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The present study was conducted to reveal characteristic features of albino large rabbit (JW-AKT) which we formerly established a specific pathogen-free (SPF) colony. Body weights of JW-AKT rabbit at 52 weeks old was 5.7 ± 0.4 kg in males and 6.4 ± 0.4 kg in females. Weight of body, heart, lung and kidney in JW-AKT rabbit was significantly higher than in Japanese white and New Zealand white rabbits in both sexes. Though the body weight (BW) was rather lower in males, body length and brain weights tended to be higher in males than in females. Since body fat was significantly higher in females, what affects difference in BW is body fat, rather than the physical constitution of female JW-AKT rabbit. No critical sex difference was found in hematological parameters in JW-AKT rabbit. The results indicated that JW-AKT were about 1.5 times larger than the general laboratory rabbits with common properties in hematology. Thus, JW-AKT rabbit could be used as a novel SPF experimental animal model with some advantages in surgical experiments or collection of large amount of biological specimen.

A tumor-associated antigen RCAS1 (receptor binding cancer antigen expressed on SiSo cells) induces cell cycle arrest and apoptosis to a putative RCAS1 receptor (RCAS1-R) expressing cells such as T, B, and natural killer cells. Its expression is related with clinical poor prognosis of some malignant tumors. It is suggested that the expression of RCAS1 in tumor cells plays an important role in evasion from host immune system resulting tumor progression, invasion and metastasis. However, the mechanism of RCAS1 induced cell cycle arrest and apoptosis has not been clarified. In this study, we established a mouse L cell line transformed with tetracycline-induced rcas1 gene expression system and analyzed the RCAS1 functions. We showed that RCAS1 induced cytochrome c release and activation of caspase-3 for apoptosis. Moreover, we investigated cell cycle associated proteins and revealed that cyclin D3 decreased significantly and no change was seen in the expression levels of the other proteins. These results suggest that cyclin D3 is one of the key target molecules in the RCAS1-RCAS1-R signaling pathway.

Some gliomas are not noticeably enhanced on initial computer tomography (CT) scans. Such low-density non-enhancing gliomas have a relatively long period between onset and surgery ranging from 5 to 25 months. The mechanism causing the low density over a certain period of time in the sequential CT findings was retrospectively investigated. Characteristic histological findings associated with such low-density areas were microcystic formation, necrosis, intratumoral edema, infiltrative growth, and absence of capillary proliferation. Proliferation of capillary vessels is characteristic of CT enhancement.

A 50-year-old female was admitted because of nausea, vomiting, and cerebellar ataxia. Computed tomography scan revealed an enhanced mass accompanied with a cyst in the right cerebellar hemisphere. The mass situated in the subcortical region was removed. Histologically, highly vasculated tumor cells lined the cavities. Postoperative radio and chemotherapy were administered and the clinical symptoms improved gradually. Two months later, the patient complained of dyspnea. Chest X-ray on second admission demonstrated cardiomegaly. Hemorrhagic pericardial effusion amounting to 1000 ml was aspirated by pericardial puncture. Papillary clusters of tumor cells were demonstrated in the pericardial effusion. The patient died of cardiac failure. At necropsy solid tumors were located in the heart, lung, left inguinal region, and cerebellum. Histological diagnosis was mesothelioma arising from the heart. Primary pericardial mesotheliomas are rare; approximately 106 cases have been reported. Pericardial mesothelioma frequently spreads to the adjacent pleura and mediastinum, but distant metastases are extremely rare because patients with pericardial mesothelioma tend to die early due to cardiac failure or cardiac tamponade.

The clinical status of patients with glioma is influenced by 1) the histological malignancy of the tumor, 2) the tumor volume, 3) secondary status such as brain edema or intracranial hypertension due to the tumor, and 4) the host immunity. Due to some improvement in at least 2) and 3) by the initial treatment, most low grade glioma cases pass through a clinically silent postsurgical period. However, at a certain point, transition to a high grade tumor malignant transformation may occur with exacerbation of the symptoms. Twenty-two cases of histologically established low grade glioma experienced over the past 7 years, in which immunological status was evaluated, were analyzed. Nine cases (41%) showed malignant transformation. Characteristic pictures of the clinical symptoms, computed tomography (CT) scan findings, immunological status, and morphological findings (mainly immunohistochemical examination) in nine cases were delineated. The findings at the time of exacerbation of the symptoms were as follows. In all cases CT scan demonstrated the change in the main lesion from low density to mixed density and were compatible with a high grade glioma. Reduction in host immunity was verified. Morphological increase in the tumor volume, increase in histological malignancy and deterioration in the secondary status due to the tumor were confirmed. Necrosis of the tumor cells as well as increase in giant cells and gemistocytes were observed. Immunohistochemical analysis revealed a decrease and irregularity in glial fibrillary acidic protein positive cells and positive processes as well as increase in vimentin intensity. These findings demonstrate change in the biological characteristics of the tumor. It was not possible, however, to clarify the factors causing malignant transformation in low grade glioma.

We have proposed a “glioma score” that includes malignancy as determined histologically, the patient’s age, and the MIB-1 proliferating cell index (PCI) as the prognostic indicator for patients with malignant gliomas. Each part of the glioma score (GS), is assigned points from 1 to 4 based on histological malignancy, patient’s age, and value of MIB-1 PCI, respectively. The total score then sums the points of each group. The MIB-1 PCIs for glioma patients were correlated with tumor grade. Cases with a GS of 10 points or more showed a shorter time to progression (TTP) of less than 2 years. The incidence of cases with a TTP of less than 2 years is significantly higher for a GS of 10 points or more and less than 10 as analyzed by contingency table analysis (P=.02). Kaplan-Meier proportional survival curves were generated for cases with GS of 10 or over and less than 10. Patients whose GS was more than 10 had a tendency toward a shorter TTP than those patients whose GS was less than 10 but no significant survival advantage was demonstrated between them. Therefore, the proposal of a glioma score may provide important information for therapeutic intervention and prognosis of patients with gliomas.

The short arm of chromosome 9 is frequently deleted in malignant gliomas. We used locus-specific probes for interferon-A (IFNA) and D9S3 in combination with a chromosome 9 centromeric probe to detect genetic aberrations on a cell-by-cell basis in touch preparations of 30 glioblastomas by fluorescence in situ hybridization. Seven (23%) of 30 tumors had deletions in > 70% of cells; the IFNA locus was deleted in all seven, but the D9S3 locus was deleted in only five of the seven. The latter data confirm that a tumor suppressor gene on 9p relevant to glioblastoma multiforme lies between D9S3 and IFNA. Eleven tumors had deletions in 20-40% of cells, more than three standard deviations above the level in control tissues. The remaining tumors had deletions in < 20% of cells. The seven tumors with the lowest percentage of deleted cells each had more than one genetically abnormal population of cells. In total, 10 cases were of this type (i.e., aneusomic for chromosome 9). Three of these 10 tumors had hybridization patterns consistent with polyploidy.

Bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR) are known to be incorporated into cellular DNA during DNA synthesis, and can be recognized by immunohistochemical or immunofluorescent techniques utilizing anti-BUdR or anti-IUdR monoclonal antibodies [1–4]. Recently, two new monoclonal antibodies were developed by Vanderlaan et al.: Br-3[5], which recognizes only BUdR, and IU-4[6], which recognizes both BUdR and IUdR. By administering IUdR and BUdR at different time sequences, it is possible to determine not only the S-phase fraction but also to measure the rate of cell cycle progression and thus calculate the duration of S-phase, the cell cycle time or growth fraction of an individual tumor from a single tumor biopsy. This report describes double-labeling and staining techniques for estimating the duration of S-phase and the doubling time of biopsied materials.

Alkaline phosphatase (ALPase) and Mg2+-activated ATPase (Mg2+-ATPase) activities were demonstrated in human brain tumors by light and electron microscopy. Four cases of glioma, i.e., two cases of astrocytoma, grade II, and two cases of glioblastoma, were used as materials. At the light microscopic level, Mg2+-ATPase activity was observed in the capillary wall and glial cells of both astrocytoma and glioblastoma. ALPase activity was restricted to the capillary wall. Its activity was stronger in glioblastoma than in astrocytoma. By electron microscopy, in astrocytoma, reaction product representing Mg2+-ATPase activity was distributed in the plasma membranes of endothelial cells and pericytes. Activity was primarily localized at the abluminal surface of endothelial cells and the surface of pericytes facing endothelium. The plasma membrane of glial cells was also positive. ALPase activity revealed essentially the same distribution pattern in blood vessels as above. In glioblastoma, on the other hand, activities of both phosphatases were markedly positive on the luminal surface of the plasma membrane of endothelial cells. They were much stronger than those along the abluminal endothelial surface. Phosphatase activities in brain tumor appear to change in localization pattern in association with glioma malignancy. This might reflect a functional aspect of changes in blood-brain barrier in glioma.

Morphological features of the autopsied specimens of 15 adult patients with supratentorial gliomas were analysed and the characteristics of recurrence of gliomas were searched for. The correlation between the computed tomography (CT) findings before death and the microscopic findings of a whole mount section of the brain was also analysed. The cases consisted of 2 grade II, 7 grade III and 6 grade IV astrocytomas. The characteristic CT findings before death were regrowth of the tumor mass or the occurrence of a new enhanced lesion in 14 out of 15 patients. The enhanced lesion showing regrowth of the tumor was located in the same site as the previous tumor mass. The new enhanced lesion, resulting in a trans or subependymal tumor spread, was seen in the ventricular wall, and this was a characteristic feature of the recurrence of gliomas. In morphological analysis, tumor regrowth and recurrent tumor cell infiltration into the brain parenchyma occurred in several patterns. One was the extending mode caused by regrowth of the residual tumor in spite of adjuvant therapy. CT scan correctly showed such tumor recurrence as an enhanced lesion, especially as a ring or nodular enhancement. In the second pattern, a spread of tumor cells occurred along the interfiber spaces to the brain stem, or to the contralateral cerebral hemisphere through the corpus callosum. CT scan could hardly show such a type of tumor cell infiltration. The third mode of tumor propagation was cerebrospinal fluid seeding, with intraventricular or subarachnoid tumor growth. The CT scan examined before death could display the tumor invasion of the intraventricular seeding in 3 out of 8 patients. Histologically, reinvasion of the tumor cells from the subarachnoid space to the brain parenchyma was along the Virchow-Robin spaces of penetrating blood vessels. If tumor regrowth was accompanied by angiogenesis, CT scan could show the recurrence as an enhanced lesion. Marked angiogenesis occurred in the margin of the residual tumor with central necrosis due to adjuvant therapy.

The possibility of using the Plastimed® Sensor (No. 8645-14), developed by Dr. Hirsch for measurement of intracranial pressure (ICP) of infants was investigated in adults. The Plastimed Sensor was used to measure ICP in 27 adult cases (10 cases of head injury, eight cases of ruptured intracranial aneurysm, six cases of hypertensive intracranial bleeding, and three other cases) for periods ranging from one to 10 days with an average of 6 days. Both intraventricular pressure and epidural pressure were monitored. In four cases, a Konisberg Sensor was simultaneously used to monitor epidural pressure for comparison. The ICP monitored with the Plastimed Sensor was almost the same as the epidural pressure monitored by the Konisberg Sensor and intraventricular pressure monitored by conventional means. The Plastimed Sensor can be used in adult cases. It is economical and disposable, and installation is simple. In addition, it can be used for long-term monitoring of ICP because there is no risk of meningitis.

Gliomas are sometimes encountered which are not noticeably enhanced in initial computerized tomography (CT) scans. The sequential CT findings of such gliomas, including three malignant astrocytomas, three benign astrocytomas and one malignant oligodendroglioma, were evaluated. The initial symptoms in all subject cases were convulsive seizures. There was no correlation between the mass effect of the low density zone and the grade of histological malignancy. Rather, malignant gliomas disclosed less prominent mass effects, despite the later appearance of an enhanced high density zone. In one case each of malignant astrocytoma and of malignant oligodendroglioma, an enhanced high density zone first appeared 6 to 13 months later. Neither gave evidence of increasing mass effects, either during the follow-up or after appearance of the enhanced high density zone. Questionable low density zones in CT scans should be followed-up for at least 6 months or more in conjunction with other studies.

Morphological features and microscopic characteristics of the autopsied specimens of 14 adult cadavers with supratentorial recurrent gliomas were studied. One of the specific findings in the morphological change of the tumor cells was giant cell formation. These giant cells were subdivided into 3 types: 1) monstrous cell, 2) giant cell, and 3) gemistocytic cell. 1) Monstrous cells were found in 12 cases, 4 grade 3 astrocytomas and 8 glioblastomas out of 14 recurrent gliomas. These cells were defined as those larger than 150μm in diameter and having bizarre, irregular and hyperchromatic multinuclei. The glial fibrillary acidic protein (GFAP) stain of monstrous cells was negative. These cells were scattered in the periphery of the tumor or necrosis. 2) Giant cells were demonstrated in 3 glioblastoma cases. They were 100-150μm in diameter and had single or multiple nuclei. These cells were scattered in the periphery of both the tumor and necrosis, and contributed major cells of the tumor in two cases. The GFAP stain was negative in two cases and positive in one. 3) Gemistocytic cells were noted in 8 cases, 5 grade 3 astrocytomas and 3 glioblastomas, and were about 100μm in diameter. They had a single distinct nucleus. The distribution of the cells was in the marginal zone of the tumor or necrosis, or grouped around vessels in the tumor. The GFAP stain was positive. These results suggest that the specific cells indicated herein may be degenerative changes of the tumor cells exposed while withstanding such adverse conditions as hypoxia, irradiation, and chemotherapy.

Since the importance of monitoring the intracranial pressure (ICP) was pointed out by Lundberg et al. in 1965 (2), a number of papers have been published on the methods of measuring the ICP. They could be classified into two major categories. One is a group of simple, practical and non-electronic devices and the other is a group of more elaborate electronic instruments. Each has its own advantages and disadvantages over others. Unfortunately, no ideal perfect device has yet been seen on the market. Therefore, one has to chose a device by compromising with its performances and one’s specific requirements.

Glioma often recurs after apparently successful treatment and clinical remission. The effect of the host's immunologic status in such cases is unknown. In this study, the authors attempted to answer the following questions: 1) Is there a relationship between immunity and the recurrence of glioma? 2) Is immunologic monitoring useful in predicting the recurrence of glioma? 3) Which immunologic monitoring system is the most reliable? The subjects were 17 patients with gliomas who were treated between 1980 and 1985 and had tumor recurrence after an interval of clinical remission. They were evaluated during and after remission by means of clinical signs, computed tomography, and immunologic testing, which included measurement of purified protein derivative (PPD), phytohemagglutinin (PHA), the blastogenic response of T-lymphocytes to PHA, the OKT4 and OKT8 lymphocyte subsets, and serum complement CH50. The patients were divided into two groups. Group 1 comprised five patients whose tumors showed malignant transformation from grade 2 to grade 3. Group 2 included patients whose tumors were of the same histologic grade initially and on recurrence. In Group 2, six tumors were grade 3 and six were grade 4. Lowered immunity at the time of recurrence was demonstrated by the following: 1) a negative change in PPD and/or the PHA skin reaction in 80% of Group 1 and 75% of Group 2 patients; 2) elevation of CH50 in 40% of Group 1 and 58% of Group 2 patients; 3) a change in the blastogenic response of T-lymphocytes to PHA in 40% of Group 1 and 25% of Group 2 patients; and 4) an decrease in OKT4/OKT8 cell ratio in 60% of Group 1 and 38% of Group 2 patients. These patients were immunologically competent during remission. The immunologic changes at the time of tumor recurrence were accompanied by clinical deterioration. However, tumor recurrence could not be predicted from the immunologic parameters studied. Thus, it appears that extension or recurrence of the gliomas was responsible for lowered immunity in these patients, rather than the opposite.