[Pineal lesion tumors (germinoma)].
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Biomarkers, Tumor↗
Biomedical subjects
Toshihiko Wakabayashi
Publications and source records attributed to Toshihiko Wakabayashi.
EGFR mutations in patients with brain metastases from lung cancer: association with the efficacy of gefitinib.
Gefitinib--a specific inhibitor of epidermal growth factor receptor (EGFR)-associated tyrosine kinase--has demonstrated efficacy in a subgroup of patients with non-small-cell lung carcinoma (NSCLC) who fail conventional chemotherapy. It is also reported to have an antitumor effect in brain metastases from NSCLC. Additionally, EGFR mutations have shown a strong association with gefitinib sensitivity for NSCLC. Here, we assessed the efficacy of gefitinib in brain metastases from NSCLC and evaluated the association of this efficacy with EGFR mutations. We retrospectively reviewed eight cases in which patients were suffering from brain metastases before the initiation of gefitinib treatment. Brain tumor response could be evaluated by MRI in these patients; EGFR gene analyses were also available. We evaluated whether objective tumor response was observed after gefitinib treatment and assessed the efficacy of gefitinib as effective, noneffective, or not assessable in consideration of the influence of previous radiotherapy. Of the eight patients, the efficacy of gefitinib was assessed as effective in three and as noneffective in three. All three patients demonstrating effective efficacy had EGFR mutations in the tyrosine kinase domain (deletion mutation in two patients and point mutation in one patients), whereas none of the three patients demonstrating noneffective efficacy had EGFR mutations. Gefitinib appears to be effective in treating brain metastases in a subgroup of patients. Our data suggested a possible association between the efficacy of gefitinib in the treatment of brain metastases and EGFR mutations.
Adult↗
[Glioma].
This chapter outlines the current clinical application of interferon for treatment of brain tumor, especially glioma. Since approved as a therapeutic drug for brain tumor originally produced in Japan, interferon-beta has been reported to be effective when it was used alone, in combination with chemo-radiotherapy (ACNU/MCNU as a nitrosourea derivative chemodrug, and radiation for 60 Gy totally). Recently, the regimen of combination with interferon-beta have been improved to obtain a higher efficacy rate. For example, as a fundamental study, temozolomide is an enthusiastic chemodrug to enhance the anti-tumor effect of interferon-beta when it is combined, pre-clinical and clinical trial will be scheduled. As for interferon-beta gene therapy by means of liposome as ad drug delivery system, already clinical trial has been performed and clinical safety and effectiveness have been proved, and it is expected that newly development in the field of gene therapy will be established and improvement of therapeutic results for malignant brain tumor will be achieved.
Antineoplastic Agents↗
[Efficacy and safety of monotherapy with temozolomide in patients with anaplastic astrocytoma at first relapse--a phase II clinical study].
The efficacy and safety of temozolomide were evaluated in 32 patients with anaplastic astrocytoma at first relapse. Temozolomide was administered orally once daily for the first five days of a 28-day cycle, at a dose of 150 or 200 mg/m(2)/day. The response rate determined by independent central review of MRI was 34% (95% confidence interval: 18.6%-53.2%), with 3 complete response and 8 partial response. The rate of "no change or better" was 91% (95% confidence interval: 75.0%-98.0%). Progression-free survival (PFS) at 6 months was 40.6%, and the median PFS was 4.1 months. The incidence of constipation (50%) and nausea (25%) was high,but these events were all mild or moderate in severity except in one subject with constipation,and could be managed with standard laxatives and antiemetics. The main laboratory test abnormalities (total incidence and incidence of grade 3/4 change) were lymphocytopenia (50%, 25%), neutropenia (47%, 6%), leukopenia (38%, 3%), thrombocytopenia (31%, 9%), and increased GPT (25%, 3%). Temozolomide was shown to have good efficacy and tolerability in patients with anaplastic astrocytoma at first relapse.
Adult↗
Brain metastases from apocrine carcinoma of the scalp: case report.
Apocrine carcinoma is an extremely rare malignant neoplasm that occurs most frequently in the axilla. Although it usually shows an indolent clinical course, it often metastasizes to regional lymph nodes and sometimes to lungs or bones. However, a literature search did not reveal any report describing the detailed clinical course of brain metastases from apocrine carcinoma. We report a case of a 54-year-old male who suffered from multiple brain metastases from apocrine carcinoma that had originated in the scalp 6 years before. The brain metastases appeared in spite of several regimens of chemotherapy for lung metastases for two years. The tumor in the right frontal lobe was successfully operated. However, the small tumor in the right occipital lobe was not cured by gamma knife surgery, and eventually required second operation. The operation had contributed to his neurologically independent life for about one year until he died for gradual progression of lung metastases. To our knowledge this is the first reported case of metastatic brain tumor from apocrine carcinoma.
Apocrine Glands↗
IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide.
Alkylating agents, such as temozolomide, are among the most effective cytotoxic agents used for malignant gliomas, but responses remain very poor. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistance to alkylating agents. IFN-beta can act as a drug sensitizer, enhancing toxicity against a variety of neoplasias, and is widely used in combination with other antitumor agents such as nitrosoureas. Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide. By means of oligonucleotide microarray and RNA interference, we reveal that the sensitizing effect of IFN-beta was possibly due to attenuation of MGMT expression via induction of the protein p53. Our study suggests that clinical efficacy of temozolomide might be improved by combination with IFN-beta using appropriate doses and schedules of administration.
Antineoplastic Agents, Alkylating↗
Management and survival of pineoblastoma: an analysis of 34 adults from the brain tumor registry of Japan.
Pineoblastoma is a rare tumor in adults, and factors influencing survival are poorly understood. Data from the Brain Tumor Registry of Japan (BTRJ) was analyzed to examine patient, tumor, and treatment characteristics associated with increased survival in adults with pineoblastomas. All pineoblastoma cases in adults aged 16 years or older were identified in the BTRJ. Data were extracted on demographics, presentation, tumor characteristics, treatments, and outcomes. Kaplan-Meier plots, the log rank method, and p value <0.15 was used to screen variables for inclusion in a multivariate Cox regression estimating survival. In the final Cox multivariate model, all variables with p values <0.05 were considered significant predictors of survival, and all variables with p values 0.05-0.099 were considered trends. The BTRJ contained 34 adults with pineoblastomas diagnosed from 1969-1998. The patients were predominantly male (22 patients), with a median age of 35 years (range 16-66 years). Median survival from diagnosis was 25.7 months, with a median follow up of 20.5 months. Median surgical resection was 75-94%, and five of the 34 patients had gross total resection. Twenty-nine of the 34 patients received cranial irradiation therapy with a median dose of 50 Gy (range 30-70 Gy). In the final multivariate model, cranial irradiation > or =40 Gy (p=0.014) and gross total resection (p=0.034) were associated with improved survival. There was a trend towards improved survival for women (p=0.099). Adult pineoblastoma patients have poor survival prognosis. Cranial irradiation therapy using at least 40 Gy and complete surgical resection are associated with improved survival.
Adolescent↗
Intraventricular chordoid meningioma presenting with Castleman disease due to overproduction of interleukin-6. Case report.
A rare case of chordoid meningioma in the lateral ventricle observed in an adult is reported. The first clinical manifestation of the disease was a prolonged fever of unknown origin. Abnormalities in the patient's blood chemistry, principally polyclonal hypergammaglobulinemia (immunoglobulin [Ig]G, IgA, and markedly IgE) and an elevated serum level of C-reactive protein, were associated with the disease. The tumor was histologically confirmed to be a chordoid meningioma, and its surgical removal resulted in complete resolution of the patient's symptoms. By combining reverse transcription-polymerase chain reaction and immunohistochemical analysis, it may be shown that cytokine production, including that of interleukin (IL)-6, IL-1beta, and vascular endothelial growth factor, plays a role in the pathogenesis of chordoid meningioma associated with Castleman syndrome.
Adult↗
Multicentric atypical teratoid/rhabdoid tumors occurring in the eye and fourth ventricle of an infant: case report.
Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive malignant tumors found in infants and young children. The tumor is characterized by the presence of a rhabdoid cell component in all cases, but the histological origin is still unclear. Recently, germline mutation of the hSNF5/INI1 gene has been reported in association with AT/RTs. The authors report a rare case of an intraocular AT/RT followed by a fourth ventricular tumor. The results of immunohistochemical studies of the surgical specimens revealed the presence of an AT/RT and from this finding the neural origin was inferred. A novel missense mutation of the hSNF5/INI1 gene was demonstrated by DNA analysis. High-dose chemotherapy with stem cell rescue was effective in treating this patient. The immunohistochemical relationship between rhabdoid cells and the neurogenic zone, which has not been described in AT/RTs, is of great interest in view of the nature of rhabdoid cells.
Antineoplastic Combined Chemotherapy Protocols↗
Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes.
Transfer of interferon beta gene via cationic liposomes has been found to induce regression of experimental glioma. We performed a pilot clinical trial of safety and effectiveness of this interferon beta gene therapy in five patients with malignant glioma (glioblastoma multiforme or anaplastic astrocytoma). Transgene expression and antitumor activity were detected in four patients. Two patients showed a partial response (>50% tumor reduction) and two others had stable disease 10 weeks after beginning therapy. One patient could not be evaluated because of previous treatment with gamma-knife therapy. This study suggests the feasibility and safety of interferon beta gene therapy, which may become an important treatment option for patients with malignant glioma.
Adult↗
Interferon-beta gene therapy for cancer: basic research to clinical application.
Interferon-beta gene therapy for cancer is the first such protocol developed in Japan. Here we describe the development process of our interferon-beta gene therapy from basic research to clinical application. Interestingly, the biological and biochemical characteristics of interferon-beta gene therapy through transfer of the interferon-beta gene into tumor cells by means of cationic liposomes differed from those of conventional interferon-beta protein therapy. Interferon-beta gene transfer could induce apoptosis in interferon-beta protein-resistant tumor cells, such as glioma, melanoma, and renal cell carcinoma. Induction of apoptosis was related to the level of intracellular mRNA of interferon-beta, prolongation of the phosphorylation time of molecules in the interferon-beta signal transduction pathway, such as JAK1, Trk2, and STAT1, and activation of DNase gamma. In our preclinical study we developed lyophilized cationic liposomes containing interferon-beta gene (gene drug) for clinical use and confirmed their safety. Thereafter, we performed a pilot clinical trial in patients with malignant glioma and confirmed the safety and effectiveness of this interferon-beta gene therapy. In this review we also comment on the status of gene therapy regulation in Japan. Interferon-beta gene therapy is expected to become widely available for clinical use in cancer patients, and this new strategy might be extended to molecular targeting therapy, or used in combination with cell therapy or other therapies.
Apoptosis↗
Aurora-B dysfunction of multinucleated giant cells in glioma detected by site-specific phosphorylated antibodies.
OBJECT: The origin of multinucleated giant cells in glioma has not been made clear. In a previous paper the authors studied multinucleated giant tumor cells by using mitosis-specific phosphorylated antibodies to determine the phosphorylation of intermediate filaments and demonstrated that these cells stay in the early mitotic stage, undergoing neither fusion nor degeneration. In the current study the authors investigated the possible genetic causes of multinucleated giant tumor cells. METHODS: Cultured mono- or multinucleated human glioma cells were immunostained with monoclonal antibodies (mAbs) 4A4, YT33, TM71, HTA28, YG72, and alphaAIM-1. The three former antibodies revealed a particular mitotic cell cycle through site-specific phosphorylation of vimentin; that is, the early phase, mid phase, and late phase, respectively. The three later antibodies demonstrated phosphorylation of H3 at Ser28, phosphorylation of vimentin at Ser72, and aurora-B, respectively, making it possible to identify aurora-B distribution and function during mitosis. In addition, paraffin-embedded tissue sections obtained in three patients with giant cell glioblastoma were also examined. Multinucleated giant tumor cells immunoreacted with the mAb 4A4 and alphaAIM-1 but not with YT33, TM71, HTA28, and YG72 in vitro and in vivo. CONCLUSIONS: Findings in this study indicated that multinucleated giant tumor cells remain in the early mitotic phase because of aurora-B dysfunction, effecting aberrations in cytoplasmic cleavage without affecting nuclear division.
Antibodies, Monoclonal↗
Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles.
In this study we demonstrated that heat shock protein (HSP) 70 expression by hyperthermia induced antitumor immunity in the T-9 rat glioma. Our hyperthermic system using magnetic nanoparticles induced necrotic cell death that correlated with HSP70 expression. We purified the HSP70-peptide complexes from the tumor after hyperthermia to investigate whether HSP70 was involved in the antitumor immunity, and we found that in the F344 rats immunized with T-9-derived HSP70 the tumor growth of T-9 was significantly suppressed. Tumor rejection assay after hyperthermic treatment of implanted T-9 cells with incorporated magnetite cationic liposomes (MCL) was performed to investigate whether antitumor immunity was induced by release of HSP70 from the necrotic cells in the F344 rat. Tumor growth was strongly suppressed in the rats subjected to hyperthermia of implanted T-9 cells, and 50% of rats were protected from challenge with T-9 cells. Immunogenicity was enhanced when the HSP70-overexpressing T-9 cells were killed via necrosis in rats by hyperthermia, after which all rats were completely protected from challenge with T-9 cells. Our hyperthermic system produces vaccination with HSP70-peptide via necrotic tumor cell death in vivo, resulting in antitumor immunity. This phenomenon, which may be termed in situ vaccination, has important implications for the development of novel antitumor therapies.
Animals↗
Radioimmunoscintigraphy of intracranial glioma xenograft with a technetium-99m-labeled mouse monoclonal antibody specifically recognizing type III mutant epidermal growth factor receptor.
The type III mutant epidermal growth factor receptor (EGFR) is expressed on the cell surface of a subset of glioma, but not of normal tissues. In this study, we investigated the in vivo kinetics of 3C10 mouse monoclonal antibody (mAb), specifically recognizing the type III mutant EGFR (EGFRvIII), using athymic nude mice bearing the intracranial glioma xenograft overexpressing the EGFRvIII. Human glioma cell line, U87MG, expressing the wild type EGFR and the transfectant, named U87MG x deltaEGFR, expressing the EGFRvIII, were transplanted subcutaneously or intracranially to nude mice. 3C10 mAb labeled with a technetium-99m (99mTc) was intravenously injected into these nude mice and then the mice were sacrificed at 24 h later, and the 99mTc-uptake by xenografts and major normal organs was measured to determine the biodistribution of mAb. Furthermore, at 3, 6 and 24 h after injection of 99mTc-labeled 3C10 mAb, whole-body scintigraphy was obtained with a gamma camera to localize the tumor site. 3C10 mAb significantly accumulated to U87MG x deltaEGFR xenografts transplanted subcutaneously or intracranially in nude mice, showing high tumor-to-blood ratio of 10.30 and 4.01, respectively. In contrast, uptake of control antibody in the intracranial tumor was as low as 0.43. In scintigrams, intracranially transplanted U87MG x deltaEGFR xenografts were detectable at 3 h after injection of 99mTc-labeled 3C10 mAb. These results suggest that intravenously injected 3C10 mAb specifically accumulated to the subcutaneous or intracranial glioma xenograft expressing the EGFRvIII and 3C10 mAb is a potential diagnostic and therapeutic agent for patients with gliomas expressing the EGFRvIII.
Animals↗
Effective induction of antiglioma cytotoxic T cells by coadministration of interferon-beta gene vector and dendritic cells.
As type I interferons (IFNs) enhance the stimulatory activity of dendritic cells (DCs), we hypothesized that transfection of glioma cells with the IFN-beta gene in the presence of DCs would provide particularly effective antitumor activity by both facilitating apoptosis of glioma cells and presenting the resulting glioma antigens to T cell by DCs, thereby inducing specific T-cell responses against glioma cells. A mouse glioma cell line 203G was first transfected with cDNA encoding IFN-beta using cationic liposomes, then cocultured with syngeneic bone marrow-derived DCs and naïve splenic T cells. The 203G cells were almost completely killed following 96-hour coculture with DCs and T cells, and strong tumor-specific cytotoxic T-lymphocyte (CTL) activity accompanied by high level interleukin (IL)-12 and IFN-gamma production was observed in culture. In addition, omission of either IFN-beta gene delivery, DCs or T cells from the coculture completely abrogated the induction of the CTL activity, suggesting that the combination of these components was required to elicit an optimal effect. On the basis of these in vitro data, syngeneic animals bearing subcutaneous 203G tumors received intratumoral injections of IFN-beta gene and DCs. Suppression of the tumor growth by this combinational therapy was superior to treatment with DC or IFN-beta gene solely. This combination may constitute a new therapeutic strategy to induce potent antiglioma immune responses.
Animals↗
Morphological assessment of the development of multinucleated giant cells in glioma by using mitosis-specific phosphorylated antibodies.
OBJECT: The nature and origin of multinucleated giant cells in glioma have not been made clear. To investigate the phosphorylation of intermediate filaments, the authors studied multinucleated giant cells in vitro and in vivo by using mitosis-specific phosphorylated antibodies. METHODS: Cultured human glioma cells were immunostained with monoclonal antibodies (mAbs) 4A4, KT13, and TM71, which recognized the phosphorylation of vimentin at Ser55, glial fibrillary acidic protein at Serl3, and vimentin at Ser71, respectively. Subsequently, the nature of multinucleated giant cells was investigated using laser scanning confocal microscopy. In addition, paraffin-embedded tissue sections obtained in three patients with giant cell glioblastoma were also investigated. Multinucleated giant cells were immunoreacted with the mAb 4A4 and not with KT13 and TM71 in vitro and in vivo. In addition, the authors obtained these results in multinucleated giant cells under natural conditions, without drug treatments. CONCLUSIONS: Findings in this investigation indicated that multinucleated giant cells are those remaining in mitosis between metaphase and telophase, undergoing neither fusion nor degeneration.
Antibodies, Neoplasm↗
Effective solitary hyperthermia treatment of malignant glioma using stick type CMC-magnetite. In vivo study.
Various kinds of hyperthermic treatment for malignant glioma had been inhibited due to both their incomplete feverish action and strict cooling effect of the brain. The author shows an effective results of hyperthermia for the treatment of malignant glioma in an in vivo study using stick type carboxymethylcellulose (CMC)-magnetite, a newly manufactured magnetite-product. A stick type CMC-magnetite, containing magnetite particles, was inserted into the T-9 glioma in the rat brain stereotactically, and the rats were exposed to an alternative magnetic field (AMF). The application time of AMF, which measured 88.9 kHz and 380 Oe, was 30 min a day. The rats were divided into three groups: three AMF applications (group I), one AMF application (group II) and no application but only injection of CMC-magnetite (control). As a result, the mean survival in days of these three groups measured 44.2+/-10.9 (group I), 17.0+/-1.5 (group II) and 14.4+/-1.5 (control). This investigation showed both significant effectiveness in attacking malignant glioma and significant prolonging of the survival time in rats. It is also a characteristic feature of the magnetite particles to spread through the tumor diffusely after three applications of AMF. This feature seemed to be one of the main factors that caused greater hyperthermic effect on glioma in this study. This method of hyperthermic treatment could be a useful strategy in the treatment of malignant glioma.
Animals↗