Feasibility of noninvasive thermometry for hyperthermia is addressed in this article. It is pointed out that the microwave radiometry, among various physical principles proposed for this purpose, appears to be the prime candidate by which a practical system can be developed in a foreseeable future.
An experimetal three-band microwave radiometer system along with a data analysis procedure developed by the authors is described. Results of the animal experiments performed on the abdoninal region of rabbits using this system are presented to demonstrate that the system is capable of measuring tissue temperatures at various depths up to 4cm from the body surface with a reasonable accuracy.
The results were encouraging, and the prospect looks bright for developing a practical noninvasive thermometry based on the multiple-frequency-band microwave radiometry.

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The Second Semi-annual Meeting of Research Project on “Hyperthermia Oncology” by Grant-In Aid for Cancer Research (60010035) in 1985 of Ministry of Education Science and Culture, Japan was held in Tokyo February 8 and 9, 1986 organized by E, Kano of Fukui Medical University.
In this meeting, a workshop on current topics of hyperthermia oncology was held which covered fields of medical biology, medical engineering and clinic of hyperthermia oncology, including laser photobiology and it's clinic.
Papers on this workshop were presented hereupon by a courtesy of Japanese Journal of Hyperthermic Oncology.

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The effect of hyperthermia on adriamycin cytotoxicity toward cultured cells was varied with the cell lines used; In human carcinoma cell line HeLa and KB, cell killing of adriamycin increased at 42 and 43°C, but in Chinese hamster ovary cells (CHO) and SV40-transformed rat fibroblasts (W3Y), the cytotoxicioy was decreased at the elevated temperatures. Heating CHO and W3Y cells at 43°C induced a resistance to adriamycin cytotoxicity in subsequent drug treatment at 37°C. The cytotoxic effect of peplomycin was increased by 43°C hyperthermia, but the enhancing effect was very much decreased in thermotolerant cells. On the other hand, verapamil equally enhanced peplomycin cytotoxicity in unheated and thermotolerant cells. Benzaldehyde and its derivatives are not cytotoxic at 37°C, but the combination with hyperthermia greatly enhanced the cytotoxicity in transformed cells rather than untransformed cells.

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Effects of hyperthermic treatment on animal tumors in vivo were reviewed in order to examine clinical cancer treatment. Response of tumors to heat is not simple compared to cultured cells in vitro. Tumors are of mixed population of growing and nongrowing cells, and of aerobic and hypoxic cells. Some cells in tumors are thermosensitive due to low pH. Damages induced by hyperthermic treatment alter the tumor response.
Hyperthermic treatment at 43°C for 30 minutes reduced the surviving fraction to 19%, and the surviving fraction continued to reduce until 7% at 3 hours of the treatment; this might due to the damages of blood vessels. The fraction of hypoxic cells in tumors increased after hyperthermic treatment 24 hours of the treatment. When animals bearing tumors were bred at 4°C, thermosensitivity of tumors increased. And hyperthermic treatment as low as 40°C produced tumor control. It might be recommended that hyperthermic treatment can be repeated with 3 - 5 hour intervals, however irradiation should not be applied within 24 hours after hyperthermic treatment. And cooling tumors, if possible, might increase the tumor curability.

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The exposure of cells from a variety of species to an increase in temperature results in the enhanced synthesis of several proteins, which have been referred to as heat shock proteins (HSPs). This phenomenon has been called the heat shock response even though recovery from anoxia, ethanol, heavy metals and a number other chemicals have been shown to induce the synthesis of the same proteins. Therefore, the response should, perhaps, more appropriately be referred to as a stress response.
When prokaryotic and eukaryotic cells are heated, those that survive acquire resistance to subsequent heat challenge as shown by an increase in cell survival. This phenomenon is termed thermotolerance. Thermotolerancce is a transient and nonheritable phenomenon which develops over a period of several hours following heat shock and decays within 3-6 days. Although the molecular mechanism (s) for the development of thermotolerance is not yet fully understood, several lines of experiments have demonstrated that enhanced synthesis of HSPs is closely related to the development of thermotolerance.
Here, we reviewd recent findings of biochemical characterization of HSPs and correlation of HSPs and thermotolerance.

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Exposure of living cells from bacteria to man to heat shock results in a drastic change in their pattern of protein synthesis. The heat shock response is characterized by the induction of the synthesis of a set of several proteins called heat shock proteins, accompanied by a general reduction of the overall pattern of protein synthesis. Of the heat shock proteins, two major ones having molecular weights of about 70, 000 and 85, 000 have structural similarities in a variety of organisms and seem to be conserved through evolution. Various treatments of cells other than heat, including tissue damages, anoxia, some poisons, transition metals, and amino acid analogues, can induce heat shock proteins in cells. The heat shock proteins may protect the cells following the stresses.
Here, we review recent findings on the biochemistry of heat shock proteins.

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Over the past decade or so, various types of heating equipment have been proposed in the field of hyperthermia, some of which have been getting clinical trials to a considerable extent. In the area of thermometry systems, systems with thermocouples have been applied for clinical use in many institutes and hospitals, and also systems with optical fibers have been making great progress. In this article, we will mainly review the features, including clinical response, of the various types of heating equipment and thermometry systems which are at present undergoing clinical trials.

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This article reviews the clinical application of local hyperthermia in cancer therapy. Local hypertermia alone can cause regressions in human neoplasms, but its low response rates shown make the clinical value limited. Several clinical trials demonstrate that hyperthermia plus radiotherapy can produce higher tumor response rates than radiotherapy alone or hyperthermia alone.Therapeutic gain of thermoradiotherapy is demonstrated in clinical trials for superficial tumors. The relationships of tumor response rates of thermoradiotherapy with histology, tumor volume, radiation dose, number of hyperthermia treatment and tumor temperature are also demonstrated.

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The clinical results and problems of extracorporeally - induced total - body hyperthermia (TBHT) for recurrent or unresectable cancers were presented. In our clinic, a total of 108 hyperthermic treatments were performed in 39 patients who had had unsuccessful conventional systemic anticancer chemotherapy. Partial response was observed in 10 of 30 evaluable patients (33%). In analysing the anticancer effects of TBHT according to cancer site, a high efficacy was observed in patients with their main tumor in the lung, liver and lymphnodes, irrespective of whether tumorigenesis was primary or secondary. The anticancer effects were most enhanced when TBHT was performed in combination with cis - diamminedichoroplatinum (II) and 5 - fluorouracil. We also retrospectively evaluated 168 patients treated with TBHT in 7 Japanese hospitals, including our patients. The analysed data were almost same as our results above mentioned.
In order to augment the anticancer effects of TBHT, the choice of combined agent (s) and administration timing are important. A useful method for determining the thermosensitivity of individual cancer cells to agents selected for drug treatment is the human tumor stem cell assay. Further, the usefulness of angiotensin II - induced hypertensive chemotherapy during TBHT for augmenting selective drug delivery to cancer tissue is stressed.

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A pulsed gold vapor laser (GVL, 628 nm) was experimentally compared with a continuous wave argon - dye laser (ADL, 630 nm) in terms of tissue penetration depth and photodynamic tumor destruction.
Using white rabbit auricles without hematoporphyrin derivative (HpD) injection, the extinction length of GVL light was increased with increasing output from 10 mW to 100 mW, but there was no increase in extinction length in case of ADL irradiations within this output range. At the output of 100 mW, the extinction length of GVL was 3.3 times larger than ADL. Using a two - laser excitation system including ADL, GVL and rabbit liver sections obtained 48 hr after HpD injection, the transmitted light power of both irradiations given alone or together to the section was studied. In combination of both irradiations which crossed at right angles, a synergistic increase in transmitted light power was obtained. A laser flash photolysis system consists of a Xe - lamp, monochromater, photomultiplier, pulser and delay circuit, excimer laser, oscilloscope, and quartz cell containing KK - 47 cells with/without HpD was used to determine the changes in light absorption after laser irradiation. KK - 47 cells containing HpD irradiated with excimer laser one puls exhibited a transient decrease in the light absorption rate for 240μs, while KK - 47 cells without HpD showed no acceleration of the transmission rate. This transient absorption, photobleaching, was thought to be a result of high density excitation of HpD resulting from the high peak power of the excimer laser. Furthermore, using a two - laser excitation system including GVL, ADL and the liver sections with/without HpD, a synergistic increase in transmitted light was observed. In addition, a comparative study of photodynamic tumor destruction and temperature increase during laser irradiations by GVL and ADL in nude mice transplanted KK - 47 tumors was performed. At irradiations showing no hyperthermia contribution, the CR rate and the number of days needed to achieve CR in a GVL group were significantly superior to those in a ADL group. This significance was accelerated by GVL irradiations contributing hyperthermia. Hyperthermia of the entire tumor was obtained at an average output of GVL 300 mW/cm². However, there was no hyperthermia contribution at the output of ADL 300 mW/cm², and even at the output of ADL 600 mW/cm2 only the tumor surface reached hyperthermia temperatures.
These results support the superiority of GVL over ADL in enhancing photodynamic antitumor activity.

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Experimental mouse leukemia L1210 cells were subjected to hyperthermia (43.0±0.05°C, waterbath) and photodynamic therapy (50μg/ml HpD, 630 ± 5nm at 0.1mW/cm²) for varying lengths of time and sequences. The results show that the two modalities intract in a manner which is more cytotoxic than the sum of the individual treatments, and the sequence of treatments is a determining factor in the degree of interaction of the HpD-uptake by the tumor cells. The most cytotoxic effect of photodynamic therapy is seen when the photodynamic therapy is treated after hyperthermia with HpD. When hyperthermia is done after HpD-uptake and photodynamic therapy, additive cytotoxic effect is obtained by analysis of dose-response curves. These data are supported on DNA damage (amount of single strand DNA) and RNA damage with analysing by flow cytometer to which the treated cells are stained with acridine orange (AO). Furthermore, an application to the clinical treatment, namely, the photodynamic therapy after the hyperthermia with HpD injection was able to propose as an useful combination therapy from the obtained finding in vitro experiments.

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The combined effect has been investigated using KK-47 cells and colony forming assay system. From the heat-response curve at 43°C hyperthermia, 20% growth inhibition time (IT20) was calculated, and the IT20 was combined with the following photoradiations. In combination of hyperthermia and photoradiation, a pronounced cell killing effect was obtained when hyperthermia was carried out after one hour of photoradiation. Damage repair from the photoradiation was observed when hyperthermia was performed 3 or 5 hours after photoradiation. The reverse sequence of hyperthermia and photoradiation, no combination effect was obtained. In addition, the uptake of HpD was investigated with measuring of the fluorescence intensity of HpD bound to KK-47 cells at various temperatures. It was shown that the fluorescence peak appeared at 614 nm at 7 and 37°C, and its peak appeared at 635 nm at 41°C, respectively. It was considered that the former spectra were assigned to the weak binding mode and the latter one stable binding mode, respectively.

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A device which can heat a certain area of the liver homogeneously to desired temperature is required in order to investigate the histopathological changes of the liver by local hyperthermia. We therefore have developed a radiofrequency (RF) current heating device employing an applicator with parallel arrays of needles, and examined the temperature distributions in agar phantoms and the liver of rabbits with this device. In both phantom study and rabbit liver experiment, central area of the applicator was homogeneously heated without hot spot appearance around the needles. Liver injury caused by the needles was negligible. These studies have demonstrated that an RF current heating device developed by us is a useful tool to heat the liver of rabbit homogeneously and precisely.

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Acute heat injury in lung during whole body hyperthermia was studied in 54 mongol dogs, especially in regard with Extra Vascular Lung Water (EVLW).
The following results were obtained.
1) Lung edema was observed as a result of severe acute heat injury during whole body hyperthermia. The mesurement of EVLW during whole dody hyperthermia was the most useful parameter for quantitative evalution and early diagnosis of lung edema.
2) Increased permeability in pulmonary capillaries appeared to be the main cause of the increase in EVLW during whole body hyperthermia.
3) Increase in EVLW during whole body hyperthermia correlated well with both mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). The measurement of mPAP and PVR also assumed the changes in EVLW.
4) Lung edema during whole body hyperthemia was reduced by administration of steroid hormone but not with positive end-expiratory pressure.

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Using AH100B tumor-bearing rats, effect of local heating by water bath immersion at 41, 43 and 45°C on tissue blood flow was studied in tumor and tumor-adjacent normal muscle. This expermental results showed that 41°C and 43°C local heating caused decrease of tumor blood flow with time dependency. Its reduction could disadvantageously influence the transport of anticancer agents into tumor tissue during lacal hyperthermia. We made another attempt to measure tumor blood flow during experimental hyperthermia combined with Angiotensin II (AGT II), It was recognized that AGT II suppressed decrease of tumor blood flow and led to augment tumor blood flow selectively during hyperthermia. It was thought that hyperhtermochemotherapy combined with AGT II was useful to heighten anticancer effects.

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The in vitro antiproliferative effect of recombinant murine interferon-β (Rec- MuIFN-β) combined with hyperthermia against mouse malignant glioma was evaluated. An increase in temperature enhanced the antiproliferative of Rec-MuIFN-β in the range of 40°C-43°C. In order to probe the mechanism of the enhanced antiproliferative effect, prostaglandin E₂ and 2 - 5A synthetase activities in the culture medium were measured. Rec-MuIFN-β treatment resulted in greater prostaglandin E₂ and 2-5A synthetase induction at 43°C than at 37°C. Flowcytometry studies of the DNA histogram showed that combined therapy prolonged the accumulation in the G₂M phase. Thus, these cellular effects resulting from Rec-MuIFN-β were enhanced by elevated temperature. These results indicate the possibilities of a significant antitumor effect produced by the combination therapy of interferon and hyperthermia against human malignant gliomas.

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Photoradiation therapy using hematoporphyrin derivative (HpD) and laser has been applied as a new modality of cancer therapy. At present the indications of this therapy are limited to superficial tumors because of the limitation of light penetration. 13.56 MHz radiofrequency (RF) used in hyperthermia can penetrate into the deep regions. Present studies were carried out to evaluate an anti-tumor effect of heat plus HpD in malignant brain tumors.
C-6 and Rous sarcoma virus-induced glioma cells (RSV cells) were incubated for 24 hours in the medium containing HpD (0-125 μg/ml). Hyperthermic treatment was performed by either water bath or 13.56 MHz RF in the range of 37-43°C. Every procedure was carried out in the dark. Anti-tumor effect of the treatment was evaluated by observing the growth curve of glioma cells.
Results were as followed; 1) HpD itself affected C-6 and RSV cells dose-dependently. 2) HpD acted synergistically with heat for the killing of glioma cells. C-6 cells were more sensitive than RSV cells. The response was related to heating time and temperature. 3) In C-6 and RSV cells, the effects of heat by water bath and RF were similar in the same temperatures.
These data suggest that hyperthermia plus HpD may become one of the main therapeutic modalities for human gliomas.

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A hyperthermia system, whose thermometry was continuously done at several points with a multisensor probe, was developed and clinical studies employing hyperthermia combined with radiotherapy were carried out. Of eighty seven cases treated from 1980 to 1985, sixty eight cases were qualified for evaluation. Complete responses were observed in 28% (19/68), partial responses in 51% (35/68) and no responses in 21% (14/68). The response rates for superficial (less than 6cm from the skin surface) and deep seated tumors (more than 6cm from the skin surface) were respectively 90% (44/49) and 53% (10/ 19). Acute severe complications occurred in four cases. They were burns and a pneumothorax induced during the insertion of a probe and considered to be overcome with the improvement of techniques.
No correlation could be found between treatment effects and observed temperatures. The investigation of recorded temperatures in tumors proved that thermometry at few points did not necessarily indicate the magnitude of hyperthermic, treatment, i.e. heat dose, due to irregular temperature distribution especially in neck and deep seated tumors, and indicated that the knowledge of temperature distribution was requisite to analyze clinical results from the viewpoint of heat dose.
I believe that hyperthermia with radiation can be rather safely applied in the treatment of malignant disease and yield remarkable results in the eradication of local cancers.

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The experimental system to obtain two - dimensional temperature distribution in a phantom was developed. The changes of thermal distribution during and after heating and the dependence of distribu-tion upon the volumes of phantom were investigated. The phantoms were heated with an 8 MHz RF capacitive heating unit with a pair of electrodes of 15 cm in diameter.
1. The temperature distribution tended to become rather uniform due to thermal diffusion with the increase of the heating time and the time after the end of heating. To approximate temperature distribution to SAR (specific absorption rate) distribution, the heating time and the interval between heating and thermometry must be short.
2. The temperature distribution got inhomogeneous with the increase of volume of phantoms heated with similar size electrodes. The standard phantom is necessary to evaluate the equipments and methods of heating.
3. The coefficient of variation of temperature in the phantom was used to express the inhomogeneity of temperature distribution. The values agreed with the visual estimation.
4. For the display of temperature distribution, it is necessary to define the reference point for normalization according to heating methods and equipments. In our paper, the center of a phantom where only a littele effect of thermal diffusion was observed, was defined as the reference point.

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