Clinical research in hyperthermic oncology began in 1978, when the research group chaired by Prof. T. Sugahara, supported by a grant from the Ministry of Education, played an important part. Six years later, the first annual meeting of the Japanese Society of Hyperthermic Oncology (JSHO) was held in Kyoto, and the 23rd meeting was held in Nara in 2006. Over this period, the number of members as well as the number of scientific papers presented have decreased. However, new technologies such as immuno-stimulation, high temperature ablation, and mild hyperthermia have been introduced into clinics. The health insurance control committee of the JSHO conducted a survey on the clinical applications of hyperthermia. Data obtained through the use of questionnaires have been used to present the state of hyperthermic treatment in the major hospitals in Japan. An outline of the patients and diseases treated with hyperthermia, heating conditions including combination therapy, and clinical outcomes were summarized in this study. From the viewpoint of fiscal responsibility at each hospital, the difference between income and expenses for hyperthermic therapy is something which cannot be ignored. Further analysis of survey data and additional survey studies might be essential to resolve this problem.

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Heat shock proteins (HSPs) are induced by various environmental (physical, chemical and biological) stresses in virtually all organisms. Most HSPs are also synthesized constitutively at normal growth temperatures, and possess fundamental and indispensable functions in protein biogenesis through their role as molecular chaperones. HSPs also play a role in protecting cells from deleterious and proteotoxic stresses. Although the molecular chaperone functions of HSPs are usually conducted inside of cells, recent reports indicate that HSPs can also be detected on the cell surface and outside of cells in the cellular milieu. HSPs have been shown to be secreted by the exosome pathway, and they are released from cells which have died through necrosis. There is growing evidence that these extracellular HSPs derived from dead cells, or purified exogenous HSPs can stimulate the innate immune system. Thus, HSPs can be considered to be a danger signal or warning signal to tissues or an organism. In this review, the dual functions of HSPs, as molecular chaperones inside of cells and as warning signals outside of cells, is discussed.

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Microwave energy is a heating source used for localized hyperthermia. Depending on the position and size of the target tumor, several types of antennas, which radiate microwave energy to the target, can be selected. This paper describes two types of heating schemes which can be used with microwave energy, and provides brief explanations of the basic engineering involved. In addition, methods use for evaluations of antenna performance are described.

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The mechanism of hyperthermia-induced apoptosis in HL-60 cells was investigated. HL-60 cells were heated at 43°C for 1 h and then incubated at 37°C for 4 h. During and after the hyperthermia treatments, apoptosis induced by hyperthermia was assessed by observing morphologic changes and DNA fragmentation. A significant and rapid induction of apoptosis in HL-60 cells treated at 43°C for 1 h was associated with morphological changes, and DNA fragmentation was demonstrated. These results suggest that hyperthermia treatment at 43°C has the potential to induce apoptosis in HL-60 cells. The induction of apoptosis by a hyperthermia treatment was associated with the activation of caspase-3 and was completely suppressed by a caspase-3 inhibitor. These observations suggest that the activation of caspase-3 by hyperthermia treatment is essential for the commitment of cells to undergo apoptosis. Furthermore, inhibitors of caspase-8 and -9 blocked caspase-3 activation and hyperthermia induced apoptosis. These results may imply that caspase-8 and -9 mediate caspase-3 activation during hyperthermia-induced apoptosis in HL-60 cells.

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Although mild hyperthermia (MHT) cannot directly kill tumor cells, an augmented immunological effect resulting from MHT has been reported to induce injury of malignant tumors. In this study, the impact of regional MHT on lymphocyte subpopulations was investigated. Of particular interest was the effect of MHT on natural killer (NK) cells and T cells, which are important in the innate and adaptive immune systems. Regional MHT treatment was performed using an 8-MHz capacitive heating device, the Thermotron RF8 (Yamamoto Vinita Co., Ltd., Osaka, Japan). An average continuous radio-frequency irradiation of approximately 900 W was applied between two 30-cm electrodes placed on opposite sides of a volunteer's upper abdominal region for 30 min. In healthy volunteers exposed to this thermal treatment, NK cell activity and the percentage of NK cells and cytolytic NK cells (CD3^-CD56^dim cells) in lymphocyte populations increased significantly at 1 and 7 days after regional MHT treatment compared with pre-treatment numbers. The number of cytolytic NK cells also increased significantly at 1 day after treatment. The percentage of T cells and CD4⁺ T cells decreased significantly from 1 to 7 days following the heating procedure. However, no significant changes in the percentage and the number of CD8⁺ T cells was observed. Interestingly, the percentage and the number of CD4⁺CD25⁺ T lymphocytes which are recognized as regulatory T lymphocytes (T_reg) decreased significantly during the 7 day post-treatment period. These results suggest that regional MHT may activate both, the innate and adaptive immune systems, through activation of NK cells and through a decrease in the number of regulatory T cells.

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