Biomedical subjects
M Kochi
Publications and source records attributed to M Kochi.
[Anaplastic (malignant) oligo-astrocytoma].
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[Neoadjuvant chemotherapy for advanced gastric cancer using FLEP therapy].
Combination chemotherapy with 5-FU, LV, ETP and CDDP (FLEP) for advanced gastric cancer uses a combination of regional and systemic delivery for the control of both local and disseminated disease in the intra- and extra-abdominal regions. We performed this regimen as neoadjuvant chemotherapy (NAC). Fifteen patients with unresectable primary advanced gastric cancer underwent FLEP. The treatment regimen was 5-FU at 370 mg/m2, LV at 30 mg/body (days 1 to 5, i.v. 24 h) and ETP and CDDP each at 70 mg/m2 (days 7 and 21, ia 2 h). This regimen was repeated every four weeks. The overall response rate was 46.7% (7/15), and the 50% and median survival times were 11.43 and 12.35 months, respectively. The adverse events were Grade 3 leukocytopenia, Grade 3 thrombocytopenia, and Grade 3 stomatitis in 20.0%, 13.3%, and 6.7% of the patients, respectively. The 50% and median survival time overall were 11.43 and 12.35 months, respectively. Of the 15 NAC patients, curability B patients showed a statistically higher survival rate than curability C and unresected patients. In conclusion, FLEP was effective for unresectable advanced gastric cancer.
[Significance of neoadjuvant chemotherapy for gastric cancer].
Neoadjuvant chemotherapy for high-risk patients with advanced gastric cancer is important to increase the chance for curative resection and make unresectable gastric cancer tumors resectable by down-staging of the tumor. Tumors with H0, P0, T3, T4, or N3 are the best candidates for this therapy. Randomized controlled phase III studies are needed in conjunction with accurate staging of the disease by laparoscopy. The results of histopathologic evaluation of resected materials following preoperative chemotherapy using oral fluoropyrimidine are thought to be useful as an indicator of chemosensitivity for postoperative adjuvant setting.
Tissue factor expressed in pituitary adenoma cells contributes to the development of vascular events in pituitary adenomas.
BACKGROUND: Tissue factor (TF) was initially identified as an important factor in the initiation of coagulation. TF has recently been found to be expressed highly in certain types of malignant tumors. It has also been reported to be involved in systemic coagulopathy in cancer patients and in the proliferative and invasive activities of tumor cells. Tissue factor pathway inhibitor (TFPI) is a strong biologic inhibitor of TF. To the authors' knowledge, this is the first study of the expression of TF and TFPI in human pituitary adenoma. METHODS: The expression of TF and TFPI were analyzed by immunohistochemical methods in human pituitary adenoma samples. To examine whether TF and TFPI expression influence the proliferative and/or invasive character of pituitary adenomas, the authors determined the MIB-1 labeling indices and invasiveness of all the pituitary adenomas they examined. Furthermore, to determine whether TF contributes to coagulation inside adenoma tissues, the incidence of cysts or hematomas in adenomas was analyzed. RESULTS: In cells from 29 of 83 pituitary adenomas, overexpression of TF was observed. This was not the case for normal pituitary gland cells. TFPI was not expressed in either the adenomas or the normal pituitary glands from adenoma-bearing individuals. The expression of TF was significantly correlated with the formation of cysts or hematomas in pituitary adenomas. However, no such correlation with either the proliferative activity or the invasive character of the adenomas was observed. CONCLUSIONS: Locally overexpressed TF in adenoma cells may contribute to the development of vascular events, such as infarction and/or hemorrhagic infarction, in pituitary adenomas.
High-dose chemotherapy with autologous hematopoietic stem-cell rescue for patients with malignant brain tumors.
This article reviews recent reports on high-dose chemotherapy combined with autologous stem-cell rescue for patients with newly diagnosed or recurrent malignant brain tumors. Children with newly diagnosed malignant central nervous system (CNS) tumors are included - in these patients it was desirable to avoid radiotherapy. The drugs used were thiotepa, etoposide, cyclophosphamide, busulfan, melphalan, and carboplatin. At a toxic death rate of 8-13%, their toxicity was considered acceptable. However, in patients receiving high-dose chemotherapy, neurologic complications were not uncommon. Therefore, the effects of this drug therapy on the post-treatment cognitive function of long-term survivors must be examined prospectively. Regarding the types of tumor that respond to drug therapy, medulloblastoma and cerebral primitive neuroectodermal tumor (PNET) appear to be good candidates, as are malignant astrocytic tumors in the cerebral hemisphere of children younger than 3 years. On the other hand, brain stem gliomas do not appear to respond well to high-dose chemotherapy. Radiotherapy can be avoided in a significant proportion of young children with malignant brain tumors. Larger patient series need to be studied to determine which patients are most likely to benefit from high-dose chemotherapy and to pinpoint the optimal time for treatment intervention.
Cloning and functional characterization of the 5'-flanking region of the human monocyte chemoattractant protein-1 receptor (CCR2) gene. Essential role of 5'-untranslated region in tissue-specific expression.
The human monocyte chemoattractant protein-1 receptor designated hCCR2 is an essential co-receptor in cell entry by the human immunodeficiency virus as well as a receptor for monocyte chemoattractant protein-1, a member of the family of C-C chemokines that mediate monocyte chemotaxis. To elucidate the molecular mechanisms underlying the transcriptional regulation of hCCR2, we cloned and sequenced the hCCR2 gene; it was approximately 8 kilobase pairs in length and consisted of three exons divided by two introns. In the 5'-flanking region, there were the typical mammalian promoter consensus elements, a CAAT box and a TATA box, resulting in a single transcription initiation site. In addition, we found clustered tissue-specific cis-regulatory elements such as GATA consensus sequences, Oct-1 binding sequences, and CAAT/enhancer-binding protein binding sequences. Luciferase assays with various promoter deletions and gel mobility shift assays indicated that three cis-regulatory elements located within the region from -89 to +118 are required for basal activity in THP-1 cells. One element is an octamer sequence 36-base pair upstream from the TATA box; it binds mainly to Oct-1 and is capable of increasing transcriptional activity. The other two elements, which are tandem recognition sites of the CAAT/enhancer-binding protein family, are located in the 5'-untranslated region and account for the transcriptional activation as well as the tissue specificity of hCCR2.
A novel human nucleoside diphosphate (NDP) kinase, Nm23-H6, localizes in mitochondria and affects cytokinesis.
Nucleoside diphosphate kinases (NDP kinases) are enzymes known to be conserved throughout evolution and have been shown to be involved in various biological events, in addition to the "housekeeping" phosphotransferase activity. We present the molecular cloning of a novel human NDP kinase gene, termed Nm23-H6. Nm23-H6 gene has been mapped at chromosome 3p21.3 and is highly expressed in heart, placenta, skeletal muscle, and some of the cancer cell lines. Recombinant Nm23-H6 protein has been identified to exhibit functional NDP kinase activity. Immunolocalization studies showed that both endogenous and inducibly expressed Nm23-H6 proteins were present as short, filament-like, perinuclear radical arrays and that they colocalized with mitochondria. Cell fractionation study also demonstrated the presence of Nm23-H6 protein in a mitochondria-rich fraction. Moreover, induction of overexpression of Nm23-H6 in SAOS2 cells, using the Cre-loxP gene activation system, resulted in growth suppression and generation of multinucleated cells. Flow cytometric analysis also demonstrated that the proportion of cells with more than 4N DNA content increased to 28.1% after induction of Nm23-H6, coinciding with the appearance of multinucleated cells. These observations suggest that Nm23-H6, a new member of the NDP kinase family, resides in mitochondria and plays a role in regulation of cell growth and cell cycle progression.
Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas.
The purpose of this study was to evaluate the utility of diffusion-weighted magnetic resonance imaging (MRI) with echo-planar imaging (EPI) technique in depicting the tumor cellularity and grading of gliomas. Twenty consecutive patients (13 men and 7 women, ranging in age from 13 to 69 years) with histologically proven gliomas were examined using a 1.5 T superconducting imager. Tumor cellularity, analyzed with National Institutes of Health Image 1.60 software on a Macintosh computer, was compared with the minimum apparent diffusion coefficient (ADC) and the signal intensity on the T2-weighted images. The relationship of the minimum ADC to the tumor grade was also evaluated. Tumor cellularity correlated well with the minimum ADC value of the gliomas (P = 0.007), but not with the signal intensity on the T2-weighted images. The minimum ADC of the high-grade gliomas was significantly higher than that of the low-grade gliomas. Diffusion-weighted MRI with EPI is a useful technique for assessing the tumor cellularity and grading of gliomas. This information is not obtained with conventional MRI and is useful for the diagnosis and characterization of gliomas.
Preliminary observations for a new treatment in children with primary intracranial yolk sac tumor or embryonal carcinoma. Report of five cases.
The authors evaluated the effect of adjuvant therapy (preoperative chemotherapy combined with radiotherapy) followed by radical tumor removal in the treatment of children with primary intracranial yolk sac tumor, embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor components. Between 1988 and 1995, five consecutive patients were treated with adjuvant therapy followed by total tumor removal. The diagnosis was based on markedly elevated concentrations of serum alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (beta-HCG) in four children and the results of biopsy sampling in one child. The chemotherapy regimen consisted of cisplatin (20 mg/m2) and etoposide (60 mg/m2) daily for 5 days (one course) given three times at 4-weeks intervals. Radiotherapy consisted of 30 to 40 Gy to the whole brain or an area including all ventricles and a 15- to 20-Gy boost to the tumor site. Spinal radiation of 25 Gy was added in one patient. In all patients the serum level of AFP and beta-HCG gradually decreased during the adjuvant therapy and disappeared completely on its completion. In two of the five patients the tumor disappeared as well. In the other three patients the tumor size was moderately or markedly reduced and the remaining tumor was totally removed; there were no neurological deficits. Chemotherapy was maintained after the initial treatment and was repeated every 2 to 4 months for less than 2 years. All children are alive and well without recurrence at 33 to 118 months (average 88 months) after the start of adjuvant therapy. Our preliminary results indicate that adjuvant therapy consisting of combination chemotherapy with cisplatin and etoposide and concomitant radiotherapy, followed by removal of the tumor, is highly effective in the treatment of pediatric patients with primary intracranial yolk sac tumor, embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor components.
Expression of p120 nucleolar proliferating antigen in human gliomas and growth suppression of glioma cells by p120 ribozyme vector.
p120 is a nucleolar proliferating antigen which is expressed in tumor cells but not normal resting cells. The expression and localization of p120 in human gliomas were studied by Northern blot analysis, Western blot analysis and immunohistochemistry. All five of the glioma cell lines and all of the glioma specimens we investigated expressed p120 at both the mRNA and protein levels. p120 expression was not detected in adjacent brain tissues. A ribozyme vector was constructed to cleave the first GUC sequence in the coding region of p120 mRNA. This p120 ribozyme vector was transfected into the glioma cell line SF188, which expresses p120. The reduced p120 expression of the transfectant at both the mRNA and protein levels was confirmed. An MTT assay indicated that the transfected cells grew more slowly than control cells. These results indicate that i) p120 has an important role in the proliferation of gliomas, and ii) the ribozyme against p120 mRNA can suppress glioma cell growth.
Induction of apoptosis by N-(4-hydroxyphenyl)retinamide in glioma cells.
N-(4-hydroxyphenyl)retinamide (fenretinide) is a synthetic retinoid with anticancer properties. We investigated the effects of fenretinide on the growth of glioma cells. Four glioma cell lines (C6, 9L, Med3 and U87) were treated with fenretinide. Cell viability and independent growth was determined by MTS assay and soft agar assay, respectively. The induction of apoptosis was evaluated by microscopic examination, flow cytometric DNA content analysis, and in situ TdT methods. Fenretinide markedly reduced cell viability of all the glioma cell lines examined at a range of concentrations from 1 to 10 microM. In all cell lines examined, fenretinide also induced morphological changes consistent with apoptosis, including cellular shrinkage, chromatin condensation, and nuclear fragmentation. Flow cytometric analysis also revealed an apoptotic pattern of the DNA content, and in situ detection of apoptosis showed increased incorporation of digoxigenin-nucleotide triphosphate in fenretinide-treated glioma cells. These findings indicate that fenretinide inhibits the growth of glioma cells via the induction of apoptosis, suggesting potential clinical use of fenretinide for treatment of glioma patients.
Intraspinal osteogenic meningioma: report of a case.
Dense calcification and psammomatous bodies are common in spinal meningioma, but are rarely reported in osteogenic meningioma. We present a 73-year-old woman with an extramedullary, intradural tumor located at the T5 vertebra. The tumor showed mixed intensity and heterogeneous enhancement on the T1-weighted image and hypointensity on the T2-weighted image, and was situated near the spinal nerve root. The tumor's initial symptom was myelopathy, as is usual with spinal meningioma. We successfully removed the tumor under microscopy and found it to be separated from the vertebral column by the epidural space. The symptoms and signs improved gradually after the operation. Because the pathologic examination revealed areas of lamellar bone with bone marrow in the transitional meningioma, and because these were not related to the psammomatous bodies, osteogenic meningioma was diagnosed. Metaplasia of arachnoid cells is considered to be the putative etiology of osteogenic meningioma.
[Treatment of children with malignant brain tumors].
The current treatment of children with malignant brain tumors is reviewed. Multidisciplinary treatment is essential for malignant gliomas or glioblastoma. The prognosis of children with glioblastoma remains dismal and a new treatment approach needs to be established. Recent aggressive multi-drug chemotherapy in combination with radiotherapy and surgery have markedly improved the treatment of children with medulloblastoma and primary intracranial malignant germ cell tumors. The number of long-term survivors and even cure rates have been increasing.
Prognostic significance of the MIB-1 labeling index for patient with craniopharyngioma.
Proliferative activity of 17 craniopharyngiomas were determined using an immunohistochemical method with monoclonal antibody MIB-1. A considerable variation of the MIB-1 labeling indices was found between the different tumors with a minimum of 0.4% and a maximum of 32.5% (median, 10.84%). The mean MIB-1 labeling index (LI) for 4 craniopharyngiomas that showed no evidence of recurrence (n=4) was 3.4 +/- 2.3%. This was significantly lower than that for craniopharyngiomas that showed recurrence and regrowth (13.2 +/- 7.7%) (n=13), based on the initial resected tumors. Statistical analysis reveal that craniopharyngiomas with an MIB-1 LI of 7% or more have a significantly high tendency for recurrence and regrowth during clinical course. Our data suggest that a MIB-1 LI greater than 7% may be a useful predictor of regrowth/recurrence of craniopharyngiomas and may be useful for planning of adjuvant therapy.
Identification of a novel human homolog of the Drosophila dlg, P-dlg, specifically expressed in the gland tissues and interacting with p55.
We have identified a novel human homolog of the Drosophila dlg tumor suppressor gene, termed P-dlg, which has been mapped at chromosome 10q23. Unlike other human dlg homologs, P-dlg is expressed in placenta and various gland tissues but not in brain. The P-dlg protein is localized at the plasma membrane and cytoplasm, and it is expressed in the gland epithelial cells in normal prostate tissue but not in prostate cancer cell lines. Furthermore, we identified interaction between P-dlg and p55 palmitoylated membrane protein by yeast two-hybrid screening. These findings suggest that P-dlg forms a complex with p55 at the plasma membrane and plays roles in maintaining the structure of epithelial cells and transmitting extracellular signals to the membrane and cytoskeleton, which may negatively regulate cell proliferation.
Pineal germinomas with granulomatous inflammation. Report of two cases and review of the literature.
The authors report on two cases of pineal germinomas with granulomatous inflammation (granulomatous germinomas). Macroscopically, both tumors were relatively hard and grayish in color. Histological examination revealed a germinoma with multinucleated giant cells and Schaumann bodies in one case, and a germinoma with the background of acellular fibrillated matrix in the other. On immunohistochemical analysis, the granulomatous germinomas were shown to contain many macrophages, T- and B-lymphocytes, and glial fibrillary acid protein-positive cells infiltrating the specimens, compared to nongranulomatous germinomas. Analysis of Masson's trichrome staining tests showed that large areas of the granulomatous germinomas were occupied by a collagenous component; this was not the case in cases of nongranulomatous germinomas. Analysis of monoclonal anti-human Ki-67 results showed that the granulomatous germinomas had a lower score than nongranulomatous germinomas (p < 0.05, unpaired t-test), indicating that germinomas with granulomatous inflammation may have a better prognosis.