Teruaki Mori

Induction of vascular endothelial tubular morphogenesis by human glioma cells. A model system for tumor angiogenesis.

We have developed two different models of tumor angiogenesis by human brain tumors: one being tube formation by bovine aortic endothelial (BAE) cells cocultured with tumor cells in vitro, and other being in vivo angiogenesis in mice when tumor cells are transplanted into the dorsal sac. We investigated whether tube formation could be induced in BAE cells in type I collagen gel when these cells were cocultured with seven human glioma cell lines. Four of the seven glioma cell lines, which had high levels of basic fibroblast growth factor (bFGF) mRNA, induced tube formation by BAE cells. The tube formation was blocked by coadministration of anti-bFGF antibody. In in vivo model system of tumor angiogenesis in mice, these four cell lines were highly angiogenic. In contrast, with the other three glioma cell lines, which had poor expression of bFGF, BAE cells showed no apparent tube formation. These three cell lines did not efficiently develop capillary networks in mice. The results demonstrated a correlative relationship in the tubulogenesis of BAE cells, bFGF mRNA levels and angiogenesis in mice. The present study with two model systems of tumor angiogenesis suggests that the angiogenesis of some human glioma cell lines is mediated by bFGF, possibly via paracrine control.

Interhemispheric approach through the lamina terminalis to tumors of the anterior part of the third ventricle

Operative approaches to tumors of the third ventricle, mainly the bifrontal approach through the lamina terminalis, are discussed. The latter approach has several advantages. First, the main arteries can be exposed and the operative field is sufficiently wide to render the operative procedure safe. Second, cortical incision or excision is unnecessary. By cutting the lamina terminalis, which is usually thin and expanded as a result of hydrocephalus, even a large tumor can be removed. In addition, lethal complications are avoided, because this approach has less possibility of damage to the lateral wall of the third ventricle. Seventeen cases of tumor in the third ventricle underwent operation via this approach. The operative technique for the bifrontal approach through the lamina terminalis and three representative cases are reported. This approach can be applied not only to tumors, but to arteriovenous malformations or giant aneurysms adjacent to the third ventricle.

Up-regulation of Urokinase-type Plasminogen Activator and its Receptor Correlates with Enhanced Invasion Activity of Human Glioma Cells Mediated by Transforming Growth Factor-α or Basic Fibroblast Growth Factor

Glioblastoma multiforme is a highly malignant tumor that is extremely refractory to therapy. One reason is its highly invasive nature into brain tissue. Metalloproteinases and their inhibitors, plasminogen activators (PA) and their inhibitors and cathepsins are thought to be involved in invasion by tumor cells. In this study, we determined if the urokinase-type plasminogen activator (uPA) and/or the urokinase-type plasminogen activator receptor (uPAR) were responsible for the invasion activity of a human glioma cell line. We determined the invasion activity of a human glioma U251 cell line using an in vitro invasion assay system. A 2.4- to 5.8-fold increase in invasion activity was observed in the presence of basic fibroblast growth factor (bFGF) or transforming growth factor (TGF)-α. Northern blot analysis showed that bFCF and TGF-α treatment was associated with increases in cellular mRNA levels of uPA and uPAR. Zymographic activity correlated to mRNA levels of uPA and uPAR. Addition of an anti-uPAR monoclonal antibody significantly inhibited the invasion activity induced by bFGF- and TGF-α. Irsogladine, an inhibitor of uPA synthesis, also blocked the invasion activity. These observations suggest that uPA and its receptor have a role in the invasion process of human gliomas.

Effect of spinal cord stimulation on cerebral blood flow in cats.

Effects of electric spinal cord stimulation (SCS) on cerebral blood flow (CBF) were investigated in anesthetized adult cats. SCS was performed under various stimulus conditions for 1 h via a wire electrode inserted into the dorsal epidural space at various levels in the spinal cord. CBF was measured in the subcortex of the parietal lobe by hydrogen clearance method before, during, and after SCS. After the start of SCS in the high cervical cord with a frequency of 20 Hz, CBF gradually increased up to 140% of the pre-SCS value, and remained high for 15 min after the end of SCS. SCS of the low cervical or midthoracic cord under the same condition caused no significant increase in CBF. Nor did SCS of the high cervical cord with frequencies of 200 and 2,000 Hz increase CBF. No CBF increase was observed after SCS of the high cervical cord with 20 Hz when the dorsal column was sectioned at the medullo-cervical junction. These results suggest that the ability of SCS to increase CBF is peculiar to high cervical cord stimulation with moderately low frequencies.

Intracranial Ectopic Recurrence of Craniopharyngioma after Ommaya Reservoir Implantation

We present a very rare case of a craniopharyngioma showing intracranial ectopic recurrence after the total removal of recurrent craniopharyngioma arising at the primary site accompanied by Ommaya reservoir implantation. A 2-year-old boy underwent a bifrontal craniotomy and total removal of the adamantinomatous craniopharyngioma via the interhemispheric translamina terminalis approach. Four months later, he underwent total removal of recurrent craniopharyngioma and implantation of an Ommaya reservoir via the same approach. Ten months later, total removal of the ectopic recurrent craniopharyngioma following the placement of the Ommaya reservoir cannula, which was placed within the surgical route, was performed via the same craniotomy.

Traumatic lesions of the corpus callosum.

We investigated the mechanism of damage to the corpus callosum in a study of 46 brains obtained at the autopsies of patients with head injuries. After correlating the gross findings with the site of impact on the head, we think that such lesions in the corpus callosum are caused by stretching of callosal fibers and/or shearing forces in cases in which lateral movement or twisting of the brain occurs. This mechanism of the dynamic development of callosal injuries is also supported by the retraction bulb formation of axons found histologically in the corpus callosum.

The exogenous control of transfected c-fos gene expression and angiogenesis in cells implanted into the rat brain

Previously, we established a stable transfectant, Nf-1, from normal rat kidney (NRK) fibroblasts transfected with a human metallothionein II A (hMT-IIA) promoter/human genomic c-fos fusion gene to produce c-Fos protein. Since the hMT-IIA promoter can be activated by heavy metals, the level of human c-fos gene expression can be increased by addition of heavy metals to the culture medium of Nf-1 cells and the anchorage-independent growth of Nf-1 in soft agar is markedly enhanced in the presence of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF). In this study, we found that the hMT-IIA promoter can be activated by zinc, resulting in the elevation of fused c-fos gene expression in Nf-1 cells. We transplanted NRK and Nf-1 cells into the striatum of the rat brain and investigated whether expression of the human c-fos gene could be modified in the brain by exogenous zinc. After 8 weeks, we found that the Nf-1 cells could survive in the rat brain without any immunosuppression and grafts of Nf-1 induced angiogenesis when zinc was administered. Such implants enhanced the expression of c-fos mRNA by zinc. These results indicated that the transplanted cells continued expressing the c-fos transgene when the rats were given drinking water containing zinc, resulting in the promotion of cell growth and of neovascularization. This study will present a useful animal model of gene therapy by control of transgene expression in the brain.

Gastrointestinal bleeding in cases of ruptured cerebral aneurysms.

SummaryAmong 1,000 cases of patients undergoing direct surgery on cerebral aneurysms, two, showed clear signs of preoperative, and 19 cases showed postoperative gastrointestinal bleeding. We have made a clinical analysis of various aspects of the 19 cases in which the bleeding developed postoperatively.1.Gastrointestinal bleeding was most frequent postoperatively in cases of AComA aneurysms (4.3%) and ICA aneurysms (2.0%), and less common in MCA and ACA aneurysm cases.2.Gastrointestinal bleeding was most frequently seen in those cases operated on between the third and seventh days after the last subarachnoid haemorrhage (8.9%) and was more common in cases with a relatively poor preoperative grade.3.The development of such bleeding in cases with a good preoperative grade was due to problems with the surgical operation in most cases, although the influence of vasospasm must not be ignored. The development of bleeding in cases with a poor preoperative grade is thought to be due primarily to vasospasm and transitory brain damage to the hypothalamus and the orbital portion of the anterior lobe due to a haematoma caused by aneurysm rupture.4.First, the location of gastrointestinal bleeding should be determined endoscopically and, if haemostasis is not achieved by coagulation, then the desirability of surgery should be considered early. Abdominal surgery may be performed.

Pharmacokinetics of Methotrexate in Plasma and Cerebrospinal Fluid

OBJECTIVE: To investigate the pharmacokinetics of methotrexate (MTX) in plasma and cerebrospinal fluid (CSF) during osmotic disruption of the blood-brain barrier and the intraarterial administration of combination chemotherapy postoperatively in a patient with glioblastoma. CASE SUMMARY: A 60-year-old Japanese woman with a glioblastoma received two courses of combination intraarterial chemotherapy. In the first course of treatment, 20 mL of mannitol 20%, peplomycin 10 mg, vindesine 2 mg, and MTX 500 mg were administered via the right internal carotid artery, and then via the right vertebral artery. In the second course of treatment, 20 mL of mannitol 20%, peplomycin 15 mg, vindesine 2.5 mg, and MTX 1000 mg were similarly administered. Blood samples and CSF samples from the ventricle and the space left by tumor removal were obtained; the MTX concentrations were measured from these sites by fluorescence polarization immunoassay. The pharmacokinetic parameters of MTX in plasma and CSF were estimated. DISCUSSION: The plasma concentration of MTX decreased in a biexponential decay pattern during each course of treatment. CSF concentrations of MTX in the ventricle and in the space left by tumor removal peaked at 2 and 6 hours, respectively, after drug administration and decreased monoexponentially. When the dose of MTX was doubled, the AUC for the plasma MTX concentration increased 2.4-fold and the AUCs for MTX in the ventricle and the space left by tumor removal increased 3.4- and 9.1-fold, respectively. The half-life of MTX in the CSF in the space left by tumor removal exceeded the half-lives of MTX in the plasma and in the ventricular CSF. CONCLUSIONS: The CSF AUCs of MTX in the ventricle and the space left by tumor removal increased markedly and in parallel with the MTX dosage increase during osmotic disruption of the blood-brain barrier and intraarterial combination chemotherapy. Such treatment improves the delivery of chemotherapy agents to the brain.

Overlapping free bone graft with galea-pericranium in reconstruction of the anterior skull base to prevent CSF leak and sequestrum formation.

SummaryBackground. Reconstruction of the skull base after resection of a tumour is important to prevent postoperative complications such as infectionsand cerebrospinal fluid (CSF) leakage. Several reconstructive methods of the anterior skull base have been reported but, their long-term results are not clear. Methods. We describe a technique used after removal of an olfactory neuroblastoma with infiltration of the skull base. The reconstructed dura was covered with a galeal patch, a replicated galeal-pericranial flap, a graft from the inner table of skull, and a vascularised galeal-pericranial flap placed on the skull base defect. All layers were fixed with fibrin glue. Conclusion. Three dimensional computed tomography (3D-CT) at bone window settings demonstrated the bone graft covered the bone defect and was not absorbed and after 11 years there have been no signs of tumour regrowth or complications.