廣瀬 雄一

Object. The Chk1 and p38 mitogen-activated protein kinase (MAPK) pathways play key roles in the G(2) arrest caused by exposing glioma cells to temozolomide (TMZ). Although inhibition of either pathway sensitizes glioma cells to TNZ-induced cytotoxicity, the relative contributions of these pathways to TMZ-induced G(2) arrest and to TMZ resistance conferred by G(2) arrest have not been defined. Methods. The authors pharmacologically inhibited the Chk1 and/or p38 pathways in U87MG human glioma cells prior to and/or after exposure to TMZ; thereafter, effects on the TNZ-induced G(2) arrest pathway and toxicity were monitored. The p38 inhibitor SB203580 or the Chk1 inhibitor UCN-01 or their combination blocked TMZ-mediated inactivation of cdc25C and cdc2, suggesting that p38 and Chk1 pathways work cooperatively and are both necessary to inactivate cdc25C and cdc2. Consistent with this idea, the inhibition of both Chk1 and p38 pathways did not lead to greater bypass of TMZ-induced G(2) arrest or greater cytotoxicity than inhibition of either pathway alone. Inhibition of p38 did not alter TMZ-induced Chk1 activation/phosphorylation and vice versa, suggesting that p38 and Chk1 do not cooperatively bring about G(2) arrest by reciprocal activation/phosphorylation. The two pathways, however, are not functionally identical; the Chk1 pathway was required for both the initiation and maintenance of TMZ-induced G(2) arrest, whereas the p38 pathway played a role only in the initiation. Conclusions. The Chk1 and p38 pathways cooperate to bring about TMZ-induced G(2) arrest, and the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity.

Although human cells exposed to DNA-methylating agents undergo mismatch repair (MMR)-dependent G(2) arrest, the basis for the linkage between MMR and the G(2) checkpoint is unclear. We noted that mitogen-activated protein kinase p38alpha was activated in MMR-proficient human glioma cells exposed to the chemotherapeutic methylating agent temozolomide (TMZ) but not in paired cells made MMR deficient by expression of a short inhibitory RNA (siRNA) targeted to the MMR protein Mlh1. Furthermore, activation of p38a in MMR-proficient cells was associated with nuclear inactivation of the cell cycle regulator Cdc25C phosphatase and its downstream target Cdc2 and with activation of the G(2) checkpoint, actions which were suppressed by the p38alpha/beta inhibitors SB203580 and SB202590 or by expression of a p38alpha siRNA. Finally, pharmacologic or genetic inhibition of p38alpha increased the sensitivity of MMR-proficient cells to the cytotoxic actions of TMZ by increasing the percentage of cells that underwent mitotic catastrophe as a consequence of G(2) checkpoint bypass. These results suggest that p38alpha links DNA MMR to the G(2) checkpoint and to resistance to chemotherapeutic DNA-methylating agents. The p38 pathway may therefore represent a new target for the development of agents to sensitize tumor cells to chemotherapeutic methylating agents.

Although human cells exposed to DNA-methylating agents undergo mismatch repair (MMR)-dependent G(2) arrest, the basis for the linkage between MMR and the G(2) checkpoint is unclear. We noted that mitogen-activated protein kinase p38alpha was activated in MMR-proficient human glioma cells exposed to the chemotherapeutic methylating agent temozolomide (TMZ) but not in paired cells made MMR deficient by expression of a short inhibitory RNA (siRNA) targeted to the MMR protein Mlh1. Furthermore, activation of p38a in MMR-proficient cells was associated with nuclear inactivation of the cell cycle regulator Cdc25C phosphatase and its downstream target Cdc2 and with activation of the G(2) checkpoint, actions which were suppressed by the p38alpha/beta inhibitors SB203580 and SB202590 or by expression of a p38alpha siRNA. Finally, pharmacologic or genetic inhibition of p38alpha increased the sensitivity of MMR-proficient cells to the cytotoxic actions of TMZ by increasing the percentage of cells that underwent mitotic catastrophe as a consequence of G(2) checkpoint bypass. These results suggest that p38alpha links DNA MMR to the G(2) checkpoint and to resistance to chemotherapeutic DNA-methylating agents. The p38 pathway may therefore represent a new target for the development of agents to sensitize tumor cells to chemotherapeutic methylating agents.

Grade II astrocytoma is defined as a low-grade tumor, yet patients have a wide range of survival and tumors can quickly progress to high-grade astrocytoma/glioblastoma. Previous studies using comparative genomic hybridization (CGH) failed to demonstrate frequent copy number aberrations (CNA) in these tumors. This may be related to technical difficulties because infiltrating astrocytic tumors are often intermixed with normal brain tissue. We developed methods to exclude most normal tissue and use small amounts of DNA for CGH by microdissecting small regions of tumor from paraffin sections and amplifying extracted DNA using degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR). Using this method, we examined 30 grade II astrocytoma cases. We found CNA in 25 cases (83%), with a mean of two CNA per case. The most frequent CNA were gains on 7q (12 cases), 5p (5 cases), 9 (5 cases), and 19p (3 cases), and losses on 19q (7 cases), 1p (6 cases), and Xp (3 cases). Gain on 7q and losses on 1p/19q were mutually exclusive. This is the first report on the genetic characterization of low-grade astrocytomas using CGH from microdissected and formalin-fixed tissue. The comparatively large number of cases in this study allows us to suggest that these tumors are genetically subgrouped. (C) 2003 Elsevier Science Inc. All rights reserved.

Grade II astrocytoma is defined as a low-grade tumor, yet patients have a wide range of survival and tumors can quickly progress to high-grade astrocytoma/glioblastoma. Previous studies using comparative genomic hybridization (CGH) failed to demonstrate frequent copy number aberrations (CNA) in these tumors. This may be related to technical difficulties because infiltrating astrocytic tumors are often intermixed with normal brain tissue. We developed methods to exclude most normal tissue and use small amounts of DNA for CGH by microdissecting small regions of tumor from paraffin sections and amplifying extracted DNA using degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR). Using this method, we examined 30 grade II astrocytoma cases. We found CNA in 25 cases (83%), with a mean of two CNA per case. The most frequent CNA were gains on 7q (12 cases), 5p (5 cases), 9 (5 cases), and 19p (3 cases), and losses on 19q (7 cases), 1p (6 cases), and Xp (3 cases). Gain on 7q and losses on 1p/19q were mutually exclusive. This is the first report on the genetic characterization of low-grade astrocytomas using CGH from microdissected and formalin-fixed tissue. The comparatively large number of cases in this study allows us to suggest that these tumors are genetically subgrouped. (C) 2003 Elsevier Science Inc. All rights reserved.

Object. Temozolomide (TMZ)-induced O-6-methylguanine (MG) DNA lesions, if not removed by MG-DNA methyltransferase (MGMT), mispair with thymine, trigger rounds of futile mismatch repair (MMR), and in glioma cells lead to prolonged G(2)-M arrest and ultimately cell death. Depletion of MGMT by O-6-benzylguanine (BG) sensitizes tumor cells to TMZ, and this combination is currently used in clinical trials. The use of the TMZ+BG combination in gliomas, however, is complicated by the prolonged TMZ-induced G(2)-M arrest, which may delay activation of poorly defined cell death pathways and allow for MGMT repletion and reversal of toxicity. Methods. To address these issues, the actions of TMZ were monitored in DNA MMR-proficient SF767 glioma cells depleted of MGMT by BG, and in cells in which BG was removed at various times after TMZ exposure. In MGMT-depleted cells, TMZ exposure led to DNA single-strand breaks and phosphorylation of cdc2, followed by G-M arrest, induction of p53/p21, and DNA double-strand breaks. Although DNA single-strand breaks, phosphorylation of cdc2, and G(2)-M arrest could be reversed by repletion of MGMT up to 5 days after TMZ exposure, TMZ-induced cytotoxicity could only be prevented if MGMT was replenished within 24 hours of the onset of G(2)-M arrest, and before the creation of DNA double-strand breaks. Conclusions. These results indicate that although SF767 glioma cells undergo a prolonged G(2)-M arrest in response to TMZ, their ability to escape TMZ-induced cytotoxicity by MGMT repletion is limited to an approximately 24-hour period after the onset of G(2)-M arrest.

We investigated c-Met expression in cultured astrocytes and their regulation by cytokines. Immunocytochemistry revealed that c-Met was expressed in cultured astrocytes. Western blotting revealed that acidic and basic fibroblast growth factor (FGF) enhanced and hepatocyte growth factor (HGF) reduced c-Met expression. Reverse transcription-polymerase chain reaction revealed that FGFs and HGF enhanced c-met expression. These findings suggest that c-Met expressed in astrocytes may have important roles during the nervous system regeneration. (C) 2002 Elsevier Science B.V. All rights reserved.

Object. Thrombomodulin is a thrombin receptor on vascular endothelial cells that is highly expressed when these cells are injured, and it has anticoagulating activity. The authors investigated thrombomodulin expression to clarify why chronic subdural hematomas (CSDHs) continue to grow slowly, like a tumor, and are liquefied. Methods. Burr hole craniotomy and drainage were performed in all 35 patients with CSDH who were included in the study. The plasma-soluble thrombomodulin and blood clotting factor values were determined in the hematoma and in peripheral blood. In the seven most recent cases, the plasma-soluble thrombomodulin values were determined in the residual hematoma collected from the drainage tube the day after surgery. The outer membranes of the CSDH that were obtained as specimens at operation were stained with monoclonal antibody against thrombomodulin for immunohistochemical studies. The plasma-soluble thrombomodulin values were higher (p < 0.0001), and conversely the values for factors V and VIII were lower in the hematoma than in peripheral blood (p < 0.0001). The plasma-soluble thrombomodulin values were lower in the residual hematomas than in the same lesions at operation (p = 0.018). The endothelial cells on the sinusoidal vessels exhibited immunoreactivity with thrombomodulin antibody in 28 (93%) of 30 cases. Conclusions. The thrombomodulin is expressed on the sinusoidal vessels, and the blood coagulation system is inhibited in the hematoma. These findings indicate that these vessels are continuously injured and fail to heal. As a result, the bleeding from the sinusoidal vessels may persist, and the hematoma may grow slowly and fail to coagulate. It is suspected that transmitted pulsation variations in the hematoma cavity generate sinusoidal vessel injury.

Temozolomide (TMZ) produces O-6-methylguanine in DNA, which in turn mispairs with thymine, triggering futile DNA mismatch repair (MMR) and ultimately cell death. We found previously that in p53-proficient human glioma cells, TMZ-induced futile DNA MMR resulted not in apoptosis but rather in prolonged, p53- and p21-associated G(2)-M arrest and senescence. Additionally, p53-deficient cells were relatively more TMZ resistant than p53-deficient glioma cells, which underwent only transient G(2)-M arrest before death by mitotic catastrophe. These results suggested that prolonged G(2)-M arrest might protect cells from TMZ-induced cytotoxicity. In the present study, we therefore focused on the mechanism by which TMZ induces G2-M arrest and on whether inhibition of such G(2)-M arrest might sensitize glioma cells to TMZ-induced toxicity. U87MG glioma cells treated with TMZ underwent G(2)-M arrest associated with Chk1 activation and phosphorylation of both cdc25C and cdc2. These TMZ-induced effects were inhibited by the Chk1 kinase inhibitor UCN-01. Although not in itself toxic, UCN-01 increased the cytotoxicity of TMZ 5-fold, primarily by inhibiting cellular senescence and increasing the percentage of cells bypassing G(2)-M arrest and undergoing mitotic catastrophe. In addition to enhancing TMZ-induced cytotoxicity in p53-proficient cells, UCN-01 also blocked TMZ-induced Chk1 activation and transient G(2)-M arrest in p53-deficient U87MG-E6 cells and similarly enhanced TMZ-induced mitotic catastrophe and cell death. Taken together, these results indicate that Chk1 links TMZ-induced MMR to G(2)-M arrest. Furthermore, inhibition of the cytoprotective G(2) arrest pathway sensitizes cells to TMZ-induced cytotoxicity and may represent a novel, mechanism-based means of increasing TMZ efficacy in both p53 wild-type and p53 mutant glioma cells.

The formation of human malignant gliomas is thought to involve the accumulation of multiple genetic alterations, To define the function of specific alterations in glioma formation, we serially introduced genetic alterations functionally equivalent to those noted in human malignant gliomas into normal human astrocytes (NHAs). We then monitored the ability of each of these alterations to contribute to the growth of otherwise genetically stable NHAs into intracranial malignant gliomas. Using this model, we show that expression of human telomerase catalytic component (hTERT), but not E7-mediated inactivation of pRb or E6/E7-mediated inactivation of p53/pRb, was sufficient to initiate the tumorigenic process by circumventing cellular senescence in astrocytes, hTERT expression, even in combination with inactivation of p53/pRb, did not transform astrocytes. These alterations together, however, cooperated with ras pathway activation (initiated by expression of mutant H-Ras), but not with phosphatidylinositol 3-kinase pathway activation (initiated by expression of myristoylated Akt) or epidermal growth factor receptor activation, to allow for the formation of intracranial turners strongly resembling p53/pRb pathway-deficient, telomerase-positive, ras-activated human grade m anaplastic astrocytomas. These results identify four pathways as key in the development of human anaplastic astrocytomas.

We amplified various amounts of DNA derived from frozen SF210 and U251NCI human glioblastoma cells, carried out comparative genomic hybridization (CGH) using degenerate oligonucleotide primed-PCR (DOP-PCR) products as test probes, and compared results to analyses performed with probes prepared by standard nick translation, Next we extracted DNA from hematoxylin-eosin (HE)- and methyl green (MG)-stained, microdissected sections of formalin-fixed and paraffin-embedded U251NCI cells, amplified and labeled it by DOP-PCR, and subjected it to CGH, Finally, we used the same methods in multiple samples from a single human mixed glioma tissue. DOP-PCR products from 50 pg to 250 ng of DNA were equally effective in generating the same CGH profiles as the standard method. DOP-PCR products from microdissected pieces of MG-stained cells were effective probes for CGH, but HE-stained samples were not desirable, As the proportion of HE-stained sample Increased, CGH profiles deteriorated. DOP-PCR products from microdissected pieces of MG-stained paraffin sections of glioma tissue produced CGH profiles compatible with their histological features, CGH performed with DOP-PCR products from microdissected paraffin blocks allows for the accurate investigation of the cytogenetic characteristics from invasive tumors and of cytogenetic heterogeneity within neoplastic tissue.

Temozolomide (TMZ) is a DNA-methylating agent that has recently been introduced into Phase II and III trials for the treatment of gliomas, TMZ produces O-6-methylguanine in DNA, which mispairs with thymine during the next cycle of DNA replication. Subsequent futile cycles of DNA mismatch repair can lead to a p53-associated apoptotic cell death, although this mechanism has been described mostly in hematopoietic neoplasms, We studied the action of TMZ in gliomas and the role p53 might play by using U87 glioma cells that were either p53-wild-type or p53-deficient (by virtue of expression of the viral oncoprotein E6), LN-Z308 cells, in which p53 gene is deleted, were also used. p53-proficient U87 MG cells underwent a prolonged, p53- and p21(Waf1/Cip1)-associated G(2)-M arrest beginning 2 days after TMZ treatment. Although very few of these cells underwent apoptosis, most underwent senescence over a 10-day period. p53-deficient (EC-transfected U87 and LN-Z308) cells similarly underwent G(2)-M arrest in response to TMZ, but this arrest was accompanied by only minor changes in p53 or p21(Waf1/Cip1) and reversed within 7 days of TMZ treatment in association with the appearance of cells with either 8n or subG1 DNA content, These results suggest that glioma cells respond to TMZ by undergoing G(2)-M arrest, p53 is not necessary for this G(2)-M arrest to occur but is important in the duration of G(2)-M arrest and in the ultimate fate of TMZ-treated cells. Therefore, the integrity of the G(2)-M cell cycle checkpoint may be important in the cytotoxicity of TMZ in glioma cells.

Ependymoma occurs most frequently within the central nervous system of children and young adults. We determined relative chromosomal copy-number aberrations in 44 ependymomas using comparative genomic hybridization, The study included 24 intracranial and 20 spinal cord tumors from pediatric and adult patients. Frequent chromosomal aberrations in intracranial tumors were gain of 1q and losses on 6q, 9, and 13, Gain of 1q and loss on 9 were preferentially associated with histological grade 3 tumors. On the other hand, gain on chromosome 7 was recognized almost exclusively in spinal cord tumors, and was associated with various other chromosomal aberrations including frequent loss of 22q. We conclude that cytogenetic analysis of ependymomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed.

A 69-year-old female suffered from sudden onset of severe headache. Computed tomography showed subarachnoid hemorrhage primarily located in the posterior fossa. Initial angiography demonstrated a fenestration of the vertebral artery and an extracranial origin of the posterior inferior cerebellar artery, However, no bleeding points could be clearly detected. The operative findings revealed a massive clot in subarachnoid space, but no bleeding point. Serial angiography demonstrated dissection in one of the limbs of the fenestrated vertebral artery on the 25th day after the onset, On the 100th day, the lesion was spontaneously occluded, The patient is presently doing well at 8 years after surgery.

A 69-year-old female suffered from sudden onset of severe headache. Computed tomography showed subarachnoid hemorrhage primarily located in the posterior fossa. Initial angiography demonstrated a fenestration of the vertebral artery and an extracranial origin of the posterior inferior cerebellar artery. However, no bleeding points could be clearly detected. The operative findings revealed a massive clot in subarachnoid space, but no bleeding point. Serial angiography demonstrated dissection in one of the limbs of the fenestrated vertebral artery on the 25th day after the onset. On the 100th day, the lesion was spontaneously occluded. The patient is presently doing well at 8 years after surgery.

BACKGROUND Vertebral artery dissection lesions tend to resolve spontaneously, but abnormal findings such as aneurysmal dilatation occasionally persist. However, the clinical features and pathological findings in such cases have never been verified. CASE DESCRIPTION A 62-year-old man presented with left cerebellar infarction. Angiography showed the "pearl and string sign" in the left vertebral artery, and he was diagnosed as having left vertebral artery dissection. Repeated angiography showed persistent aneurysmal dilatation with irregular stenosis. Eleven years after the cerebellar infarction, the patient presented with a subarachnoid hemorrhage from an aneurysm of the left vertebral artery, and the lesion was explored via the left suboccipital approach. The vertebral artery was firm, making the placement of a clip impossible, so the lesion was treated by coating of the bleeding point. The patient died of pneumonia and hyperglycemia on postoperative day 15. Postmortem examination revealed an organized intramural hematoma, thickening of the intima, and fibrous degeneration of the media of the vertebral artery, a fusiform, distended thin arterial wall with intimal disruption at the aneurysmal dilatation, and arteriosclerosis of all cerebral arteries. CONCLUSION This case indicates that persistent aneurysmal dilatation of a dissection is a pseudoaneurysm prone to rupture, and that healing of the affected vessels might be severely compromised in the presence of pathological conditions such as arteriosclerosis and disturbed intraluminal blood flow in the dissected lesions. (C) 1999 by Elsevier Science Inc.

A 61-year-old female presented with headache, malaise, and left oculomotor nerve paralysis. Computed tomography (CT) demonstrated a diffuse pituitary mass and enlarged pituitary stalk with homogeneous contrast enhancement. Her symptoms gradually resolved without treatment. Gallium-67 scintigraphy showed abnormal uptake in the pituitary lesion. Serial CT every 2 weeks after admission showed homogeneous contrast enhancement and shrinking of the pituitary mass to a normal size 12 weeks after the onset. The final diagnosis was lymphocytic adenohypophysitis without biopsy. Recurrence has not been observed for 8 years after discharge. The patient did not need hormone replacement therapy. Histological examination is not always necessary to diagnose probable lymphocytic adenohypophysitis with the characteristic feature of rapid onset, abnormal gallium-67 uptake in the lesion, and resolution of symptoms in the acute stage with shrinking of the lesion on neuroimaging.

A 61-year-old female presented with headache, malaise, and left oculomotor nerve paralysis. Computed tomography (CT) demonstrated a diffuse pituitary mass and enlarged pituitary stalk with homogeneous contrast enhancement. Her symptoms gradually resolved without treatment. Gallium-67 scintigraphy showed abnormal uptake in the pituitary lesion. Serial CT every 2 weeks after admission showed homogeneous contrast enhancement and shrinking of the pituitary mass to a normal size 12 weeks after the onset. The final diagnosis was lymphocytic adenohypophysitis without biopsy. Recurrence has not been observed for 8 years after discharge. The patient did not need hormone replacement therapy. Histological examination is not always necessary to diagnose probable lymphocytic adenohypophysitis with the characteristic feature of rapid onset, abnormal gallium-67 uptake in the lesion, and resolution of symptoms in the acute stage with shrinking of the lesion on neuroimaging. © 1999, The Japan Neurosurgical Society. All rights reserved.

The clinical importance of the expression of c-Met protein, the receptor of hepatocyte growth factor/ scatter factor, was evaluated in neuroepithelial tissue tumors. c-Met immunohistochemistry was performed using the streptavidin-biotin-peroxidase complex method with anti-c-Met polyclonal antibody. Specimens were classified as c-Met negative (< 30%) or c-Met positive (greater than or equal to 30%) according to the proportion of immunopositive cells under microscopic examination. All c-Met-positive cases occurred in high grade astrocytic tumors, not in other neuroepithelial tissue tumors. Mast c-Met-positive astrocytic tumors were classified histologically as high grade tumors. Epidermal growth factor-receptor (EGFR) and MIB-1 immunohistochemistry were also performed for high grade astrocytic tumors. Survival analysis was performed for patients with these tumors with variables including c-Met positivity, EGFR positivity, and MIB-1 labeling index. Positivity of c-Met was independent from EGFR positivity and MIB-1 labeling index, and the c-Met-positive group showed a significant shorter survival (p < 0.05). c-Met immunopositivity may be a parameter of biological aggressiveness in high grade astrocytic tumors. Examination of c-Met expression in astrocytic tumors provides significant clinical information, especially as a prognostic factor.

A 45-year-old female presented with gliomatosis cerebri manifesting as hemiballismus-like involuntary movement in the arm, motor weakness in the leg, and hypesthesia in her left side. Computed tomography showed only diffuse swelling of the right cerebral hemisphere, but T-2-weighted magnetic resonance imaging revealed a diffuse lesion spreading from the right thalamus to the temporal, parietal, and occipital lobes on the same side. No abnormal enhancement was recognized. Cerebral angiography showed no specific finding. A right occipital lobectomy was performed to confirm the diagnosis of gliomatosis cerebri. Anaplastic transformation was recognized 5 months later. The disease did not resolve with radiation or interferon administration, but steroid therapy achieved remarkably effective tumor regression. The patient died due to pneumonia. Autopsy showed the features of diffuse glioblastoma. Steroid therapy may be an effective treatment for gliomatosis cerebri before the terminal stage.

各種神経上皮由来脳腫瘍におけるc-Met蛋白の発現状況について免疫組織学的に検討した。c-Met陽性細胞が高倍率顕微鏡視野下で全腫瘍細胞の30%以上を占めた症例はアストロサイト由来腫瘍に限られた。悪性グリオーマにおいてc-Metの発現が患者の予後判定因子になりうるかについてepidermal growth factor receptorの発現やMIB-1 labeling indexとの対比をしながら検討したところ、c-Met陽性症例では有意に生存期間が短く、c-Met免疫組織化学は他の2種の指標よりも有用であった。c-Metは分化度の高いアストロサイト系細胞に発現していたが、同蛋白は悪性グリオーマ組織中の各種サイトカインにより誘導されている可能性がある。

A 64-year-old female presented with hemangiopericytoma arising from a dural fascia graft placed after a previous operation for the total removal of a benign meningioma. The patient also had multiple pulmonary metastases identified as hemangiopericytoma. The tumor resected at the first operation was benign based on all grading systems for meningiomas. We considered that the tumor was a kind of scar tumor. The hemangiopericytoma probably developed from a scar tumor at the graft. We emphasize the importance of long-term follow-up for patients who have undergone surgery for benign tumors.

From January 1984 to December 1997, a total of six patients with malignant gliomas accompanied with visceral malignancies were treated in our department. We reviewed their radiological findings and clinical course. They consisted of four patients with glioblastoma and two patients with anaplastic astrocytoma. Classified according to visceral malignancies, three cases had colon cancer and the rest consisted of thyroid, uterus and prostate cancers. In radiological examinations of the brain (CT scans and MR images), these gliomas were relatively well-circumscribed as ii they were metastatic brain tumors. Of all these six cases, two cases:survived more than five years and there were two cases in which there was recurrence within a year. Particularly, in four cases, whose gliomas developed after the treatment for visceral malignancies, two cases survived long-term (more than five years) and there was recurrence in only one case. We speculated that visceral malignancies could affect the nature of glioma progression. Thinking about its mechanisms, we. hypothesized as follows; (1) visceral malignancies may activate non-specific, or common antitumor, immunity. (2) visceral malignancies may produce some factors which could affect the biological nature of gliomas. (3) glioma accompanied with visceral malignancy may have genetic uniqueness. Although the cases were limited in number, the present study may be helpful in designing the treatment for such cases and in elucidating the invasive nature of gliomas.

A 68-year-old male presented with progressive spastic quadriparesis. Twelve years previously he had undergone anterior decompression with bone grafting for cervical ossification of the posterior longitudinal ligament associated with spinal trauma. Radiological examination showed ossification of the transverse ligament of the atlas (TLA) and severe stenosis of the upper cervical canal, Anterior dislocation of the atlas was also present, but the occiput/atlas/axis unit was perfectly stable due to the prior anterior fusion. Suboccipital decompression and laminectomy of the atlas were performed, and his symptoms improved. Based on the atlanto-axial dislocation, the TLA might have been damaged at the time of the primary trauma and became the trigger for the ossification of the TLA, showing that marked ossification of a vertebral ligament can occur after injury.

A 47-year-old male presented with abducens nerve palsy due to basilar impression associated with atlanto-occipital assimilation manifesting as slowly progressive bilateral trigeminal neuralgia and diplopia in the right lateral gaze. X-ray and computed tomography of the skull confirmed the diagnosis of basilar impression and atlanto-occipital assimilation, and magnetic resonance imaging disclosed tightness of the posterior cranial fossa. Surgical suboccipital decompression resulted in gradual resolution of the patient's complaints, and no additional symptoms were recognized. Impairment of the sixth cranial nerve is a rare symptom compared to those of the fifth or the eighth cranial nerve in a patient with a craniocervical malformation. However, the present case shows the possibility of cranial nerve dysfunction due to tightness of the posterior cranial fossa, and suggests that surgical treatment for basilar impression with atlanto-occipital assimilation should be considered in patients with uncommon and unusual symptoms.

A 45-year-old female presented with gliomatosis cerebri manifesting as hemiballismus-like involuntary movement in the arm, motor weakness in the leg, and hypesthesia in her left side. Computed tomography showed only diffuse swelling of the right cerebral hemisphere. but T2-weighted magnetic resonance imaging revealed a diffuse lesion spreading from the right thalamus to the temporal. parietal, and occipital lobes on the same side. No abnormal enhancement was recognized. Cerebral angiography showed no specific finding. A right occipital lobectomy was performed to confirm the diagnosis of gliomatosis cerebri. Anaplastic transformation was recognized 5 months later. The disease did not resolve with radiation or interferon administration, but steroid therapy achieved remarkably effective tumor regression. The patient died due to pneumonia. Autopsy showed the features of diffuse glioblastoma. Steroid therapy may be an effective treatment for gliomatosis cerebri before the terminal stage. © 1998, The Japan Neurosurgical Society. All rights reserved.

A 47-year-old male presented with abducens nerve palsy due to basilar impression associated with atlanto-occipital assimilation manifesting as slowly progressive bilateral trigeminal neuralgia and diplopia in the right lateral gaze. X-ray and computed tomography of the skull confirmed the diagnosis of basilar impression and atlanto-occipital assimilation, and magnetic resonance imaging disclosed tightness of the posterior cranial fossa. Surgical suboccipital decompression resulted in gradual resolution of the patient's complaints, and no additional symptoms were recognized. Impairment of the sixth cranial nerve is a rare symptom compared to those of the fifth or the eighth cranial nerve in a patient with a craniocervical malformation. However, the present case shows the possibility of cranial nerve dysfunction due to tightness of the posterior cranial fossa, and suggests that surgical treatment for basilar impression with atlanto-occipital assimilation should be considered in patients with uncommon and unusual symptoms. © 1998, The Japan Neurosurgical Society. All rights reserved.

A 68-year-old male presented with progressive spastic quadriparesis. Twelve years previously he had undergone anterior decompression with bone grafting for cervical ossification of the posterior longitudinal ligament associated with spinal trauma. Radiological examination showed ossification of the transverse ligament of the atlas (TLA) and severe stenosis of the upper cervical canal. Anterior dislocation of the atlas was also present, but the occiput/atlas/axis unit was perfectly stable due to the prior anterior fusion. Suboccipital decompression and laminectomy of the atlas were performed, and his symptoms improved. Based on the atlanto-axial dislocation, the TLA might have been damaged at the time of the primary trauma and became the trigger for the ossification of the TLA, showing that marked ossification of a vertebral ligament can occur after injury. © 1998, The Japan Neurosurgical Society. All rights reserved.

A 64-year-old female presented with hemangiopericytoma arising from a dural fascia graft placed after a previous operation for the total removal of a benign meningioma. The patient also had multiple pulmonary metastases identified as hemangiopericytoma. The tumor resected at the first operation was benign based on all grading systems for meningiomas. We considered that the tumor was a kind of scar tumor. The hemangiopericytoma probably developed from a scar tumor at the graft. We emphasize the importance of long-term follow-up for patients who have undergone surgery for benign tumors. © 1998, The Japan Neurosurgical Society. All rights reserved.

Hepatocyte growth factor/scatter factor (HGF/SF), which has various physiological functions, and its receptor c-Met, the human c-met proto-oncogene product, are thought to be determinant in the pathological processes of various malignancies. To investigate the possible role of HGF/SF in the progression of development of astrocytic tumors, we examined the expression of c-Met in these tumors. Immunohistochemistry using the streptavidin-biotin peroxidase complex method and immunofluorescence double staining with anti-c-Met polyclonal and anti-glial fibrillary acidic protein monoclonal antibodies were performed. Positive c-Met expression was detected in 31 of the 42 astrocytic tumors and some of the control cases analyzed. c-Met-positive cells showed morphological characteristics of astrocytes. Especially in the cases of high-grade tumors, c-Met positivity was abundant in cells in both vascular-rich and peripheral regions of the tumors but not in the cells with distinctly malignant features. Immunofluorescence double staining revealed that the c-Met-positive cells were in part of astrocytic origin. We suggest that c-Met-positive cells are affected by some factors in the lesions where the pathological processes are in a state of development. Our studies indicated that c-Met expression might take part in glioma invasion but not in the development of malignancy.

A 69-year-old female presented with a meningioma of the pineal region manifesting as gait disturbance and mental dysfunction. Magnetic resonance imaging revealed a homogeneously well-enhanced circumscribed round mass of about 5 cm in diameter in the pineal region. Angiography demonstrated that the tumor was fed mainly by the bilateral middle meningeal arteries (MMAs), and preoperative intravascular embolization was performed through the bilateral MMAs using estrogen-alcohol and polyvinyl acetate. The tumor was very soft and easily totally resected via the right occipital transtentorial approach. Preoperative embolization is a very useful technique to facilitate removal of deep-seated tumors.

Since 1990, early surgery within 3 days following subarachnoid hemorrhage has been performed routinely in our hospital even for ruptured posterior circulation aneurysms. Our experience with early surgical management of 25 patients with posterior circulation aneurysms, including two patients who underwent endovascular surgery, is reported. Fourteen patients had an aneurysm on the basilar, the posterior cerebral or superior cerebellar artery (BA), and 11 patients had an aneurysm on the vertebral or posterior inferior cerebellar artery (VA). The mortality and morbidity of the BA group were 7% and 29%, respectively, and those of the VA group were 27% and 9%, respectively. In BA, the incidence of symptomatic vasospasm and hydrocephalus was definitely high compared with VA, and the outcome in elderly patients was significantly unfavorable. Early surgery for posterior circulation aneurysms to prevent rebleeding might be considered in selected cases.

A 38-year-old male suffered sudden onset of rotational vertigo without headache. Consciousness disturbance developed on the 3rd day after the onset. Computed tomography showed cerebellar infarction with obstructive hydrocephalus. External ventricular drainage was performed. Angiography showed bilateral extracranial vertebral artery dissection. Antiplatelet therapy was given. Repeat angiography showed improvement of the dissection. His neurological deficits completely resolved. Vertebral artery dissections may cause both lateral medullary or cerebellar infarction and hydrocephalus due to the cerebellar infarction manifesting as various symptoms, so careful evaluation and treatment are required. © 1997, The Japan Neurosurgical Society. All rights reserved.

A 34-year-old female presented with occlusive cerebrovasculopathy without definite ischemic symptoms and regrowth of a cystic tumor in the third ventricle. She had been treated for a craniopharyngioma 19 years previously by internal irradiation with 198Au colloid combined with intracavitary administration of bleomycin via an Ommaya reservoir. Cerebral angiography demonstrated complete occlusion of the clinoid portion of the left internal carotid artery and stenosis of the left posterior cerebral artery, and numerous transdural anastomoses which had developed after craniotomy. Endoscopic management achieved collapse of the cystic tumor. No treatment for the occlusive cerebrovasculopathy was necessary because of the collateral blood supply. Careful follow-up examinations to detect occult cerebrovasculopathy after such treatment is recommended. © 1997, The Japan Neurosurgical Society. All rights reserved.

We report a case of idiopathic intracranial hypertension, a clinically rare syndrome. A 28 year old woman was admitted with orthostatic headaches associated with nausea secondary to intracranial hypertension. Lumbar puncture yielded an opening pressure of 4 cmH2O in the lateral recumbent position, and the spinal fluid protein concentration was 56 mg/dl. There was no history of lumbar puncture or clear history of head trauma before the onset of symptoms. Spinal and cranial MRI showed no evidence of CSF leakage, and there was diffuse meningeal enhancement following gadolinium infusion. Cranial MRI showed no evidence of brain displacement due to low CSF pressure, such as tonsillar herniation. Radioisotope cisternography (RIC) showed rapid accumulation of isotope within the bladder and early disappearance of radioactivity from the head. About 2 months later the headaches resolved spontaneously, and repeated lumbar puncture yielded opening pressure elevation to 10.5 cmH2O with a decrease in protein concentration to 28 mg/dl. The abnormal MRI and RIC findings had become normal. On the other hand, the patient had a low blood concentration of vitamin A, which is thought to play some role in the production of CSF. The results of RIC suggested that the patient may have become symptomatic because of undetectable CSF leakage or hyperabsorption, but diminished production of CSF due to lower blood vitamin A concentration may also have been a factor predisposing to this syndrome.

The secreted form of amyloid precursor protein (APP(s)) including most of the extracellular domain of APP is released from the cell surface, suggesting physiological significance of APP(s) in vivo. We used the methylotrophic yeast Pichia pastoris as a host system for the production of recombinant APP(s) (rAPP(s)). Two rAPP(s)s derived from isoforms of APP (APP695 and APP770) were secreted into the culture medium from the yeast, which carried cDNA encoding the N-terminal portion of APP under the control of a P. pastoris alcohol oxidase promoter. Like APP(s)s produced by the transfected COS-1 cells, the purified rAPP(s)s from yeast were shown to be biologically active in terms of neurite outgrowth of embryonic rat neocortical explants. These rAPP(s)s could be valuable tools for investigating the biological functions of APP(s)s. (C) 1995 Academic Press, Inc.

A 25-year-old female suddenly developed headache and diplopia. On admission, neurological examination revealed neck stiffness and left abducens nerve paresis. A computed tomographic scan suggested subarachnoid hemorrhage. Left vertebral angiogram showed an aneurysm on the anterior pontine segment of the right superior cerebellar artery (SCA) and marked flexion and meandering of the basilar artery to the left. At surgery, an atherosclerotic, fusiform aneurysm was found through the right subtemporal transtentorial approach, and the right SCA was clipped just proximal to the aneurysm. Thirteen cases of SCA aneurysm have been described in the literature, but none was a fusiform aneurysm. © 1990, The Japan Neurosurgical Society. All rights reserved.