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We report the case of a 60-year-old man who first presented with transient difficulty of word recall. Subsequent MRI revealed an invasive brain tumor in the left frontal lobe. The patient underwent open biopsy, and diffuse astrocytoma(WHO grade II)was diagnosed. However, the malignant potential of this tumor was not particularly low because of a few enhancement on preoperative evaluation, and radiation therapy was initially performed. Four months after ending irradiation, temozolomide treatment was introduced for tumor regrowth. After another 2 months, combined chemotherapy with bevacizumab was also started due to tumor enlargement, which was evaluated as malignant transformation to glioblastoma. Two focal lesions with signal hyperintensity on DWI appeared in the frontal and temporal lobes at different locations 3 months after starting bevacizumab. The left temporal lesion subsequently changed to a ring-enhanced tumor, and glioblastoma(WHO grade IV)was finally diagnosed at decompressive surgery. Another frontal lesion, however, continued to maintain a favorable course without any changes in signal despite appearing as similar signal-hyperintense lesions. The temporal hyperintense lesion may undergo malignant transformation into glioblastoma with typical radiological appearance. Recent studies on image changes following bevacizumab treatment have attracted widespread attention, and the clinical significance of such hyperintense lesions has gained attention. This present case was thought to be valuable because of the contradistinctive aspects at the same time, in which the hyperintense lesions of the frontal and temporal lobes seemed to represent antitumor activity or drug refractory effects based on bevacizumab treatment.

The most important prognosticator for malignant brain tumor patients is the degree of tumor removal. On the other hand, surgical removal should not induce aggravation of the patient performance status. In accordance with the result, surgical planning for glioma should be carefully considered. However, there is no standard guide for preoperative planning to date. However, there is no standard guide for preoperative planning to the present. We attempted to divide gliomas into 5 stages according to the difficulty of the surgery and analyzed the relation between the removal rate and each stage. The results demonstrated that the stage is correlated with the removal rate. This staging might contribute to standardization of glioma surgery. For surgical planning of tumors around the motor area, fiber tractography and magnetoencephalography should be very useful. As an intraoperative examination, monitoring of motor evoked potential is necessary to resect tumors around the motor area. For resection of tumors around the speech area, functional brain mapping under awake surgery is the most reliable method. In addition to these techniques for safe surgery, neuro-navigation and chemical navigation using 5-aminolevulinic acid are used to achieve of the maximum removal rate. Finally, development of preoperative examinations, microsurgical technique, and intraoperative monitoring enabled us to do safer and move sure surgery.

Preoperative identification of precentral gyrus and intraoperative monitoring of motor evoked potentials (MEPs) were performed to preserve postoperative motor function in seven patients with gliomas near the primary motor cortex. Tumors were astrocytomas in 3 patients, glioblastomas in 2 patients, anaplastic astrocytoma and mixed glioma in one patient each. Preoperative identification of the primary motor cortex was performed by three-dimensional (3D) display of magnetic resonance (MR) images and by functional images using MR imaging and single-photon emission tomography. The primary motor cortex identified by 3D display of MR images coincided well with that identified by functional images. 3D display of MR images was also useful for detecting the relationship between the tumor and the primary motor cortex. Intraoperatively, the central sulcus was confirmed by the finding of phase reversal of cortical somatosensory evoked potential, and this corresponded with the preoperative identifications by 3D display and by functional mapping. The primary motor cortex was stimulated electrically, and MEP (corticospinal evoked potential) was continuously monitored during surgery using electrodes inserted in the cervical epidural space. The amplitude of direct waves of MEPs during surgery was maintained above half of that recorded at the beginning of tumor removal, and all patients showed preservation of preoperative motor function. These results suggest that preoperative identification of precentral gyrus and intraoperative MEP monitoring provide useful information for preserving motor function in patients with gliomas near the primary motor cortex.

Auditory evoked magnetic field (AEF) is known to be suitable to separate left and right hemispheric activities while auditory evoked potential is not. To evaluate cortical auditory function in ten patients with temporal lobe gliomas, we measured AEF for monaural tone stimuli using a helmet-shaped 66-channel MEG system. Latency of the N 100 m, the most prominent peak with a latency around 90 ms, was measured in the hemisphere contralateral to the stimulus onset. In five patients, the N 100 m latency was within our normal range (mean +/- 2 s.d.). In these five cases, tumor was located in the anterior or the inferior part of the temporal lobe. We observed significant delay of the N 100 m latency in four patients and disappearance of the N 100 m in another patient. In the later five patients, tumor extended to the superior and posterior part of the temporal lobe. AEF can be used to evaluate cortical auditory function noninvasively in cases with temporal lobe gliomas.

Examination was made of the effects of nilvadipine on membrane potential in cultured neuroblastoma-glioma hybrid NG108-15 cells using the current clamp method. The NG108-15 cells line differentiates into neuronal cells following the addition of 1mM dibutyryl cAMP to the culture medium. This agent (nilvadipine) was found to inhibit both sodium and calcium current on the cell membranes of differentiated NG108-15 cells. The inhibitory effect was reversible in a dose-dependent manner between 10 and 100 microM. A substantial washing-time with normal saline, over 20 minutes, was needed for complete recovery from inhibition. The higher the concentration of nilvadipine, the more suppressive was the action on the membrane potential. A higher dose of nilvadipine, 100 microM, caused the disappearance of the peak membrane potential. This effect appeared irreversible, when cells were incubated in the presence of 100 microM nilvadipine for a longer time. Nilvadipine may thus exert inhibitory effect on the electrophysiological activity of neuronal cells, especially the calcium current of the membrane.

The effect of enalaprilat on the membrane potential of cultured neuroblastoma-glioma hybrid NG108-15 cells was investigated using the current clamp method. The NG108-15 cell line characteristically differentiates into neurons after addition of 1 mM dibutyryl cAMP to the culture medium. First it was found that enalaprilat inhibits both sodium and calcium currents in the cell membrane of differentiated NG108-15 cells. At concentrations between 10 and 100 microM, this inhibitory effect was reversible and transient, and occurred in a dose-dependent manner. Prolonged washing with normal saline (> 20 min) was needed to completely reverse the inhibitory effect of enalaprilat. The higher the concentration of enalaprilat, the greater its suppressant action on the membrane potential, and at high concentrations (100 microM), enalaprilat caused the peak membrane potential to disappear. When cells were incubated with enalaprilat, 100 microM, for longer periods, however, this inhibitory effect appeared to become irreversible. These findings suggest that enalaprilat has an inhibitory effect on the electrophysiological activity of neurons especially on membrane calcium currents.

Neuropeptide Y (NPY) was continuously administered to Wistar rats in the normal and glioma bearing conditions intracarotidly via the external carotid artery and local cerebral blood flow (LCBF) was measured by a [14C] iodoantipyrine technique. In the normal rats, the LCBF at the injecting side of NPY markedly reduced in 2 minutes after beginning of drug administration. In glioma-bearing rats, LCBF in the cerebral cortex and caudate nucleus reduced to the same level as normal rats. However reduction of LCBF in the tumor was not significantly different from that of ipsilateral cortex and caudate nucleus. The results of this study suggest that flow moduration by NPY injection increases delivery of intra-carotid administered anticancer drugs to the brain tumor with concomitant decrease of neurotoxicity to the normal brain.

The changes of cerebral blood flow (CBF) and metabolism of normal brain tissue after surgery, radiation, and chemotherapy in brain tumor patients were measured by positron emission tomography (PET). The subjects consisted of 6 men and 3 women, and were from 11 to 62 years old. Those were four patients with glioblastomas, one patient with malignant oligodendroglioma, one patient with astrocytoma grade II, one patient with astrocytoma grade III, one patient with pontine glioma, one patient with pineal germinoma. Seven patients were operated and pathohistologically diagnosed. Two patients with pineal germinoma and pontine glioma were not operated and radiologically diagnosed. Of 7 operated patients, first PET was performed before operation in 3 patients, and from 10 to 16 days after operation in 4 patients. Following first PET, the patients were treated with irradiation (1 case), or with both irradiation and chemotherapy (8 cases). The total radiation dose for tumor was from 59 to 61 Gy distributed in a period of 6-8 weeks. Whole brain irradiation was performed up to 30 or 40 Gy, with a remaining dosimetry (20-30 Gy focused on the tumor field. Chemotherapy consisted of intravenous administration of ACNU and oral administration of FT-207. Second PET was performed 1 month after therapy (9 cases), and third PET was performed from 4 to 24 months after therapy (6 cases). Fourth PET was performed in 2 patients (22 and 35 months after therapy), and fifth PET was performed in one patient (35 months after therapy).(ABSTRACT TRUNCATED AT 250 WORDS)

Etoposide delivery to 9L gliosarcoma model in Fischer 344 rats was evaluated. Etoposide 2 mg/body was given intravenously (IV) or intracarotidly with (IHIC) or without (IC) intravenously administrated angiotensin II. Mean etoposide concentration of tumors was 5.08 micrograms/g for IHIC group, 2.27 micrograms/g for IC group and 0.70 micrograms/g for IV group. The difference in etoposide concentration between IHIC group and IV group was statistically significant (p less than 0.05). In addition, etoposide concentrations of the normal brain tissues were lower than concurrent plasma concentrations in all groups. The etoposide concentration was increased in the tumor and very low in the normal brain tissues in Fischer 344 rats with 9L gliosarcoma by induced hypertension with angiotensin II. These studies might suggest that intraarterial chemotherapy by induced hypertension with angiotensin II was useful on treatment of malignant brain tumors.

A high resolution PET-HEADTOME III has been employed to quantitate regional cerebral hemodynamics and metabolism in gliomas using O-15 and 18FDG tracers, and to evaluate histological malignancy preoperatively. Hemodynamic and metabolic indices of regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), oxygen consumption (rCMRO2), oxygen extraction (rOEF), and glucose consumption (rCMRGl) were studied on thirteen preoperative gliomas involving one recurrent case. Regions of interest (ROIs) on PET were placed over the corresponding lesions in CT scans. In high grade gliomas, ROIs were also focused on the corresponding parts of central low density area, contrast enhanced area, and peritumoral low density area. rCBF and rCBV were variable and unrelated in both low and high grade gliomas. rCMRGl values were 5.99 +/- 3.99 mg/100 ml/min for high grade gliomas, and 3.01 +/- 0.48 mg/100 ml/min for low grade gliomas. Lesions with high uptake of radioisotope were proved to be high grade gliomas. lesions with low uptake being low grade gliomas. In comparison with the contralateral gray matter around the sylvian fissure, rCBV was significantly higher(p less than 0.02) in high grade gliomas, and rCMRGl was lower (p less than 0.05) in low grade gliomas. rCMRO2 and rOEF values were reduced markedly (p less than 0.01) in both low and high grade gliomas. These results support that anaerobic glycolysis increased with malignancy in the metabolism of gliomas. The hemodynamics and metabolism of central low density area and peritumoral low density area reflect the pathophysiological state of necrosis and edema respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to know the characteristics of frontal and parietal SEP components following median nerve stimulation, 25 patients with unilateral cerebral lesions above the thalamus were examined, and their SSEPs were carefully compared with the clinical and radiological findings. In 10 normal subjects, there were three cortical components of the frontal SEPs (P 20-N 28-P 44) and four those components of the parietal SEPs (N 18-P 22-N 26-P 42). In patient's group, central conduction times (CCTs) between components P 13 and each cortical component were measured and the latency differences between normal side and affected side were calculated. When the latency differences increased over 3 S.D. from the mean of the control values or the some cortical components disappeared, they were regarded as abnormal. According to the combination of the abnormalities in frontal and parietal SEPs, three groups were classified as follows: group 1; frontal and parietal SEPs were normal (n = 10), group 2; frontal and parietal SEPs were both affected (n = 10), group 3; parietal SEPs were affected but frontal components were preserved in normal range (n = 5). CT scan showed that the region from internal capsule to cortex around the central sulcus remained intact in the patients of group 1, while this region was involved in various degrees in all cases of the group 2. In patients of group 3, frontal or parietal regions were variously affected. Both the motor and sensory functions were mainly intact in group 1, and disturbed in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant transformation in tumors is characterized by changes in cell surface components such as glycolipids and glycoproteins and is determined by the sialic acid content of the glycoconjugates. Our purpose was to investigate whether or not a similar change occurred in the brain tumor cells during malignant transformation. Change in the electrical charge of the cell surface was studied by means of cell electrophoresis. Experimental cell lines of rat gliomas and fibroblasts were cultured and compared for electrical charge by cell electrophoresis. Four various grade gliomas and three meningiomas from human subjects were cultured and compared for electrical charge by cell electrophoresis. Free flow electrophoresis (Elphar Vap 5) was used because it characteristically does not interfere with the use of the cells for biochemical and biological studies following electrophoresis and because it also allows the possibility of subsequent cell culture. The rat glioma cells had lower electrical charges than the fibroblasts, and the human malignant brain tumor cells exhibited lower electrical charges than the benign tumor cells. These findings suggest a lower sialic acid content in malignant than in benign tumors and agree with theories which postulate a decrease in sialic acid content accompanying malignant transformation. This differentiation between benign and malignant tumors was made on the basis of the cell surface electrical charge and could be used for clinical diagnosis and treatment.

A high resolution positron emission tomography (PET), HEADTOME III, has enabled us to visualize heterogeneous parts, i.e. viable, necrotic, and edematous portions in malignant gliomas, and to quantify regional hemocirculation and metabolism of the tumors using 15O and 18F-fluorodeoxyglucose tracers. Hemocirculatory and metabolic indices of regional cerebral blood flow (rCBF), blood volume (rCBV), oxygen extraction fraction (rOEF), oxygen consumption (rCMRO2) and glucose consumption (rCMRGl) were studied in eight patients with untreated malignant gliomas. Regions of interest (ROIs) in PET images were focused on lesions corresponding to contrast enhancing areas, central low density areas of the tumors, and peritumoral low density areas in CT scans. In the viable portion of the gliomas, rCBV (5.20 +/- 1.18ml/100ml, mean +/- SD, n = 8) was significantly higher than that of the contralateral gray matter (p less than 0.05), which is suggestive of high vascularity; rOEF (0.36 +/- 0.16) and rCMRO2 (1.66 +/- 0.45ml/100ml/min) values markedly decreased (p less than 0.05, p less than 0.01). On the other hand, rCBF (36.3 +/- 13.0ml/100ml/min) and rCMRGl (5.94 +/- 1.15mg/100ml/min) were similar to that of the contralateral gray matter. A relative dissociation between oxygen and glucose metabolism indicates anaerobic glycolysis in the energy metabolism of malignant gliomas. In the central low density area, rCBF, rCBV, rOEF, rCMRO2, rCMRGl values decreased significantly from the viable portion and the contralateral gray matter. rOEF was markedly reduced in the central low density area as compared with that of the peritumoral low density area. The rOEF reduction indicates that oxygen metabolism of gliomas is the first to fail, accompanied by autoregulatory impairment of vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood flow of transplanted intracerebral rat gliomas was measured before and after a constant I.V. infusion of angiotensin II-induced arterial hypertension using hydrogen clearance method. The brain tumor model was produced in syngeneic Wistar-King-Aptekman male rats by stereotaxic inoculation of ethylnitrosourea-induced glioma cells (KEG-1). Induced hypertension by angiotensin II infusion resulted in a significant increase in tumor blood flow compared with control levels (P less than 0.001). In addition, the therapeutic effect of administration of 3-[(4-amino-2-methyl-5-pyrimidinyl) ethyl] -1-(2-chloroethyl)-1-nitrosourea (ACNU) during angiotensin II-induced hypertension was evaluated. At 12 days after implantation, tumor-bearing rats were administrated angiotensin II as the mean blood pressure reached 150 mmHg, followed by ACNU injection, maintained the same blood pressure for 20 minutes. ACNU with induced hypertension group showed a median survival time of 27.0 days, which was significantly (P less than 0.02) longer than that of ACNU alone (22.0 days). It is therefore suggested that chemotherapy with angiotensin II-induced hypertension has a enhancing effect on chemotherapy for improving the drug delivery to tumor tissue by a increased tumor blood flow.

In order to evaluate physiological significance of F-wave in the diagnosis of spasticity, 10 patients with intracranial mass lesion who did not show clinically lateralizing evidence especially in DTRs were examined and the data were compared with the results obtained from 10 other normal subjects. F-wave was recorded from thenar muscle with supramaximal stimulation to the median nerve at wrist. Latency and amplitude of F-wave failed to show any significant difference in patients compared with normal subjects both on affected sides, however, frequency of F-wave was found to be significantly higher on affected side except for 2 cases who had a mass lesion in occipital lobe in one case and the other was in the state of diaschisis due to recent hemorrhage in the parietal tumor. The site of lesion was carefully determined with CT scan and it was concluded that the F-wave could be detected quite in early stage of intracerebral mass lesion if the process had affected to internal capsule or cerebral peduncle under indirect mass effect such as cerebral edema. On the contrary, it was interesting to note that the mass with no affection to the premotor cortex likely showed higher frequency of F-wave on the ipsi-lateral side of lesion. As the conclusion, F-wave was found to have advantage in the diagnosis of spasticity in the early stage of illness and more accurate information on spasticity could be obtained compared with T or H-wave.

The vascular permeability of 50 brain tumors of various kinds was examined by means of dynamic CT. The degree of the vascular permeability within the tumor was evaluated according to the theoretical basis that the regression of the time-density curve after the peak to the base line became less in accord with the increase in vascular permeability. The time-density curves obtained from dynamic CT were classified into the following four types. Type 1; This type shows a similar pattern to normal brain tissue and is thought to reveal the normal vascular permeability. Type 2; this type shows intermediate pattern between type 1 and type 3. And the vascular permeability is thought to have been moderately increased. Type 3; This type shows the flattening or gradual increase in the time-density curve after forming the peak. The vascular permeability is thought to have increased markedly. Type 4; The peak of the time-density curve is lower than that of the white matter. This type of tumor is regarded to be least vascularized. All tumors except for gliomas and AVMs showed type 2 or 3 and their vascular permeability was thought to be increased. Most of the gliomas showed type 2 or 3, although some gliomas showed type 1 even in the lesion with positive contrast enhancement. In the lesions of such cases, it was thought that the vascular permeability was not affected significantly, so that blood brain barrier modification therapy by intraarterial mannitol infusion may be quite effective. All AVMs showed type 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood flow and glucose metabolism of the tumors and perifocal edematous tissues were evaluated using positron emission tomography (PET). Thirty-one brain tumor cases were investigated 12 non glial tumors (9 meningiomas and 3 metastatic tumors) and 19 gliomas (these were classified in 5 astrocytomas, 7 anaplastic astrocytomas and 7 glioblastomas, according to the malignancy). The diagnosis were confirmed pathologically in 30 cases. Cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), oxygen extraction fraction (OEF) and cerebral blood volume (CBV) were measured by O-15 labeled gases inhalation methods. Cerebral metabolic rate for glucose (CMFglu) were measured by F-18 Deoxyglucose intravenous injection method and calculated by Hutchins's formula. The rate constant (ks) and lumped constant (LC) used in this study were the same as those published by Phelps et al. in 1979. The blood flow and glucose metabolic rates of tumors were measured by the same methods. The results were as follows: 1) Meningiomas showed very high blood flow and blood volume with a wide range. The OEF and metabolic rate for glucose (MRglu) values were very low. 2) Metastatic tumors showed the low values of blood flow, metabolic rate for oxygen (MRO2) and OEF. 3) The blood flow and MRglu values on gliomas were varied with no significant differences between the three subgroups. On the other hands, as the malignancy of the glioma increased, a statistically significant increase in blood volume and a decrease in OEF were noted. 4) The OEF values from the various types of tumors studied were significantly lower than those obtained from the normal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional cerebral blood flow of rat brains bearing ethylnitrosourea induced glioma of various size was investigated with 14C-antipyrine autoradiography. In the small tumors (less than 2 mm in diameter), blood flow was uniformly reduced when compared to the adjacent brain. Even in tiny tumors (0.3-0.4 mm in diameter), reduction in blood flow was evident. In the medium (2-4 mm in diameter) and large (greater than 4 mm in diameter) tumors, the blood flow increased in the viable center of the tumor and decreased in the necrosis and peripheral edge. High blood flow in the viable center may be attributable to the neovascularization of the tumor. Blood flow in the brain tissue adjacent to medium and large tumors was lower than control brain tissue probably due to local edema. This reduction in blood flow may be partly attributable to the appearances of the focal neurologic deficits. The result obtained may provide some information about growth regulation of glioma and also pharmacokinetic delivery of chemotherapeutic drugs to the malignant brain tumors.

Capillary permeability of rat brains bearing ethylnitrosourea induced rat glioma was measured with quantitative autoradiography. In the small tumors (less than 2mm in diameter), no changes in capillary permeability was noted. When tumors became larger and neovascularization of the tumor occurred, increase in capillary permeability was evident. This change was more prominent in the center of the tumor than in the periphery. In the large tumors, the capillary permeability was markedly increases, and the value was similar to that in the choroid plexus. This indicates that blood-brain barrier(BBB) completely disappeared in the large tumors. This BBB change may be the main cause of tumor induced brain edema. The data also provide the information about pharmacokinetics of water soluble drugs in the brain tumors.

The regional cerebral blood flow (CBF) was determined on seventeen patients with brain tumors. Ring type single photon emission CT (SPECT) was used following intravenous injection of 133Xe. Case materials included eleven meningiomas and six malignant gliomas. Evaluation was performed with emphasis on the following points; Correlation of the flow data within tumors to the angiographic tumor stains, Influence of tumors on the cerebral blood flow of the normal brain tissue, Correlation between degree of peripheral edema and the flow data of the affected hemispheres. There was significant correlation between flow data within tumors and angiographic tumor stains in meningiomas. Influence of tumors on cerebral blood flow of the normal tissue was greater in meningiomas than in gliomas. There was negative correlation between the degree of peripheral edema and the flow data of the affected hemisphere. It has been concluded that the measurement of CBF in brain tumors is a valuable method in evaluation of brain tumors.

Anticipating to get some new informations about the cerebral circulations of the comatous patients, two kinds of radioisotopic techniques were combined and applied to twelve unconscious patients of various etiologies. The first step was the conventional gas clearance method using xenon 133 as the indicator. Regional cerebral blood flows were measured at the six areas over each hemisphere. Immediately following this procedure, about 150 muCi of I-131 MAA (I-31 macroaggregated human serum albumin) were injected into internal carotid artery via the same catheter inserted already for the first procedure. Radioactivities of the head and lungs were measured and the relative shunt flow was calculated based on the formula already described elsewhere. Profil scanning of the whole body of the patient was also performed after the intracarotid injection of I-131 MAA. Consciousness states of the ten patients were all severely damaged and causes of the disturbed consciousness were various, including 5 of subdural hematoma, 2 of occlusive cerebrovascular disease, 2 of brain tumor and 1 of ruptured intracranial aneurysm. This investigation revealed the following results; 1) In all patients, regional cerebral blood flows were shown decreased over all areas detected. The regional cerebral blood flows could not be increased by 5% carbon dioxide inhalation, suggesting angioparalysis in these areas. 2) Graphical analysis of the clearance curves revealed triphasic flow pattern in rCBF in four cases. In three cases among the four, the intracarotid injection of I-131 MAA showed the radioisotope labelled particles were captured not only in the brain, but also in the lungs and the relative shunt flow calculated increased up to twice as much as normal controls. It indicates that some of the particles larger than the cerebral capillary size passed through the brain and were captured by the capillary net work of the lungs. From the above described data, it might be concluded that the initial rapid component of triphasic flow pattern in rCBF measurement does not represent the hyperemia of luxury perfusion of metabolic origin, but arteriovenous shunting blood flow, probably, through the precapillary thoroughfare channels which have been anatomically demonstrated by Hasegawa et al.