Since high levels of hyperthermia induce immunosuppression to a certain extent (i.e., granulocytosis and lymphocytopenia) in patients, we applied mild hyperthermia in volunteers using equipment enabling well-controlled hyperthermia. Restricted control of rectal temperature at 39.4 (± 0.2)°C for 30 min was conducted and various parameters of the body were examined. The most prominent change observed during exposure to hyperthermia was elevated levels of pH and PO 2 in the blood, even in the venous blood. A transient elevation of ACTH, cortisol and growth hormone in the blood was also seen during this time. In parallel with this phenomenon, the number of total lymphocytes and those of its subsets (especially CD57 + or CD56 + NK cells and NKT cells) increased. More interestingly, the proportion of HLA-DR (MHC class II antigens) increased in NK and NKT cells, and their intensity on the surface of CD20 + B cells increased. These results suggest that mild hyperthermia is important for modulation of the functions of the circulatory, endocrine and immune systems.It is widely known that hyperthermia induces the production of heat shock proteins (HSPs) and that such HSPs are able to induce immunopotentiation via the augmented expression of MHC class I or II antigens on lymphocytes and tissue cells (2, 3, 10, 15). Hyperthermia is therefore expected to have potential as cancer immunotherapy. Another strategy for use of hyperthermia in cancer therapy is based on the notion that cancer cells are sensitive to thermal stress, which results in apoptotic death (5,20,23). However, we have encountered severe granulocytosis and lymphocytopenia in patients or animals during the exposure to various types of stress, including hyperthermia (4,12,16,17). This experience is contrary to our expectation for immunopotentiation by hyperthermic therapy.In light of these findings, we conducted mild hyperthermia in volunteers using the "Thercura System," a well-controlled hyperthermia device. We found that restricted control of rectum temperature to 39.4 (± 0.2)°C for 30 min was able to induce a prominent potentiation of many parameters in the circulation, endocrine system and immune system. Especially, the immunopotentiation induced by the present protocol of mild hyperthermia seems to be of great value for cancer patients and other diseased persons for treatment of their decreased levels of the immune functions.

The effect of mild hyperthermia on venous blood pH was examined in 6 cancer patients. Mild hyperthermia was induced by continuation of a rectal temperature of 39.5°C for 30 min. All 6 patients were diagnosed as suffering from advanced cancer with or without surgery and chemotherapy pretreatments. In Cases 1 to 5, but not Case 6, venous blood pH was alkalized up to pH 7.7 by this mild hyperthermia and the effect was reproduced depending on the application of hyperthermia. At this time, alkalized pH was accompanied by increased PO 2 and decreased PCO 2 in the blood. These patients showed good physical conditions and improved clinical data. On the other hand, hyperthermia could not be continued in Case 6 due to his worsened physical condition. The present data suggest that mild hyperthermia is a useful method to improve circulation failure, physical condition and clinical data.Many cancer patients are suffering from hypothermia and circulation failure (8,11,12,18) due to vessel constriction induced by sympathetic nerve activation (1, 19). As a result, immunosuppression is often accompanied with these patients, showing lymphocytopenia. Restoration from this circulation failure seems to be important for the treatment of cancer. In this regard, there have been many trials of hyperthermia for the treatment of malignancy (6,9,17,20). Hyperthermia indeed ameliorates not only immune functions but also other physical conditions. In the course of these studies, we have noticed that hyperthermia (i.e., > 40°C) sometimes induced rather immunosuppression as a thermal stress (14). At this time, persons who experienced with hyperthermia showed granulocytosis and lymphocytopenia after the treatment. This might be due to the fact that overexposure of hyperthermia induced stressassociated sympathetic nerve activation and that granulocytes bear surface adrenergic receptors but lymphocytes bear surface cholinergic receptors (13,15). A similar response was also reported in animal studies (16). Dogs and cats which experienced with severe hyperthermia showed immunosuppression, showing granulocytosis and lymphocytopenia.In an earlier study, we showed that hyperthermia at the level up to 39.5°C (rectal temperature) for 30 min did not induce granulocytosis but rather induced immunopotentiation (14). In the present study, we applied this condition of hyperthermia for 6 cancer patients. As shown previously and in this study, an appropriate condition of hyperthermia is well correlated with the alkalization of blood pH with increased PO 2 and decreased PCO 2 after the application of hyperthermia. MATERIAL AND METHODS Subjects. Diagnosis of all cancer patients, including

Two patients with co-existing meningeal and pulmonary cryptococcosis were successfully treated by pulmonary resection and chemotherapy. Under cover of miconazole and 5-fluorocytosine, pulmonary mass lesions were successfully removed despite the fact that the patients had meningitis. The patients recovered from meningitis immediately after the surgical procedures and show no recurrence of meningeal symptoms more than 2 years after the operation. It appears that early removal of a pulmonary cryptococcal focus combined with antifungal agents may give a quite favourable outcome for meningitis.

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