As amphibians such as frogs and newts are poikilothermal animals, they can be placed in the wide ranges and changes of temperature without any physiological damage. Thus, an investigation using the tumor cells of these animals might reveal some information on the effects of temperature on the tumors.
The effects of temperature on two types of amphibian tumor are reviewed. Naturally occurring tumors show a clear seasonal dependence both in Lucké renal adenocarcinoma in the frog, Rana pipiens and papilloma in the newt, Cynops pyrrhogaster. Frogs bearing Lucké renal adenocarcinoma are seen most frequently in spring and autumn. In the natural field, the percentage of newts with papillomas is the highest in autumn, ranging from 1.93 to 5.45% of the total average. These values are more than four times as high as those obtained in the other three seasons. Virus particles are absent in the tumors of frogs obtained in summer, though keeping frogs at low temperatures induces the appearance of viruses. Winter tumors display virus particles. When they are kept at high temperatures, tumor cells containing viruses degenerate. Similar effect of temperature on the growth of papilloma in newts has been reported.
Papilloma continues its growth in medium temperatures (10-13°C), while in high (25-30°C) and low (4°C) temperatures it reversibly regresses. Biochemical changes such as microtubules and protein synthesis between tumor cells and normal cells are also observed, and the characteristics of tumor cells are discussed.

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Clinical results of hyperthermia applied to 47 patients with resistant superficial malignant tumors were reported. In 47 patients, 33 were treated by hyperthermia combined with radiation therapy (RT+HT), and the other 14 by hyperthermia alone (HT alone). Hyperthermia was applied once or twice a week and 2-12 times in total. 2450MHz microwave hyperthermia system was used for heating tumors. Complete response was obtained in 10 patients (30.3%) by RT +HT, and in 2 (14.3%) by HT alone. Partial response was obtained in 19 patients (57.6%) by RT +HT, and in 2 (14.3%) by HT alone. The response rate was elevated in the patients treated by hyperthermia not less than 8 times, and no tumor response was obtained by less than 8 times HT alone. This suggested that not less than 8 times therapy was necessary to sufficient therapeutic effect in hyperthermia.

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A very thin needle heatpipe (1.48mm in outer diameter) was developed for interstitial thermotherapy and its performance was evaluated using experimental tumors in the rat. Temperature gradient of approximately 1 to 4 degree in centigrade / mm on the perpendicular plane of the heatpipe was obserbed. The gradient strongly depended on size of tumors; the larger the tumor was, the less it became. Tissue damage correlated to the temperature gradient. Tumor growth curve analysis showed succesful treatment of relatively larger tumors as big as 7mm³. Larger tumors responded better than smaller ones. These results suggest heatpipe may be a promissing tool for interstitial thermotherapy.

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Eight MHz radiofrequency hyperthermia using a Thermotron-RF 8, and its combination with THP-adriamycin (CH) or irradiation (RH), were carried out for a total of 35 bladder carcinoma patients : 12 with carcinoma in situ (CIS) of the bladder, 21 with invasive bladder carcinoma and 2 with metastatic lesions of bladder carcinoma. The hyperthermia (H) was given twice a week, totaling 10 sessions 5 weeks for 2 patients with CIS of the bladder and 1 with invasive one. Sixteen Patients, including 5 with CIS of the bladder, 9 with invasive bladder carcinoma and 2 with metastatic lesions of bladder carcinoma, received a combined treatment of intravenous THP-adriamycin, one of the derivatives of adriamycin, and RF-heating (CH). The remaining 16 patients, including 5 with CIS of the bladder and 11 with invasive bladder carcinoma, were treated with RH. Intratumoral temperature was kept above 42.5°C for 30 to 40 minutes during a one-hour heating. After the treatment for 12 patients with CIS of the bladder, responders were obtained in 3 of the 5 patients treated with CH and 2 of the 5 patients treated with RH, whereas no responder was attained in the group treated with H. In 11 patients with invasive bladder carcinomas treated with RH, CR, PR and MR were obtained in 1, 5 and 3 patients, respectively, and in 9 patients with invasive bladder carcinoma treated with CH, 1 of PR and 2 of MR were attained. As side effects, mild skin burns and anorexia were observed in 10 patients. Six patients, who had the subcutaneous tissue of 15 mm thick or more, developed fat tissue induration during or after treament.

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Induction heating following transcatheter embolization with iron microspheres has been studied to develop a new method for embolo-hyperthermia to deep-seated tumors. In addition, percutaneous iron microspheres injection into tumor cavity, either alone or with a combination of arterial embolization has been attempted as a method of magnetic implant.
The induction heating device was composed of radio-frequency generator (500kHz, 6-12kW) and circular applicator coil. Thermometry was made using fluoroptic thermometer with a thin, flexible glass fiber probe which readily passed through a 5 French angiographic catheter.
The procedure was performed on experimental animals as well as on a patient with large gluteal tumor. The results indicated that the procedure would be applicable for clinical practice with safety and reliable heating effect on deep-seated tumors.
However, the heat distribution within the tumor varied in some degrees depending not only on the dose and distribution of iron microspheres, but also on the inhomogenity of tumor itself, giving rise to some problems of this procedure.

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Cationic fluorescent dye Rhodamine 123 (Rh 123) is selectively accumulated in mitochondria on living cells, reflecting the mitochondrial transmembrane potentials. A rapid redistribution of mitochondria to the perinuclear region has been showed by heat treatment. Whereas, these changes of localization after heat treatment were inhibited by addition of Cholcemid. On HeLa cells and colon26 cells, we have studied the growth curve and clonogenic ability to evaluate heat sensitivity and Rh 123 uptake was estimated in concurrence. The decrease in Rh 123 uptake correlated with the loss of clonogenic ability. It was suggested that the uptake of Rh 123 is a useful marker to estimate whether the cell viability after heat treatment exists or not.

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Lipid- filmed magnetite particles associated with tumor-localizing hematoporphyrin (hematoporphy rin liposomal magnetite : HP-LM) were prepared by sonication of hematoporphyrindimethylester-as-sociated liposome solution with ferromagnetic magnetite (Fe₃O₄) particles (ca. 150 Å). The HP-LM solution was fully suspended. HP-LM is expected to be small enough to get through the blood capillary and to have no immunogenicity. The HP-LM solution can be inductively heated by the magnetic hysteresis loss with the application of a high frequency magnetic field (HFMF). Temperature rises, with applications of HFMF (2MHz), of the HP-LM solution and the homogenized mouse liver tissue with addition of HP-LM showed linear increase with HP- LM concentrations. BALB/c mice implanted with Meth- A tumor were intravenously administrated with HP- LM and HP- free LM. Removed, at 24, 48 and 72 hours after administration, tumors and tissues (liver, kidneys, spleen and lungs) were applied with HFMF (2MHz), and temperature rises were measured. Tumor tissues of the mice administrated with LM's, especially with HP- LM, had some temperature rises, which suggested that LM's were distributed to tumor tissues. Liver and spleen, as well, of the mice administrated with LM's had high temperature rises, showing that LM's were highly uptaken by the reticuloendothelial system.

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Microwave radiation is one of the most useful techniques for creating thermal fields in tissue, but its use is limited because of the rapid attenuation of propagation through the body. Therefore, a superficial localized tumor is only the object of microwave hyperthermia.
This study was designed to perform fundamental experiments with localized hyperthermia induced by 2450 MHz microwave radiation. In order to improve the temperature distribution and heating efficiency produced by Microtizer (Minato Medical Science Co., Ltd), we used a cylindrical cardboad cone covered with alminum foil and a collimator with a hole in the alminum plate that were specially designed. The characteristics of temperature distribution patterns using these applicators were tested using a tissueequivalent agar phantom and an unhomogeneous phantom which contained a ham or animal muscle with fat.
The conclusions were drawn from our experimental results as follows;
1) By the use of specially desinged cone and collimator, focusing microwave radiation was improved, that is, both the homogeneity of temperature distribution patterns and the high elevation of temperature were achieved.
2) The relation between the distance from an antenna-tip to phantom surface and the heating efficiency depended on conditions of microwave radiation. With a single refrector, the heating effect decreased in inverse proportion to the distance. With the use of a cone and a collimator, however, the optimum distance of 13 cm exsisted, depending on a given frequency.
3) The hole diameter of collimators for obtaining effective temperature distribution patterns depended on a frequency employed. The heating efficiency was not achieved when the hole diameter was less than λ/4.
4) There was no relationship between VSWR (voltage standing wave ratio) and heating effect.

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One of very important problems in clinical sessions of hyperthermotherapy is the reduction of thermosensitivity (thermotolerance) in cancer cells induced by heating. The development and disappearance of thermotolerance were studied using a human colon carcinoma line (WiDr), and the effects of anticancer drugs on thermosensitivity of WiDr cells were examined. Following 30- min heating at 40°C, 42°C and 44°C, WiDr cells were incubated at 37°C for 0, 1, 6, 12, 24 and 48 hr, and reheated at 40°C, 42°C and 44°C for 30 to 150 min. Then, thermosensitivity was evaluated through serial determination of the cell viability. The anticancer drugs used were 0.2 and 1.0 μg / ml of cis- diamminedichloroplatinum, 0.006 and 0.03 μg/ml of mitomycin C, and 1.0 and 2.0 μg/ml of 5- fluorouracil, contacted with WiDr cells before, at the same time with and after the first heating.
The thermosensitivity of WiDr cells was not reduced when the cells were heated first at 40°C and then 44°C. When the cells were heated first at 42°C and then 44°C, the thermosensitivity was reduced. The thermotolerance was maximal when the interval between the 1st and 2nd heatings was 6 hr, and disappeared when the interval was 24 hr. When the cells were heated first at 44°C and then 42°C, the thermotolerance was maximal when the interval was 6 hr, and disappeared when the interval was 48 hr. When the cells were heated both times at 44°C, the thermotolerance was maximal when the interval was between 6 and 12 hr, and disappeared when the interval was 48 hr. The cytotoxicity of the cells was augmented by the combined use of anticancer drugs with heating, but the thermotolerance was not influenced.
These results proved that heating caused the development of the thermotolerance even in a human colon cancer cell line. Further approachs are important to inhibit the development of the thermotolerance of cancer cells.

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The combined effect of hyperthermia and anticancer drugs (CDDP, MMC, THP, 5-FU) on cultivated KK 47 cells using a colony forming assay system. From the heat response curves obtained at 42 and 43°C hyperthermia, 20% growth inhibition time (IT20) at 42 and 43°C hyperthermia, and 50% growth inhibition time (IT50) at 43°C were calculated. IT20 and IT50 hyperthermia were combined with a 2- hour treatment of each of the anticancer drugs. In these combinations, a synergistic increase in cell killing effect, characterized by a prominent decrease of the slope on the dose-survival curve, was obtained when the hyperthermias were combined with various concentrations of CDDP ranging from 0.3 to 3.0 μg/ml. A marked decrease of the shoulder on the dose-survi al curve was attained when the hyperthermia were combined with MMC. In combination of hyperthermia with THP, additive increases in cell killing effect were obtained at various concentrations of less than 0.05μg/ml of THP, whereas, there was no increased cell killing effect at various concentrations of more than 0.05μg/ml of THP. No increased cell killing effects were observed in the combinations of 5-FU and the hyperthermias.

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In the hyperthermic terapy for cancer, the estimation of temperature distributions in human bodies without invasion has bee strongly desired.
For the case of RF capacitive heating (f =8MHz), both SAR (Specific Absorption Rate) distributions in the initial phase and temperature distributions in the final stage are numerically calculated by solving the heat balance equation by means of two - dimensional FEM (Finite Element Method). At the same time, the temperature distributions measured at the stational state in the real clinical case are also presented. The results obtained by the calculation show quite resemble features to those of the actual measurements. The maximum temperature difference between them was 3°C. The investigation of the cause for this difference are made. The method to improve this computer program to obtain the more acurate temperature map in an actual body has been discussed.

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