Six autopsy cases of craniopharyngioma were examined macro and microscopically. The causes of death were as follows: four cases died of recurrence, one of postoperative bleeding and one of sudden herniation due to the tumor. In four cases the tumors were located behind the chiasm with large cyst expanding in the postero-superior direction. In the remaining two cases solid tumors filled a large cyst in the third ventricle. Internal hydrocephalus was seen in all cases.
The large cystic walls were composed of two layers. The inner layer was tumor tissue and the outer layer was gliosis. The mean widths of the tumor layer and gliosis were 0.2 mm and 0.5 mm, respectively. The mean distance between tumor layer and adjacent hypothalamic nuclei was 2 mm. Usually the tumor wall and gliosis firmly adhered to the adjacent brain tissues. Only in the case of one child, the connection between the cyst wall and brain tissue appeared to be very loose. There were thin layers of hypervascularization in the surrounding brain tissue. These vessels were 20 to 500 microns in diameter.
The results indicate that a complete removal of the tumor, particularly the large cystic wall, produces severe damage to the surrounding brain structures. For the treatment of the large cyst, intermittent aspiration of the cystic fluid and intracystic irradiation and chemotherapy (using Bleomycin) are useful.

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In spite of the emphasis on the clinical importance of plateau waves, the precise mechanism of the plateau waves is still obscure.
Continuous intracranial pressure recording is performed in patients with normal pressure hydrocephalus after rupture of an intracranial aneurysm and in a patient with a pontine hemorrhage. Recordings in these patients showed frequent acute transient rises of intracranial pressure resembling the plateau waves. These transient intracranial pressure elevations developed from a low basic level of intracranial pressure and the height of each waves usually ranged only between 20 and 40 mmHg, i.e., the waves seen in these patients were smaller than those seen with increased intracranial pressure from brain tumors. Nevertheless, they had characteristics of plateau waves.
The cerebral circulation was studied with carotid angiography and by the Xenon 133 clearance method. With the clearance method, a decrease in the cerebral blood flow was revealed in normal pressure hydrocephalus. A slow circulation time determined with angiography was shown in a pontine hemorrhage patient.
From such experience, we speculated the following possibility for development of the plateau waves. A marked reduction in cerebral circulation may produce hypoxic metabolites of the brain, and these in turn induce dilatation of cerebral vessels responsible for producing the plateau waves.

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It is well known that acute brain swelling is caused by extreme vasoparalysis due to loss of autoregulation. Although the basic mechanism of cerebral autoregulation is still controversial, metabolic, chemical, myogenic and neuronal factors have been considered and examined experimentally. The hypothalamus is stated by some workers as a major neuronal aggregate participating in autoregulation of the cerebral circulation.
In the present experimental study, neuronal components rostral and caudal to the hypothalamus were examined to determine if they were involved in the autoregulation mechanism.
Topical application of epinephrine to either the sigmoid, orbital, or cingulate gyrus or cerebellar cortex of a cat caused the systemic blood pressure rise temporally, but when application was performed to other cortices, no change in blood pressure was observed. This phenomenon disappeared when the hypothalamus was destroyed. With the model of acute swelling caused by ischemia and the balloon compression method, application of epinephrine to the sigmoid gyrus caused a considerable decrease of intracranial pressure concomitant with an increase in cerebral blood flow. However in an animal with acute brain swelling with destruction of the hypothalamus or transection of the spinal cord at the Th₂ level, no improvement of cerebral vascular tonicity was observed. It was suggested that the neuronal pathway, the cerebral cortices and the cerebellar cortex converging on the hypothalamus and descending to the spinal cord at Th₂ level play an important role in cerebral vascular tonicity.

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Ventricular fluid concentrations of homovanilic acid (HVA) and dopamine (DA) were measured in 20 patients with the various types of hydrocephalus (seven with congenital hydrocephalus, five with aqueduct obstruction, five with secondary hydrocephalus after subarachnoidal hemorrhage and three with postoperative hydrocephalus of head trauma or a brain tumor.
Probenecid loading test was also performed. By estimating changes in HVA, two types of hydrocephalus were differentiated (responder and non-responder).
HVA concentrations were high in cases with acute hydrocephalus and responded well to probenecid loading. No response was observed in other types of hydrocephalus.
In cases of acute aqueduct obstruction, the preshunting value of HVA was high and did not respond to probenecid loading. This result suggests that there is an active transport system for the acid metabolites, particularly HVA in man, in the choroid plexus of the fourth ventricle.
When compared with the acute stage of hydrocephalus, ventricular dopamine concentrations were lower in the chronic stage of congenital hydrocephalus, and hydrocephalus secondary to a subarachnoidal hemorrhage or brain tumor.
These results show that HVA excretion into the cerebrospinal fluid is lower in such hydrocephalic patients and that in some cases, administration of L-DOPA could be reasonably effective in ameliorating clinical pictures.

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CT-cisternography performed on 35 neurological cases with spinal administration of meglumine iocarmate (Dimer-X) or metrizamide (Amipaque) was analysed digitally with a series of our original programs developed using the system computer of an EMI-1010 scanner. RI-cisternography with In-111 was performed for comparison in four of these cases, within 2 weeks after CT-cisternography.
Since the attenuation coefficients (CT-No.) correlated well with the concentration of iodine dye in CSF, temporal changes of the average CT-No. in geometrically defined areas (ROI) within lateral ventricles and various cisterns present useful information for the differential diagnosis of pathological CSF kinetics. This density method, however, may be available only for cases with marked dilatation of the CSF space which allows placing of large ROIs of sufficient size to compensate for a wide variation of CT-No. due to statistic errors of radiation and excluding the partial volume effect of bone or brain tissue.
The principle of our weight method is to analyze the weight of dye contained in the CSF of each slice. The CT-weight, and integrals of (CT-No.)×(pixel No.) and of CSF space of each slice were assumed to be parallel to the weight of the dye. This was calculated for a certain range of CT-No., excluding data involved in the partial volume effect of bone or air and was plotted on a logarithmic scale.
A close similarity was observed between the temporal changes of total CT-weight of dye and total counts per minute in RI-cisternography in the same case.
Total CT-weights of the upper and lower halves of slices show characteristic patterns of hydrocephalus, ventricular reflux of dye, impairment of absorption, etc, especially when combined with the temporal changes in CT-weight of the normal CSF range.
Digital analysis of CT-cisternography gives valuable information for objective and quantitative evaluation of the pathological process of CSF kinetics.

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9L tumor cells were transplanted into the left lobe of the brain in Fischer 344 rats. In one group, the brain tumor was grossly removed from the rats microsurgically on the 14th to 18th day after transplantation (operated group). These rats were decapitated 1, 6, 24, or 48 hr after surgery, having received 250 μc ³H-thymidine (³H-TdR) intraperitoneally 30 min before sacrifice. Both frontal lobes (operated left side and non-operated normal side) were removed and DNA was extracted using a modified Schmidt-Thannhauser method. ³H activity was then measured with a liquid scintillation spectrometer (LSC) to determine the ³H-TdR uptake into the DNA of the remaining tumor cells. A second group of rats which did not undergo tumor removal (non-operated group) received the same dosage of ³H-TdR 30 min before decapitation; the brain was removed postmortem, the tumor was then removed from the brain, and the same extraction procedures and uptake measurements were performed. For comparison of the two groups, the relative increased radioactivity (RIRA) in the brain was determined as a ratio of the counts per gram (cpg) in the tissue of the left lobe, from which tumor was removed, to the cpg in the normal right lobe. RIRA in the non-operated group was 5.7, indicating that the ³H-TdR uptake of tissue in the left lobe, which contained some remaining tumor cells, was 5.7 times higher than that in the normal lobe. In the operated group, RIRA was 1.5 and 1.7 respectively in the rats sacrificed 1 and 6 hr after surgery, which indicated that remaining tumor cells had virtually ceased to proliferate; however, in rats sacrificed 24 hr after surgery, RIRA was 4.9, which approached the same level as that in the non-operated group. In the rats sacrificed 48 hr after surgery, RIRA was as high as 9.5. These results showed that for at least 6 hr after surgery there was almost no proliferation, but by 24 hr after surgery, active division of the remaining tumor cells had resumed. To confirm both ³H-TdR perfusion in the tissue and tissue permeability, a third group consisting of operated rats received ³H-TdR and ¹⁴C-urea before being decapitated. Both frontal lobes were lyophilized and activities of the ³H and ¹⁴C were measured with LSC. During an observation time of up to 48 hr, there was no significant fluctuation in the level of available ³H-TdR in tissue or in the tissue permeability, as indicated by ¹⁴C-urea space.

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Valiabilities in labeling indices (LI) by ³H-thymidine (TdR) were analysed using the 9L rat brain tumor model with the following procedures.
1. Continuous labeling was carried out delivering ³H-TdR by means of a minipump implanted in the rat flank. Tumors were excised 2, 6, 12, 18, 24, 30 and 34 hours after the implantation of the pump. Differences in LI were computed in terms of a) geometry of the tumor (from the periphery to the center of each tumor), b) time interval of infusion and c) population of the tumor cells in each unit area (4.84×10⁴ u²).
2. Other groups of rats with tumors were infused firstly with ³H-TdR and secondly with ¹⁴C-TdR 0, 30, 60 and 180 minutes later, and were killed 5 minutes after the ¹⁴C-TdR injection. Several normal brain tissues and 4-5 pieces of tumor (ca. 20 mg) were excised and lyophilized and activities of ³H and ¹⁴C were measured with a liquid scintillation counter.
3. DNA from tumor and normal brain, double labeled as above, was extracted by the Schmidt-Thannhauser method. In this group, the rats were sacrificed 30 minutes after administration of ¹⁴C-TdR.
LI's remained less than 20% up to 12 hours after implant of the pump, but the LI's increased to 43% in 18-24 hours and decreased thereafter. There were no differences in LI obtained from the peripheries and central part of each tumor. Also, no correlation was observed between the LI and geometry or population of tumor cells per unit area (400-1, 000 cells/unit area).
Lyophilized normal tissue and tumor pieces showed variable amounts of ³H and ¹⁴C activities when they were normalized to counts per gram. However, the ratio ³H activity to ¹⁴C activity was constant throughout the specimens obtained from each rat.
DNA extracted from normal brain showed almost no ³H and ¹⁴C uptake, whereas DNA extracted from tumors showed variable uptake of each isotope when compared in terms of counts per gram. However, ³H/¹⁴C values were fairly constant in pieces obtained from each tumor.
These results were interpreted to indicate that variabilities of LI in tumors were assumed to represent variabilities in the actual proliferating population in each tumor and were not due to abnormalities in availability of exogenous TdR caused by abnormal blood flow or permiability. Thus, average LI's of such a tumor should be computed by screening a considerable number of tumor cells.

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The anti-tumor effect of ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride], a new nitrosourea derivative, was studied in Rous sarcoma virus-induced transplanted mouse malignant gliomas.
1) The survival time of mice with intracerebrally transplanted tumors was markedly prolonged by a single intraperitoneal dose of ACNU : the mean survival times were 26.2 in control mice, and 36.8 days in mice given doses of 10 mg/kg. Larger doses of 20 or 40 mg/kg produced large numbers of long-term survivors (more than 100 days). Similar effects of ACNU were noted in mice with subcutaneously transplanted tumors: the mean survival times were 27.8 in control mice, 30.2 in mice given doses of 10 mg/kg, 34.4 in mice given doses of 20 mg/kg, and 43.0 days in mice given doses of 40 mg/kg. The results showed a dose dependent anti-tumor effect on this experimental brain tumor within a dose range from 10 to 40 mg/kg.
2) When the total dose was kept at 40 mg/kg, a single administration of ACNU was found to be more effective than fractionated administration for the inhibition of subcutaneous tumors. The loss of body weight was more evident in mice given a single dose than in mice with fractionated administration.
3) The intraneoplastic injections were more effective in the median survival time than the intraperitoneal injections (p<0.05) when the animals were given the drug at 2 mg/kg/day for 7 days.
4) Combined therapy with ACNU and irradiation caused a greater anti-tumor effect than the additional effect on the subcutaneous tumors. Simultaneous combined therapy using both was much more effective than combined therapy in which irradiation was performed 2 or 3 days after ACNU administration.
5) Combined therapy with ACNU (10 mg/kg × 1) and PSK (300 mg/kg×10), a non-specific immunopotentiator, showed prolongation of the survival time of mice with subcutaneous tumors.
6) Uptake and distribution of ¹⁴C-ACNU in intracerebral and subcutaneous tumors were investigated by radioactive assay. The radioactivity in the intracerebral tumors was approximately two times higher than that in the normal brain tissues and was similar to that in subcutaneous tumors.

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