel log-rank test) and frequently had leptomeningeal dissemination (P = 0.0016, chi2 test). The multivariate analysis confirmed that the cathepsin D expression level was an independent predictor for short survival (P = 0.0102, Cox proportional hazard regression model). Measurement of the serum cathepsin D concentrations by ELISA showed a significant increase in the patients with high-grade gliomas as compared with the low-grade tumors (P = 0.0081, chi2 test). These results collectively suggest that cathepsin D could be a potential serum marker for the prediction of aggressive nature of human gliomas.
Astrocytoma↗
Recombinant Sendai virus vector induces complete remission of established brain tumors through efficient interleukin-2 gene transfer in vaccinated rats.
PURPOSE: Sendai virus (SeV), a murine parainfluenza virus type I, replicates independent of cellular genome and directs high-level gene expressions when used as a viral vector. We constructed a nontransmissible recombinant SeV vector by deleting the matrix (M) and fusion (F) genes from its genome (SeV/DeltaMDeltaF) to enhance its safety. We also estimated the therapeutic efficacy of the novel vector system against a rat glioblastoma model. EXPERIMENTAL DESIGN: We administered the recombinant SeV vector carrying the lacZ gene or the human interleukin-2 (hIL-2) gene into established 9L brain tumors in vivo simultaneous with peripheral vaccination using irradiated 9L cells. Sequential monitoring with magnetic resonance imaging was used to evaluate the therapeutic efficacy. RESULTS: We found extensive transduction of the lacZ gene into the brain tumors and confirmed sufficient amounts of interleukin 2 (IL-2) production by hIL2-SeV/DeltaMDeltaF both in vitro and in vivo. The magnetic resonance imaging study showed that the intracerebral injection of hIL2-SeV/DeltaMDeltaF brought about significant reduction of the tumor growth, including complete elimination of the established brain tumors. The (51)Cr release assay showed that significant amounts of 9L-specific cytotoxic T cells were induced by the peripheral vaccination. Immunohistochemical analysis revealed that CD4(+) T cells and CD8(+) T cells were abundantly infiltrated in the target tumors. CONCLUSION: The present results show that the recombinant nontransmissible SeV vector provides efficient in vivo gene transfer that induces significant regression of the established brain tumors and suggest that it will be a safe and useful viral vector for the clinical practice of glioma gene therapy.
Animals↗
Proteome-based identification of molecular markers predicting chemosensitivity to each category of anticancer agents in human gliomas.
To identify the protein markers that are clinically useful for predicting efficacy of anticancer agents, we investigated the correlation between the proteome profiling patterns and the in vitro chemosensitivity in human gliomas. The proteome of 93 surgical samples were analyzed with two-dimensional gel electrophoresis (2DE) and mass spectrometry. The in vitro chemosensitivities to 10 different kinds of anticancer agents (cyclophosphamide, nimustine, cisplatin, cytosine arabinoside, mitomycin C, peplomycin, adriamycin, etoposide, vincristine, paclitaxel) were measured by flow cytometric detection of apoptosis. We identified a set of 41 proteins that significantly affected the in vitro chemosensitivity to each category of anticancer agents. Many of the proteins that correlated with chemoresistance were categorized into the signal transduction proteins including the G-proteins. The present study showed that the proteome analysis using 2DE could provide a list of proteins that may be the potential predictive markers for chemosensitivity in human gliomas. They can also be direct and rational targets for anti-glioma therapy and be used for sensitization to the conventional chemotherapeutic regimens.
Antineoplastic Agents↗
Treatment of low-grade oligodendroglial tumors without radiotherapy.
The authors prospectively treated 18 consecutive patients with low-grade oligodendroglial tumors without postoperative radiotherapy. The treatment strategy was as follows: follow-up after total resection and chemotherapy after subtotal resection or biopsy. All patients were alive and 17 patients (94%) were progression-free after a median follow-up of 4.7 years. The results suggested that radiotherapy could be postponed until clinical progression in the treatment of low-grade oligodendroglial tumors.
Adult↗
Molecular classification and survival prediction in human gliomas based on proteome analysis.
The biological features of gliomas, which are characterized by highly heterogeneous biological aggressiveness even in the same histological category, would be precisely described by global gene expression data at the protein level. We investigated whether proteome analysis based on two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry can identify differences in protein expression between high- and low-grade glioma tissues. Proteome profiling patterns were compared in 85 tissue samples: 52 glioblastoma multiforme, 13 anaplastic astrocytomas, 10 atrocytomas, and 10 normal brain tissues. We could completely distinguish the normal brain tissues from glioma tissues by cluster analysis based on the proteome profiling patterns. Proteome-based clustering significantly correlated with the patient survival, and we could identify a biologically distinct subset of astrocytomas with aggressive nature. Discriminant analysis extracted a set of 37 proteins differentially expressed based on histological grading. Among them, many of the proteins that were increased in high-grade gliomas were categorized as signal transduction proteins, including small G-proteins. Immunohistochemical analysis confirmed the expression of identified proteins in glioma tissues. The present study shows that proteome analysis is useful to develop a novel system for the prediction of biological aggressiveness of gliomas. The proteins identified here could be novel biomarkers for survival prediction and rational targets for antiglioma therapy.
Amino Acid Sequence↗
Glioma-specific cytotoxic T cells can be effectively induced by subcutaneous vaccination of irradiated wild-type tumor cells without artificial cytokine production.
Effective induction of systemic antitumor immunity is a crucial step for success of immune gene therapy for intracerebral gliomas. We examined in this study the ability to induce glioma-specific cytotoxic T lymphocytes (CTL) by subcutaneous (s.c.) immunization of irradiated whole-tumor cell vaccine with or without artificial cytokine production, and also examined in vivo efficacy of the induced CTL against a rat brain tumor model with 9L gliosarcoma cells. Murine neuroblastoma C1300 cells transduced with the interleukin-2 (IL-2), IL-4 or granulocyte-macrophage colony-stimulating factor (GM-CSF) gene (C1300/IL-2, C1300/IL-4 or C1300/GM-CSF) were used as cytokine-producers. Glioma-specific CTL activity was equivalently induced in the rats vaccinated s.c. with irradiated 9L, irradiated IL-2-producing 9L cells or the mixed population of irradiated 9L and C1300/IL-2 cells, while the activity was relatively lower in the rats vaccinated with irradiated 9L cells mixed with either C1300/IL-4 or C1300/GM-CSF cells. In the rats immunized s.c. with irradiated 9L cells, intracerebral (i.c.) 9L tumors implanted together with either C1300/IL-2 or C1300/IL-4 were completely rejected. Pre-established brain tumor also could be eliminated by the s.c. immunization of irradiated 9L cells and i.c. transplantation of IL-2-producers. These results suggest that glioma-specific CTLs could be effectively induced by s.c. immunization of irradiated wild-type tumor cells without artificial cytokine production.
Animals↗
Acquisition of drug resistance by constitutive suppression of NF-kappaB in ras-transformed NIH3T3 mouse fibroblasts.
Apoptotic cell death is frequently suppressed by NF-kappaB transcription factor. We examined the effects of NF-kappaB on the sensitivity to anti-cancer drugs by using two NF-kappaB-inhibitory molecules, IkappaBalpha-super-repressor (IkappaBalpha-SR) and dominant negative IKKbeta (IKKbeta-DN). Ha-ras-transformed NIH3T3 (ras-NIH3T3) mouse fibroblasts were stably transfected with these cDNAs, and suppression of NF-kappaB activity was confirmed by electrophoretic mobility shift assays. Cell viability analysis revealed that IkappaBalpha-SR- or IKKbeta-DN-transfected cells were more resistant to peplomycin, mitomycin C, and camptothecin. Flow cytometric analysis indicated partial G1 arrest of these transfected cells. Consistently, elevated expression of IkappaBalpha-SR and IKKbeta-DN was accompanied by increased levels of p21 but not of Bax. Transfection of p21 into ras-NIH3T3 cells caused similar reduced chemosensitivity to the anti-cancer drugs. These results collectively indicate that constitutive suppression of NF-kappaB activity reduced the chemosensitivity to anti-cancer drugs via enhanced expression of p21.
Animals↗
Identification of the small interstitial deletion at chromosome band 1p34-p35 and its association with poor outcome in oligodendroglial tumors.
To narrow down the putative tumor-suppressor gene locus and to assess the predictability of clinical courses by genomic alterations, we analyzed 46 oligodendroglial tumors for loss of heterozygosity (LOH) in the distal region of the short arm of chromosome 1. LOH at 1p was found in 43 tumors (93.5%), including all 28 oligodendrogliomas, all eight oligo-astrocytomas, six of eight anaplastic oligodendrogliomas, and in one of two anaplastic oligo-astrocytomas. Thirty-seven tumors showed LOH patterns consistent with a large terminal deletion, whereas six tumors showed LOH suggesting interstitial deletions. Our data also showed two small regions of overlap at 1p34-p35 (approximately 5.7 Mb) and at 1p36.1-p36.2 ( approximately 12 Mb). Among the six tumors with interstitial deletion, the proximal region was deleted in five tumors, whereas the distal region was deleted in only half of them. Overall, 91% of tumors showed deletion including this proximal region. To examine the clinical significance of the LOH pattern, the samples were classified into three groups: tumors without 1p LOH (Group 1, n = 3), tumors with an interstitial deletion (Group 2, n = 6), and tumors with a large terminal deletion (Group 3, n = 37). Both overall and progression-free survival of patients in Group 2 was extremely poor compared with those included in Group 3 (P = 0.0006 and P = 0.003, respectively). As to the clinical response to chemotherapy, nimustine prevented tumor recurrence in Group 3 (P = 0.034) but not in Group 2. Our results demonstrate that a putative tumor-suppressor gene(s) in oligodendroglial tumors is localized at 1p34-p35 and that small interstitial deletions, in contrast to large terminal deletions, are strongly predictive of both chemoresistance and aggressive characteristics of these tumors.
Adolescent↗
Hypervascular vestibular schwannomas.
BACKGROUND: Vestibular schwannoma (VS) is usually hypovascular and can be resected totally without major morbidity. Resection of the more uncommon hypervascular VS is complicated by excessive tumor bleeding. We have attempted to clarify the clinical characteristics and management of hypervascular VS. METHODS: Surgical reports and videos of 78 patients with unilateral VS (5 hypervascular, 73 nonhypervascular) were retrospectively reviewed and clinical characteristics, radiological findings, and case management were compared. RESULTS: Hypervascular VS presented at a younger age than nonhypervascular VS (29 +/- 12 vs. 52 +/- 16 years old) (p < 0.01). Magnetic resonance imaging (MRI) showed that hypervascular VS was solid, without tumor cyst, and significantly larger than nonhypervascular VS (p < 0.05). The surface of hypervascular VS consistently showed multiple flow voids representing large draining veins. The characteristic angiographical findings of hypervascular VS were extensive tumor vessels, tumor stains, and early filling of draining veins; vertebrobasilar arteries supplied hypervascular VS. A multi-stage surgical approach was used since torrential tumor bleeding in the first surgery interfered with resection, resulting in partial tumor removal. Angiography before the second surgery showed much reduced tumor vascularity, bleeding was much reduced, and tumor was resected with less difficulty. In this approach, all 5 hypervascular VS were resected totally (1 case) or near-totally (4 cases) without major morbidity. CONCLUSIONS: Hypervascular VS, a solid and large tumor, presents at an earlier age. Although angiography provides characteristic findings, MRI can confirm the diagnosis of a hypervascular VS by showing multiple flow-voids on the tumor surface. Since partial tumor removal (first surgery) extensively reduces tumor vascularity and intraoperative tumor bleeding considerably, hypervascular VS should be managed by a multi-staged surgical approach.
Adolescent↗
Differential chemosensitivity in human intracerebral gliomas measured by flow cytometric DNA analysis.
The present study was designed to investigate the chemosensitivity of human intracerebral gliomas using the flow cytometric (FCM) analysis of DNA integrity as an in vitro drug sensitivity testing. We also correlated the in vitro results and the clinical responses to chemotherapy. Forty-one fresh tumor specimens were obtained at surgery, and exposed to 30 currently-available anticancer agents. Drug-induced nuclear damage such as chromatin condensation or DNA degradation were assessed both by morphological observation and FCM analysis of DNA integrity. The FCM assay could be performed in all the cases (100% success rate). The chemosensitivities of anaplastic astrocytoma, oligodendroglial tumors, and medulloblastoma were generally higher than those of glioblastoma multiforme and ependymoma. The in vitro chemosensitivity was markedly heterogeneous among patients with the same histological tumor. Clinical sensitivity was predicted in 86% of all evaluable patients and clinical resistance in 81%; the overall accuracy of the FCM assay was 82%. The FCM analysis of DNA integrity proved to be feasible and sufficiently reliable as a routine clinical examination for the purpose of screening new chemotherapeutic agents and individualizing chemotherapy regimens for patients with intracerebral gliomas.
Antibiotics, Antineoplastic↗
Interleukin-12-mediated induction of systemic immunity in the periphery and recruitment of activated T cells into the brain produce limited antitumor effects compared with interleukin-2.
Interleukin-12 (IL-12) stimulates the type 1 helper T (Th1) cell responses and augments antitumor immunity. We examined possible antitumor effects of IL-12 secreted intracerebrally (i.c.) and/or subcutaneously (s.c.) in an experimental glioblastoma model and compared the effects with those of IL-2. Rat 9L gliosarcoma cells retrovirally transduced with the IL-12 or IL-2 gene (9L/IL-12 and 9L/IL-2, respectively) were completely rejected when they were s.c. inoculated. The transduced cells, implanted i.c., developed progressive brain tumors at reduced rates compared with 9L brain tumors and the growth retardation of 9L/IL-2 tumors was greater than that of 9L/IL-12 tumors. When rats were s.c. immunized with either 9L/IL-12 or 9L/IL-2 cells, the growth of 9L brain tumors developed in the rats was suppressed compared with that of 9L tumors in naive rats. Among various combinations of simultaneous inoculations of cytokine producers s.c. and i.c., 9L/IL-2 but not 9L/IL-12 cells inoculated i.c. were rejected when the rats were s.c. immunized with either 9L/IL-12 or 9L/IL-2 cells. The synergistic antitumor effects induced were correlated with the infiltration levels of CD8+ and CD4+ T cells into brain tumors. Tumor-specific cytotoxic activity was induced in the rats immunized s.c. with 9L/IL-2 but not fully in the rats with 9L/IL-12 cells. These results collectively suggest that the antitumor activity with IL-2 was superior to IL-12 both in the induction of cytotoxic T cells and in the recruitment of activated T cells into brain tumors.
Adjuvants, Immunologic↗
Whole-brain radiation therapy is not beneficial as an adjuvant therapy for brain metastases compared with localized irradiation.
BACKGROUND: We investigated the role of whole-brain radiation therapy (WBRT) which has been widely used as an adjuvant therapy for brain metastases. PATIENTS AND METHODS: The authors retrospectively reviewed 132 patients who underwent surgical resection for brain metastases. They were classified into five groups according to the dose of radiation therapy to the local brain (L) or to the whole-brain (W), independently; 0 Gy (Group A[L or W]), 20-29 Gy (Group B[L or W]), 30-39 Gy (Group C[L or W]), 40-49 Gy (Group D[L or W]) and 50 Gy or more (Group E[L or W]). RESULTS: Local recurrence rates and times to tumor progression (TTP) of the original tumor were 53% and 3 months for Group A(L), 25% and 6 months for Group C(L), 11% and 7 months for Group D(L) and 12% and 12 months for Group E(L). Median survival times (MST) were 6 months for Group A(L), 8 months for Group C(L), 8 months for Group D(L) and 11 months for Group E(L). Distant recurrence rates and the TTP of new lesions in the distant area were 27% and 7 months for Group A(W), 20% and 6 months for Group B(W), 8% and 9 months for Group C(W), 13% and 13 months for Group D(W) and 4% and 14 months for Group E(W). The MST were 11 months for Group A(W), 11 months for Group B(W), 10 months for Group C(W), 9 months for Group D(W) and 6 months for group E(W). CONCLUSION: The present results suggest that WBRT is unnecessary and that local radiation therapy of 40 Gy or more would be the primary choice of adjuvant therapy for the majority of patients treated with surgical resection for brain metastases.
Adult↗