Single Hyperthermia Research Articles

AIPH-Encapsulated Thermo-Sensitive Liposomes for Synergistic Microwave Ablation and Oxygen-Independent Dynamic Therapy.

Microwave ablation (MWA) is a novel treatment modality that can lead to the death of tumor cells by heating the ions and polar molecules in the tissue through high-speed vibration and friction. However, the single hyperthermia is not sufficient to completely inhibit tumor growth. Herein, a thermodynamic cancer-therapeutic modality has been fabricated which could be able to overcome hypoxia's limitations in the tumor microenvironment. Using thermo-sensitive liposomes (TSLs) and oxygen-independent radical generators (2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride [AIPH]), a nano-drug delivery system denoted as ATSL is developed for efficient sequential cancer treatment. Under the microwave field, the temperature rise of local tissue could not only lead to the damage of tumor cells but also induce the release of AIPH encapsulated in ATSL to produce free radicals, eliciting tumor cell death. In addition, the ATSL developed here would avoid the side effects caused by the uncontrolled diffusion of AIPH to normal tissues. The ATSLs have shown excellent therapeutic effects both in vitro and in vivo, suggesting its highly promising potential for clinic.

Detailed in vitro analyses of the impact of multimodal cancer therapy with hyperthermia and radiotherapy on the immune phenotype of human glioblastoma cells

Purpose Improvements of heat-delivery systems have led to hyperthermia (HT) being increasingly recognized as an adjunct treatment modality also for brain tumors. But how HT affects the immune phenotype of glioblastoma cells is only scarcely known. Materials and Methods We therefore investigated the effect of in vitro HT, radiotherapy (RT), and the combination of both (RHT) on cell death modalities, immune checkpoint molecule (ICM) expression and release of the danger signal HSP70 of two human glioblastoma cell lines (U87 and U251) by using multicolor flow cytometry and ELISA. Hyperthermia was performed once or twice for 60-minute sessions reaching temperatures of 39 °C, 41 °C, and 44 °C, respectively. RT was administered with 5 x 2 Gy. Results A hyperthermia chamber for cell culture t-flasks regulating the temperature via a contact sensor was developed. While the glioblastoma cells were rather radioresistant, particularly in U251 cells, the combination of RT with HT significantly increased the percentage of apoptotic and necrotic cells for all temperatures examined and for both, single and double HT application. In line with that, an increased release of HSP 70 was seen only in U251 cells, mainly following treatment with HT at temperatures of 44 °C alone or in combination with RT. In contrast, immune suppressive (PD-L1, PD-L2, HVEM) and immune stimulatory (ICOS-L, CD137-L and Ox40-L) ICMs were significantly increased mostly on U87 cells, and particularly after RHT with 41 °C. Conclusions Individual assessment of the glioblastoma immune cell phenotype with regard to the planned treatment is mandatory to optimize multimodal radio-immunotherapy protocols including HT.

Mild hyperthermia accelerates doxorubicin clearance from tumour-extravasated temperature-sensitive liposomes.

Mild hyperthermia (HT) (40-43 °C) has been combined with temperature-sensitive liposomes (TSL), offering on-demand drug release for increased drug bioavailability and reduced systemic toxicity. Different HT regimens have been applied to trigger liposome drug release in the blood vessels (intravascular) of heated tumours or following tumour extravasation (interstitial). The present study systematically assessed the in vivo doxorubicin (Dox) release and therapeutic efficacy of Dox-loaded TSL with different release profiles. Low temperature-sensitive liposomes (LTSL-Dox), traditional-temperature-sensitive liposomes (TTSL-Dox), and non-temperature-sensitive liposomes (NTSL-Dox) were combined with a single or two HT in different tumour models (murine melanoma B16F10 tumour and human breast MDA-MB-435). The efficacy of each treatment was assessed by monitor tumour growth and mice survival. The level of Dox in tumour tissues was quantified using 14C-Dox and liquid scintillation while Dox release was assessed using live imaging and confocal laser scanning microscopy. Applying a second HT to release Dox from extravasated TTSL-Dox was not therapeutically superior to single HT application due to Dox clearance from the extravasated TTSL-Dox. Our findings revealed that enhanced blood perfusion in heated tumours during the second water bath HT could be seen as a hurdle for TTSL-Dox's anticancer efficacy, where the systemic toxicity of the redistributed Dox from the tumour tissues could be potentiated.

Assessment of changes in the main homeostasis indicators in mammals after hyperthermic exposure

Introduction. The occupation of firefighters is characterized by the impact of both hazardous fire factors and a complex of harmful and dangerous characteristics of various natures, often exceeding the expected values. High air temperature is typical for almost all types of fire and is one of the main adverse physical factors affecting the body of firefighters. Experimental models on animals are of leading importance in studying extreme fire factors, including hyperthermic exposure. Material and methods. The study was carried out on 124 outbred white male rats of 3 months of age weighing 250-300 g, divided randomly into two groups. The first group (62 rats) was subjected to a single hyperthermic load. The second group (62 rats) was subjected to daily hyperthermic load during 14 days. The study of the leading indicators of the acid-base state and water-electrolyte balance, biochemical and clinical blood tests, cellular and humoral immunity was carried out before and after hyperthermic exposure. Results. The obtained data indicate high ambient temperatures cause changes in homeostasis indices in laboratory animals. At the same time, there are alterations in the indicators of water-electrolyte balance, acid-base state, clinical and biochemical blood tests and the immune system. Conclusion. An experimental model of extreme heat exposure on animals showed the emergence and persistence of changes in the leading indicators of homeostasis. In the group of single hyperthermia, these parameters were restored to the background levels in a day. In the group of multiple hyperthermia, they remained altered.

Evaluation of the effect of high air temperature on the behavioural activity and physical performance of animals (in a rat model)

Introduction. The profession of firefighters belongs to extreme activities. Fire hazards include flames, sparks, heat flow, elevated ambient temperatures, increased concentrations of toxic combustion and thermal decomposition products, decreased oxygen concentrations, and reduced visibility in smoke. High air temperature during fire extinguishing is one of the main adverse physical factors affecting firefighters’ bodies. Material and methods. The study was carried out on 124 outbred white male 3-month rats weighing 250-300 g, divided randomly into two groups: the first group (62 rats) underwent single hyperthermia. The second group (62 rats) experienced daily hyperthermia for 14 days. The study of the behavioural activity of animals was carried out after single and prolonged hyperthermia using the following methods: “Open field”, “Elevated cruciform maze”, Porsolt’s test, running on a treadmill. The tests were performed two times: the first time - before exposure, the second - after, with intervals between tests of at least two weeks. Results. The data obtained indicate that the high ambient temperature causes changes in the behavioural responses in animals, which is expressed by an increase in the level of anxiety, a decrease in motor and research activity, the development of depressive states, and a decrease in physical endurance. Conclusion. An experimental model of extreme heat exposure on animals showed the emergence and persistence of changes in animals’ behavioural activity and physical performance indicators. This experiment can be used to study the long-term effects of high temperatures on firefighters’ bodies.

A Phase I Prospective Clinical Trial Using Volumetric Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) Hyperthermia (HT) Combined with Radiotherapy and Chemotherapy for Recurrent Rectal Cancer

Non-operable locally recurrent rectal cancer following chemotherapy (CT), radiation therapy (RT) and surgery (Sx) presents an extremely challenging clinical scenario as it portends both poor outcomes and challenging palliation. The addition of HT may improve the local control and quality of life by providing additional sensitization. Herein, we report on the results of our first in human phase I prospective clinical trial of MR-HIFU hyperthermia combined with RT and CT for non-operable recurrent rectal cancer. This ethics-approved study enrolled 6 patients with recurrent inoperable rectal cancer following CT, RT and Sx who were candidates for re-irradiation and chemotherapy; and with an MRI-visible and HIFU-accessible lesion. Patients were prescribed 30.6 Gy delivered in 1.8Gy fractions delivered daily with concurrent oral capecitabine. MR-HIFU HT was delivered immediately before RT on days 1, 8, and 15 under procedural sedation. Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Colorectal cancer (FACT-C) were collected prospectively at baseline and 1, 2, 3, 4 and 12 weeks after treatment. Statistical analysis was performed using paired-samples t-test and repeated measures ANOVA. A p value of ≤ 0.05 was considered significant. Median age of patients was 59.5 (range: 39-76). All had received previous CT, RT and Sx for a prior adenocarcinoma of rectum. 1 patient withdrew from the study due to pre-existing pain issues and received only 1/3 planned HT treatments. There were no intraoperative complications, no adverse events or unintended tissue damage attributable to HT, RT, or CT. Table 1 shows the best single continuous HT and mean temperatures (T90, T10), cumulative time in range (TIR), cumulative number of equivalent minutes at 43oC (CEM43) and day 90 imaging response. There were no attributable grade 2-5 toxicities associated with the intervention. 2 patients had transient grade 1 GI toxicity following intervention. At 90 day follow up, 2 patients had partial response, 2 patients had stable disease and 1 patient had progressive disease. There was no statistically significant difference found using repeated measures ANOVA in FACT-C scores (p = 0.63) and BPI (p = 0.45). Table 1 – HT quality and T2 weighted MRI response. The addition of MR-HIFU HT to re-irradiation with chemotherapy is a novel, feasible and safe treatment modality with no negative impact on patients’ quality of life. Further investigation with a phase II clinical trial in primary rectal cancer may be warranted.Abstract 3424; TableBest Session TemperatureCumulative TIR 40-45°CCumulative CEM43,T50Radiologic ResponsePtMean [oC]T90 [oC]T10 [oC][min][min]0140.6 ± 1.040.1 ± 1.642.1 ± 1.022.72.5PR0242.5 ± 0.241.6 ± 0.243.3 ± 0.251.841.3SD0341.9 ± 0.540.9 ± 2.043.1 ± 0.449.017.7PD0441.5 ± 0.539.9 ± 0.542.8 ± 0.516.36.8Withdrew0539.4 ± 0.638.9 ± 0.940.2 ± 0.54.20.4SD0642.3 ± 0.740.5 ± 0.743.7 ± 0.732.313.5PR Open table in a new tab

Thermoresponsive magnetoliposome encapsulating doxorubicin and high performance Ferumoxytol for effective tumor synergistic therapy in vitro

Owing to the multiple pathogenic routes and enormous proliferative capacity of tumor cells, conventional drug carriers find it difficult to fulfill clinical treatment gradually, for instance liposomes with single chemotherapy mode. New nanodrug carriers capable of multimodal therapy have emerged in an attempt to find an effective treatment; however, very few of them could be approved eventually, mainly because they could not reach the strict pharmaceutical quality standards. In this context, high-performance liposome synthesis based on typical medical materials may be an effective resolution strategy. Herein, a novel magnetoliposome coencapsulating doxorubicin and iron oxide nanomedicine Ferumoxytol was designed. After the formulation process screening, the magnetoliposome was found to be in stable dispersion with high Doxorubicin payload. In particular, a prominent magnetocaloric effect and thermoresponsive drug release profile were obtained. This is due to the combination of high performance Ferumoxytol with thermosensitive phospholipids dipalmitoylphosphatidylcholine. Compared with single hyperthermia or single chemotherapy, the chemotherapy and magnetic hyperthermia dual-modal synergetic treatment of the magnetoliposome present distinct advantages on cell viability assay in vitro. The novel temperature stimuli-responsive liposome enriches the anti-cancer nanomedicine species available in clinics, motivating the development of the clinical treatment strategy.

Ultrasound microbubble potentiated enhancement of hyperthermia-effect in tumours.

It is now well established that for tumour growth and survival, tumour vasculature is an important element. Studies have demonstrated that ultrasound-stimulated microbubble (USMB) treatment causes extensive endothelial cell death leading to tumour vascular disruption. The subsequent rapid vascular collapse translates to overall increases in tumour response to various therapies. In this study, we explored USMB involvement in the enhancement of hyperthermia (HT) treatment effects. Human prostate tumour (PC3) xenografts were grown in mice and were treated with USMB, HT, or with a combination of the two treatments. Treatment parameters consisted of ultrasound pressures of 0 to 740 kPa, the use of perfluorocarbon-filled microbubbles administered intravenously, and an HT temperature of 43°C delivered for various times (0–50 minutes). Single and multiple repeated treatments were evaluated. Tumour response was monitored 24 hours after treatments and tumour growth was monitored for up to over 30 days for a single treatment and 4 weeks for multiple treatments. Tumours exposed to USMB combined with HT exhibited enhanced cell death (p<0.05) and decreased vasculature (p<0.05) compared to untreated tumours or those treated with either USMB alone or HT alone within 24 hours. Deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and cluster of differentiation 31 (CD31) staining were used to assess cell death and vascular content, respectively. Further, tumours receiving a single combined USMB and HT treatment exhibited decreased tumour volumes (p<0.05) compared to those receiving either treatment alone when monitored over the duration of 30 days. Additionally, tumour response monitored weekly up to 4 weeks demonstrated a reduced vascular index and tumour volume, increased fibrosis and lesser number of proliferating cells with combined treatment of USMB and HT. Thus in this study, we characterize a novel therapeutic approach that combines USMB with HT to enhance treatment responses in a prostate cancer xenograft model in vivo.

A phase I study of MR-HIFU hyperthermia (HT) with radiation (RT) and chemotherapy (CT) for recurrent rectal cancer.

78 Background: HT may improve cancer control and quality of life by sensitizing tumors to RT and CT. Inoperable recurrent rectal cancer has marginal outcomes with current retreatment regimens. We report the results from a first-in-human phase I study of MR-HIFU hyperthermia combined with RT and CT for recurrent rectal cancer. Methods: This ethics-approved study enrolled 6 patients fit for re-irradiation and chemotherapy; and with a MRI-visible and HIFU-accessible lesion. Patients received 30.6 Gy (17 fractions) and daily oral capecitabine, plus MR-HIFU HT immediately before RT on days 1, 8, and 15. Primary objectives were safety (acute toxicity) and treatment feasibility. Secondary objectives included late toxicity, pain palliation, quality of life, and radiologic response. HT was delivered with the Sonalleve MR-HIFU system on a 3T MRI. MR-based feedback control parameters were prescribed to achieve a mean temperature of 42.5°C in an 18 mm diameter target region for 30 minutes without exceeding 45°C. Results: One patient withdrew after completing 1/3 HT sessions due to scheduling and sedation difficulties. Five patients completed HT, RT and CT. There were no intraoperative complications, no adverse events or unintended tissue damage attributable to HT, RT, or CT. Table shows the best single continuous HT and mean temperatures (T90, T10), cumulative time in range (TIR), cumulative number of equivalent minutes at 43oC(CEM43) and day 90 imaging response. Sonication and MRI suite times were 36±13 and 226±78min. Conclusions: MR-HIFU HT was safely delivered in patients with recurrent rectal cancer. Treatment planning and patient set-up times decreased while beam-on time increased with experience. MR-HIFU HT combined with RT and CT appears feasible for primary tumours. Clinical trial information: NCT02528175. [Table: see text]

Localized delivery of therapeutic doxorubicin dose across the canine blood–brain barrier with hyperthermia and temperature sensitive liposomes

Most drugs cannot penetrate the blood–brain barrier (BBB), greatly limiting the use of anti-cancer agents for brain cancer therapy. Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug in response to hyperthermia (>40 °C). Since hyperthermia also transiently opens the BBB, we hypothesized that localized hyperthermia can achieve drug delivery across the BBB when combined with TSL. TSL-encapsulated doxorubicin (TSL-Dox) was infused intravenously over 30 min at a dose of 0.94 mg/kg in anesthetized beagles (age ∼17 months). Following, a hyperthermia probe was placed 5–10 mm deep through one of four 3-mm skull burr holes. Hyperthermia was performed randomized for 15 or 30 min, at either 45 or 50 °C. Blood was drawn every 30 min to measure TSL-Dox pharmacokinetics. Nonsurvival studies were performed in four dogs, where brain tissue at the hyperthermia location was extracted following treatment to quantify doxorubicin uptake via high-performance liquid chromatography (HPLC) and to visualize cellular uptake via fluorescence microscopy. Survival studies for 6 weeks were performed in five dogs treated by a single hyperthermia application. Local doxorubicin delivery correlated with hyperthermia duration and ranged from 0.11 to 0.74 μg/g of brain tissue at the hyperthermia locations, with undetectable drug uptake in unheated tissue. Fluorescence microscopy demonstrated doxorubicin delivery across the BBB. Histopathology in Haematoxylin & Eosin (H&E) stained samples demonstrated localized damage near the probe. No animals in the survival group demonstrated significant neurological deficits. This study demonstrates that localized doxorubicin delivery to the brain can be facilitated by TSL-Dox with localized hyperthermia with no significant neurological deficits.

Hyperthermia-Induced Febrile Seizures Have Moderate and Transient Effects on Spatial Learning in Immature Rats.

The aim of this study was to characterize a novel animal model hyperthermia-induced febrile seizure and to investigate the impacts of repetitive febrile seizures on spatial learning and memory performances in immature rats. Methods. Rats were subjected to hyperthermia exposure one, two, or three times in 10-day intervals during 30 min in a water bath warmed at 45–50°C and their behaviour was monitored. Morris water maze spatial learning and memory were examined for control and treated groups. Results showed that rats subjected to 30-minute hyperthermia hot water developed rapidly myoclonic jerks and then generalized seizures. After a single hyperthermia exposure, the time for generalised tonic-clonic seizures appearance was 16.08 ± 0.60 min and it decreased gradually with repetitive exposure to reach 12.46 ± 0.39 min by the third exposure. Febrile seizures altered the spatial learning and memory abilities in Morris water maze and increased the time spent to attain the platform after one or two exposures, while after a third exposure rats exhibited the same latency compared to controls. Similar results were obtained in probe test where rats, subjected to hyperthermia for one or two episodes, spent less time in the target quadrant compared to corresponding controls. Further, when platform was moved from northwest to southwest quadrant, memory transfer test indicated that after one or two hyperthermia exposures cognitive performances were slightly altered, while after a third exposure the latency to escape increased significantly compared to untreated group. It was concluded that 30 min of hyperthermia hot water was sufficient to induce febrile seizures in immature rats and an increase of susceptibility was observed with repetitive hyperthermia exposure. Hyperthermia treatment impaired cognitive performances but the effects were mostly transient and moderate.

The effect of KNK437, a heat shock protein inhibitor, on angiogenesis of endothelial cells

Aim: Hyperthermia is an effective therapy for cancer and tumor angiogenesis. However, the development of thermotolerance is an important problem. We aimed to investigate the effects of KNK437 and quercetin on angiogenesis and thermotolerance in endothelial cells (ECs). Materials and methods: ECs were grown in EGM-2 medium. ECs were preincubated with KNK437 or quercetin and then treated with single and fractionated hyperthermia. Tube formation assay on Matrigel Matrix was performed in these cells to investigate angiogenesis. Results: Tube formation was suppressed in cells that were treated with KNK437 and quercetin at 37 °C. Single hyperthermia (45 °C for 1 h) inhibited tube formation. KNK437 and quercetin pretreatment decreased capillary-like structures more effectively than single hyperthermia treatment. In cells that acquired thermotolerance induced by fractionated hyperthermia, tube formation was dramatically increased, but KNK437 and quercetin reversed the effects of thermotolerance on angiogenesis. KNK437 was found to be more effective than quercetin in all study groups. Conclusion: This study is original in that KNK437 inhibited angiogenesis and thermotolerance in ECs. This compound may be an essential molecule contributing to the efficient treatment of hyperthermic therapy in human cancers.

Morphogenesis of Adaptation and Compensatory Reactions in Mouse Adrenals during Restitution after Thermal Exposure

Single hyperthermia session causes an appreciable decrease in adrenocorticocyte count in the adrenal cortex in mice on day 3 of postthermal restitution. Morphological changes in the adrenals under conditions of developing stress reaction manifested in increased structural and functional heterogeneity of adrenocorticocytes in all cortical layers, exhaustion of lipid incorporations in the zona fasciculata cells, pronounced shrinkage of zona reticularis, developing against the background of hemodynamic disorders. Recovery of the total count of adrenocorticocyte population was associated with the appearance of small accumulations of immature cells in the subcapsular area of zona glomerulosa. Despite the absence of pronounced changes in the architectonics of all adrenocortical zones during postthermal restitution, recovery of zona reticularis was incomplete, which manifested in its shrinkage and persistence of degenerative changes in adrenocorticocytes.

Metabolism in perfused rat lived at different terms after short-term hyperthermia.

The metabolic state of rat liver was studied in vivo 1, 6, and 18 h after single hyperthermia (42 degrees C). It was shown that intracellular compensatory reactions involved in restoration of the energy state and realization of endogenous cytoprotective mechanisms play a role during recovery.

Heat shockin vivo modulates cytotoxicity of xenobiotics

Heat shock was modeledin vivo for induction of cross-thermotolerance to acrylamide, a xenobiotic inductor of oxidative stress. Single hyperthermia (40–41°C, 25 min) reduced neuro- and hepatotoxicity of xenobiotic toxifying by phenobarbital-, but not methylcholanthrene-induced cytochrome P-450 isoforms (the hexenal test).

Zur Wirkung einer iterativen milden Ganzkörperhyperthermie auf den Fibromyalgieschmerz - Pilotstudie

Fibromyalgia is a very common non-inflammatory rheumatic disease. Main symptoms are wide-spread pain, multiple tender points, and irritations of autonomous nervous system which are often accompanied by depression and sleep disturbances. The disease is very resistant against pharmacological as well as physical treatment, but may be ameliorated by heat applications. Objective: Investigations about a possible influence of repeated moderate hyperthermia on pain. Methods: Using Iratherm 1000 (von Ardenne GmbH, Dresden) whole-body hyperthermia was induced (duration: 30 min, mean body temperature: 38±0,32°C, 3 treatments per week for 3 weeks). In addition, all patients received an identical standardized drug and a physical treatment program. Pain threshold was measured at 42 tender points using a dolorimeter (Pain Diagnostics and Thermography Inc., Great Neck, USA). For subjective pain intensity, a pain score and a visual pain analog scala were used. Results: Immediately after a single hyperthermia treatment, pain was significantly reduced. At the end of 3 weeks' treatment, pain no longer reached the pretreatment level. Conclusions: Moderate whole body hyperthermia has a significant analgesic effect in fibromyalgia, especially under repeated application. Further investigations in controlled studies are necessary.

Potentiation of hyperthermia in a murine tumour by metabolic inhibitors rhodamine 123 and 2-deoxy-D-glucose or 5-thio-D-glucose.

Rhodamine 123 injected into mice on 3 days consecutively before a single hyperthermia treatment (45 degrees C for 15 min) potentiated hyperthermia as evidenced by an increased mean tumour growth delay of a transplantable murine mammary adenocarcinoma (MTG-B). Addition of three daily injections of either 2-deoxy-D-glucose, or 5-thio-D-glucose, coordinated with the rhodamine 123, and administered before hyperthermia, resulted in an additional tumour growth delay, but not large enough to suggest an additional significant interaction between the two drugs and heat. This effect was obtained using doses of the glucose analogues which did not potentiate therapeutically when combined with heat without rhodamine 123. On the third day of treatments, rhodamine 123 or 5-thio-D-glucose, or the two drugs together, 60 min before heating, produced a longer growth delay compared with each combination treatment with drugs administered 15 min before heating. However, this effect was not significant. Results of these experiments suggest that in this murine tumour thermopotentiation can be attained by combining these two classes of metabolic inhibitors with hyperthermia.

Hyperthermia enhances mitoxantrone cytotoxicity on human breast carcinoma and sarcoma xenografts in nude mice

In this preclinical in vivo study, we measured antitumor response, local side effects and systemic toxicity of locally applied water-bath hyperthermia given alone or simultaneously with mitoxantrone (3 mg/kg b.w. i.v.; LD 10) on a human derived breast carcinoma (MX 1) or a human sarcoma (S 117) transplanted to female athymic (nude) mice. A single hyperthermia treatment at a tumor temperature up to 43°C for 1 hr caused in both tumor lines only minor tumor regressions and transient tumor growth delay. However, the antitumor effect of mitoxantrone was significantly enhanced by local hyperthermia at 42°C and particularly at 43°C. In both tumor lines complete tumor regressions were achieved only if mitoxantrone was combined with hyperthermia. Undesired side effects and drug toxicity were not enhanced by hyperthermia. According to in vitro data and the results of the present in vivo study mitoxantrone seems to be a good candidate for clinical trials in combination with locoregional hyperthermia.

Interstitial hyperthermia of experimental brain tumor using implant heating system.

New experimental system of induction hyperthermia for brain tumor using ferromagnetic implant with low Curie point has been developed. The metal implant is cylindrical needle and made of Fe-Pt alloy with low Curie point suitable for hyperthermia (50-60 degrees C). Induction coil and generator which produce maximum power of 200W and variable frequency of 100-500kHz, yielding magnetic power of 16.7Oe, have been developed. Interstitial hyperthermia was made on rat brain tumor model (T9 gliosarcoma) by this system. Significant effects of single hyperthermia (45 degrees C for 30 minutes) were observed by the extension of life span and morphological changes of the tumor.

Thermal enhancement of low dose rate irradiation in a murine tumour system

The effects of localized hyperthermia (HT) in combination with low dose rate irradiation (brachytherapy) have been investigated in vivo using a murine mammary adenocarcinoma. Flank tumours were grown to 0.45-0.70 cm3 in volume, at which time their treatment course was initiated. Tumours were locally heated in a water bath for 15 min at either 44 or 45 degrees C. For tumour irradiations a non-invasive cap was devised to permanently house three iodine-125 sealed sources located at 120 degree intervals around the circumference of the hemispherical cap. During treatment, mice were secured in a modified syringe tube allowing mobility while restricting access to the cap which was placed over the tumour. Calculated dose rates ranged from 15 to 40 cGy/h. Brachytherapy (BT) was delivered for 48 or 72 h to obtain a dose range of 830-2378 cGy. Mice were randomized into one of 10 treatment protocols: BT alone, HT-BT, BT-HT, HT-BT-HT, 1/2BT-HT-1/2BT, four control groups of HT alone and a sham treatment group. Normalized tumour doubling volume growth delays (GDDv) were used to calculate the thermal enhancement ratios (TER). In the 44 degrees C experiments, HT before BT (TER = 1.33 +/- 0.071) was more efficacious than HT after BT (TER = 1.07 +/- 0.042). Two HT treatments, one given before and one after BT (TER = 1.38 +/- 0.152), were not different from a single HT treatment given before BT. However, a single HT treatment given in the middle of an interrupted course of BT resulted in the greatest thermal enhancement (TER = 1.64 +/- 0.072) compared to any other treatment sequence. These data suggest that potentiation of low dose rate irradiation by a single heat treatment may be maximized if the HT is given either in the middle of, or simultaneously with, the BT.