The authors' attitudes toward the diagnosis and treatment of pineal tumors have been dramatically changed in recent years by several important factors: (1) Histological classification has been well established by introduction of the concept of germ cell tumors including germinomas and a variety of teratomas. (2) The value of radiotherapy for germinomas has been firmly established. (3) Operative procedures have been refined by introduction of microsurgical techniques. (4) Preoperative diagnosis has been made easier and more accurate by development of CT and better techniques of cerebrospinal fluid (CSF) cytology, and by the discovery of tumor cell markers such as alphafetoprotein (AFP) and human chorionic gonadotrophin (HCG).
One hundred and thirty-four cases of pineal tumors were experienced in the Department over a period of 38 years from 1941 through 1979, which corresponded to 4.9% of all intracranial tumors treated in the same period. There were 82 cases of germinomas (28 histologically verified and 54 histologically non-verified), 23 teratomas, seven pineoblastomas and 22 others. Among the 82 germinoma cases, there were 71 males and 11 females, with a marked male preponderance. A male preponderance was also found for teratomas. It is well known that germinomas are extremely radiosensitive and some of them are radiocurable. The 5-year survival rate of 35 cases of pineal germinomas treated by radiotherapy was 73% and the 10-year survival was 60%, as compared to 9.0% and 5.0%, respectively, in 22 cases of pineal germinomas without radiotherapy. In the cases of teratomas, however, radiotherapy was not effective and the general prognosis was poorer than in germinomas. Surgery is still the treatment of choice in teratomas and occasionally, long-term survival was obtained after total removal of well differentiated teratomas.

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Excessive accumulation of CSF was found in the supratentorial intracranial extracerebral space of many infants by means of computerized tomography. CT head scanning was carried out 220 times in 153 clinically normal infants during the last year. The accumulation was most notable in the bifrontal convexity space, bitemporal convexity space, interhemispheric cistern, suprasellar cistern and Sylvian cistern.
The space was not remarkable in new-born infants, but soon began to expand gradually until the infant became four months of age. The space was most remarkable four to seven months after birth. Then, the space decreased in volume gradually and disappeared between twelve and eighteen months of age, without any developmental, neurological or psychological troubles. Accidents during the fetal or delivery periods did not notably influence the with of the space.
This phenomenon may be regarded as a physiological state in early infancy.

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In a series of 161 consecutive patients with severe closed head injuries which were rated 8 or less on Glasgow Coma Scale (GCS), 85 patients received barbiturates intravenously (i.e. thiamylal or pentobarbital) to protect against brain damage and control intracranial pressure (ICP). Thiamylal was given to 69 patients. The initial dose of thiamylal was 30 mg/kg and the maintenance dose was 3.20±0.16 (average±SE) mg/kg/hr for 2 ?? 7 days. Pentobarbital was given to 16 cases at a dose of 1.19±0.13 mg/kg/hr. Seventy-six patients who did not receive barbiturates were used as controls. These patients were controlled under moderate hyperventilation (PaCO₂ was between 25 ?? 30 mmHg and PaO₂ remained at 80 to 150 mmHg). Since barbiturate-coma was made it impossible to assess the neurological status, it was necessary to follow ICP, EEG and serial CT scans. All of these patients received pharmacologically high doses of beta-methasone. It was usually possible to obtain CT scans within one hour after admission. If necessary, osmotic agents were given and/or appropriate surgical procedures were performed. ICP was monitored in 34 patients of the barbiturate group using an epidural sensor or a subarachnoid catheter.
The mortality rate was 40% in the barbiturate group and 48.7% in the control group. The barbiturate group with GCS ratings of 3, 4, 5 or 6 showed a lower mortality rate than the control group with the corresponding GCS ratings, but these differences were not statistically significant. In GCS 3/4 group, mortality in the barbiturate group was 63.6%, whereas that of the control group was 89.7%. The difference was statistically significant (X²=5.69, P<0.02).
Barbiturate overloading might reduce the mortality in severe closed head injury patients.

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Thirteen cases of lumbosacral spinal lipoma were described with respect to neurological assessment, neuroradiological examination and follow-up results.
The age ranged from 3 days to 25 years, and 38% of the patients were less than one year of age. The sex distribution revealed a preponderance of females over males at a ratio of 8: 5. No family history of spinal dysraphism was noted. A semifluctant soft tissue mass in the lumbosacral area was found in all of the cases. Five patients had other skin abnormalities in the area of the mass. Neurological examination was normal in three patients and abnormal in 10 patients. The commonest neurological abnormalities were bladder difficulty and motor weakness.
Three patients were symptom-free until the age of 5 months to 5 years. In five out of 10 cases in which a certain neurological abnormality was found, a history of apparent progression was obtained. Plain X-rays of the spine showed evidence of spina bifida occulta in all of the cases. Myelography was performed in 11 patients and unanimously showed abnormalities. Water soluble contrast medium (Metrizamide) was used in six cases. Surgery was performed in all the patients and six lipomyelomeningoceles, four lipomeningoceles and three lipomas were encountered. All of the cases were followed up for 2 to 6 years, with a mean follow-up period of 3 years. Three patients who had had no neurological abnormalities before surgery remained free of deficits for 3-4 years of follow-up. In four out of five patients, progressive deterioration which had been noted before surgery was arrested, although neurological deficits could not be completely resolved. These fatty swellings were apparently benign but they commonly had a continuation passing deeply to connect with the spinal cord, filum terminale, or cauda equina which was liable to injury by traction during the course of growth or by pressure owing to the increase in fat content within the theca. The authors believe that early corrective surgery can prevent the onset or progression of neurological complications. It is wise to perform myelography even before there are any signs of neurological involvement, and any abnormality in myelography justifies early preventive operations. The authors advocate preventive surgery as essential treatment for this disease.

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Recently the authors investigated the therapeutic effects of specific and non-specific immunotherapies used as adjuvant therapy to surgical resection of malignant gliomas followed by ⁶⁰Co radiation therapy, and obtained some results suggesting the effectiveness of these therapies.
For the purpose of non-specific activation of cell-mediated immunity, the authors administered an immunopotentiator, OK-432, intramuscularly to 13 patients with intracerebral gliomas over a long period. Cell-mediated immunity of these patients before and during immunotherapy was investigated by means of various tests including delayed cutaneous hypersensitivity reactions against PPD and PHA, and lymphocyte and T-cell counts in the peripheral blood.
The following methods of specific immunotherapy were used in nine patients with malignant gliomas. Resection of the tumor was first carried out and a link between the space left after the tumor resection and the lateral ventricle of the lesioned side was produced provided that no malfunction would result from this procedure. An appropriate amount of autologous lymphocytes separated from the peripheral blood of the patient was repeatedly infused through a catheter inserted into the space left after the tumor resection, either before or after ⁶⁰Co irradiation therapy. When a recurrence of the glioma was found, resection of the recurrent tumor was again performed and a histopathological investigation of the tissue was carried out.
The average survival period of the nine patients who received the afore-mentioned specific immunotherapy was statistically compared by the Wilcoxson test with that of twelve control patients with glioblastomas who underwent only tumor resection followed by radiation therapy.
Cell-mediated immunity of patients with gliomas tended to be reinforced by non-specific immunotherapy.
Successive CT scannings of the head performed on patients who received specific immunotherapy revealed that the space left after the tumor resection appeared to be a low density area poorly demarcated from the surrounding brain tissue. With the lapse of time, the low density area became clearly demarcated and remained as it was, even though a tumor recurred in the surrounding brain. Histological observation revealed that the brain tissue adjacent to a space filled with CSF was covered with a thick fibrous membrane with abundant newly developed capillaries or sinusoid-like vessels. Recurrent tumors tended to be located beneath the membrane. Numerous foci of necrosis were actually observed in association with abundant lymphocyte infiltration, suggesting that there is a possibility of immunologically competent cells wandering into the tumor tissue through the newly developed vessels.
The average survival periods of patients with and without specific immunotherapy were 23 months and 10.3 months respectively. There was a statistically significant difference in the survival periods between the two groups (P<0.05).

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Fetal brain cells transferred to long-term cell cultures one hour after ENU treatment at a lethal dose (250 mg/ kgw) in vivo became neoplastic after the 18th serial in vitro passage, which was assayed by back transplantation into syngeneic CDF rats. This was preceded by characteristic morphological and biological changes of the cultured cells. During the early culture period, both ENU and buffer treated cultures exhibited monolayers of glial, epithelial and fibroblastic cells. In contrast to control cultures which died within 200 days in vitro, ENU treated fetal brain cells exhibited malignant transformation. The transformed cells (YE2-2) were glial cells with fine processes and they grew without contact inhibition to form pile-up foci. Electron microscopy showed abundant glial filaments in the cytoplasm.
Serological assay by the immune adherence test (IA) and anti-C₃ mixed hemadsorption test (C₃-MHA), and the qualitative absorption test were performed to analyze the cell surface antigens of the transformed cells. The C₃ MHA reactivities of two sera obtained from tumor bearing rats and immunized rats, were absorbed by autologous transformed cells but not by normal fetal brain cells. The result suggests that fetal brain cells obtained a new cell surface antigen in accordance with malignant transformation in vitro.

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It was previously proposed that spasmogenic activity of oxyhemoglobin was stronger than that of methemoglobin and that oxyhemoglobin induced marked and continuous vasospasms on the exposed basilar artery in the cat. Therefore, oxyhemoglobin may be one of the most important spasmogenic substances following subarachnoid hemorrhages. It was also reported that, due to autoxidation, oxyhemoglobin produced superoxide, and that lipid peroxidation induced by superoxide with an Fe-complex was inhibited by superoxide dismutase, catalase, 1, 4-diazabicyclo [2, 2, 2] octane (DABCO), etc.
In this experiment, the spasmogenic activity of oxyhemoglobin on the exposed basilar artery was reduced to that of methemoglobin by superoxide dismutase, catalase and DABCO. On the other hand, methemoglobin induced marked contraction of the arteries after the xanthine oxidase system, which is believed to be a superoxide producing system, was injected into the subarachnoid space together with EDTA-Fe and FeCl₃. The authors have therefore concluded that the strong spasmogenic activity of oxyhemoglobin is due to a change in reactivity of the artery which is affected by lipid peroxidation, induced by superoxide generated by autoxidation of oxyhemoglobin, on the cellular membrane of nerve-endings or smooth muscle of the artery.

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Ultrastructural and histochemical changes in experimental vasospasms were studied in 46 cats. Prolonged vasospasms of the exposed basilar artery were produced by continuous irrigation with a solution of serotonin (1—10 Mg/ml) or calcium gluconate (0.2 M). Vasospasms lasting for less than 10 hours were relieved by topical application of vasodilating agents such as ascorbic acid (25 mg/ml) and methylprednisolone (10 mg/ml). However, spasms continuing for more than 10 hours failed to respond to such treatment.
In the vessels responsive to vasodilators, aggregation of granules and vesicles in extracellular spaces of the media was revealed by electron microscopy. The electron density remained unchanged after treatment by 5-hydroxydopamine, while that of the vesicles in adrenergic terminals increased. The granules and vesicles morphologically resembled the adrenergic vesicles but were biochemically different from them. Necrotic changes in the vessel wall such as fragmentation of myofilaments were observed in the vessels unresponsive to vasodilators.
The potassium pyroantimonate staining technique demonstrated fine deposits within the nucleus, sarcoplasm, sarcoplasmic reticulum and mitochondria, and along the sarcolemma in normal vessels. It was confirmed by X-ray microanalysis and EGTA-chelation that they contained calcium. The deposits along the sarcolemma decreased in number in the lanthanum-loaded vessel walls, and it was confirmed that most of them were present on the outer surface of the sarcolemma.
Calcium deposits somewhat increased in number in the sarcoplasm of spastic vessels responsive to vasodilators, but the deposits along the sarcolemma remained unchanged.
The most characteristic change was that calcium along the sarcolemma disappeared in the spastic vessels unresponsive to vasodilators.
The morphological and functional changes in the arterial smooth muscle cells were discussed in relation to the timing of treatment of cerebral vasospasms.

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Effects of compression of the brain at various pressures were studied histopathologically and enzyme-histochemically. Sixty two adult mongrel dogs were used under general anesthesia with pentobarbital sodium. After craniotomy, the frontal lobe was compressed for an hour directly by a plastic disc 10 mm in diameter, which was connected to a spring.
(1) Degree of brain damage under various compression pressures. Eighteen dogs were divided into three groups. For each group, the brain was compressed with pressures of 60 mmHg, 100 mmHg and 240 mmHg respectively. The brains compressed with a 60 mmHg pressure showed vasogenic brain edema histopathologically. Those with a 100 mmHg pressure showed mainly softening and necrosis due to venous infarction and they were dominant in the white matter. The brains compressed with 240 mmHg demonstrated venous infarction and hemorrhagic infarction secondary to pericapillary diapedetic hemorrhage.
(2) Effect of subarachnoid hemorrhage on the compressed brain. In eight dogs, 1 ml/kg of autogenous blood was injected into the cisterna magna. Two days later, these dogs underwent brain compression under 240 mmHg of pressure. Histopathologically the brains showed no significant differences compared to the brains without subarachnoid hemorrhage which were compressed with the same pressure.
(3) Effect of cortical vein section on the compressed brain. In 12 dogs, bridging veins were sectioned before brain compression with 240 mmHg of pressure. Five of them showed macroscopic hematomas predominant in the white matter. Seven of them showed microscopic hemorrhage. In another five dogs, bridging veins were sectioned but compression was not performed. Two of them showed only scattered pericapillary hemorrhage without hematoma or infarction. The rest showed neither edema, infarction nor hemorrhage. These data demonstrated that disturbance of the venous return aggravated the degree of brain damage by brain compression, and suggested that bridging veins should be preserved whenever possible during any operation.
(4) Enzyme-histochemical changes were investigated with phosphorylase (P-Pase), glucose-6-phosphate dehydrogenase (G6PD), lactate dehydrogenase (LDH), alkaline phosphatase (Al-Pase). adenosine triphosphatase (ATPase) and cytochrome oxidase (Cyt. ox.). The infarcted area showed decreased activities of all these enzymes except LDH in some cases. Edematous and peri-infarctic areas demonstrated increased activities of P-Pase, G6PD and LDH in the astroglial cells, and increased Al-Pase in the capillary walls, but decreased activities of ATPase and Cyt. ox. in the astroglial cells. These enzyme-histochemical findings indicated increased aerobic glycolysis, disturbed metabolism in the mitochondria, and permeability changes in the astroglial cells and the capillary walls, mainly due to the impaired blood-brain barrier.
(5) Effects of therapeutic agents were investigated by the enzyme-histochemical technique in 19 dogs. Ten percent glycerol (5 ml/kg/day i.v.) reduced the activity of G6PD and increased the activity of LDH and ATPase. Glycerol seemed to be utilized to preserve enzyme activity and energy metabolism. Dexamethazone (2 mg/kg/day i.m.) increased the activity of LDH which could accelerate the glycolysis. Therefore it had the effect of improving the metabolism. Dimethyl sulfoxide (DMSO, 4 ml/kg/day i.v.) had no effect on the compressed brain. Histopathologically, however, these three agents had no effect on the infarcted brain.

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Twenty healthy mongrel dogs weighing 8 to 15 kg were used in this study. As an experimental model of cerebral infarction, the right common, internal, and external carotid arteries were dissected and silastic cylindrical emboli (diameter: 1.1 mm, length: 6-7 mm) were introduced through the right internal carotid artery to the right middle cerebral artery under pentobarbital anesthesia (25 mg/kg of body weight). The emboli reached the proximal portion of the right middle cerebral artery and occlusion of this site was obtained in each dog except for one case. Following this method, right hemispheric cerebral ischemic lesions were observed in 19 dogs.
CT scans (EMI 1010) were performed at an interval of a week after the occlusion of the artery. Low density areas were noticed in CT scans of 19 dogs. In 16 out of 19 cases, positive contrast enhancement (CE) was noted.
Five out of the 16 dogs had positive CE in the acute stage after the arterial occlusion and all of these five dogs showed typical hemorrhagic infarction histologically. There were marked hemorrhages and perivascular edema in the infarcted area microscopically. These findings suggested that the positive CE in the acute stage may be attributed to extravasation of contrast medium following opening or damage of the blood brain barrier (BBB) in the infarcted area.
Positive CE in the chronic stage was seen in the remaining 11 dogs. The positive CE appeared seven or more days after the surgery on the arterial occlusion. In these cases numerous new capillaries, macrophages and reticulin fibers were seen in the infarcted area microscopically. Evans blue solution was administered intravenously before sacrifice and marked extravasation of the dye was seen in the region where the positive CE was noted. Electron microscopically, numerous pinocytotic vesicles and microvacuoles were seen in the hypertrophic cytoplasm of the endothelium. However, no opening of the tight junction between the endothelial cells was seen. These findings suggested that the positive CE in the chronic stage was caused by extravasation of contrast medium by active pinocytotic vesicles through the newly formed vessels for scavenging infarcted cerebral tissue.

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