Hyperthermia for brain tumors: improved delivery with a new cooling system.

Hyperthermia has emerged as an adjunct to other forms of brain tumor therapy. Interstitial microwave irradiation is an effective method of inducing localized brain hyperthermia. One of the problems with this technique, however, is the overheating of tissue adjacent to the antenna. In this study, a cooling system for the interstitial microwave antenna was developed for the purpose of providing uniform and accurate heating by the elimination of overheating. The ability to generate more uniform hyperthermic fields was evaluated in normal monkey brains. Six monkeys under general anesthesia and controlled respiration underwent parietooccipital craniectomies 4 x 4 cm in size. The antenna cooling system was constructed of a silicone tube 5.0 mm in outer diameter. Silicone-coated interstitial microwave antennae 1.5 mm in diameter were used. A single antenna or a square array (1.6 cm on a side) of 4 antennae was inserted into the brain with the coupled system to a depth of 2 cm. The brain tissue was heated by 2450-MHz microwave irradiation. Temperature distributions were mapped using nonperturbing thermocouples. These thermal profiles were compared with those generated without the cooling system. In the experiments with the single antenna, the antenna cooling system eliminated the overheating and rapid radial falloff in temperature, without a reduction of the hyperthermic field. In the four-antennae experiments using the cooling system, the thermal field was dramatically flattened with minimal reduction in size; however, the area maintained at a therapeutic temperature range (42-45 degrees C) was significantly enlarged by the cooling system.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical demonstration of DNA polymerase alpha in human brain-tumor cells.

The proliferative capacity of brain-tumor cells was analyzed in vitro and in situ using monoclonal antibody (MAb) against deoxyribonucleic acid (DNA) polymerase alpha. For the in vitro studies, two cultured human glioma cell lines were investigated using MAb against DNA polymerase alpha, the MAb Ki-67, a serum against proliferating cell nuclear antigen (PCNA/cyclin), bromodeoxyuridine (BUdR), and an anti-BUdR MAb. During exponential growth of the cells, the percentage of polymerase alpha-positive cells (the "polymerase alpha score") ranged from 72.0% to 77.1%, the Ki-67-positive cells (the "Ki-67 score") ranged from 43.4% to 59.4%, the PCNA/cyclin-positive cells from 30.9% to 41.4%, and the BUdR labeling index from 28.6% to 39.3%. For the in situ studies, tissue from 60 human brain tumors and from two normal human brains was investigated and the polymerase alpha scores and Ki-67 scores were compared. In normal brain tissue, no immunostaining was found by either method. In brain tumors, both the polymerase alpha scores and the Ki-67 scores correlated with the histological grade of malignancy. Polymerase alpha scores were generally higher than Ki-67 scores in the same specimen, especially in malignant brain tumors. These findings suggest that immunostaining of DNA polymerase alpha is a convenient and important new method by which to estimate the cellular proliferation rate of brain tumors. Polymerase alpha scores may be closer to the growth fraction of the individual tumor than the MAb Ki-67 or other scores.

Thermal damage threshold of brain tissue--histological study of heated normal monkey brains.

The thermal damage threshold of normal brain tissue was evaluated from immediate and delayed histological changes caused by hyperthermia treatment of normal monkey (Macaca fuscata) brains. A 2450 MHz microwave antenna and an antenna cooling system devised by our group were used for interstitial hyperthermia treatment. The antenna within the cooling system was inserted through a small craniectomy under general anesthesia. The temperature at a reference point, 4 mm radially away from the surface of the cooling system, was maintained at 42, 43, 44, 45, or 46 degrees C for 60 minutes. Eighteen animals were treated and sacrificed immediately after the treatment, while nine animals were treated and sacrificed 7 days after the treatment. The histological changes were studied microscopically on sections stained with HE or Kluver-Barrera's method. The non-survival experiment demonstrated that areas heated at 44 degrees C or below showed no obvious irreversible changes. The survival experiment showed areas heated at 44 degrees C or above developed coagulative necrosis. These histological findings indicate that thermal damage occurs in normal brain tissue after heating at 44 degrees C or above for 60 minutes, suggesting that the safety limit for brain hyperthermia is 43 degrees C for 60 minutes.

[Immunohistochemical study for choroid plexus papillomas and ependymomas].

An immunohistochemical study of glial fibrillary acidic protein (GFAP), S-100 protein, cytokeratin (CKER), epithelial membrane antigen (EMA), and transthyretin (TTR) was carried out on 11 cases of choroid plexus papilloma (CPP) and 19 of ependymoma, using the peroxidase antiperoxidase technique. Among the 11 cases of CPP, all 11 were positive for CKER, EMA, and TTR, 10 for S-100 protein, and five for GFAP. Most of the GFAP-positive papilloma cells were simultaneously positive for CKER. However, these GFAP-positive cells were negative for TTR. Among the 19 cases of ependymoma, 16 were positive for GFAP, 17 for S-100 protein, three for CKER, eight for EMA, but none for TTR. Some GFAP-positive cells were also stained for CKER. However, TTR was not found in any of the ependymal cells. These findings suggested that CPP cells which show ependymal or glial differentiation lost the ability to synthesize TTR which is known to be synthesized in the epithelial cells of the choroid plexus. The more GFAP-positive cells present in a CPP, fewer TTR-positive cells are present. Though CPPs are usually easily distinguishable from ependymomas, occasional doubt arises concerning the differential diagnosis between CPP and papillary ependymoma. TTR can be a very useful diagnostic marker of CPP.

[Fundamental study of differential hypothermia treatment of brain tumor using an interstitial microwave antenna].

An interstitial microwave antenna system was devised for differential hypothermia treatment. It was evaluated for its ability to induce localized brain hyperthermia in hypothermic monkey. Ten brain hyperthermia trials have been performed in 6 monkeys. Under general anesthesia, the animals were put into ice water bath to keep the total body temperature at 30 degrees C. Following parieto-occipital craniectomy, a microwave antenna of 1.5 mm in diameter was inserted into the brain at depth of 2 cm, and the brain tissue was heated by 2450 MHz microwave irradiation. Thermal distribution was measured by thermistor probes and local cerebral blood flow (1-CBF) before and after heating was simultaneously measured by hydrogen clearance method. After the experiment, the animals were sacrificed and histopathological changes of the heated brain tissue were studied. Under total body hypothermia of 30 degrees C, the maximum cross-sectional diameter of the heated brain to 37 degrees C or above was about 4 cm. The temperature profile on the vertical plane presented a bell-shaped distribution. The 1-CBF of the heated brain increased with the elevation of the brain temperature and the blood flow at 37 degrees C is nearly twice as much as that of 30 degrees C. After one hour DH treatment, necrotic tissue was noted along the antenna axis where the temperature was maintained more than 50 degrees C, and this change was not recognized at a distance of 1 cm from the antenna where the temperature was maintained at 42 degrees C. This study indicates that interstitial microwave hyperthermia system can be used effectively to heat the localized brain tissue.

[Opsoclonus-polymyoclonia syndrome suppressed with reserpine].

A 38-year-old man was admitted to Iwakuni National Hospital on July 6, 1978, with the complaints of difficulty seeing and walking. Two weeks before admission, he first experienced dizziness and it slowly progressed to uncontrollable tremor-like movements of the whole body. On admission, he was alert, oriented and afebrile. He had not experienced nausea, vomiting nor headache. He showed irregular horizontal oscillations of the eyes. Electronystagmographic study showed that this jerky eye movement appeared especially with changes of fixation of the eyes. It was also recorded during conjugate eye movement, and while he closed his eyes. He was ataxic, unable to walk, but no other abnormalities in cerebellar functions were observed. Spinal tap was performed and yielded watery clear cerebrospinal fluid containing 9/mm3 mononuclear cells. Clonazepam was given, 1.5 mg per day, for three days followed by doses of 3 mg per day. Improvement in walking was observed one week after starting the medication, when reserpine was started at a dose of 1 mg per day and increased to a dose of 1.5 mg per day in three days. One week after starting reserpine, opsoclonus improved markedly and he became able to read again. He was discharged home on September 3, 1978. Six months after admission, reserpine was decreased to 0.5 mg per day. Difficulty in reading developed within a month. Reserpine was given 1.0 mg per day and the doses was continuously given for next three months. One year after admission, he is back to his former occupation without medication. He complains of slight difficulty in reading for more than an hour, and in watching TV.(ABSTRACT TRUNCATED AT 250 WORDS)

[Immunohistochemical study on distribution of transthyretin in normal human brain tissue and tumors].

Immunohistochemical examination of transthyretin (TTR), which is known to be synthesized in the epithelial cells of the choroid plexus as well as in the liver cells, was carried out on normal brain tissues and 84 human brain tumors, using a peroxidase-antiperoxidase (PAP) technique. TTR was demonstrated diffusely and strongly in the cytoplasm of normal choroid plexus cells, but not in ependyma and other tissues of normal brain. In all of 10 choroid plexus papillomas, TTR was found within the cytoplasm of tumor cells. In contrast, neither the two papillary ependymomas nor any other brain tumors contained TTR. Among the choroid plexus papillomas, some cases showed clear positive reactions in almost all tumor cells, while others had only a few TTR-positive cells. With these immunohistochemical findings, TTR proved a very useful marker of normal choroid plexus and choroid plexus papilloma.

[Analysis of activated lymphocytes and antigen-present macrophage in human brain tumors using double immunofluorescence staining].

Twenty-eight human brain tumors (18 gliomas and 10 metastatic brain tumors) were examined immunohistochemically using anti-Leu 1, -Leu 2 a, -Leu 3a + 3b, -LeuM 5, -HLA-DR, IL-2 receptor, -HLA-ABC and Ki-67 monoclonal antibodies (MoAb). Also, in the specimens, in which Leu 1+ cells and Leu M5+ cells infiltrate, simultaneous detection of Leu 2a, Leu 3a + 3b, or Leu M5 and HLA-DR, was performed by double immunofluorescence staining to analyze the T cell activation and antigen-present macrophage (M phi). Most of low-grade gliomas with low percentage of Ki-67+ cells showed only little lymphocyte and M phi's infiltration. THEre was a tendency toward a marked degree of T cell and M phi infiltration in malignant glioma with higher percentage of Ki-67+ cells. However, in metastatic brain tumors, M phi did not tend to infiltrate. IL-2 receptor+ cells was absent in the majority of brain tumors. Tumor cells and vascular endothelial cells also expressed HLA-DR antigens. The majority of tumor cells expressed HLA-A, B, C antigens. There were no correlation among the degree of T cell and M phi infiltration, MHC antigen expression, and percentage of Ki-67+ cells. Double immunofluorescence staining demonstrated that 42.4% of Leu 2a+ cells, 34.7% of Leu3a+ + 3b+ cells and 32.7% of M5+ cells are HLA-DR positive in glioma, and that 50.2% of Leu2a+ cells, 59.4% of Leu3a + 3b+ cells and 67.3% of LeuM5+ cells are HLA-DR positive in metastatic brain tumors.(ABSTRACT TRUNCATED AT 250 WORDS)