Immunohistochemical expression of Ets-1 transcription factor and the urokinase-type plasminogen activator is correlated with the malignant and invasive potential in meningiomas.

BACKGROUND: The Ets-1 transcription factor has been proposed to play an important role in the invasive process of tumor cells through the induction of urokinase-type plasminogen activator (u-PA). METHODS: Because meningiomas are potentially invasive tumors, irrespective of their malignancy grades, the authors immunohistochemically investigated Ets-1 and u-PA expression in tissues obtained from 50 benign (16 meningotheliomatous, 14 fibrous, 13 transitional, 6 angiomatous, and 1 microcystic), 4 atypical, and 6 anaplastic meningiomas and correlated their results with the malignancy and invasive potential. RESULTS: Ets-1 protein was expressed in 19 of the benign meningiomas (38%)whereas 31 (62%) were u-PA positive. The percentage of positive cells frequently was < 50%. In contrast, Ets-1 and u-PA expression was observed in all 4 atypical (100%) and all 6 anaplastic (100%) cases, respectively. The proportion of cells positive for Ets-1 and u-PA frequently were > or = 50%. A significant difference was observed between Ets-1 and u-PA expression in benign and high grade meningiomas (P < 0.0001). Moreover, Ets-1 expression was found to correlate significantly with u-PA positivity in meningiomas (P < 0.0001). Twenty-one of 60 meningioma cases (35%) showed infiltration either to the brain, dura mater, or bone. Eighteen of these 21 cases (85.7%) were positive for Ets-1 and u-PA. Ets-1 and u-PA positivity was found to correlate well with the invasive phenotype in meningiomas (P < 0.001). CONCLUSIONS: The findings of the current study support the possibility that the Ets-1 transcription factor, through u-PA induction, may be involved in the invasive process in meningiomas.

[Intracranial and orbital extension of a nasal cavity adult T-cell leukemia: a case report].

Adult T-cell leukemia (ATL) is one kind of leukemia induced by human T lymphotropic virus type I (HTLV-I) infection. An unusual case of ATL is presented. A fifty-one-year-old male patient was admitted to our hospital because of nasal obstruction and blindness in the left eye. Imaging study revealed a mass lesion in the nasal cavity, the left paranasal sinus extending to the left orbit and intracranial frontal base. Biopsy of the mass from the paranasal sinus was carried out and the histological diagnosis was a granulomatous lesion with non-specific inflammation. The clinical impression of the lesion was lethal midline granuloma. After steroid therapy and 50 Gy of local radiotherapy, the patient's symptoms disappeared except for his blindness in the left eye. Imaging study revealed that the mass lesion had become smaller. In spite of local improvement, new lesions such as cervical lymph node swelling and multiple nodular shadows in the lung fields appeared on CT scan. Histological diagnosis of the biopsied cervical lymph node was T-cell dominant non-Hodgkin's lymphoma of the diffuse type. Serologically, anti-HTLV-I antibody was positive. Southern blot analysis of lymph node biopsy showed monoclonal proliferation of ATL cells. We made the diagnosis of our case as ATL. The patient died 16 months later despite repeated systemic chemotherapy with cyclophosphamide, vincristine, adriamycin, and prednisolone. ATL can involve the central nervous system (CNS) and manifest CNS symptoms. The neurosurgeon also should consider the CNS involvement of ATL especially in Japan.

In-vivo microdialysis study of the distribution of cisplatin into brain tumour tissue after intracarotid infusion in rats with 9L malignant glioma.

Simultaneous brain microdialysis in tumour and non-tumour tissues has been used for kinetic determination of the local distribution of an anticancer agent, cisplatin, in rats. Rat brain was implanted with 9L malignant glioma and cisplatin (3.5 mg kg-1) was administered as a selective intracarotid infusion for 30 min to rats prepared for brain microdialysis. The amount of platinum in the dialysate collected from tumour and non-tumour brain tissues was determined by atomic absorption spectrophotometry, as representative of cisplatin. Total and free platinum concentrations in plasma were also measured. Free platinum is accumulated preferentially in the tumour tissue and the brain tumour distribution coefficient (the ratio of brain tumour platinum AUC to plasma free platinum AUC, where AUC is the area under the platinum concentration-time curve) was 0.69, although there was little distribution into normal brain tissue. Drug binding to plasma proteins was 65%. It is concluded that simultaneous microdialysis is an easy and available method for assessing in-vivo local pharmacokinetics and distribution of cisplatin in tumour and non-tumour tissues of the brain.

Effect of tumor necrosis factor-alpha on the permeability of bovine brain microvessel endothelial cell monolayers.

The administration of chemotherapy to patients with tumors of the central nervous system is often blocked by the blood-brain barrier. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that promotes vascular permeability in addition to its pro-inflammatory effects. However, no direct evidence exists as to whether TNF-alpha may increase permeability of the BBB. We evaluated the effect of TNF-alpha on the transport of cisplatin (CDDP) or high molecular weight dextran labeled with fluorescein isothiocyanate (FITC-dextran) across bovine brain microvessel endothelial cell (BMEC) monolayers that was conducted on side-by-side diffusion chambers in vitro. The permeability coefficient for the transport of CDDP across the untreated monolayer was 3.80 x 10(-5) cm sec-1 at 30 minutes. After treating the BMEC monolayer with TNF-alpha (50 U ml-1 and 500 U ml-1) for 36 hours, the PC of CDDP increased significantly to 8.94 x 10(-5), and 14.43 x 10(-5) cm sec-1 respectively (p < 0.01). TNF-alpha had no effect on the transport of FITC-dextran across the BMEC monolayers. Electron microscopy showed that the tight junctions between the BMECs persisted even after treatment with TNF-alpha, whereas they had been partially disrupted following exposure to mannitol, 1600 mOsm kg-1. TNF-alpha selectively promoted the in vitro permeability of the blood-brain barrier to CDDP without disrupting tight junctions. This system could be used as a model for experimental studies of chemotherapy. Findings suggested that the combined administration of TNF-alpha and CDDP may be clinically useful.

Endothelin receptor in microvessels isolated from human meningiomas: quantification with radioluminography.

1. We characterized specific 125I-endothelin-1 (125I-ET-1) binding sites in microvessels isolated from human meningiomas, using an in vitro quantitative receptor autoradiographic technique coupled to a radioluminographic imaging plate system. 2. This newly developed and highly sensitive method revealed high-affinity ET receptors present in pellet sections of the microvessels from all the meningiomas studied, regardless of histological subtypes (dissociation constant, 1.2 +/- 0.3 nM; maximum binding capacity, 185 +/- 56 fmol/mg; means +/- SE for nine tumors). 3. In five cases of meningiomas, ET-3 competed for 125I-ET-1 binding to microvessels from those tumors with a low affinity [50% inhibiting concentration (IC50) of 1.6 +/- 0.4 x 10(-6) M], and a selective ETB receptor agonist, sarafotoxin S6c, up to 10(-6) M, did not displace ET binding from the sections. 4. In the sections of microvessels from four other tumors, biphasic competition curves were obtained in the case of incubation in the presence of increasing concentrations of ET-3, with an IC50 of 1.1 +/- 0.2 x 10(-9) M for the high-affinity component and 1.6 +/- 0.3 x 10(-6) M for the low-affinity component, respectively. In addition, S6c competed for ET binding to those sections (IC50 = 2.3 +/- 0.2 x 10(-10) M) and 10(-6) M S6c displaced 30% of the control, corresponding to the high-affinity component of competition curves obtained in the presence of ET-3. 5. Our results suggest that (a) capillaries in human meningiomas express a large number of high-affinity ETA (non-ETB) receptors with a small proportion of ETB receptors, and (b) ET may have a role in neovascularization, tumor blood flow, and/or function of the blood-tumor barrier in meningioma tissues by interacting with specific receptors present on the surface of the endothelium.

Enhanced expression of an endothelin ETA receptor in capillaries from human glioblastoma: a quantitative receptor autoradiographic analysis using a radioluminographic imaging plate system.

We identified and characterized 125I-endothelin-1 (125I-ET-1) binding sites in tumor capillaries isolated from human glioblastomas, using the quantitative receptor autoradiographic technique with pellet sections. Quantification was done using the computerized radioluminographic imaging plate system. High-affinity ET receptors were localized in capillaries from glioblastomas and the surrounding brain tissues (KD = 4.7 +/- 1.0 x 10(-10) and 1.6 +/- 0.3 x 10(-10) M, respectively; Bmax = 161 +/- 38 and 140 +/- 37 fmol/mg, respectively; mean +/- SEM, n = 5). BQ-123, a selective antagonist for the ETA receptor, potently competed for 125I-ET-1 binding to sections of the microvessels with IC50 values of 5.1 +/- 0.3 and 5.1 +/- 1.5 nM, and 10(-6) M BQ-123 displaced 84 and 58% of ET binding to capillaries from tumors and brains, respectively. In addition, competition curves obtained in the presence of increasing concentrations of ET-3 showed two components (IC50 = 5.7 +/- 2.5 x 10(-10) and 1.4 +/- 0.2 x 10(-6) M for tumor microvessels, 1.8 +/- 0.6 x 10(-10) and 1.1 +/- 0.3 x 10(-6) M for brain microvessels, respectively). Our results indicate that (a) the method we used is simple and highly sensitive for detecting and characterizing various receptors in tumor capillaries, especially in the case of a sparse specimen, and (b) capillaries in glioblastomas express specific high-affinity ET binding sites, candidates for biologically active ET receptors, which predominantly belong to the ETA subtype.

[A case of multiple myeloma associated with a large subcutaneous mass in the frontal region].

A case of multiple myeloma having plasmacytoma in the frontal bone and clivus is reported. A 68-year-old female was referred to our hospital because of a subcutaneous mass in the frontal region. She was diagnosed as having multiple myeloma 7 years ago and had been treated with chemotherapy. On admission, severe anemia, hyperproteinemia and elevation of serum lambda type immunoglobulin G (IgG) were pointed out. Plain skull X-rays showed numerous punched out lesions with a large bone defect of the frontal bone. CT scan and MRI revealed a mass lesion in the clivus in addition to a large epidural tumor in the frontal region. The encapsulated frontal epidural tumor was totally resected and cranioplasty was performed with resin. Histological diagnosis was plasmacytoma of IgG lambda type. The postoperative course was uneventful, and chemotherapy was continued. There was no tumor recurrence in the frontal region and no neurological deterioration, but she died of DIC 15 months after the operation. Twenty seven cases in the literature of multiple myeloma forming cranial or intracranial plasmacytoma were briefly reviewed. Although the prognosis of such cases is poor, total resection of medullary plasmacytoma is warranted especially in multiple myeloma patients who don't have another extramedullary plasmacytoma or plasma cell leukemia.

A selective endothelin ETA antagonist, BQ-123, inhibits 125I-endothelin-1 (125I-ET-1) binding to human meningiomas and antagonizes ET-1-induced proliferation of meningioma cells.

1. We studied the effects of BQ-123, a selective ETA receptor antagonist, on 125I-endothelin-1 (125I-ET-1) binding to cell surface receptors in surgically exercised human meningiomas and on ET-1-induced DNA synthesis in cultured human meningioma cells in vitro, using a quantitative receptor autoradiographic technique with radioluminography and 3H-thymidine incorporation, respectively. 2. All of the human meningiomas expressed high-affinity binding sites for 125I-ET-1, regardless of differences in histological subtypes (Kd = 2.6 +/- 0.2 nM, Bmax = 374 +/- 93 fmol/mg; mean +/- SE; n = 9). 3. BQ-123 competed for 125I-ET-1 binding to sections of meningiomas with IC50S of 3.2 +/- 0.9 x 10(-7) M, and 10(-4) M BQ-123 displaced 80% of the binding. 4. ET-1 significantly stimulated DNA synthesis in cultured human meningioma cells, up to 170% of the basal level in the presence of 10(-9) M ET-1. BQ-123 inhibited ET-1 (10(-9) M)-induced DNA synthesis in meningioma cells, in a dose-dependent manner, and 10(-5) M BQ-123 reduced it to 120% of the basal level. 5. The number of meningioma cells determined after 4 days in culture was dose dependently increased in the presence of ET-1 (10(-9) and 10(-7) M). The growth rate of meningioma cells, incubated with 10(-9) M ET-1, was reduced by 50% in the presence of 10(-7) M BQ-123.(ABSTRACT TRUNCATED AT 250 WORDS)

[Shotgun pellet embolus in the cerebral circulation via the internal carotid artery in the neck; a case report].

A 57-year-old hunter was shot accidentally and admitted to our hospital without any neurological deficits. Plain X-ray films of the neck revealed the presence of several shotgun pellets, one of which was thought to be in the vicinity of the right internal carotid artery at the C1 level. One week later, while surgical removal of pellets was being performed under fluoroscopic control, the pellet entered into the lumen of the artery and migrated to the intracranial vessels. Right carotid angiogram revealed that the pellet occluded in the right angular artery about 1.5cm distal from its outlet. Although embolectomy was performed, we could not get a patency of the vessel. CT scan taken 3 days after operation showed the occurrence of massive cerebral edema. Angiogram taken 2 weeks after confirmed occlusion of the vessel. The patient was discharged with left lower quadrantanopsia one month after the operation. In the literature, 20 similar cases have been hitherto reported and briefly reviewed. Of these 20, 6 cases died of cerebral infarction. We believe that embolectomy is warranted as soon as possible when patients show a condition building up to a stroke.