Biomedical subjects
N Shitara
Publications and source records attributed to N Shitara.
Morphological change in tumor endothelial cells induced by natural-type human tumor necrosis factor.
The effects of natural-type human tumor necrosis factor (nh-TNF) on tumor endothelial cells of experimental brain tumors were investigated electron microscopically. Tumor vessels with hypertrophic endothelial cells were observed 12 and 24 hr after an intralesional administration of 5,000 U of nh-TNF. Increased biosynthetic organelles such as the Golgi complex and rough endoplasmic reticulum were evident in the plump cytoplasms. These endothelial cells resembled those in high endothelial venules (HEV) functionally characterized by the high permeability of leukocytes. In addition, close interactions between these endothelial cells and leukocytes were observed. Our findings indicated that nh-TNF could promote the morphological change in tumor endothelial cells into HEV-like cells.
[Retrospective analysis of prognostic factors for survival and intracranial control in postoperative radiotherapy for metastatic brain tumor: examination of localized field irradiation].
To analyze the prognostic factors for postoperative radiotherapy of metastatic brain tumors, we retrospectively analyzed the clinical records of 127 cases that received more than 30 Gy of postoperative radiotherapy. The overall one-year survival rate (SR) was 48.2%, while the intracranial control rate (ICR) was 51.7%. Univariate analysis (UVA) revealed that female sex (p = 0.02), higher radiation dose (p = 0.05), and late onset (p = 0.05) were significantly favorable factors of SR. With multivariate analysis (MVA), the approving factors were higher radiation dose (p = 0.02), small number of metastases (p = 0.004), lesser extracranial metastasis (p = 0.02), and female sex (p = 0.02). In MVA, greater radiation dose (p = 0.004), lung cancer (p = 0.02), and late onset (p = 0.05) were found to be significantly good factors for ICR. Our unique method of localized field radiation as applied to well-resected and solitary metastatic tumors, was significantly correlated with better SR in this study. As long as patients are carefully selected, this technique is though to be useful for both the reduction of late complications and dose escalation in postoperative radiotherapy.
p300 gene alterations in colorectal and gastric carcinomas.
Colorectal tumors frequently have loss of heterozygosity on chromosome 22q, suggesting that inactivation of tumor suppressor gene(s) on 22q participates in the tumor development. Neurofibromatosis 2 (NF2) gene and E1A binding protein p300 gene, recently identified on 22q, are thought to be candidates for tumor suppressor genes. In this study, mutation of the NF2 gene in 59 colorectal carcinomas, and mutation of the p300 gene in 27 colorectal and two gastric carcinomas, were analysed using PCR-SSCP, RT-PCR-SSCP and direct sequencing methods. Missense mutations of p300 gene were detected in a colorectal carcinoma, and in a gastric carcinoma, though no mutation of NF2 gene was detected. Both p300 mutations were somatic and coupled to deletion of the second allele of the gene, which suggests inactivation of the p300 gene, in these carcinomas. The mutations are located within the Cys/His-rich regions, which are assumed to play important roles in the function of p300. These are the first cases in which p300 gene has been found to be altered in both alleles, suggesting that inactivation of the p300 gene may be involved in the development of carcinomas, and that this gene may be the target of loss of 22q in carcinomas of the digestive tract.
Usefulness of Ga-67 brain SPECT in patients with CNS malignant lymphoma.
The efficacy of Ga-67 SPECT imaging of CNS malignant lymphoma was investigated in 14 studies of 11 patients. As compared with planar images, the SPECT imaging improved the detectability of the focus of CNS malignant lymphoma. All untreated cases showed L/N ratios higher than 3.0. And the L/N ratios also changed according to remission or relapse of CNS malignant lymphoma.
Antitumor activity of natural-type human tumor necrosis factor on experimental brain tumors in rats.
The effects of intralesional injection of newly synthesized natural-type human tumor necrosis factor (nh-TNF) on experimental brain tumors in rats were investigated. The repeated injection of 5,000 U of nh-TNF into the tumor resulted in the prolongation of the survival time of the rats. More than half of the nh-TNF treated tumors were red, and were characterized by histopathological features of marked congestion of tumor vessels. Fibrin formations were also found in the tumor vessels. These histological findings were not observed in the control tumors. Furthermore, coagulative necrosis was observed in the center of some reddish tumors. Leukocytes adhering to vascular endothelium and infiltration of the leukocytes were also observed in the tumors of nh-TNF treated rats. In the immunohistochemical examination, these infiltrated cells were primarily polymorphonuclear leukocytes and macrophages. Expression of intercellular adhesion molecule-1 (ICAM-1) increased on the tumor endothelial cells after the administration of nh-TNF. These results suggest that repeated injection of nh-TNF has a therapeutic effect on brain tumors through its extensive influences on tumor vasculature.
[A case of cerebral aspergillosis associated with induction chemotherapy for acute lymphoblastic leukemia].
A case of cerebral aspergillosis during induction chemotherapy for acute lymphoblastic leukemia was described. A 5-year-old boy complained of headache and left homonymous hemianopsia during induction chemotherapy for acute lymphoblastic leukemia. CT scan and MR imaging survey demonstrated cerebral fungal lesion as well as multifocal lung lesions. A cerebral lesion appeared as a low density mass in right occipital lobe with marginal enhancement on CT scan, and iso- and high-signal intensity appeared with marginal gadolinium enhancement on T1- and T2-weighted MR imaging. Although fungus balls in the lung responded well to daily intravenous administration of amphotericin-B for 2 months, the cerebral lesion showed a rather expansive character as invading into neighbouring falx, opposite occipital lobe, meninges, and occipital bone. Extensive removal of the brain lesion from the parenchyma, falx, invaded dura, and skull was surgically performed. The lesion was confirmed as aspergillosis by Grocott's methenamine histological stain. Surgical intervention and concomitant use of amphotericin-B for a month resulted in complete remission of the aspergillosis. After 6 years, a cranioplasty was successfully completed for the occipital bone defect.
The antitumor activity of the DNA fraction from Mycobacterium bovis BCG (MY-1) for glioblastoma.
The antitumor activity of the DNA fraction extracted from Mycobacterium bovis BCG (MY-1) for glioblastoma was investigated in the experimentally produced brain tumor in rats. The tumor-bearing rats were given intralesional injection of 1 mg of MY-1 twice a week for three weeks, and were sacrificed for comparison with those of control rats. The main macroscopic features of the tumors treated with serial injections of MY-1 were cystic and destructive structures, which were histologically characterized by multiple microcysts containing macrophages. Furthermore, infiltration of leukocytes as well as the perivascular cuffing in the marginal area was observed. These findings suggested that the serial injections of MY-1 into the brain tumor have the therapeutic potential for glioblastoma.
Prediction of survival in patients with suspected recurrent cerebral tumors by quantitative thallium-201 single photon emission computed tomography.
PURPOSE: To assess whether quantitative 201Tl single photon emission computed tomography (SPECT) can be used as a prognostic test in patients with suspected recurrent cerebral tumor, regardless of various combined therapies given. METHODS AND MATERIALS: The study population consisted of 22 patients with grade 4, 3, or 2 glioma and 7 patients with solitary cerebral metastasis. All patients had undergone combined radiotherapy and chemotherapy after or during surgical debulking. Each patient underwent 201Tl brain SPECT to differentiate recurrent tumor from cerebral radiation necrosis, because the prior computed tomography and/or magnetic resonance imaging showed a mass lesion with an irregularly enhanced rim in the irradiation field. RESULTS: Higher values of 201Tl index (L/N ratio) showed a tendency for shorter survival (r = -0.502, p < 0.05). In patients with grade 3 glioma or solitary cerebral metastasis, survival time was definitely dependent upon 201Tl index values, that is, above or below the baseline index of 2.5. Grade 4 glioma patients, however, had a very short-term survival independent of 201Tl index values. CONCLUSION: Quantitative 201Tl SPECT may be a useful tool for predicting survival of patients with suspected recurrent cerebral tumor and may be used in place of fluorine-18-2-deoxy-2-fluoro-D-glucose (18F-FDG) scan.
Opposite effects of the overexpression of protein kinase C gamma and delta on the growth properties of human glioma cell line U251 MG.
In order to address the question of whether protein kinase C (PKC) is involved in the growth regulation of human glioma cells, we introduced PKC cDNA expression vectors into a human glioma cell line, U-251 MG, and established sets of stable cell clones that overexpress PKC gamma or delta. Cell clones obtained by the transfection of PKC gamma cDNA express 3.6 to 5 times more PKC activity than parental cells that express predominantly endogenous PKC alpha. These PKC gamma overexpressing cell clones show an increased rate of growth in monolayer culture, increased colony-forming efficiency on soft agarose, and increased DNA synthesis in response to epidermal growth factor and basic fibroblast growth factor. Cell clones obtained by transfection with PKC delta cDNA express 2 to 10 times more PKC than that produced endogenously. PKC delta overexpressing cells show a decreased rate of growth and decreased colony-forming efficiency. However, these PKC delta cell clones show no significant changes in responsiveness to the growth factors described above. These results clearly indicate that different PKC family members have distinct regulatory functions in cell growth and that PKC is involved in several aspects of the growth regulation of human glioma cells.
New treatment protocol by intra-operative radiation therapy for metastatic brain tumours.
In patients with brain metastasis from lung cancer, we have been able to control local recurrence in approximately 80% of cases. But many of them tend to show brain atrophy with mental deterioration developing a few months after whole brain radiation. To prevent brain atrophy, we have attempted treating patients, whose metastasis was diagnosed as single, by intra-operative radiotherapy (IOR) alone following surgical resection. Among 43 patients, 19 patients who had no metastases other than the brain metastases, were chosen as subjects for active treatment (surgical resection+IOR). Their 1-year survival rate was 75%. Fourteen out of 27 patients with brain metastases from lung cancer received active treatment and their 1-year survival rate was 74%. This result was not inferior to our result of 71 patients who received surgical resection and whole brain irradiation. When no preventive whole brain irradiation was performed, patients were observed every 8 weeks by CT scan in order to ascertain tumour recurrence limited to the treated site or appearance of any new metastatic lesion remote from the treated site. Among all 43 patients, local recurrence was recognized in 7 cases and remote recurrence was observed in 7 cases. Within 6 months, local and remote recurrence was found in 3 cases each. These results were almost the same as those for the usual therapy (surgery plus whole brain irradiation). If such a new lesion is detected, additional radiation can be performed with the possibility of achieving complete remission.
[Differential diagnosis between recurrence of gliomas and radiation necrosis by 201TlCl SPECT].
We studied the value of quantitative 201Thallium Chloride brain SPECT (Tl SPECT) in the differentiation between glioma recurrence and radiation necrosis. A total of 44 patients--26 patients with recurrent malignant glioma, 10 patients with low grade glioma and 8 patients with radiation necrosis--underwent Tl SPECT. The patients had early SPECT images taken 15 minutes after intravenous injection of 3mCi of 201TlCl and also had delayed SPECT images taken 4 hours after injection. Count ratios of a lesion to normal brain (L/N) were calculated from the rectangular ROI for the quantitative analysis. Count ratios of the lesion seen on the delayed image to that on the early image (D/E) were also calculated. In 26 patients with recurrent malignant gliomas, L/N ratio ranged from 2.6 to 12.6 with a mean of 4.4 +/- 2.3 on early images. All patients had L/N ratios greater than 2.5. However, in 8 patients with cerebral radiation necrosis, L/N ratios ranged from 1.5 to 2.4 with a mean of 2.0 +/- 0.3 on early image. L/N ratios were always 2.5 or less. In 8 patients with cerebral radiation necrosis, there were little differences between the L/N ratios for early and delayed images. D/E ratios ranged from 1.0 to 1.3 with a mean of 1.2 +/- 0.1. These results confirmed the validity of Tl SPECT in differentiating cerebral radiation necrosis from recurrent malignant gliomas. In 10 patients with low grade astrocytoma there was a subtle uptake or no uptake of Tl and the ratios of these patients were rated at 1.0.(ABSTRACT TRUNCATED AT 250 WORDS)
Germ-line p53 mutation is uncommon in patients with triple primary cancers.
We examined five patients with multiple primary cancers who had a history of three different types of primary cancers for germ-line p53 mutations. The germ-line p53 mutation was detected in a patient who conformed to the Li-Fraumeni syndrome, but not in the other four patients. The diagnosis of these four patients did not fall in the category of Li-Fraumeni syndrome. This result indicates that germ-line p53 mutations are uncommon even in patients with triple primary cancers.
Prognosis of intracranial germ cell tumours: effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16).
A co-operative study for patients with intracranial germ cell tumours was performed to analyze their prognosis and the effectiveness of Cisplatin/Etoposide (CDDP/VP-16) chemotherapy. A total of 46 patients; 30 primary and 16 recurrent cases were registered from 15 participating neurosurgical institutions in Japan. Based on histological criteria and tumour markers, they were classified into three groups; germinoma, germinoma with syncytiotrophoblastic giant cell (STGC), and non-germinomatous malignant tumour. Sixteen patients were treated with CDDP/VP-16 chemotherapy alone and the other 30 patients were treated by a combination of surgery and/or radiation in addition to chemotherapy. Eleven out of 13 patients (85%) with germinoma showed a complete (n = 10) or partial (n = 1) response to CDDP/VP-16 chemotherapy even if their tumours were recurrent and there was evidence of CSF dissemination. For the germinoma with STGC and non-germinomatous malignant tumour, a high response rate; 100% for the former and 78% for the latter, could also be achieved in both the primary and the recurrent cases except in those cases of immature teratoma. Their survival times were still different between them. Two-year survival was 50% in germinoma with STGC and 48% in non-germinoma, while it was 88% in germinoma cases.
Supraophthalmic chemotherapy with long tapered catheter: distribution evaluated with intraarterial and intravenous Tc-99m HMPAO.
Supraophthalmic intraarterial chemotherapy has not become popular due to a high incidence of damage to the normal brain and eye. This damage is due to inhomogeneous distribution of the agent secondary to streaming and other flow-related phenomena. To try to minimize this complication, the authors developed a catheter and studied different infusion techniques. A 4.5-F catheter tapered to 2.5 F was used to perform supraophthalmic intraarterial chemotherapy in 26 patients with malignant gliomas. Forty-one of 45 catheterizations were successful. In 17 patients (20 procedures), technetium-99m hexamethyl-propyleneamine oxime (HMPAO) was then injected through the catheter and single photon emission computed tomography was performed to assess the cerebral distribution of the radiopharmaceutical with either a pulsatile or continuous infusion technique. Diffuse and relatively homogeneous distribution of Tc-99m HMPAO was observed with fast pulsatile infusion (10 of 10 procedures); however, inhomogeneous distribution was mostly seen with slow continuous infusion (eight of 10 procedures).
Effect of chemoradiotherapy using ACNU, vincristine, and nicardipine with high-dose irradiation on malignant astrocytomas.
Fifty-two patients with malignant astrocytoma were treated with cellular synchronization radiation therapy at the University of Tokyo Hospital between 1977 and 1989. Twenty-five patients (Group 1) received 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU), vincristine, and 60 Gy of irradiation, and 27 patients (Group 2) ACNU, vincristine, the Ca-channel blocker nicardipine, and 72 Gy of irradiation. Median survival times for Groups 1 and 2 were 15 and 30 months, respectively. Although there was no significant difference, Group 2 achieved longer survival with 1-, 2-, and 3-year survival rates of 85.2, 65.8, and 46.9% compared to rates of 66.7, 40.0, and 26.7%, respectively, for Group 1.
Radiotherapy for pediatric brain stem glioma: radiation dose, response, and survival.
An analysis of 39 patients under 20 years of age with brain stem glioma treated with radiotherapy between 1977 and 1991 was undertaken. Twenty-eight (71.2%) of the patients responded well to initial radiotherapy, and 11 (28.8%) responded poorly. Median survival for the total patient population was 10 months. Response rates and median survivals were influenced by radiation dose: 45.5% and 9 months at doses less than 4499 cGy (n = 11), 83.3% and 13 months at doses between 4500 and 5499 cGy (n = 12), 66.7% and 11.5 months at doses between 5500 and 6499 cGy (n = 9), and 100% and 10 months at doses more than 6500 cGy (n = 7). Multivariate analysis revealed the response to initial radiotherapy was the only predictor of survival with radiation doses up to 6499 cGy. Four of the patients who responded well demonstrated radiological and/or histological calcification within or around the tumor at the time of clinical deterioration. Radiation injury was confirmed in two autopsy cases. The possibility that intratumoral radiation injury causes clinical deterioration is suggested.
Leptomeningeal dissemination of cerebellar pilocytic astrocytoma. Case report.
A case of surgically treated pilocytic astrocytoma in the cerebellar vermis is reported in a patient who subsequently demonstrated multiple subarachnoid nodular masses in the cerebrum and spinal cord 6 years after the initial surgery. The nodular tumors did not indicate a growth tendency on computerized tomography or magnetic resonance imaging over a 2-year observation period. The histology of the nodular masses in the cerebrum and spinal cord was similar to that of the original tumor. The bromodeoxyuridine labeling index indicated low proliferative activity (0.5%). The peculiar pattern of dissemination of the pilocytic astrocytoma is described.