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The phylogenetically-conserved vertebrate transcription factor, NFIB, is an orchestrator of glial differentiation in the developing mammalian central nervous system. We found NFIB expression to be reduced in glioblastoma (GBM), the commonest and most lethal primary adult brain cancer, so investigated what effect increased expression of NFIB had on GBM. Increased expression of NFIB in primary GBM cell lines induced expression of markers of glial differentiation, inhibited cell proliferation, reduced stem/progenitor cell growth, altered cell cycle progression and inhibited tumor growth in murine models of GBM. We thus identified NFIB to be a novel tumor suppressor gene in GBM.

Objectives: On the determination of treatment for preoperative primary brain tumors, it is very important for the neurosurgeons to predict the grade of malignancy or the extent of the tumors. The aim of this study is to evaluate the usefulness of FDG PET and MET PET when considering the plan of operation for the primary brain tumors. Methods: We examined 12 patients with preoperative brain tumors who underwent FDG PET and MET PET. Moreover, we estimated the correlations between WHO grading and the tumor/normal brain uptake ratios (T/N ratio). Results: The T/N ratios of FDG in GIV were significantly higher than that in GII (p

There are few papers comparing FDG and MET uptake in miscellaneous brain tumors. In the present study, we demonstrated both PET studies of five patients with untreated brain tumors (gemistocytic astrocytoma, tanycytic ependymoma, astroblastoma, gliomatosis cerebri and medulloblastoma). The results show more marked MET uptake into the tumors compared with FDG. As MET PET has an advantage for FDG in delineation of tumor margins, it will be a more promising method to evaluate biological behavior and for instructing surgical procedure or radiotherapy in various brain tumors.

Of the many methods and techniques for in vivo gene transfer, some have already been used in clinical trials. In most cases, genes are transferred into tissues using the infectivity of viral particles. However, viral systems have some known drawbacks (1,2). If an efficient and specific transfer method could be developed, naked plasmid DNA would be an ideal system for gene transfer. Plasmid-mediated methods would be economical and easy. Also, the transfer procedure could be easily repeated, as naked plasmid DNA has little antigenicity for the host (3,4).

We developed five different hybridoma cell lines that produced mAb against human monocyte chemoattractant protein-1 (MCP-1). The subclass of all five antibodies was IgG1. All five mAb formed complexes with metabolically labeled MCP-1 that could be demonstrated by immunoprecipitation. The antibodies were specific for MCP-1. They did not cross-react by immunoprecipitation with structurally related host defense cytokines present in metabolically labeled PHA- or LPS-stimulated mononuclear cell culture fluids, nor did they cross-react in a direct ELISA with neutrophil attractant/activation protein-1, with crude platelet lysate proteins, or with pure platelet proteins that have amino acids sequences similar to that of MCP-1. The mAb also reacted with rMCP-1 expressed in Escherichia coli, suggesting that they recognize protein structure rather than the glycosylated portion of human MCP-1. When the mAb were mixed with MCP-1, the monocyte chemotactic response to MCP-1 was inhibited. A sandwich ELISA was developed to detect MCP-1 in biologic fluids containing relatively high concentrations of other proteins. The sensitivity was 300 pg/ml, or 30 pg/ELISA well. An anti-MCP-1 mAb column was used in an improved method of MCP-1 purification. Approximately 240 micrograms of MCP-1 were purified from 5 liters of FCS-containing U-105MG cell culture supernatant. The yield was at least 60%. In addition to two forms of MCP-1 reported previously by us, two more forms of MCP-1 were found in a mixture of culture supernatants of PHA- and LPS-stimulated human PBMC.

SUMMARY: It is unknown whether dilated perivascular spaces can affect the adjacent neuronal fibers. We describe conventional MR and diffusion tensor imaging findings of a case with multiple, prominent dilated perivascular spaces in the left cerebral hemisphere. Diffusion tensor imaging showed no alterations in the fractional anisotropy and apparent diffusion coefficient values for the corona radiata, posterior rim of the internal capsule, and the cerebral peduncle, indicating no wallerian degeneration associated with dilated perivascular spaces.

We analyzed serial changes in the regional cerebral blood flow (rCBF) of 13 patients with intracerebral hemorrhage by single photon emission computed tomography (SPECT) during the acute- to chronic stage (2 hr to 55 weeks). The (99m)Tc-ethyl cysteinate dimmer ((99m)Tc-ECD) was used as the nuclear mediator. The SPECT timing within 48 hours after the onset was considered to be acute stage, from 48 hours to 4 weeks to be subacute stage, and after 4 weeks to be chronic stage. The region of interest was each hemisphere in the whole brain without ventricles at the thalamic level. For semi-quantitative analysis of rCBF, we used the Brain Uptake Ratio method. Of the 13 patients (mean age 65.5 years), 3 had thalamic-, 4 putaminal-, 5 subcortical-, and one a cerebellar hemorrhage; the hematoma volume varied from 4-50 ml (20 ml, n=9; 20-30 ml, n=1;30 ml, n=3; mean 17 ml). The rCBF changes during the long-term follow-up were classified as increase-, decrease-, and unchanged type. Of 5 patients with increased rCBF, 4 made a good recovery and one was severely disabled; of 5 patients with decreased rCBF, 1 made a good recovery, 3 were moderately-, and one was severely disabled. All 3 patients with unchanged rCBF were moderately disabled. Our findings suggest that among patients with hypertensive intracerebral hemorrhage, those with increased rCBF over time may have a favorable outcome. We further need more cases with intracerebral hemorrhage to clarify this trend.

Although mutational inactivation and allelic loss in the NF2 gene appear to be causal events in the majority of vestibular schwannomas, involvement of another potentially important mechanism, transcriptional inactivation, has not been investigated.We cloned and functionally characterized the 5'-flanking region of the human NF2 gene and identified the molecular mechanisms that regulate NF2 expression. Luciferase assay and site-directed mutagenesis demonstrated that a 70-base pair (bp) region (-591 to -522 bp from the translation start site) was essential for the basic expression of the NF2 gene. A gel mobility shift assay indicated recognition by nuclear protein of the unusually long ( approximately 66 bp) sequences in this region. Recognition was inhibited by either mutation of the binding core sequence or by methylation of three CpG sites. Point mutations at these CpG sites significantly decreased promoter activity, suggesting the importance of these sites. In 14 of 23 vestibular schwannomas, these three CpG sites were methylated in a site-specific manner and the methylation status was consistent with the expression of NF2 mRNA.Suppressed expression by aberrant methylation or mutation of the promoter elements could be an alternative mechanism for inactivation of the NF2 gene.

This prospective randomized trial was performed to compare the effectiveness of intra-arterial ACNU with intravenous ACNU in newly diagnosed patients with supratentorial glioblastoma. The primary end points were overall survival and progression-free survival. Within 3 weeks after surgery, patients were randomly assigned to receive either intravenous or intra-arterial ACNU (80 mg/m2) once every 6 weeks concomitant with radiotherapy. Intraarterial ACNU was administered for the first 3 courses followed by intravenous administration. Eighty-four patients were enrolled onto this study and among them 82 patients who passed eligibility criteria were analyzed. Patients characteristics were not different significantly between 2 treatment arms. Median survival and progression-free survival time was 59 and 24 weeks, respectively for intra-arterial arm and 56 and 45 weeks, respectively for intravenous arm. There was no significant difference respectively between two treatment arms. Among the prognostic variables including age, Karnofsky performance status, extent of surgery and treatment arm, Cox's proportional hazards model showed that age was the only significant factor for both survival and progression-free survival (P = 0.003 and 0.016, respectively). With regard to toxicity, there was no significant difference between two treatment arms. Leukoencephalopathy was not observed in intra-arterial arm. In conclusion, intra-arterial ACNU when administered by the method in this study does not increase the survival and progression-free survival of newly diagnosed patients with glioblastoma over that afforded by intravenous ACNU.

A 11-year-old boy presented with right temporal hemianopsia and was evaluated of a possible pituitary adenoma. At the age of six, he underwent surgery for facial deformities due to fibrous dysplasia. On admission, he had acromegalic features, was 170 cm tall, weighing 66 kg. The left side of his face was slightly deformed, and a café-au-lait spot was found on his right face. Endocrinologic examination revealed elevated basal level of serum GH (103.6 ng/ml, normal3 ng/ml) and PRL (259.1 ng/ml, normal30 ng/ml). Other endocrine functions were normal. CT showed hyperostosis of the right frontal, occipital, sphenoidal and maxillary bones. Magnetic resonance imaging (MRI) revealed a pituitary macroadenoma with intraadenomatous cyst. On the basis of physical, endocrinologic and neuroradiologic examination, our diagnosis was pituitary adenoma with McCune-Albright syndrome. Surgery was performed by subfrontal approach. By light microscopy, the pituitary tumor represented a typical acidophilic adenoma. Immunoreactivity for GH and PRL were evident in most of the adenoma cells. Double immunostaining for GH and PRL demonstrated the co-existence of the two hormones in a few adenoma cells. However the majority of cells expressed only one hormone. After surgery the right temporal hemianopsia improved. Postsurgical endocrinologic examination revealed reduction in basal serum GH and PRL levels. Administration of bromocriptine decreased blood PRL levels but it had a limited action on GH hypersecretion.

A 24-year-old male presented with a rare intracranial dural metastasis from a mediastinal germ cell tumor infiltrating the superior vena cava, pericardium, ascending aorta, and lung. Routine chest radiography incidentally revealed the abnormal mediastinum, which was partially resected after median sternotomy, followed by radiotherapy. One year after the radiotherapy, magnetic resonance imaging revealed a right parasagittal tumor mimicking a meningioma. Partial tumor removal was performed. Two cycles of chemotherapy with carboplatin and etoposide were then performed, and the residual tumor almost completely disappeared. The histological diagnosis of both the mediastinal and intracranial tumors was pure seminoma. Sections of metastatic tumor revealed several thick fibrous septa and numerous epithelioid granulomas infiltrated by plasma cells, intermingled between the clusters of tumor cells. Follow up of patients apparently in remission from mediastinal seminoma without evidence of advanced or recurrent disease at other sites is recommended.

The spinal seeding from brain tumors sometimes mimicks fungal meningitis on examination of cerebrospinal fluid.A 19-year-old woman gradually developed increased intracranial hypertension. MRI identified a mass in the right parieto-occipital area. It was totally removed and histologically diagnosed as an anaplastic ependymoma. Radiation- and chemotherapy were administered postoperatively. The patient reported low back pain 5 months after the surgical treatment. MRI disclosed neither spinal dissemination nor tumor recurrence at the primary site. Lumbar puncture was performed and the cerebrospinal fluid (CSF) was found to have an extremely low glucose level (5 mg/dl); no tumor cells were identified. Blood samples were obtained and a relative increase of WBC and CRP was noted. A slight degree of inflammation and low-grade fever were recorded. A tentative diagnosis of fungal meningitis was made and anti-fungal therapy was administered transventricularly and transvenously. However, her neurological condition continued to deteriorate gradually. Sequential CSF studies showed that the glucose level remained extremely low, it even decreased to 0 mg/dl Eight months after the surgical treatment, MRI with Gd-DTPA revealed marked subarachnoid enhancement in both intracranial and spinal areas. An open biopsy was performed and a histological diagnosis of intracranial and spinal seeding of the anaplastic ependymoma was returned.We report a patient with intracranial and spinal seeding of an anaplastic ependymoma that mimicked fungal meningitis. We discuss the difficulty of obtaining a differential diagnosis in this case and describe the mechanism of the decreased CSF glucose level.

KRN8602(MX2) is a newly developed morpholino-anthracycline that has been found to cross the blood-brain barrier and be distributed in brain tissue after intravenous administration and to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo. In order to confirm these promising preclinical observations clinically, we performed a phase II trial of KRN8602 in patients with recurrent malignant glioma. The 44 patients enrolled received at least 2 cycles of KRN8602 35 mg/m2/day at 3-4 week intervals by intravenous bolus. Of the 44 patients, 37 could be evaluated for response, and 39 for toxicity. One patient with anaplastic astrocytoma had a complete response (1/37, 3%), and 2 patients with anaplastic astrocytoma and 1 with brain stem glioma had a partial response (3/37, 8%). The overall response rate was 11% (4/37). All patients who responded had received prior chemotherapy that included nitrosoureas. No response was observed in the patients with glioblastoma. Myelosuppression was moderately severe, with 72% of patients developing grade 3 or 4 leukopenia. Severe nausea/vomiting was observed in 31% of the patients. No severe cardiotoxicity was observed. The results indicate that KRN8602 has modest activity against recurrent malignant glioma with relatively severe, but manageable toxicity. It seems to be worthwhile to further assess the efficacy and toxicity of KRN8602 against malignant glioma, which is generally less sensitive to chemotherapy.

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.

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.

The toxicity and therapeutic effect of the ventriculolumber perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl-1-1(2-chloroethyl)-1-nitros our ea hydrochloride (ACNU) against subarachnoid dissemination of gliomas were studied. Twenty-one patients (6 patients with anaplastic glioma, 7 with glioblastoma and 8 with medulloblastoma or PNET) received ventriculolumber perfusion of ACNU when they were diagnosed as having subarachnoid dissemination. The course of perfusion and cumulative dose of ACNU was 10 times and 95 mg on average, respectively. Most of the patients received systemic chemotherapy in combination with perfusion therapy and some patients with radiotherapy. Response rate was 17% and median survival time after the diagnosis of dissemination was 12 months for anaplastic gliomas, 29% and 12 months for glioblastoma, and 88% and over 25 months for medulloblastoma and PNET. The ventriculolumber perfusion of ACNU was performed for prophylactic purpose in 7 patients with high risk at the early postoperative period in combination with conventional adjuvant therapy. The course of perfusion and cumulative dose of ACNU was 2.3 times and 21 mg on average, respectively. One patient developed subarachnoid dissemination and died 22 months after surgery. Other 6 patients survived without dissemination on median over 29 months after surgery. Side effects encountered were headache in 4 patients, nausea and vomiting in 5, a convulsion in 2, right facial weakness in 1, fecal incontinence in 3 and meningitis in 2. They were all temporary except for facial weakness occurred in one patient. These data suggest that the ventriculolumber perfusion of ACNU is a safe and useful in the treatment and prophylaxis against the subarachnoid dissemination of gliomas.

A 5-year-old boy presented with a 1-year history of frontal headache and nausea. Neurological examination showed left abducens nerve palsy, left facial nerve palsy, Bruns' nystagmus, and wide-based gait. Neuroimaging demonstrated a lesion with moderate linear enhancement in the left cerebellar hemisphere. He underwent stereotactic needle biopsy. The histological diagnosis was well-differentiated small lymphocytic type of malignant lymphoma. Following the biopsy, the patient underwent radiotherapy (whole brain 30 Gy, local 20 Gy). He has been in good condition for more than 5 years. The long-term survival is attributable to the absence of aggressiveness and the good response to radiation of this subtype of malignant lymphoma.

Tissue factor (TF) is a cell surface glycoprotein that initiates the extrinsic coagulation protease cascade and it is expressed in some tumor cells. TF belongs to the interferon receptor family, and it is one of the early immediate genes, suggesting that TF has a biological function other than hemostasis. We investigated the expression of TF in gliomas. Immunocytochemistry showed the expression of TF in 3 glioma cell lines. Immunohistochemical analysis of 44 surgical specimens revealed that all gliomas were positive for TF, and 19 (95%) of 20 glioblastomas, 12 (86%) of 14 anaplastic astrocytomas and 1 (10%) of 10 benign gliomas were moderately or strongly positive for TF. Our study showed that TF is expressed in gliomas, and that the level of TF expression is correlated with the grade of malignancy of the glioma, suggesting that TF may participate in cell growth.

Between 1989 and 1995, we diagnosed primary intracranial neoplasms in 79 children younger than 15 years. All of them belonged to a well-defined population residing in Kumamoto Prefecture, Japan. Of the tumors, 64 (81.0%) were confirmed microscopically. The age-adjusted annual incidence rate was 34.3 cases per million child population. There was a marked difference in the incidence rate between boys (47.1) and girls (22.05). The age-specific annual incidence per million was 24.3 cases for the 0- to 4-year age group, 46.7 for the 4- to 9-year age group and 30.8 for the 10- to 14-year age group. The highest incidence rate was seen in 5- to 14-year-old boys (53.5), the lowest in 10- to 14-year-old girls (7.1). The most common tumors were astrocytomas (41.8%), with an incidence of 14.52 per million, followed by germ cell tumors (15.1%), with an incidence of 6.24 per million, craniopharyngiomas (15.1%), incidence 5.25 per million, ependymomas (6.3%), incidence 2.19 per million, and medulloblastomas (6.2%), incidence 2.19 per million. The distribution of tumor types varied with patient age at the time of diagnosis. Although no germ cell tumors were encountered in the 0- to 4-year age group, in the 10- to 14-year age group, they comprised about one third of all tumors. In contrast, white craniopharyngiomas were rare in the 10- to 14-year age group, they made up more than 22% in the 0- to 4-year age group. In this survey of Japanese children, we found a higher incidence of primary intracranial tumors, especially germ cell tumors and craniopharyngiomas, and a lower incidence of medulloblastomas compared to the incidence reported for Western countries.

1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), one of the chloroethyl nitrosoureas, is effective against malignant glioma. To develop its use in intrathecal chemotherapy, we encapsulated BCNU in hybrid liposomes composed of dimyristoylphosphatidylcholine and micellar surfactants (Tween 20) and dissolved it in artificial cerebrospinal fluid (lipo-BCNU). We then studied the toxicity of hybrid liposomes and cellular proliferation inhibition of lipo-BCNU in vitro. We found that 3 mM hybrid liposomes did not affect the viability of human endothelial cells and that lipo-BCNU inhibited the proliferation of human glioma cell lines U-105MG, U-251MG, and U-373MG, and rat glioma cell lines C6 and 9L in a concentration-dependent fashion. Wistar rats that were administered lipo-BCNU intracisternally showed no weight loss, neurological symptoms, or histological changes of the brain and spinal cord. A Wistar rat model of meningeal gliomatosis was established by intracisternal inoculation of 0.1 ml cell suspension containing 1 x 10(6) or 5 x 10(6) viable C6 glioma cells. Two days after inoculation, lipo-BCNU (BCNU, 2.5 mg/kg) was administered intracisternally. When 1 x 10(6) glioma cells were inoculated (experiments 1 and 2), the median survival times were 24.5 and 26 days in the control groups and 32 and 45 days in the lipo-BCNU-treated groups. respectively. When 5 x 10(6) glioma cells were inoculated (experiments 3-6), the median survival times were 17-29.5 days in the control groups and 23-44 days in the treated groups, respectively. Significantly prolonged survival was obtained in three of six experimental groups. After the administration of 1 ml lipo-BCNU (BCNU, 4.67 mM) or 1 ml BCNU solubilized with 5% dextrose/water (BCNU, 4.67 mM) into the cisterna magna of dogs, the cisterna magna cerebrospinal fluid was sampled, and the BCNU concentrations were assayed by high-performance liquid chromatography. The half-life of the lipo-BCNU was longer than that of BCNU solubilized with 5% dextrose/water. These results suggest that the intrathecal administration of lipo-BCNU may be possible for the treatment of meningeal gliomatosis.

A novel method for high-efficiency and region- controlled in vivo gene transfer was developed by combining in vivo electroporation and intraarterial plasmid DNA injection. A mammalian expression plasmid for the Escherichia coli lacZ gene (driven with a SV40 early promoter) was injected into the internal carotid artery of rats whose brain tumors (from prior inoculation) had been electroporated between two electrodes. The lacZ gene was efficiently transferred and expressed in the tumor cell 3 days after plasmid injection. However, neither any gene transfers nor any elevated lacZ activity was detected in tissues outside the electrodes. The plasmid was not transferred without electroporation. Human monocyte chemoattractant protein-1 cDNA was also transferred by this method, and its long-lasting (3 weeks) expression was confirmed by using the Epstein-Barr virus episomal replicon system. The expressed monocyte chemoattractant protein-1 protein was functional, as evident by the presence of a large number of monocytes in tumor tissue. This method, electrogene therapy, which does not require viral genes or particles, allows genes to be transferred and expressed in desired organs or tissues, and it may lead to the development of a new type of highly effective gene therapy.

The magnetic resonance imaging appearance of 40 surgically confirmed intracranial meningiomas was reviewed to correlate signal intensity on T2-weighted images with histological subtypes of meningioma. A moderate variation of signal intensity was found within a given histological subtype. The mean signal intensity scores on T2-weighted images of the fibrous type of meningioma were significantly lower than those of the other types, and were correlated with the collagen content. The signal intensity of meningiomas on T2-weighted images crudely predicts the histological type. Tumors significantly hypointense compared to the cortex are composed primarily of fibrous elements.

Suramin, a non-specific growth factor antagonist, has been reported to have pleiotrophic action on the proliferation of some kinds of tumours and has therefore attracted attention as an agent in the treatment of cancer. We studied its action on human glioma cell lines in vitro by examining the effect of suramin on the proliferation and the cell cycle and mitogen-activated protein (MAP)-kinase activity of glioma cells. We found that at low concentration (50, 100 micrograms/ml) suramin had a stimulatory effect while at higher concentrations (200, 500 micrograms/ml) it had an inhibitory effect on the proliferation of 4 human glioma cell lines. At low concentrations, suramin stimulated the transition of glioma cells from a quiescent state (G0) to the proliferative phase (S phase); MAP kinase activity was also increased. The stimulatory effect of low concentrations of suramin on the proliferation of glioma cells may have important consequences for glioma patients treated with suramin.

Osteopontin (OPN) is a phosphorylated glycoprotein that contains a functional Gly-Arg-Gly-Asp-Ser (GRGDS) cell-binding sequence. It is reported that the expression of OPN is increased in a number of transformed cell lines. This study demonstrates the expression of OPN in human glioma representative of brain tumors.The expression of OPN in human gliomas was determined with: (a) Northern blot analysis; (b) Southern blot analysis; (c) Immunofluorescent cytochemistry; (d) Western blot analysis; (e) Cloning and sequencing of complementary DNAs (cDNAS); (f) Immunohistochemistry.OPN mRNA was detected in all glioma cell lines examined, and Southern blot analysis showed that OPN DNA most likely exists as a single copy gene in these cell lines. Immunofluorescent cytochemistry showed strong staining mainly in the cytoplasm. These cell lines produced two major forms of OPN protein migrating at 53 and 47 kilodaltons, and two minor forms at 38 and 31 kilodaltons on 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels. We also isolated and sequenced three types of splice variants in OPN from human glioma cell lines through polymerase chain reaction. In addition, Northern blot analysis was carried out on RNA from human astrocytoma tissues of various malignancy grades. Expression of OPN mRNA was high in malignant astrocytomas, but low in benign astrocytomas and non-neoplastic tissue. Immunohistochemistry also showed strong staining in malignant astrocytomas and slight staining in benign astrocytomas.These findings indicate that OPN mRNA and proteins are expressed in human glioma cells, and that the extent of OPN expression may correlate with the malignancy grade of gliomas.

By immunohistochemistry using anti-rat macrophage monoclonal antibodies RM-1, ED1, ED2, ED3, TRPM-3, and Ki-M2R, we studied transplanted rat tumors of 9L (rat gliosarcoma), Ad-2 (rat mammary carcinoma), and MT-P (rat malignant fibrous histiocytoma) cell lines to examine the distribution pattern of macrophages within and around the tumors. Most tumor-associated macrophages expressed RM-1, ED1, and Ia antigens, indicating activated macrophages. Based on differences in their immunophenotypical expression, these macrophages were distinguished into two major subpopulations. One expressed TRPM-3 and/or ED3, and the other was positive for ED2 and Ki-M2R. The former was considered to be monocyte-derived macrophages, whereas the latter showed the immunophenotype of tissue-fixed, resident macrophages. Infiltration and distribution patterns in the two macrophage subpopulations differed in the three different tumors. Monocyte-derived, activated macrophages infiltrated into 9L- and Ad-2-transplanted tumors, which markedly produced monocyte chemoattractant protein-1 (MCP-1). Additionally, numerous ED2- and Ki-M2R-positive macrophages were observed within the Ad-2-transplanted tumors, and some of them expressed TRPM-3. However, there were few macrophages in the MT-P-transplanted tumors that showed no MCP-1 production. In transplanted tumors of four MT-P/MCP-1 cell lines established by transfecting a rat MCP-1 gene expression vector (pCEP4/MCP-1) into the MT-P cell line, different levels of MCP-1 production were detected, which correlated well with the numbers of intratumorally infiltrated TRPM-3-positive macrophages. In contrast, ED2- and Ki-M2R-positive macrophages were not detected in any MT-P/MCP-1-transplanted tumors. MT-P/MCP-1-transplanted tumors exhibited lower growth rate than parental MT-P-transplanted tumors. These results indicate that tumor-derived MCP-1 induces intratumoral infiltration of monocyte-derived macrophages, but not macrophages with the immunophenotype of tissue-fixed, resident type. The former population of macrophages seems to have a suppressive effect on the growth of tumors.

Despite recent attempts to improve chemotherapeutic approaches for the treatment of malignant gliomas, results remain limited and palliative. The development of effective chemotherapy for tumors of the central nervous system (CNS) is complicated in that the blood-brain barrier (B.B.B.) hampers the penetration of most drugs into the brain and cerebrospinal fluid. The factors governing delivery in the brain are the drug's molecular weight, lipophilicity and degree of ionization. Now the standard therapy for malignant glioma is maximal tumor resection followed by combination radiotherapy plus chemotherapy. Nitrosoureas are representative drugs which easily cross the B.B.B.. It has been shown that nitrosourea compounds have an additive effect to radiotherapy. The toxicity profile of nitrosoureas is leukocytopenia and thrombocytopenia as a dose-limiting factor. Furthermore, the great heterogeneity of malignant glioma tissues offered a rationale for the use of multiple drugs. Many studies were reported to show a substantial advantage for the multidrug regimen over control series utilizing single drugs alone. Despite clear examples of the effectiveness of chemotherapy, we are still far from improving the cure rate for the vast majority of patients with primary malignancies of the CNS. Further improvement in patient survival may depend upon understanding and manipulating the pathways that regulate aberrant growth in these tumors. The development of new anticancer agents, which are sensitive to malignant glioma and can reach a high concentration in glioma tissue, is warranted.

A 54-year-old woman with cerebellar metastasis from ovarian adenocarcinoma was reported. Two years before admission, she underwent 7 courses of CAP therapy (cisplatin, adriamycin, cyclophosphamide) for ovarian cancer. On admission, no extracranial tumor was noticed. After the removal of a cerebellar tumor, she was treated by combination chemotherapy with cisplatin and etoposide. Her serum level of CA-125, which was still high after surgery, decreased to the normal level following chemotherapy. Chemotherapy was repeated six times, and no recurrence was noticed 1 year after surgery. Combination chemotherapy with cisplatin and etoposide was considered effective in the treatment of intracranial metastasis from ovarian cancer.

Growths factors, defined as polypeptides that stimulate cell proliferation, are major growth-regulatory molecules for cells in culture and probably also for cells in vivo. Evidence has been derived for autocrine system in which the cell produces its own growth factor. Several growth factors as well as their cellular receptors have been identified as productions of proto-oncogenes. Furthermore, these growth factors have been identified as mitogens in tumors of the central nervous system. The roles of growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and its receptor. Insulin-like growth factors (IGFs), transforming growth factors (TGFs) and fibroblast growth factor (FGF) on the proliferation of brain tumors, especially glioma were reviewed. The activation of cellular proto-oncogenes resulting in the autocrine system of growth factors and their receptors offers the opportunity for therapeutic interference. Therapeutic efforts will be based on the concepts of neutralization of growth factors, antagonizing growth factors at their receptors, irreversibly blocking receptors, and interference with oncogene product synthesis. Specific antibody for growth factors or receptors will be able to inhibit the proliferation. Trapidil, an antagonist for PDGF, can inhibit the proliferation of a PDGF-producing glioma cell. We can assume that the further analysis of growth regulatory mechanism will allow the design of new therapeutic approaches.

To test the feasibility of intrathecal perfusion of ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitro sou rea hydrochloride) in the treatment of subarachnoid dissemination of malignant glioma, the neurotoxicity and pharmacokinetics of ACNU were studied in dogs. ACNU [1-2 mg dissolved in 10-20 ml of lactated Ringer's solution or artificial cerebrospinal fluid (CSF)] was administered via the right lateral ventricle by constant drip infusion and CSF was drained by lumbar puncture. The infusion time was from 15 to 71 min. For the control, a bolus injection was given. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord revealed only mild denudation of ependyma in the wall of the ventricles in a dog treated three times with 2 mg ACNU (perfusion twice, bolus injection once) and in 2 dogs perfused with 1 mg ACNU once a week for 10 weeks. ACNU was not detected in lumbar CSF after bolus injection into the lateral ventricle. When 1 mg of ACNU, dissolved in 10 ml of artificial CSF, was perfused for a duration of 22 to 31 min, it started to appear in the lumbar CSF 10 to 15 min after the start of perfusion, reaching a maximum concentration of 13.88 to 22.31 micrograms/ml. The area under the drug concentration-time curve was 344 to 706 micrograms x min/ml; the half-time was 15.5 to 19.5 min. The distribution volume was 30.6 to 54.1 ml. These findings suggest the feasibility of intrathecal perfusion of ACNU in the treatment of patients with subarachnoid dissemination of glioma.

A case of intracranial arterial vasospasm caused by pituitary apoplexy after head trauma is reported. In this case, pituitary apoplexy was secondary to head trauma, and the vasospasm was thought to be due to subarachnoid hemorrhage from a pituitary tumor. No such case has previously been reported in the literature.

A 45-year-old female presented with blurred vision, headache, and abnormal thirstiness. She was not pregnant nor postpartum. She had diabetes insipidus and bitemporal hemianopsia. Radiological evidence suggested a mass arising in the sella turcica with extension into the parasellar and suprasellar regions. Carotid angiography showed occlusions of bilateral internal carotid arteries at the cavernous portions. The mass was subtotally removed by the trans-sphenoidal approach and was histologically diagnosed as an adenohypophysitis. Laboratory data showed the patient to be in an active state of autoimmune disorder and hypopituitarism. When a patient presents with pituitary insufficiency and an enhanced intrasellar mass lesion on computed tomographic scan, lymphocytic adenohypophysitis must be included in the differential diagnosis.

Histochemical analysis of frozen, thin sections revealed the distribution of alkaline phosphatase (ALPase) in 47 primary intracranial neoplasms in humans. The cytoplasm of meningioma cells exhibited the strongest ALPase reactivity. Pretreatment of these materials by levamisol indicated that the isozymes of ALPase had the characteristic liver-bone-kidney form. In meningiomas and astrocytomas, there was no particular relationship between ALPase activity and malignancy. In neurinomas, there was weak ALPase reactivity in a few neoplastic cells. These findings are suggestive of diagnostic implications for fibroblastic meningiomas and neurinomas at the light microscopic level.

Angiosarcoma is a rare malignant tumor originating from vascular endothelial cells. We have experienced a case of 17-year-old man, who had angiosarcoma in the pineal region and the liver. Patient's initial symptom was headache and CT scan revealed a high density mass in the pineal region with obstructive hydrocephalus. After the radiation therapy, the tumor was disappeared completely on CT scan. One year later, he developed abdominal pain, and CT scan and angiogram revealed multiple angioma like lesions in the liver. The mass in the pineal region showed concomitant regrowth, and finally, the patient was died of abdominal hemorrhage. At autopsy, pineal tumor and hepatic tumor were both angiosarcomas, although it was uncertain which was the original tumor.

We studied the feasibility of intrathecal ACNU perfusion therapy against subarachnoid dissemination of malignant glioma. Intrathecal perfusion was performed in adult dogs by constant drip administration of 1 to 2 mg ACNU dissolved in 10 to 20 ml of lactate Ringer solution into the lateral ventricle and cerebrospinal fluid drainage through the lumbar puncture. The perfusion time was changed from 15 to 71 min. A bolus injection of 2 mg ACNU was also tested in one dog. No neurological symptom was noted during and after perfusion, and histological examination reveal only a minimum denudation of ependyma in a small area. Concentration of ACNU in CSF and serum were measured by HPLC (high-performance liquid chromatography). ACNU was detected in lumbar CSF only by perfusion, not by bolus injection, and the maximum concentrations were 6.26 to 25.76 micrograms/ml. The elimination phase of ACNU in lumbar CSF followed linear kinetics and the half-time was 18 min on average. AUCs (area under the drug concentration-time curve) were 346 to 896 micrograms.min/ml and they were the equivalent of in vitro cell kills in excess of 3 logs for rat 9L gliosarcoma and human glioma 126 cells. Serum concentration was 0.10 micrograms/ml in maximum. These findings suggest the feasibility of intrathecal ACNU perfusion therapy against subarachnoid dissemination of malignant glioma and warrant further studies.

A pharmacokinetic one-compartment model for the cerebrospinal infusion for the brain tumor chemotherapy is described together with various parameters used for computer simulation. An antitumor protein, neocarzinostatin (NCS) as a prototype drug, has been utilized since it was found effective against glioblastoma cells at extremely low concentration (less than 5 ng/ml) and it is readily inactivated by serum. A very slow infusion velocity was found necessary for an appropriate dose regimen; for example, 0.25mg of the drug should be infused into CSF for about 40 min to attain a drug level of 8 ng/ml.

Neocarzinostatin as previously reported, appeared to exhibit an intense cytotoxicity to the glioblastoma cells and some other malignant brain tumor cells, such as pineal germinoma or medulloblastoma, which are notoriously known to disseminate into the cerebrospinal fluid space. In vitro study, the minimum susceptibility of glioblastoma cells to neocarzinostatin was found to be below 0.005 microgram/ml, whereas normal glia cells were not affected at 0.3 microgram/ml. This study indicated that neocarzinostatin was extremely effective in the treatment of malignant brain tumor without affecting normal neural tissue. Pharmacokinetic study was performed in order to establish intermittent intrathecal perfusion therapy and to prevent subarachnoid dissemination of the brain tumor cells. Experimental results were applied to the treatment of 12 patients with brain tumor, who had shown positive cytology of the cerebrospinal fluid. Follow-up investigation showed quite a favorable result and it was considered that prophylactic irradiation to the entire spinal column could be replaced with intrathecal administration of neocarzinostatin. During clinical application no noticeable side effect was encountered and active stimulation of macrophages, which were mobilized into the CSF space, was another unexpected advantage of this treatment.

A case of ossifying fibroma of the cranial vault is described. Several reports emphasized the rare existence of this lesion limiting in the cranial vault. The patient was a 76-year-old woman who suffered mild headache in the parietal region after a trivial head trauma. Physical and neurological examination were normal. Plain skull X-P revealed irregularly bordered, 4 X 4 cm sized radiolucent area in the left temporal bone. The bone scintigraphy using 99mTc-MDP showed an abnormal uptake like a doughnut. Levels of serum P, Ca and alkaline phosphatase were within normal range. A tumor was softer than normal skull, and undertaken piecemeal removal. The dura was normal. After the total removal of the tumor, cranioplasty using Resin plate was performed. Microscopically the lesion was composed immature, irregular spicules of bone and fibrous tissue. Abundant fibroblasts were arranged in a random fashion in the stroma. Characteristically, the spicules of bone surrounded by rimming of osteoblasts. Ossifying fibroma is a benign fibroosseous tumor. Although this tumor is typically found in the maxillary sinus and mandible, it has also been reported in the paranasal sinuses, frontal, ethmoid, sphenoid bone and orbital roof of the young adult. But previously reported cases involving the cranial vault alone were only 7 cases. Etiology of ossifying fibroma is almost unknown.