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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頭書のワークショップは昭和61年2月8～9日昭和60年度文部省科学研究費がん特別研究I「温熱療法」加納班班会議 (3年次・東京) において行われたものである。基礎医学, ME学, 臨床医学 (放射線科の局所温熱療法と外科の全身温熱療法) 及びレーザーによるがん治療について各々の分野の第一線の研究者にして当班班員である各位を煩わせ, それらの世界的現状を概括して頂いた。その記録を本誌本号に掲載することにする。

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各種培養動物細胞を用いて, 抗がん剤アドリアマイシンに対する温熱効果を検討した.42-43°温熱効果は細胞種により異なった.43°増感効果が認められないW3YおよびCHO細胞においては, 43°加温後, 37°アドリアマイシンに対する感受性が著しく減少した.
ペプロマイシンの作用は43°との併用により増強した.しかし, 温熱耐性細胞においては, 43°温熱効果は低下した.一方, ベラパミルのPEP作用増強効果は, 温熱耐性細胞と非加温細胞とでは相違がなかった.
ベンツアルデヒドおよびその誘導体は37°では殺細胞作用を示はないが, 42あるいは43°温熱と併用すると, 相乗的な殺細胞効果を示した.この効果は形質転換細胞と正常細胞を比べると, 前者に選択的であった.

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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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あらゆる生物において,体温が至適温度より数度上昇した時に特有の反応が細胞においてみられる.この反応はheat shock反応と称され,著明な一群のたんぱく,heat shock proteis(hspと略)の誘導が特長的である.このheat shock反応はheat shockのみならず細胞への種々の侵襲によっても引きおこされるので,この反応は種々のストレスから細胞を守るための基本的かつ原始的な反応であろうと考えられる.ここでは,その時産生されるhspについて主として著者らの研究しているヒト培養細胞とラットを中心にその概略を説明し,さらにhspの誘導機構とその機能についての最新の知見とその作業仮説を,著者らの考えを混じえて概説する.
あらゆる生物においてheat shockに反応して細胞はheat shock proteinといわれる一群のたんぱくを合成する.このheat shock反応は他の種々の細胞侵襲によっても引きおこされるので, この反応は種々のストレスから細胞を守るための基本的かつ原始的な反応であると考えられる.ここではheat shock反応とその時産生されるheat shock proteinについて, またその誘導機構と機能について概説した.

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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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確固とした生物学的根拠を持つ癌の温熱療法は,医療用加温装置の開発に伴ない臨床に広く用いられようとしている.1984年,デンマークで行われた癌温熱療法に関する第3回国際シンポジウムの中でDr.Overgaardは,1977年から1984年の間に世界で213の臨床報告があり,10952人の患者が温熱治療を受けたと発表している.213の報告を加温方法,治療方法別に分類したのが表1であるが,局所温熱治療と放射線の併用治療が臨床的に最も研究されていることを示している.
本稿ではこの併用治療を中心に癌温熱療法の臨床の現況を,生物基礎実験結果と対比させながら概説する.

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広汎癌進展例に対する体外循環を用いた血液加温による全身温熱療法の臨床成績を述べた.本法により, 既往治療が無効であった未期癌症例に対しても抗腫瘍効果が得られることが確認された.本法は主として肺, 肝, リンパ節に主癌巣を有する症例に有効性が大きいが, 合併症の面から, P.S.4) 症例や閉塞性黄疸症例への適用は避けるべきと考えられた.

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HPD含有あるいは非含有KK-47細胞や家兎肝切片を試料として, EL, laser flash photolysis, two-laser excitationなどの分光学的研究により, GVLでは高いピーク出力による高密度励起からphotobleachingが発生し, 組織内光深達性がADLに比して大きいことが示された.従ってGVL照射では腫瘍組織内HT効果が得られた.HT効果を伴わないGVL出力でのPDTでも, ADLを用いたPDTに比しヌードマウス移植KK-47腫瘍の有意に高いCR率と, CR所要日数の短縮が得られた.さらにHT効果を伴ったGVL出力のPDTでは照射時間を1/10に短縮してもCR率, およびCR所要日数に有意の変化は認められなかった.以上の成績はPDT効果拡大にGVLの高い有用性を示すものと考えられた.

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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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