We demonstrated that reactive oxygen and lipid peroxidation are involved in the underlying mechanisms of hyperthermia. Neutrophils are one major source of reactitve oxygen during hyperthermia. Lipid peroxidation is believed to be an important cause of damage to cell membranes, because polyunsaturated fatty acids of the cellular membrane are degraded by lipid peroxidation. In clinical studies of the antitumor effect of hyperthermia, it was evident that in cases in which the internal temperature of the tumor could not be raised to 42°C, the efficacy of hyperthermia was reduced. In such cases, some type of combined therapy is needed. Because of the importance of neutrophils in hyperthermia, the efficacy of hyperthermia combined with recombinant human granulocyte colony stimulating factor (G-CSF) was investigated. We also investigated the efficacy of hyperthermia and polyunsaturated fatty acids on experimental carcinoma. This study focused on polyunsaturated fatty acids which are substrates for free radical reactions. These combination therapies induced a high level of lipid peroxidation in tumor tissue and a significant antitumor effect.

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First, we reviewed the characteristics of quiescent cells in solid tumors which have been inferred from findings many studies on the plateau-phase cultured cells in vitro have clarified. Second, we stated our method for the selective detection of the response of quiescent cells in solid tumors using immunofluorescence staining for BrdU and micronucleus assay. Third, we reported new findings on quiescent cells which had been made clear by some of our studies using this method. Lastly, we showed that mild hyperthermia preferentially oxygenates the chronically hypoxic fraction, probably resulting from improvement in the supply of oxygen via an increase in tumor blood flow. Therefore, radiotherapy and/or chemotherapy combined with mild heat treatment was thought to be useful for controlling high chronically hypoxic fraction including quiescent cell populations.

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Magnetite cationic liposome (MCL) encapsulating anticancer drug was developed, and the combination effect of hyperthermia and chemotherapy was evaluated. At first, two drugs which suppress cancer growth by different mechanisms were tested. From this preliminary test, it was found that cisdiamminedichloroplatinum (CDDP) enhanced the cell killing effect of the MCL, but methotrexate (MTX) did not enhance the effect. Therefore, two drugs which suppress cancer growth by similar mechanisms, CDDP or 1- (4-amino-2-methyl-5-pyrimidinyl) -methyl-3- (2-chloroethyl) -3-nitrosourea (ACNU), were encapsulated in the MCL. These drug-MCLs were added in the culture medium for T9 rat glioma cell and incorporated in the cells. High frequency magnetic field (118kHz) was applied after 8 h culture, and the killing effects to the cells by hyperthermia and drug were studied in vitro. A synergistic effect was observed in CDDP-encapsulated MCL, and additive/sub-additive effect was observed in ACNU-encapsulated MCL. Degree of the combined effects was varied with temperature and heating time.

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We estimated anti-tumor response of the thermochemotherapy (TC) to the gastrointestinal malignancies in 41 patients; hepatic cancer in 16, pancreatic cancer in 12, intra-abdominal lymph node metastasis in 10 and intra-pelvic cancer in 3, and analyzed the optimal frequency and reposing interval of thermochemotherapy from the effective cases.
Mitomycin C (MMC) and/or cis-diamine dichloroplatium (CDDP) was simultaneously given during hyperthermic treatment using a radio-frequency (13.56 MHz) capacitive heating equipment.We estimate the reduction of the tumor volume by CT scan, changes in the serum levels of tumor makers and findings of clinical improvements. We focused on the four cases which revealed more than 50 % of reduction in the tumor volume after TC; two with liver metastasis of colon cancer, one with unresectable pancreatic cancer and with hepatoma.
Complete or partial response to TC was obtained in 5/16 patients (31%) of the hepatic cancer, in 3/12 patients (25%) of pancreatic cancer in 1/10 patients (10%) of intra-abdominal lymph node metastasis and 1/3 patient (33%) of intra-pelvic cancer. Serum levels of tumor makers, which decreased lower than 50% of pre-treatment level were noted in 6/16 patients (38%) of liver cancer, in 5/12 patients (42%) of pancreatic cancer, 2/10 patients (20%) of lymph node metastasis and in 2/3 patients (66%) of intra-pelvic cancer. In contrast, clinical symptoms improved in 10/16 patients (63%) of liver tumor, in 9/12 patients (75%) of pancreas tumor in 7/10 patients (70%) of lymph node metastasis and 2/3 patients (66%) of intra-pelvic cancer. These favorable effects were not affected by the size of the lesions treated.
In three of the four markedly effective cases, the long term interruption of treatment proved to abolish the antitumor effects of TC. In the last 4 th case in which TC was regularly continued, the tumor size and the serum level of tumor maker is maintained to be effective.
TC is an useful therapy for unresectable and recurrent gastrointestinal cancer taking into account not only antitumor effect but improvement in clinical symptom. It should be noticed in mind that these effects might be disappeared after long term interruption of TC.Therefore, we should emphasize TC should be regularly continued as long as possible, and the other appropriate chemotherapeuic agent should be given when hyperthermia is resumed after the long interruption.

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In this paper, the development of a biological tissue-equivalent phantom for microwave hyperthermia is described. This phantom realizes the same complex permittivity as those of high-water-content tissues such as the muscle and the brain, over the wide range of operating frequencies from 300 MHz to 3000 MHz in single recipe. This phantom is composed from easily available materials : Agar, TX-151, Polyethylene powder, Sodium azide, Sodium chloride and Deionized water. The preparation is simple and manually performed with no special equipment. This phantom keeps its permittivity for more than a month at room temperature. Thermal characteristics such as the specific heat and the thermal conductivity are sufficient for SAR observation by thermographic method.

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Retrovesical malignant tumors are associated with a very poor prognosis due to resistance to chemotherapy or radiation and rapid metastasis. However, we have experienced a patient with long survival after exposed to more than 50 treatments of hyperthermia.
A 17 year old female, compalained of pain on her left flank since October 1991, was admitted to the affiliated Suzuka Chuo General Hospital and treated with a combination of surgical operation, chemotherapy, radiation and local hyperthermia (Japanese Journal of Hyperthermic Oncology, 10 : 150-155, 1994). The treatment of hyperthermia were repeated 26 times prior to 1993. From 1993 to 1996, 24 additional treatments were performed in combination with chemotherapy, radiation and immunotherapy. The patient had no apparent evidence of recurrence or progression of the disease in December 1996. So far as refered to the literature, it has not been reported a retrovesical malignant tumor in which long survival was given due to the treatment with hyperthermia as one of the main treatment modalities.

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