Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Usefulness of Contrast-Enhanced 3D-FLAIR MR Imaging for Differentiating Rathke Cleft Cyst from Cystic Craniopharyngioma.

BACKGROUND AND PURPOSE: Because it can be difficult to discriminate between a Rathke cleft cyst and cystic craniopharyngioma by conventional MR imaging alone, we investigated whether contrast-enhanced 3D T2-FLAIR MR imaging at 3T helps to distinguish a Rathke cleft cyst from a cystic craniopharyngioma. MATERIALS AND METHODS: We evaluated pre- and postcontrast T1-weighted and 3D T2-FLAIR images of 17 patients with pathologically confirmed Rathke cleft cyst (n = 10) or cystic craniopharyngioma (n = 7). All underwent 3T MR imaging studies before surgery. Two neuroradiologists independently recorded the enhancement grade of the lesion wall as grade 2 (most of the wall enhanced), grade 1 (some of the wall enhanced), and grade 0 (none of the wall enhanced). One neuroradiologist performed a blinded reading study of conventional MR images with/without 3D T2-FLAIR images. Interobserver agreement was determined by calculating the κ coefficient. Statistical analyses, including receiver operating characteristic curve analysis were performed. RESULTS: Interobserver agreement for postcontrast T1WI and 3D T2-FLAIR images was excellent (κ = 0.824 and κ = 0.867, respectively). Although the difference in the mean enhancement grade of Rathke cleft cysts and cystic craniopharyngiomas was not significant on postcontrast T1WIs, it was significant on postcontrast 3D T2-FLAIR images (P = .0011). The area under the receiver operating characteristic curve of the conventional MR alone and conventional MR with 3D T2-FLAIR readings was 0.879 and 1.0, respectively, though there was no significant difference in the area under the curve between the 2 readings. CONCLUSIONS: Contrast-enhanced 3D T2-FLAIR imaging at 3T helps to distinguish a Rathke cleft cyst from cystic craniopharyngioma.

Characterization of Carotid Plaque Components by Quantitative Susceptibility Mapping.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage in the carotid artery is related to an increased risk of cerebrovascular ischemic events. We aimed to investigate whether quantitative susceptibility mapping can characterize carotid artery plaque components and quantify the severity of intraplaque hemorrhage. MATERIALS AND METHODS: For this ex vivo quantitative susceptibility mapping study, 9 carotid endarterectomy specimens were imaged on a 3T MR imaging scanner using a 3D multi-echo gradient-echo sequence and a microscopy coil. The samples were examined histologically using immunostains, including glycophorin A and Prussian blue. The areas of erythrocytes, iron deposits, calcification, and fibrous matrices observed on stained sections were compared with quantitative susceptibility mapping findings and their mean susceptibility values. RESULTS: Intraplaque hemorrhage and iron deposits were observed only in areas hyperintense on quantitative susceptibility mapping; calcifications and fibrous matrices were prevalent in hypointense areas. The mean susceptibility values for necrotic cores with intraplaque hemorrhage but no iron deposits, cores with iron deposits but no intraplaque hemorrhage, cores without either intraplaque hemorrhage or iron deposits, and cores with calcification were 188 ± 51, 129 ± 49, -11 ± 17, and -158 ± 78 parts per billion, respectively. There was a significant difference in the mean susceptibility values among the 4 histologic components (P < .01). The mean susceptibility values of the whole plaque positively correlated with the percentage area positive for glycophorin A (r = 0.65, P < .001) and Prussian blue (r = 0.47, P < .001). CONCLUSIONS: Our findings suggest that quantitative susceptibility mapping can characterize the composition of carotid plaques and quantify the degree of intraplaque hemorrhage and iron deposits.

Balloon catheter disruption of middle cerebral artery thrombus in conjunction with thrombolysis for the treatment of acute middle cerebral artery embolism.

BACKGROUND AND PURPOSE: The goal of this study was to prospectively assess the feasibility, safety, and efficacy of balloon disruption of the middle cerebral artery (MCA) by using a deflated balloon catheter combined with an intra-arterial thrombolysis for the treatment of acute ischemic stroke. MATERIALS AND METHODS: Seven consecutive patients with clinical findings of acute major-vessel stroke met our criteria and underwent balloon disruption of an MCA thrombus with a deflated balloon catheter. The balloon disruption was performed with a low-profile microballoon catheter. The microballoon was inflated in the distal carotid artery and then deflated and advanced just distal to the occlusion site in the MCA. Thereafter, an intra-arterial thrombolysis of the MCA was applied. The maximum time from the onset of symptoms to the start of treatment and maximum dosage of urokinase was 6 hours and 600,000 U. The outcome was classified as good for a modified Rankin Scale (mRS) score of 0 or 1, moderate for a score of 2 or 3, and poor for a score of 4 or 5. RESULTS: Complete recanalization was achieved in 5 patients and partial recanalization in 3. Three patients recovered to an mRS score of 0 or 1; 3, to scores of 2 or 3; and 1, to a score of 4. No patients died. There was no major intracerebral hemorrhage. CONCLUSIONS: The penetration of the MCA with a deflated balloon catheter combined with an intra-arterial thrombolysis may be a safe and effective treatment for acute ischemic stroke.

The correlation between 99mTc-MIBI uptake and MIB-1 as a nuclear proliferation marker in glioma--a comparative study with 201Tl.

Technetium-99m methoxy-isobutylisonitrile (MIBI), like thallium-201 (201Tl), is a highly efficient agent for the diagnosis and monitoring of glioma tumors. Although 201Tl uptake is known to be partly associated with proliferative activity, little is known about the correlation between MIBI uptake and proliferation activity in gliomas. The current study was performed to assess the correlation between MIBI uptake and proliferative activities in gliomas, estimated by the monoclonal antibody to Ki-67 antigen (MIB-1) staining method. By comparing the results with those of 201Tl, we determined which tracer would be suitable for estimating proliferative activities. Twenty-four presurgical glioma patients (six with low-grade gliomas, five with anaplastic astrocytomas, and 13 with glioblastomas) were given MIBI and 201Tl SPECT. Early (10 min after injection) and delayed images (3 h after injection) were obtained for both MIBI and 201Tl scintigraphy. SPECT parameters, early ratio (ER), delayed ratio (DR), and retention index (RI) were obtained in both radiopharmaceuticals. All patients underwent subsequent surgical excision, and the specimens were immunostained for MIB-1. The proliferative activity was measured as a percentage positive nuclear area for MIB-1 (MI; MIB-1 index). To evaluate the relationship between the proliferative activity and SPECT parameters, we performed a correlation analysis. MI correlated with the MIBI uptake ratio (r = 0.75 for ER, and r = 0.7 for DR). Both DR and RI of 201Tl also correlated with MI, but weakly (r = 0.6 for DR, and. r = 0.59 for RI). There was no significant correlation between the MIB-1 index and the other parameters. MIBI-uptake parameters demonstrated a stronger positive correlation with the MIB-1 index than that of 201Tl. With the use of MIBI SPECT, we can estimate the proliferative activity of glioma noninvasively.

Expression of emmprin (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas.

EMMPRIN (extracellular matrix metalloproteinase inducer), also called CD147, basigin or M6 in the human, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). In our study, we investigated expression of EMMPRIN in human normal brain and gliomas, since mouse basigin and chicken HT7, the species homologues of human EMMPRIN, are associated with neuronal interactions and normal blood-brain barrier function, respectively. EMMPRIN expression was detected in all samples of non-neoplastic brain and glioma tissues examined. However, expression levels of EMMPRIN mRNA and protein were significantly higher in gliomas than in non-neoplastic brain. Moreover, levels of mRNA expression and immunohistochemical staining correlated with tumor progression in gliomas: They were highest in the most malignant form of glioma, glioblastoma multiforme, followed by anaplastic astrocytoma and then low-grade astrocytoma. Also, immunolocalization revealed quite different distributions in non-neoplastic brain and glioma: EMMPRIN was demonstrated only in vascular endothelium in non-neoplastic regions of the brain, whereas it was present in tumor cells but not in proliferating blood vessels in malignant gliomas. These data indicate that an MMP inducer molecule EMMPRIN is differently expressed in human normal brain and gliomas and could be associated with astrocytoma progression. Possible mechanisms whereby glioma cell EMMPRIN could influence tumor progression will be discussed.

Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts.

Extracellular matrix metalloproteinase inducer (EMMPRIN) also called CD147, basigin or M6 in the human is a member of the immunoglobulin superfamily that is enriched on the surface of tumor cells and stimulates adjacent stromal cells to produce several matrix metalloproteinases (MMPs). In this study, we have demonstrated that coculturing of EMMPRIN-expressing human glioblastoma multiforme cells (U251) with brain-derived human fibroblasts not only stimulates production, but also activation of pro-gelatinase A (proMMP-2), an enzyme that is enriched in malignant gliomas and most likely crucial to tumor progression. Production of membrane types 1 and 2-MMPs (MT1-MMP and MT2-MMP), which are activators of proMMP-2, was also stimulated in these cocultures. Stimulation of MMP-2, MT1-MMP and MT2-MMP production was inhibited by anti-EMMPRIN monoclonal antibody in a dose-dependent manner. Thus, we have shown, for the first time, that EMMPRIN causes increased expression of MT1-MMP and MT2-MMP, as well as increased production and activation of MMP-2.

Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR.

Neuropoletic cytokines such as ciliary neurotrophic factor (CNTF) can activate multiple signaling pathways in parallel, including those involving Janus kinase (JAK)-signal transducers and activators of transcription (STATs), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamydn (mTOR)-p70 S6 kinase . Crosstalk occurs between these pathways, because studies have shown that STAT3 requires phosphorylation on tyrosine and serine residues by independent protein kinase activities for maximal activation of target gene transcription. Members of the JAK/Tyk family of tyrosine kinases mediate phosphorylation of STAT3 at Tyr705 during CNTF signaling; however, the kinase responsible for phosphorylation at STAT3 Tyr727 appears to depend on both the extracellular stimulus and the cellular context. Here we investigate the kinase activity responsible for phosphorylation of STAT3 on Ser727 in CNTF-stimulated neuroblastoma cells. We found that CNTF-induced phosphorylation of Ser727 was inhibited by the mTOR inhibitor rapamycin, but not by inhibitors of MAPK and protein kinase C (PKC) activation. A STAT3 peptide was efficiently phosphorylated on Ser727 in a CNTF-dependent manner by mTOR, but not by a kinase-inactive mTOR mutant or by p70 S6 kinase. In agreement with these biochemical studies, rapamycin treatment of cells transfected with a STAT-responsive promoter reporter decreased activation of the reporter to the same degree as a STAT3 Ser727Ala mutant The ability of mTOR to contribute to activation of STAT3 extends the function of mTOR in mammalian cells to include transcriptional regulation.

A Stump of Occluded Posterior Cerebral Artery Mimicking a Ruptured Aneurysm: Case Report.

We report on a 63-year-old female with subarachnoid hemorrhage who had a stump of occluded posterior cerebral artery (PCA) mimicking a ruptured aneurysm of the basilar bifurcation. Intraoperatively, the aneurysmal opacification on preoperative angiograms proved to be the residual lumen of the occluded right P1 segment. Because of the nodular appearance and upward direction of the stump of the right P1 segment, it was misinterpreted as an aneurysm. During operation, a tiny ruptured aneurysm missed on preoperative angiograms was found in the left A1-A2 junction and was clipped safely.

Time course of changes in mu-opioid receptor mRNA levels in the periaqueductal gray of rat brain by a single or repeated injections of antisense oligodeoxynucleotides.

The effect of phosphorothioated antisense oligodeoxynucleotide (AS ODN) against the mu-opioid receptor (MOR) on MOR mRNA level in the periaqueductal gray (PAG) of rat brain was investigated. The MOR mRNA levels at 3, 6, 12, 24, 48 and 72 h after MOR AS ODN microinjection into the PAG were determined by reverse transcriptase-polymerase chain reaction. The MOR mRNA level was significantly decreased only at 12 h after the injection of 10 microg MOR AS ODN. When 10 microg MOR AS ODN was given three times at the interval of 48 h, MOR mRNA levels were significantly decreased at 6, 12 and 24 h after the last injection of the AS ODN. However, MOR mRNA levels were not significantly changed by three injections at 48-h interval of MOR sense ODN or AS ODNs against delta- and kappa-opioid receptors, although the two latter AS ODNs significantly reduced the respective targeted mRNA levels. In conclusion, the present results show that the selective decrease in MOR mRNA is at least one reason why the reported diminished effects of MOR agonists are produced in animals pretreated with MOR AS ODN, although they could be produced through several mechanisms in which MOR mRNA level does not change.

The usefulness of Tc-99m MIBI for evaluating brain tumors: comparative study with Tl-201 and relation with P-glycoprotein

PURPOSE: This study was undertaken to determine the usefulness of Tc-99m methoxyisobutylisonitrile (MIBI) in brain tumors compared with TI-201 imaging. The authors evaluated the correlation between MIBI uptake and the presence of P-glycoprotein, and also the relation between MIBI uptake in response to combined radiotherapy and chemotherapy in glioblastoma. MATERIALS AND METHODS: Thirty-four brain tumors composed of 15 glioblastoma multiforme (GBM), 5 anaplastic astrocytomas, 5 low-grade astrocytomas, and 9 metastases were evaluated. Early and delayed images were obtained for MIBI and Tl-201 scintigraphy. P-glycoprotein status in all GBM, 2 anaplastic astrocytomas, 2 low-grade astrocytomas, and 2 metastases were evaluated immunohistochemically. Patients with GBM were divided into an effective and a noneffective group according to the change in tumor size. MIBI uptake indices were compared for these two groups. RESULTS: Both radiopharmaceuticals accumulated in all GBM and anaplastic astrocytomas. In low-grade astrocytomas, only one case showed tracer uptake. In metastasis, two cases showed high uptake on early images and marked washout on delayed images. Uptake ratio values (early uptake ratio and delayed uptake ratio) in all tumors were significantly higher in MIBI than in Tl-201. Immunohistochemical studies showed that the metastases were positive for P-glycoprotein but the GBM were not. In low-grade astrocytomas, a few cells were positively stained. In relation to the therapeutic outcome of GBM, both the early and delayed uptake ratios of MIBI were significantly greater in the noneffective group. CONCLUSIONS: Although diagnostic ability was comparable in MIBI and Tl-201, the imaging quality was better in MIBI. Both radiopharmaceuticals are useful in differentiating low-grade glioma from high-grade glioma. MIBI delayed imaging could also reflect the presence of P-glycoprotein. Intense MIBI uptake was also predictive of a poor clinical outcome in GBM.

Clinical usefulness of and problems with three-dimensional CT angiography for the evaluation of arteriosclerotic stenosis of the carotid artery: comparison with conventional angiography, MRA, and ultrasound sonography.

BACKGROUND: Prevention of stroke is aided by determination of the degree of carotid artery stenosis and progression of arterial sclerosis. Three-dimensional computed tomography (CT) angiography (3D-CTA) is a new method for evaluating the degree of arterial stenosis. The purpose of this study was to compare the accuracy of 3D-CTA with the "gold standard": conventional angiography, magnetic resonance angiography (MRA), and ultrasound sonography (US). METHODS: A total of 128 carotid bifurcations in 64 patients (42 men and 22 women; mean age, 68.5 years) were examined by 3D-CTA because of symptoms of cerebral infarction, carotid bruit, or findings suggestive of arteriosclerotic carotid artery stenosis on MRA screening. The following were used to compare 3D-CTA with conventional angiography, MRA and US: 1) estimation of the degree of stenosis; 2) depiction of irregularities in arterial walls, including calcification, intimal thickening, ulcers and plaque; and 3) surgical planning for carotid endarterectomy (CEA) and percutaneous transluminal angioplasty (PTA), and postoperative evaluation. RESULTS: A strong correlation was found between the degrees of stenosis estimated by conventional angiography and 3D-CTA MIP image (r = 0.987/p < 0.0001). On the other hand, stenosis was generally overestimated by MRA, which, however, has the advantage of being able to scan the carotid siphon to the middle cerebral artery at one time. Calcification and ulceration of the artery wall could be evaluated with 3D-CTA, whereas with US, progression of arterial sclerosis could be evaluated by differentiation of homogenous and heterogenous plaque. The anatomical relationships between the site of stenosis and the internal jugular vein and bony structures, which must be known before CEA, were confirmed by observation of rotated images using the shaded surface reconstruction (SSR) method. Because the hemodynamics of cross and collateral flows cannot be clearly imaged with 3D-CTA, standard angiography is needed to determine suitability for bypass surgery. CONCLUSIONS: The current method used in our hospital for the diagnosis of stenosis of the internal carotid artery includes MRA or US for initial screening, 3D-CTA for evaluation of the degree of stenosis and for preoperative and postoperative evaluation of CEA and PTA, and conventional angiography for evaluation of hemodynamics and determination of the indications for a bypass surgery.

Simultaneous up-regulation of urokinase-type plasminogen activator (uPA) and uPA receptor by hepatocyte growth factor/scatter factor in human glioma cells.

Several lines of evidence indicate that hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, may play an important role in progression of human glioma. In this study, effects of HGF/SF on urokinase- type plasminogen activator (uPA)-mediated proteolysis network were examined in c-Met-positive human glioma cell lines. Treatment of the glioma cells with various concentrations of HGF/SF resulted in an enhanced secretion of uPA proteins accompanying increased transcription of uPA mRNA in a dose dependent fashion. The levels of uPA receptor (uPAR) mRNAs were also elevated simultaneously upon HGF/SF stimulation, and the cell-surface associated uPA activity was also elevated by the treatment. Since concomitant expression of HGF and its receptor c-Met are frequently observed in malignant gliomas, these results suggest that HGF/SF participates in invasive process of malignant glioma cells not only by its motility-stimulating activity but also through enhanced degradation of the extracellular matrix induced by autocrine activation of uPA proteolysis network.

MRA as a Primary Screening Technique for Intra- and Extracranial Arterial Occlusive Diseases.

We designed a protocol of 3-dimensional phase contrast (3D-PC-) magnetic resonance angiography (MRA), which was performed in the axial plane to assess the circle of Willis and in the coronal plane to assess the arteries of the head and neck, for screening of the intra- and extracranial arterial occlusive diseases. We evaluated the accuracy of 3D-PC-MRA comparing it with intraarterial angiography. In 52 consecutive patients presenting with clinical suspicion of a stroke, common carotid bifurcation (CCB), petrous segment of internal carotid artery (C5 segment), carotid siphon, middle cerebral artery (MCA), posterior cerebral artery (PCA), vertebral artery (VA), and basilar artery (BA) were evaluated. Both examinations were blindly graded as normal, mild (0-29% stenosis), moderate (30-69% stenosis), severe (70-99% stenosis), or occluded. In the two readers experienced and inexperienced in MR interpretation, Spearman rank correlations between the two techniques were 0.917/0.866 (CCB), 0.803/0.758 (C5 segment), 0.837/0.702 (carotid siphon), 0.841/0.787 (MCA), 0.899/0.886 (PCA), 0.935/0.889 (VA), and 0.932/0.900 (BA), respectively (p < 0.0001). 3D-PC-MRA and intraarterial angiography had a good overall agreement, suggesting its use as a primary screening technique for intra- and extracranial arterial occlusive diseases, although the diagnostic accuracy of MRA was relatively poor in the C5 segment, carotid siphon, and MCA presumably due to phase dispersion.

Up-regulation of vascular endothelial growth factor induced by hepatocyte growth factor/scatter factor stimulation in human glioma cells.

Recent findings suggest that hepatocyte growth factor/scatter factor (HGF/SF) contributes to the malignant progression of human gliomas. We investigated the effect of HGF/SF on vascular endothelial growth factor (VEGF) expression of c-Met/HGF receptor-positive human glioma cell lines. Treatment of the glioma cells with various concentrations of HGF/SF resulted in an enhanced secretion of VEGF proteins accompanying increased transcription of VEGF mRNA in a dose-dependent fashion. Since malignant gliomas frequently co-express HGF/SF and its receptor, these results suggest that HGF/SF could act as an indirect angiogenic factor through autocrine induction of VEGF expression and secretion in malignant gliomas.

[Evaluation of brain tumor by 99mTc-MIBI: comparison study with 201Tl and predictivity of therapeutic effect].

We compared the detectability of 99mTc-MIBI and 201Tl-chloride for brain tumor in relationship with histopathology. We also evaluated correlation between therapeutic effect using ACNU, Cisplatine and the degree of MIBI tumor uptake. The subjects were 31 brain tumor histologically confirmed by operation or biopsy. Dual-isotope SPECT technique was performed at both 20 min and 180 min after tracer injection. A tumor to normal lung ratio on both early (ER) and delayed image (DR) and retention index (RI) were calculated. The positive rates of 99mTc-MIBI (90.3% and 77.4%) were comparable to that of 201Tl (90.3% and 80.6%). In the relationship with histopathology, both MIBI and Tl accumulated in 100% of glioblastoma (GBM), metastasis (meta), anaplastic astrocytoma and 25% of low grade astrocytoma on both early and delayed images. On semiquantitative analysis, there were no statistical significance among GBM, meta and anaplastic astrocytoma of ER, DR, RI in the both radiopharmaceuticals. However, both ER and DR in GBM tended to be higher than those of anaplastic astrocytoma. In spite of intense MIBI uptake, GBM patients died within six months except one patient. We concluded that MIBI can be helpful in detecting brain tumor as Tl. MIBI also might be useful in estimating the degree of malignancy in glioma. However, intense MIBI uptake did not mean favorable therapeutic effect in patients with GBM treated with ACNU and Cisplatine.

Application of SPET using technetium-99m sestamibi in brain tumours and comparison with expression of the MDR-1 gene: is it possible to predict the response to chemotherapy in patients with gliomas by means of 99mTc-sestamibi SPET?

Technetium-99m sestamibi (MIBI) is thought to be passively taken up by metabolically active tumour cells and effluxed from them by P-glycoprotein (Pgp). This 170-kDa membrane-bound protein, encoded by the MDR-1 gene, acts as an energy-dependent efflux pump for several antineoplastic agents, resulting in multidrug resistance. For this reason, it is of interest whether the tumour's response to chemotherapy can be predicted by MIBI single-photon emission tomography (SPET). In this study, MIBI SPET was compared with thallium-201 (Tl) SPET using magnetic resonance imaging as a guide in 16 patients with untreated brain tumours [ten glioblastomas (GBs), two anaplastic astrocytomas (AAs), two low-grade gliomas (LGASs) and two metastatic brain tumours) and in four patients who had received treatment for with brain tumours (two GBs, two AAs). In addition, we investigated the expression of the MDR-1 gene and its product Pgp in the same patients, and compared the results with MIBI SPET findings. MIBI, as well as Tl, was highly accumulated and retained in the enhanced region of malignant gliomas. In addition, MIBI SPET yielded sharp and well-contrasted images, and the margin of the tumour was more clearly defined than with Tl SPET due to a good signal-to-noise ratio. Follow-up MIBI SPET in patients who had received therapy showed marked uptake in a patient with malignant transformation, who deteriorated clinically. Patients with no uptake on MIBI SPET showed no sign of recurrence. Semiquantitative analysis of untreated patients showed a relationship between the early uptake index (UI, ratio of average count/pixel in the lesion to that in the contralateral area on early images) and the degree of malignancy (early UI = 1.08+/-0.06 in LGASs, 4.10+/-0.84 in AAs, 5.71+/-3.47 in GBs, and 7.52+/-1.52 in metastatic brain tumours). The retention index (RI, ratio of delayed to early UI) of MIBI was significantly lower than that of Tl in metastatic brain tumours (P<0.05), but not in malignant gliomas. Histological and biological investigation of gliomas showed that the MDR-1 gene and its product Pgp were expressed only in normal endothelial cells and not in tumour cells or proliferating endothelial cells; Pgp tended to decrease as the degree of malignancy rose. Hence, the presence of Pgp and the grade of malignancy were inversely related in gliomas. By contrast, immunohistochemical study showed strong accumulation of Pgp in metastatic brain tumour cells. These histopathological findings and MIBI SPET findings are compatible with experimental data; MIBI was washed out by Pgp. The main cause of chemoresistance is probably not an increasing drug efflux by Pgp in gliomas. Thus, MIBI SPET is useful for detecting the active lesions, but may not be useful for predicting the response to chemotherapy in gliomas.

Direct percutaneous transluminal angioplasty for acute middle cerebral artery occlusion.

PURPOSE: We review our initial experience with direct percutaneous transluminal angioplasty (PTA) as a reperfusion treatment for acute occlusion of the middle cerebral artery. METHODS: Ten patients in whom successful thrombolysis might not be expected because of the risk of hemorrhagic complications or reocclusion were treated with direct PTA. When early ischemic findings were present on the initial CT scans and/or when lenticulostriate arteries were involved, we performed direct PTA rather than thrombolytic therapy. Direct PTA was also performed when superselective local angiography via a Tracker catheter advanced just distal to the occlusion site showed the presence of a large embolus or high-grade stenosis suggestive of thrombosis. Angioplasty was performed with a Stealth balloon catheter with a maximum diameter of 2.0 to 2.5 mm. The balloon catheter was advanced into the site of occlusion and inflated to 2 atm initially, and subsequently up to 3 atm. Two to six inflations, each of 30 seconds' duration, were performed. RESULTS: Although the rate of initial recanalization was 100% (10 of 10), reocclusion occurred in two patients with atherothrombotic M2 occlusion. The final angiographic success rate of direct PTA was 80% (8 of 10). There were no hemorrhagic or technical complications, and five of 10 patients showed marked clinical improvement. In two of seven patients with cardioembolic M1 trunk occlusion, crushed fragments of the embolus obstructed M2 portions after direct PTA, necessitating local thrombolysis. CONCLUSION: Direct PTA may be performed safely as an alternative to thrombolytic therapy in patients with acute occlusion of the middle cerebral artery when early CT findings and/or lenticulostriate artery involvement are present or when superselective local angiography shows the presence of a large embolus or high-grade stenosis.

Comparative analysis of expression of hepatocyte growth factor and its receptor, c-met, in gliomas, meningiomas and schwannomas in humans.

Expression of hepatocyte growth factor (HGF) and c-met, a proto-oncogene that encodes a receptor for HGF, was examined in 45 cases of human primary intracranial tumors by means of RT-PCR. In gliomas, HGF and c-met mRNAs were preferentially expressed in high-grade tumors. Co-expression of both genes was observed in glioblastomas (6/15) and in one anaplastic astrocytoma (1/5) but not in low-grade astrocytomas (0/3). By contrast, the c-met gene was consistently expressed in meningiomas (12/14) and schwannomas (8/8). The presence of c-Met protein was confirmed in the tumor cells of glioblastoma, meningioma and schwannoma by immunohistochemical staining. Moreover, all of the schwannoma cases co-expressed the HGF gene. These observations suggest that HGF/c-met expression is somehow related to the disease progression in gliomas, whereas c-Met protein might have an important fundamental biological role in meningioma and schwannoma. Moreover, since all of the schwannoma cases concomitantly expressed the ligand (HGF) and the receptor (c-met) genes, HGF may act in an autocrine fashion in schwannoma.