The concept of “INTRACELLULAR HYPERTHERMIA” is selective heating of cancer cells after administration of magnetic submicron particles. We have reported the characteristics of some kind of particles in previous paper.
In this paper, we examined properties of Dextran Magnetite (DM) in inductive field of 500 kHz. DM was used as the submicron particles in addition to iron metal, stainless steel, Fe₃O₄ and 3C. DM is 5-15 nm in diameter and 3/gFe in susceptibility. DM particles are not simple mixture of dextran and ferrate but submicron complex. The heating unit (type TY-1) was a 7 kW generator of 500 kHz with a pancake type coil of 4 turns creating electro-magnetic field. The temperature of phantom with particles was measured at the inductive field of 500 kHz.
The temperature of DM was raised predominantly rather than that of other particles at the field of 500 kHz but wasn't at the field of 13.56 MHz. The relation of DM and temperature was positive in concentration of DM aqueous sol, susceptibility of DM aqueous sol and diameter of ferrate and nagative in molecular weight of dextran.
We could to create DM for most adequate purpose. This biological approach represents a new technology for effective treatment of cancer by hyperthermia.

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The concept of “INTRACELLULAR HYPERTHERMIA” is local inductive heating of cancer cells after administration of submicron particles producing magnetic excitation. These particles were taken in the cancer cells intracellularly by phagocytosis, resulting in selective destruction of cancer cells with little effect on normal cells and tissues.
We examined effects of intracellular hyperthermia on Meth-A and AH60C tumor cells and a phagocytosis of AH60C, NTF reticulum cell sarcoma and cultured human esophageal cancer cells (SGF -8a). Dextran magnetite was used as, the submicron particle. DM particles were injected in animals with tumor cells intraperitoneally or intratumorously. These animals were exposed to the external inductive field of 500 kHz for 20 min. at a temperature of more than 43 °C.
The phagocytosis of tumor cells was examined microscopically. DM particles were taken intracellularly in tumor cells at 24 hours after administration. The ILS (Increase in life span) of mice was longer in the group of DM than that of Fe₃O₄ suspension. The inhibition ratio of solid tumor of rats was better in the group of DM than control group. The survival rate of rats and mice were most evident in the each groups of 2 times of hyperthermia. DM particles were very promising in inductive heating of 500 kHz.

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前立腺癌とその転移に対するサイトカインの効果を検討するため, ヌードマウス移植ヒト前立腺癌とそのリンパ節自然転移に対し温熱療法と遺伝子組み換えヒト腫瘍壊死因子 (rhTNF) の併用療法を試みた.rhTNF単独療法としてrhTNF10000単位を投与し, リンパ節転移巣に対しすぐれた抗腫瘍効果を認めた.温熱療法とrhTNFの併用療法として40℃20分のmild hyperthermiaと2000単位のlow dose rhTNFを併用し, ヌードマウス移植前立腺癌の原発巣および転移巣に対し相乗効果を得た.さらに治療を繰り返す事により抗腫瘍効果が高められることを確認した.40℃20分のmild hyperthermiaのみでは十分な抗腫瘍効果は得られなかった.以上よりlow doseのrhTNFと温熱療法の併用療法は, rhTNFの抗腫瘍効果を高める意義のある治療方法と考えられた.

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The studies with agar phantoms demonstrated that, with the symmetric, three-electrodes capacitive device employed, central axis heating patterns can be manipulated significantly without appreciable distortion of lateral heating patterns produced at midphantom depths. Problems of excessive heating of subcutaneous fat will exist in most applications of deep tumor hyperthermia with capacitive devices. Five patients with cancer recived hyperthermic treatment using a Jasmin 3, 1000. No severe side effects were experienced, it was found that through reduction of the ratio of net power to the upper electrode and lower two electrodes, steady-state temperatures in the rectum and bladder could be raised from 4 °C to 5 °C above temperature within 20 minites after heating. In this report, the possibilities and consequences of manipulation of lateral heating patterns also will be evaluated. A prototype of Jasmin 3.1000, a capacitive heating device (operating at 13.56MHz) with an upper electrode and two symmetrically placed lower electrodes is an useful equipment clinically. We investigated that clinical application and thermal distribution with agar phantoms using three-electrodes capacitive device Jasmin 3.1000

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Human blood was incubated in the water bath at various temperature (050°C) for various time (5 90min), to experiment the effects of temperature on APTT, PT, fibrinogen, activities of clotting and fibrinolytic factors, platelete aggregation and its morphology. The results were as follows.
1. APTT and PT prolonged significantly at the border temperature, 43°C
2. Fibrinogen was clottable at 045°C, and unclottable at 50°C. But the changes of fibrin clot strand was observed under scaning at 43 °C. Prothrombin activity decreased at 50 °C, and factor X at 45 °C.
3. Plasminogen activity increased at 43 and 45°C, but decreased at 50 °C. Prekallikrein showed almost no change throughout 050 °C.
4. Platelets lost their aggregative function at 43°C using collagen, at 40°C using ADP. Simultaneously morphorogical change was observed at 43°C under scanning electron microscope.
From these results, we concluded that 43°C might be critical very important temperature in blood coagulation and fibrinolitic system as well as cell-survival in hyperthermia.

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In this report we describe our treatment protocol for malignant gliomas with an interstitial hyperthermia using 2450 MHz microwave irradiation and report a representative case of a recurrent malignant glioma treated with this protocol.
The protocol is as follows; the Brown-Roberts-Wells (BRW) stereotactic system is used for implantation of catheters. Cooling tubes intended for interstitial microwave antennas are implanted into the tumor approximately 10mm inside the margin of the contrast enhanced lesion on CT scans, equally spaced about 20mm apart. Catheters for housing thermisters are placed at the periphery of the tumor or in the center of the implant array. Postoperatively, microwave antennas and thermisters are inserted into the implanted catheters. The treatment goal of the interstitial hyperthermia is to keep steady state temperatures for 60 minutes. The desired minimum temperature is 43°C.
A 63-year-old woman with recurrent glioblastoma in bifrontal lobes was admitted to our hospital. Interstitial hyperthermia was performed. Enhanced CT scans obtained two days after hyperthermia revealed low density area in the region heated above 43°C and the area was consistent for 7 months. The efficacy, the problems of this protocol, and the possibility of combination with other therapeutic modalities were discussed.

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In order to improve local heating of hyperthermia, we carried out a heating experiment using a TX -150 phantom into which a balloon was placed as the model of the bladder. The balloon was filled with air or a mixture of ferromagnetic powder and TX-150. Local heat was applied with 13.56MHz radiofrequency (RF) capacitive heating equipment (500W). The temperatures in the phantom were measured by thermocouples attached to the balloon. The results of the heating experiment are summarized as follows : 1) When the balloon was filled with air, the lateral side of the balloon became remarkably heated up. 2) When the balloon was filled with a mixture of ferromagnetic powder and TX-150, the upper side was remarkably heated up. Although these results have been previously observed by other researches, these heating methods are thought to be clinically applicable and advantageous for more localized heating pf bladder tumors and protection of the normal bladder wall against overheating.

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Effect of systemic hyperthermia of different intensity which was used in combination with a chemical agent (CDDP) and BRM (OK-432) for the treatment of murine ascites tumor was comparatively investigated.
Animals used were adult male mice of F1 hybrid between C57L and A/HeMs. Tumor cells were of a syngeneic cloned cell line FMA3 which was derived from Furth's mastocytoma. Number of cells transplanted into the abdominal cavity was at 10⁵. Single uses of systemic hyperthermia of 39, 40, 41 and 42°C for 10 min or OK-432 which was given at a dose of 5 KE/kg did not cause a significant extension of mean survival fime (M. S. T.). CDDP, administered singly at a dose of 4 mg/kg, 1, 2, 3 or 4 times, caused the M. S. T. to extend 1.85, 3.96, 4.15 or 3.87 times longer than that in the control group, respectively. Additional use of the OK-432 to the CDDP of 4 mg/kg extended M. S. T. 1.47 times more than that achieved with the single use of CDDP (P < 0.01). Further addition of the systemic hyperthermia of 39°C to the combination of the CDDP and OK-432 further extended 1.82 times longer than the level attained with the combination of CDDP and OK-432 (P < 0.01). The magnitude of the extension of M. S. T. was comparable to that achieved with a single use of CDDP given more than twice, whereas the extent of irreparable renal disturbance was much slighter.
However, such beneficial effects on M. S. T. as well as on nephrotoxicity were not observed with the hyperthermia of temperatures examined higher than 39°C.

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We propose a new capacitive type heating method using distributed electrodes. Many capacitive type electrodes are arranged on boli, below which the heating material is placed. Proper potentials are applied to them so as to minimize the SAR in the fat layer of the heating material. SAR distributions in a model consisting of fat, muscle and fat layers are calculated with the finite element method. The results show that the SAR at the mid-point of the muscle layer is greater than that in the fat layer.

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この特集は日本ハイパーサーミア学会が重点課題として進めている癌温熱化学療法研究班の現時点での成果をまとめたものである.

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