In the treatment of malignant tumors, hyperthermia (HT) has been considered to be effective for tumoricidal conditioning in combination with radiation therapy (RT) and/or chemotherapy (CT). Low pH and nutritional deprivation sensitize cells to hyperthermia-induced killing. Furthermore, it is possible that decreased blood flow could further selectively reduce intratumor pH leading to enhanced cytotoxicity. In the experimental studies, the combined effects of flavone acetic acid (FAA) and hyperthermia were investigated on B16 melanoma cells and shown with enhanced cytotoxicity under the condition of their combined treatment regime.
In clinical study, patients with deep seated malignant tumors were treated with HT combined with RT and/or CT. A comparison of these results showed that the long survival was obtained on the groups where patients with tumors originated from breast, soft tissue, colorectal and uterine/ovarian sites and with good local response belonged. Concerning histopathological classification, no definite difference was found on the survival except for sarcoma. The role of hyperthermia, including a thermosimulator, and its current evolution in the multidisciplinary treatment of cancer were discussed especially with emphasis on quality assurance in the hyperthermic treatment.
Finally, possible future perspectives of clinical research on HT combined with RT and/or CT were discussed especially on the election of appropriate clinical sites, selection of suitable HT devices, and design of clinical studies.

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Confirming enhanced effects of mitomycin C, cisplatin, and etoposide by 43°C-thermal treatment with SDI test using the cell line of KATO III and COLO 320 and clinical materials, we developed chemohyperthermic peritoneal perfusion (CHPP) for the treatment of peritoneal dissemination in gastrointestinal and ovarian cancers. The CHPP with heated perfusate containing these drugs was carried out at 42.5°C in intraperitoneal temperature. The (CR+ PR) rate was 13/58 (22%), in gastric cancer; 6/12 (50%), in colon cancer; and 3/5 (60%), in ovarian cancer, respectively. The survival curve of the CHPP (+) group was significantly better than that of the CHPP (-) group in gastric cancer (logrank test, p =0.04). This preferable tendency was same in the tubercular-tupe dissemination of gastric cancer, but there was few effect in the nodal-and diffuse-type dissemination.

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In the patients who receive intaperitoneal hyperthermo-chemotherapy, scald injury on the normal peritoneo-serosal surface is inevitable due to high temperature in the peritoneal cavity. In an attempt to reduce this scald injury, cimetidine (histamine H₂-receptor antagonist) was used for the patients who underwent intraperitoneal hyperthermic perfusion (IPHP), and catheter duodenostomy was placed for these patients in order to decrease postoperative morbidity.
IPHP was performed for 60 advanced gastric cancer patients who were allocated to two groups. One was the cimetidine group of 23 patients who received 50 mg/kg of cimetidine intravenously just before IPHP. The other was the control group of 37 patients who did not receive cimetidine. IPHP was performed just after surgery under hypothermic general anesthesia for 90120 minutes. Heated perfusate which contained 10 μg/ml of mitomycin C was circulated in the peritoneal cavity with the inflow and the outflow temperature of 45.546.5°C and 43.544.5°C respectively. The amount of peritoneal exudate and the amount of protein in it of the cimetidine group were significantly smaller than those of the control group after IPHP. There was no anastomotic leakage in the patients who underwent catheter duodenostomy in the cimetidine group. These results suggest that the side effects of IPHP can be reduced by the use of cimetidine and catheter duodenostomy.

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A considerable study has been carried out to substantiate the selective killing effect of heat on neoplastic versus normal cells, and generally revealed higher thermosensitivity of the former obtained from human or animal tumors. Recently, the neoplastic cells experimentally induced by chemicals, ionizing radiation, tumorigenic viruses or oncogenes has become available and important for the strict analysis. Among tumorigenic viruses, adenovirus is well known to transform rodent cells, whose genome is a linear duplex DNA molecule encoding for 20-30 polypeptides. Oncogenes of adenovirus are identified as E1A and E1B, which are tandemly located on the left end of the template r-strand. The 53k/44k proteins translated from 13S mRNA of E1A immortalize embryonic cells to accomplish the first step of transformation. E1B encodes for the 15-19k and 53-54k proteins which stabilize cellular and viral DNA to be essential for the complete transformation. Very interestingly, the thermosensitivity of adenovirus transformed cells was coincident with E1A expression and on the contrary E1B gene exerted inhibitory effect on the cell death by heat. Moreover, heat-treated E1A cell represented the immediate chromosomal change and the internucleosomal nucleolysis compatible for programmed cell death (apoptosis), while the transformed cells with ElB or E1A + E1B showed the delayed morphological change and the less amount of degraded DNA. Consequently, E1A plays an important role either in cell transforation (immortalization) and in enhancement of thermosensitivity. As it has been evident that E1A interacts some cellular proteins intimately concerned with cell replication, such as pRb (p105), p107, p130 and p300, E1A may function to endow the cells with thermal instability via these proteins.

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³¹P-MRS is a powerful and non invasive tool for investigation of in vivo brain metabolism under hyperthermia. To examine the energy metabolism of brain and confirm the critical temperature for the brain by hyperthermia, ³¹P-MR spectra of the brain were obtained under hyperthermia at various temperature. On the other hand, cell death takes two distinct forms, necrosis and apoptosis. We study the cell death of the brain by hyperthermia, using the method of nick end labeling. The results were as follows.
1) According to heating temperature, the cycle of high energy compounds shortened. (39°C ; 40min, 42°C; 23min, 45°C; 12min)
2) Half the number of mice died at 43°C (head temp.) during hyperthermia (LD50/60min)
3) Survival time (MRS' dead time) of mice decreased according to heating temperature. (39°C; alive, 42°C; alive, 45°C; 45.8min, 48°C; 24.6min, 51°C; 17.2min)
4) Rectum temperature of mice increased according to heating temperature. (39°C ; 35.9°C, 42°C; 37.9°C, 45°C; 39.6°C, 48°C; 40.1°C, 51°C; 40.2°C)
5) Heating at 39°C, some of the nuclei were stained with nick end labeling, exhibiting the stage of apoptosis. The frequency of the staining cell at 42°C heating was the highest in all heating groups.
From these results, we concluded that the critical temperature of the brain by hyperthermia was 43°C, and the cell death of brain under hyperthermia was due to apoptosis.

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Retinoblastoma is a hereditary malignant tumor, mostly occurring in infants and children. Although the common treatment is the surgical extraction of eyeball, non-invasive several methods such as chemotherapy, irradiation, and hyperthermia therapy using microwave are conducted as treatments for the disease. The hyperthermia therapy using microwave tends to heat the optic nerve excessively. Therefore an intelligent heater was developed to prevent the above problem. The surface temperature of the intelligent heater was automatically maintained at constant temperatures when the room temperature or the applied voltage was changed. The intelligent heater showed the positive temperature coefficient (PTC) effect. It has conductive carbon-black distributed by grafting of polyethylene glycol as crystalline polymer. The intelligent heater reduces the risk of excessive heating of the optic nerve, because the material itself controls the temperature. Real time evaluation of the temperature distribution in cross section of the eyeball phantom was carried out using the boundary-element method. The surface temperature of the agar phantom imitating eyeball was measured as boundary conditins. The calculated temperature of the imitated eyeball phantom at the mid-point was compared with the measured temperature at thermal equilibrium. The calculated temperature approximately agreed with the measured temperature. The non-invasive temperature estimation of an imitated eyeball cross section was achieved using the boundary-element method. This device appears promising for its safe clinical applications in hyperthermic retinoblastoma therapy.

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Local hyperthermia has been applied for the radiofrequency treatment of deep seated tumors using a Thermotron RF-8. However, satisfactory temperature elevations could not be achieved due to the hot sensation caused by subcutaneous fatty tissue heating. For alleviation of this side effect, we carried out the gripping method during hyperthermia treatment and assessed how it functions.
Two patients with benign prostate hyperplasia were treated with local hyperthermia using a Thermotron RF-8. The intra-rectal temperature achieved during hyperthermia treatment was measured using a Thermocouple, and differences of temperature elevation, electric power and side effects between the standard method and the gripping method were compared. Maximum temperatures in the rectum could be elevated higher using the gripping method with less side effects such as heat sensation in subcutaneous tissue than with the standard method.
A fundamental experiment, performed using a phantom revealed slightly lower changes of electric power with the gripping method than with the standard method, but no significant differences were observed.
These results indicate that the gripping method is useful for the treatment of deep seated tumors by local hyperthermia using a Thermotron RF-8 allowing satisfactory temperature elevations to be obtained without side effects.

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