Selective drug-induced reduction of blood flow in tumor transplants

The effect of a calcium antagonist and a physiologic amine on tumor and muscle perfusion was investigated with the aim of improving the preconditions for external hyperthermia treatment of cancer. Nisoldipine (0.04-4.0 mg/kg) and 5-hydroxy tryptamine (5-HT) (0.2-8.0 mg/kg) were administered i.p. in Sprague-Dawley rats bearing Walker 256 carcinoma, Yoshida sarcoma, or a homologous tumor transplant derived from a spontaneous leiomyosarcoma of the uterus. At the maximum dosage used, nisoldipine injection caused a decrease of the regional washout rate of Xenon-133 of 63 +/- 8% (SEM) in the Walker carcinoma and an increase of 80 +/- 41% in the muscle of the hind leg. 5-HT (8 mg/kg) caused a drop of 79 +/- 29% in the Walker carcinoma and only a slight fall of the washout rate in muscle of 14 +/- 4.8%. Tumor-to-muscle uptake ratios of 11C-butanol fell from 5.63 +/- 1.98 to 3.32 +/- 1.21, and from 5.3 +/- 0.56 to 2.98 +/- 0.30, after injection of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT, respectively. Similar reaction patterns and percentage changes were observed in different tumor lines at constant doses of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT. Both drugs representing two different rationales of vasomotor action were able to reduce blood flow specifically in transplanted tumors; nisoldipine increased muscle blood flow and decreased arterial blood pressure, whereas 5-HT acted without substantial systemic effects.     

Arterial blood flow changes after hyperthermia on normal liver, normal brain, and normal small intestine

Arterial blood flow changes are studied after hyperthermia on normal liver, normal brain, and normal small intestine. A small part in left lateral lobe of rat liver was heated by RF capacity heating. Arterial blood flow in heated area of liver decreased to 69.2 +/- 8.1 and 51.3 +/- 6.6 ml/min/100 g dry weight respectively after heating at 43 degrees C for 30 min and 45 min, from 83.1 +/- 2.6 ml/min/100 g dry weight at 37 degrees C. To heat a small part in left hemisphere of rat cerebral tissue, RF interstitial heating device was utilized. Arterial blood flow in heated area increased to 289.1 +/- 41.5 ml/min/100 g dry weight after heating at 42 degrees C for 30 min from 223.6 +/- 18.8 ml/min/100 g dry weight at 37 degrees C. For small intestine heating, water bath was used. Arterial blood flow increased to 6.60 +/- 1.36, 7.44 +/- 1.16, and 11.6 +/- 2.2 ml/min/g dry weight respectively after heating at 39 degrees C, 41 degrees C, and 43 degrees C for 30 min, from 5.04 +/- 0.85 ml/min/g dry weight at 37 degrees C. These data suggest that blood flow changes after hyperthermia differ from tissue to tissue, and require further investigation on the effect of hyperthermia on blood flow changes in liver, brain, small intestine, and other normal tissues.     

Targeting liver tumors with hyperthermia: ferromagnetic embolization in a rabbit liver tumor model

BACKGROUND AND OBJECTIVES: Ferromagnetic embolization hyperthermia (FEH) consists of arterially embolizing liver tumors with ferromagnetic particles, and then applying an external alternating magnetic field to generate hysteretic heating within the embolized particles. The objective of this study was to assess the ability of FEH to selectively target liver tumors with hyperthermia. METHODS: Twenty rabbits containing hepatic VX2 carcinomas were arterially infused with ferromagnetic particles suspended in lipiodol, and then exposed to an external alternating magnetic field. Temperatures in the tumor, normal hepatic parenchyma (NHP), and rectum were recorded. Tumour and NHP were chemically analyzed for iron content, which was then correlated with the observed heating rates. RESULTS: The mean tumor-to-NHP iron concentration ratio was 5.3:1 (P < 0.001, N = 20). The mean tumor heating rates were 3.0-11.5 times greater than those in the NHP (P < 0.001, N = 20). After 5 min of heating, the greatest increase in mean tumor temperature was 11.0 degrees C and the greatest increase in mean NHP temperature was 1.3 degrees C. There was a positive relationship between tumor iron concentration and heating rate (correlation coefficient = 0.82, P < 0.001, N = 20). A tumor iron concentration of 2-3 mg/g resulted in tumor heating rates of 0.5-1.0 degrees C/min. CONCLUSIONS: Hepatic arterial infusion of lipiodol containing ferromagnetic particles can result in excellent targeting of liver tumors with hyperthermia on the subsequent application of an external alternating magnetic field. The promising results of this study warrant further investigation of FEH as a potential treatment for advanced liver cancer.     

Hyperthermia in eccentrically located pelvic tumors: excessive heating of the perineal fat and normal tissue temperatures

Regional hyperthermia in deep-seated tumors can be limited by excessive heating of normal tissues, usually associated with pain or local discomfort. In this report, 57 hyperthermia treatments in 8 patients with locally advanced presacral recurrences of colorectal cancer were analyzed with respect to normal tissue temperatures, especially with respect to the perineal fat temperature. In 27 treatments, 1 to 2 catheters had been inserted from the perineal region through a large part of the perirectal and presacral fat into the tumor, so that temperature profiles of the perineal fat could be obtained. The mean maximum temperature (+/- SD) of the vagina, rectum, bladder, muscle tissue, and perineal fat was 40.8 +/- 1.2 degrees C, 40.9 +/- 1.6 degrees C, 40.5 +/- 1.6 degrees C, 39.8 +/- 0.7 degrees C, and 42.6 +/- 1.1 degrees C, respectively. The mean maximum systemic temperature (+/- SD) was 37.7 +/- 0.7 degrees C. In 42% of the treatments, the temperature in the perineal fat ranged between 43 and 46 degrees C and was treatment-limiting. In conclusion, overheating of the perineal fat is a problem in the treatment of eccentrically located tumors of the presacral region when relatively high temperatures in the tumor will be maintained for longer time periods.     

Intra-luminal thermometry: is tissue type assignment a necessity for thermal analysis?

INTRODUCTION: Tissue type assignment, i.e. differentiation tumour from normal tissue, is a normal procedure for interstitial thermometry. In our department, thermometry in patients with a tumour in the lower pelvis is usually restricted to the intra-luminal tracks. It is unknown whether discrimination between normal and tumour tissue is relevant for deep regional hyperthermia thermal dosimetry using only intra-luminal tumour contact and tumour adjacent thermometry. This study has analysed the acquired temperature data in order to answer this question. PATIENTS AND METHODS: Seventy-five patients with locally advanced cervical carcinoma were selected randomly. Patients were treated with a two or three modality combination, i.e. radiotherapy +hyperthermia or radiotherapy + hyperthermia + chemotherapy from October 1997 to September 2003. The first 100 hyperthermia treatments fulfilling the only selection criterion: no displacement of the thermometry catheter along the insertion length during the treatment, were included in the study, resulting in 43 patients with one-to-five treatments/patient (median 2). Using RHyThM (Rotterdam Hyperthermia Thermal Modulator), for each single treatment tissue type, was defined on the basis of information given by a CT scan in radiotherapy position. A step change in the slope of the profile of the first temperature map was identified to verify the insertion length of the catheter. RESULTS: The average T50 (median temperature) in bladder tumour indicative, vagina tumour contact and rectum tumour indicative was 40.9 +/- 0.9 degrees C, 39.7 +/- 0.9 degrees C and 40.6 +/- 0.8 degrees C, respectively. The average normal tissue T50 in bladder, vagina and rectum was 40.8 +/- 0.9 degrees C, 40.1 +/- 0.9 degrees C and 40.7 +/- 0.8 degrees C, respectively. The differences between bladder tumour indicative T50 and bladder normal tissue T50 and also between vagina tumour contact T50 and vagina normal tissue T50 were significant ( p = 0.0001). No statistical difference was found between rectum tumour indicative t50 and rectum normal tissue T50. CONCLUSION: At present the cause of the temperature difference is not known. However, as the difference between tumour (indicative/contact) and normal tissue is very small and considering also the inaccuracy in the tissue type assignment it can be stated that this study does not provide sufficient evidence to conclude that the statistical difference has clinical relevance. Therefore, it was concluded that at this time there is no need to differentiate between normal and tumour tissue in intra-luminal thermometry.     

Determination of continuous atracurium infusion rate in dogs undergoing whole-body hyperthermia

Infusion rates for atracurium were calculated from multiple bolus injection data for normothermic (38 degrees C; n = 4) and hyperthermic (42 degrees C; n = 14) dogs anesthetized with thiopental and oxymorphone while undergoing whole-body hyperthermia treatment. The calculated infusion rate for atracurium at 38 degrees C was 6.2 +/- 0.3 micrograms/kg/min and the calculated infusion rate at 42 degrees C was 8.5 +/- 0.4 micrograms/kg/min. Infusion of atracurium at the calculated infusion rate of 8.5 micrograms/kg/min produced an estimated 90-100% neuromuscular blockade during heating from 38-42 degrees C and at 42 degrees C. Following discontinuation of the infusion and cooling to 38 degrees C, neuromuscular function returned to normal within 20 min with no evidence of recurarization. Atracurium infusion rates appear to be linear and related to body temperature from 26-42 degrees C. Clinically useful neuromuscular blockade in dogs may be obtained during whole-body hyperthermia by utilizing the 42 degrees C atracurium infusion rate throughout the 38-42 degrees C heating phase.     

Laser Doppler flowmetry in subepidermal tumours and in normal skin of rats during localized ultrasound hyperthermia

Laser Doppler flowmetry has been applied to normal skin and to subepidermal tumours during localized ultrasound hyperthermia in the rat. In normal skin, 40 degrees C hyperthermia only induced a marginal increase in the red blood cell flux. Significant increases occurred after 20 min at 42 degrees C and after 4 min at 44 degrees C. During 44 degrees C hyperthermia maximum fluxes were reached after 24 min. Thereafter, the flow declined and finally approached preheating values. In contrast, in subepidermal tumours 40 degrees C hyperthermia on the average induced a slight decrease of the flux. During 42 degrees C hyperthermia a significant flow decrease was found after 40 min of heating. Following a transient increase in the laser Doppler flow during the heating-up period, 44 degrees C hyperthermia led to a significant impairment of the flux after 24 min. A total shutdown of RBC flux was observed in about 30 per cent of the tumours at 44 degrees C. Upon elevated tissue temperatures, pronounced inter-tumour variabilities in the time- and temperature-dependent changes of RBC flux were observed. Rhythmic oscillations of the RBC flux were found in some subepidermal tumours (0.40 +/- 0.05 cycles/min). Upon heating, these periodic flow variations slowed down significantly (0.20 +/- 0.04 cycles/min), whereas in normal skin the frequency of the flow fluctuations increased.     

Intrinsic thermal response, thermotolerance development and stepdown heating in murine bone marrow progenitor cells.

Thermal response, thermotolerance development and stepdown heating (SDH) in the murine bone marrow granulocyte-macrophage (CFU-GM) progenitors were determined in vitro. Marrow was removed from femora and tibia, heated in McCoy's 5A medium plus 15% FBS and cultured in soft agar in the presence of three different sources of colony stimulating factor. D0's (+/- SE) for survival curves of CFU-GM heated in vitro were 147 +/- 13, 71 +/- 9, 37 +/- 2, 19 +/- 0.7, 11 +/- 1, and 4.3 +/- 0.3 min, for temperatures of 41.8, 42, 42.3, 42.5, 43 and 44 degrees C, respectively. Arrhenius analysis showed inactivation enthalpies of 812 +/- 9 KJoules/mole (193 +/- 2 Kcal/mole) above, and 2142 +/- 157 KJoules/mole (509 +/- 37 Kcal/mole) below, an inflection at 42.5 degrees C. Thermotolerance development was evident during prolonged hyperthermia exposure at temperatures below 42.5 degrees C (chronic hyperthermia) as a change in the slope of the survival curves after approximately 110 min of heating. Thermotolerance development at 37 degrees C after exposure to temperatures of 43 degrees C or greater (acute hyperthermia) was assessed by fractionated heat treatments consisting of an initial heat treatment (15 min at 44 degrees C) followed by incubation at 37 degrees C and challenge with 15 min or 25 min at 44 degrees C. Maximum thermotolerance occurred after 210 and 330 min at 37 degrees C, respectively. The half-time for maximum thermotolerance development was 36 min. Depending on the amount of heat damage and the maximum amount of thermotolerance development, the decay of thermotolerance was complete after approximately 48-72 h at 37 degrees C. An exposure of 10 min at 44 degrees C before incubation at 40 or 41 degrees C (stepdown heating) reduced the slope of the 40 or 41 degrees C survival curves by inhibiting thermotolerance development that would have otherwise occurred. D0's were 100 +/- 19 and 45 +/- 5 min for 40 and 41 degrees C incubation preceded by 10 min at 44 degrees C, respectively. These studies indicate that whole-body or regional hyperthermia protocols designed either to treat solid tumours or to purge leukemic stem cells from marrow ex vivo should avoid inadvertent temperature elevations to large volumes of marrow. Although, marrow progenitors are capable of thermotolerance development during exposure to temperatures up to 42.3 degrees C, results suggest that conditions of stepdown heating may prevent thermotolerance development.     

Initial clinical results of a 430 MHz microwave hyperthermia system using a lens applicator

The applicability of a 430 MHz microwave (MW) hyperthermia system using an electric field converging (lens) applicator was evaluated. Twenty-two tumors with a maximum tumor depth of less than 7 cm (10 chest wall tumors, 8 abdominal and pelvic tumors, 2 extremity tumors, and 2 neck tumors) were treated with the lens applicator heating system for a total of 72 sessions in conjunction with irradiation or chemotherapy. Of the 72 heat sessions, our treatment goal of 30 min of hyperthermia with all monitored tumor temperatures above 42 degrees C was achieved in 31 sessions (43%). The average tumor temperature was 42.5, 43.1, 42.0, and 42.0 degrees C for chest wall, abdominal and pelvic, extremity, and neck tumors, respectively; similarly 88, 83, 64 and 50% of monitored points exceeded 41 degrees C. A lens applicator heating system increased the penetration depth of MW, and tumor temperature of 41 degrees C at 5 cm from the surface was easily achieved with a four-aperture lens applicator. Of the 22 tumors, 10 tumors exhibited complete response (CR), 7 partial response (PR) and 5 no response (NR). These results suggest that the lens applicator heating system is useful for heating localized subsurface tumors with a maximum tumor depth of 5-6 cm.     

Comparison of noninvasive MRT procedures for temperature measuremnt for the application of medical heat therapies

Novel methods for hyperthermia tumor therapy, such as high-intensity focused ultrasound (HIFU) or laser-induced thermotherapy (LITT), require accurate non-invasive temperature monitoring. Non-invasive temperature measurement using magnetic resonance imaging (MRI) is based on the analysis of changes in longitudinal relaxation time (T1), diffusion coefficient (D), or water proton resonance frequency (PRF). The purpose of this study was the development and comparative analysis of the three different approaches of MRI temperature monitoring (T1, D, and PRF). Measurements in phantoms (e.g., ultrasound gel) resulted in the following percent changes: T1-relaxation time: 1.98%/degree C; diffusion coefficient: 2.22%/degree C; and PRF: -0.0101 ppm/degree C. All measurements were in good agreement with the literature. Temperature resolutions could also be measured from the inverse correlation of the data over the whole calibration range: T1: 2.1 +/- 0.6 degrees C; D: 0.93 +/- 0.2 degree C; and PRF: 1.4 +/- 0.3 degrees C. The diffusion and PRF methods were not applicable in fatty tissue. The use of the diffusion method was restricted due to prolonged echo time and anisotropic diffusion in tissue. Initial tests with rabbit muscle tissue in vivo indicated that MR thermometry via T1 and PRF procedures is feasible to monitor the local heating process induced by HIFU. The ultrasound applicators in the MR scanner did not substantially interfere with image quality.     

Control system for an MRI compatible intracavitary ultrasound array for thermal treatment of prostate disease.

A 16-channel ultrasound intracavitary array is currently being used in a clinical setting for localized hyperthermia treatment of prostate tumours. Currently, the individual power to each array element is adjusted based on the clinician's judgement of the temperature measured at the locations of invasive thermocouple probes. MRI-derived temperature measurements may be useful for a feedback control system that non-invasively regulates the temperature distribution by adjusting the power to the elements of the array. MRI has been shown to provide accurate, high resolution, non-invasive thermometry. A proportional-plus-integral, single-input, single-output controller was designed to evaluate the feasibility of MRI-derived temperature feedback with this applicator. Input parameters for the controller were determined by modelling the tissue response to the heating from the array. Ex vivo and in vivo experiments evaluated the ability of the MRI-based temperature feedback control system to achieve and maintain a target temperature for a sustained period similar to that of a clinical hyperthermia treatment. With the controller set to a reference temperature of 43 degrees C and a rise time of 6 min, the temperatures within the ex vivo tissue (n = 6) were 43.1 +/- 0.3 degrees C after reaching the reference temperature and had a rise time of 9.5 +/- 0.3 min. In vivo results using rabbit thigh muscle (n = 7) showed that the steady state temperatures were within +/- 1 degree C of their target temperatures. These results demonstrated the feasibility of a temperature feedback for controlling the heating from an intracavitary transrectal array based on temperature information from MR images.     

Combretastatin A-4 disodium phosphate: a vascular targeting agent that improves that improves the anti-tumor effects of hyperthermia, radiation, and mild thermoradiotherapy.

PURPOSE: To investigate the effect of combining the vascular targeting drug combretastatin A-4 disodium phosphate (CA4DP) with hyperthermia, radiation, or mild thermoradiotherapy in a transplanted C3H mouse mammary carcinoma. METHODS AND MATERIALS: The C3H mammary carcinoma was grown on the rear foot of female CDF1 mice and treated when at 200 mm(3) in size. CA4DP was dissolved in saline and injected i.p. Hyperthermia and/or radiation were locally given to tumors in restrained nonanesthetized mice. Tumor response was assessed using either a tumor growth or a tumor control assay. Mouse foot skin was used to assess normal tissue damage. RESULTS: CA4DP significantly enhanced thermal damage in this tumor model. This effect was independent of drug doses between 25-400 mg/kg, but was strongly dependent on the time interval between drug injection and heating, with the greatest improvement seen when CA4DP preceded the heating by 1 h or less. There was also a suggestion of a temperature dependency with a 1.9-fold increase in heat damage at 42.5 degrees C and a 2.6-fold increase at 41.5 and 40.5 degrees C. Heat-induced normal tissue damage was also enhanced by combining CA4DP with heat, but the degree of enhancement was less than that seen in tumors. CA4DP (25 mg/kg) significantly increased radiation-induced local tumor control and this was further enhanced by combining CA4DP with mild temperature (41.5 degrees C, 60 min) heating. CONCLUSIONS: CA4DP improved the anti-tumor effect of hyperthermia, especially at mild temperatures. More importantly, it also increased the tumor response to mild hyperthermia and radiation, which suggests that CA4DP may ultimately have an important application in clinical thermoradiotherapy.     

Localized versus regional hyperthermia: comparison of xenotransplants treated with a small animal ultrasound system and waterbath limb immersion.

The response of xenotransplants were compared with waterbath immersion vs focal ultrasound (US) hyperthermia using tumour growth delay, immunhistochemistry and histopathology assays. Waterbath hyperthermia was performed by limb immersion. Precautions were taken to minimize total body heating by surrounding the mouse with plastic insulators. Thermometry was performed with clinical-grade, 20-gauge needle thermocouples and monitored with a Labthermics unit. Significant differences in cytotoxicity between ultrasound and waterbath treatment of tumors at 43 degrees C were observed as determined by TUNNEL assay. Conversely, contralateral (non-treated) tumours in animals treated with similar temperature demonstrated no significant differences between modalities. Western blot analysis revealed increased hsp70 induction at 43 degrees C in waterbath vs focal ultrasound hyperthermia. Comparison of tumour growth delay between tumours heated with waterbath vs ultrasound at 43 degrees C but not at 41 degrees C revealed significant differences. This is the first study comparing localized vs regional hyperthermia using the small animal ultrasound system (SAHUS) delivery system. Consistent ultrasound hyperthermia can be achieved throughout a xenotransplant. At equivalent temperature of 43 degrees C for 60?min, waterbath hyperthermia demonstrated greater local response vs ultrasound hyperthermia.     

Online feedback focusing algorithm for hyperthermia cancer treatment.

PURPOSE: Magnetic resonance (MR) imaging is increasingly being utilized to visualize the 3D temperature distribution in patients during treatment with hyperthermia or thermal ablation therapy. The goal of this work is to lay the foundation for improving the localization of heat in tumors with an online focusing algorithm that uses MR images as feedback to iteratively steer and focus heat into the target. METHODS: The algorithm iteratively updates the model that quantifies the relationship between the source (antenna) settings and resulting tissue temperature distribution. At each step in the iterative process, optimal settings of power and relative phase of each antenna are computed to maximize averaged tumor temperature in the model. The MR-measured thermal distribution is then used to update/correct the model. This iterative procedure is repeated until convergence, i.e. until the model prediction and MR thermal image are in agreement. A human thigh tumor model heated in a 140 MHz four-antenna cylindrical mini-annular phased array is used for numerical validation of the proposed algorithm. Numerically simulated temperatures are used during the iterative process as surrogates for MR thermal images. Gaussian white noise with a standard deviation of 0.3 degrees C and zero mean is added to simulate MRI measurement uncertainty. The algorithm is validated for cases where the source settings for the first iteration are based on erroneous models: (1) tissue property variability, (2) patient position mismatch, (3) a simple idealized patient model built from CT-based actual geometry, and (4) antenna excitation uncertainty due to load dependent impedance mismatch and antenna cross-coupling. Choices of starting heating vector are also validated. RESULTS: The algorithm successfully steers and focuses a tumor when there is no antenna excitation uncertainty. Temperature is raised to > or = 43 degrees C for more than about 90% of tumor volume, accompanied by less than about 20% of normal tissue volume being raised to a temperature > or = 41 degrees C. However, when there is antenna excitation uncertainty, about 40% to 80% of normal tissue volume is raised to a temperature > or = 41 degrees C. No significant tumor heating improvement is observed in all simulations after about 25 iteration steps. CONCLUSIONS: A feedback control algorithm is presented and shown to be successful in iteratively improving the focus of tissue heating within a four-antenna cylindrical phased array hyperthermia applicator. This algorithm appears to be robust in the presence of errors in assumed tissue properties, including realistic deviations of tissue properties and patient position in applicator. Only moderate robustness was achieved in the presence of misaligned applicator/tumor positioning and antenna excitation errors resulting from load mismatch or antenna cross coupling.     

Hyperthermia-induced vascular injury in normal and neoplastic tissue

The sequential morphologic alterations in normal skeletal muscle in rats, Walker 256 tumors in rats, and transmissible venereal tumors (TVT) in dogs following microwave-induced hyperthermia (43 degrees C and 45 degrees C for 20 minutes), were studied by histologic and ultrastructural examination. Normal muscle and Walker 256 tumors showed edema, congestion, and hemorrhage at 5 minutes post-heating (PH), followed by suppuration, macrophage infiltration, and thrombosis at 6 and 48 hours PH, and finally by regeneration and repair by 7 days PH. Vascular endothelial damage and parenchymal degeneration were present 5 minutes PH. Progressive injury occurred for at least 48 hours PH. Two hyperthermia treatments separated by a 30- or 60-min cooling interval, were applied to Walker 256 tumors in a subsequent study. Increased selective heating of tumor tissue versus surrounding normal tissue, and increased intratumoral steady state temperatures were found during the second hyperthermia treatment. Canine TVTs were resistant to hyperthermia damage. These results suggest that vascular damage contributes to the immediate and latent cytotoxic effects of hyperthermia in normal tissue and some types of neoplastic tissue, and that selective heating of neoplastic tissue occurs in tumor tissue with disrupted microvasculature.     

Enhanced delivery of a monoclonal antibody F(ab')2 fragment to subcutaneous human glioma xenografts using local hyperthermia

The purpose of this study was to investigate the effects of tumor-localized hyperthermia at 42 degrees C on the tissue distribution of radioiodinated monoclonal antibody F(ab')2 fragments. Paired-label biodistribution measurements were performed in athymic mice bearing D-54 MG human glioma xenografts on one leg. Mice received both the 131I-labeled F(ab')2 fragment of Mel-14, reactive with human gliomas and melanomas, and nonspecific 125I-labeled RPC 5 F(ab')2. Tumor-bearing legs were placed in a 42 degrees C water bath or a 37 degrees C water bath (control) for 2 or 4 h. In mice sacrificed immediately after 2 h of heating, no hyperthermia-induced differences in the distribution of either fragment were observed. In the 4-h groups, tumor uptake of Mel-14 F(ab')2 increased from 7.04 +/- 1.59% injected dose (ID)/g at 37 degrees C to 20.65 +/- 4.53% ID/g at 42 degrees C (P less than 0.0001), and tumor localization of the control fragment rose from 5.23 +/- 1.35% ID/g to 14.51 +/- 1.37% ID/g (P less than 0.0001). In another experiment, F(ab')2 fragments were injected, tumors were heated for 4 h, and groups were sacrificed at 4, 8, and 16 h after injection. Statistically significant 2- to 3-fold higher uptake of both fragments in tumor were observed at all time points. Hyperthermic conditions also resulted in higher tumor:tissue ratios for both fragments. These results suggest that it may be possible to use tumor-localized hyperthermia to increase the therapeutic utility of radiolabeled monoclonal antibodies, particularly when labeled with short lived nuclides such as the 7.2-h alpha-emitter 211At.     

Experimental thermoradiotherapy in malignant hepatocellular carcinoma

PURPOSE: The human liver is known to be a relatively radiosensitive organ that develops clinically relevant late radiation hepatitis subsequent to whole liver treatment with total doses above 30 Gy in conventional fractionation. Experimental data, as well as clinical series, have demonstrated that hyperthermia of solid tumors in addition to radiotherapy enhances tumor growth inhibition and tumor control probability. We therefore developed an experimental model for combined radiotherapy and hyperthermia of the liver in transplantable rat Morris hepatoma 3924A. METHODS AND MATERIALS: A cube of approximately 8 mm(3) was implanted subcapsularly into the middle liver lobe of 59 male syngenic ACI rats weighing approximately 180-200 g. On Day 16 after tumor implantation, irradiation of the tumor-bearing liver with either 0 Gy/25 Gy/35 Gy/45 Gy total dose in 10 fractions +/- hyperthermia (target temperature 40-42 degrees C) twice a week was initiated. Energy deposition was monitored by temperature probes in the liver and esophagus of the rats. Determination of tumor volume with magnetic resonance imaging was performed 2 to 5 weeks after the end of therapy. The tumor growth rates could be estimated for 44 rats. If the growth rate was positive (37 rats), the inverse of the growth rate was interpreted as the time to 10-fold tumor volume. Otherwise the maximum observation time was considered as a censored value in a parametric survival analysis. RESULTS: Intrahepatic temperature probes showed a temperature plateau of greater than 40 degrees C after 5 to 8 min subsequent to initiation of hyperthermia. The target temperatures could be maintained for at least 22 min > or =40 degrees C and 10 min > or =41 degrees C, respectively. Median plateau temperature in liver, esophagus, and epicutaneously was 41.2 degrees C (standard deviation [SD] 0.7 degrees C; range 38.2 to 43.3 degrees C), 40.4 degrees C (SD 1.08 degrees C; range 38.9 to 41.8 degrees C), and 40.8 degrees C (SD 0.8 degrees C; range 38.2 to 42.7 degrees C), respectively. Elevation of the temperature in the esophagus correlated with intrahepatic temperatures in the range of 39-42 degrees C, r = 0.957. The increase in time to 10-fold tumor volume for each step of irradiation dosage was by 34% (95% confidence interval [CI] 20% to 49%) without hyperthermia and by 60% (95% CI 47% to 80%) with hyperthermia (p < 0.0001). CONCLUSION: Treatment outcome after experimental percutaneous thermoradiotherapy in intrahepatically implanted Morris hepatoma 3924A was related to total dose of irradiation and concurrently administered regional hyperthermia. An increased radiosensitivity due to hyperthermia (<42 degrees C) has to be assumed.     

Cerebral blood flow response to the tissue temperature in tumour and brain tissues

The response of regional-cerebral blood flow (rCBF) to change in the tissue temperature was studied using normal and tumour-bearing monkeys. The local brain was selectively heated by the external microwave irradiation, while the body was kept hypothermic (30.1 +/- 0.1 degrees C, mean +/- standard error) by immersion in a cold water bath. The rCBF in brain and/or tumour tissues was sequentially measured by inhalation hydrogen clearance method. In the normal animal study (n = 7), rCBF changed in response to the tissue temperatures over a range of 29.4-40.7 degrees C with a constant rate 15.2% per degree Celsius change. Similarly, rCBF in the tumour-bearing animals (n = 7) changed proportionately with change in the tissue temperatures over a range of 28.4-42.5 degrees C in tumour and 27.6-41.8 degrees C in brain tissue. The rate in rCBF change per degree Celsius was 6.5% for tumour, which was significantly smaller than that for brain tissue (13.5%) (P less than 0.01). These results indicated that rCBF can be controlled by the defined application of selective heating with temperatures ranging from shallow hypothermia to modest hyperthermia. Vascular response to temperatures in the tumour and brain tissues may play a significant role in the application of heat to brain tumour treatment.     

The significance of thermotolerance after 41 degrees C hyperthermia: in vivo and in vitro tumor and normal tissue investigations

We have investigated the development of thermotolerance in both tumors and normal tissues after 41 degrees C for durations as brief as 15 minutes. The murine RIF tumor, treated by both local radiofrequency and systemic methods, was assayed for thermotolerance by both tumor growth and cell survival analyses. The murine leg and ear, treated by conductive methods, were assayed using pre-defined tissue damage scoring systems. All of these treatments quickly induced substantial levels of thermotolerance. In the tumor studies using local heating, RIF mean diameter doubling time decreased from 17.8 days to a minimum of 13.0 days with a 9 hr interval between 41.0 degrees C for 15 minutes and 44.0 degrees C for 30 minutes (9 hr D1-D2); cell survival increased from 1.2 X 10(-2) to 3.4 X 10(-1) (same interval). Both assays showed some degree of tolerance present immediately after 41.0 degrees C for 15, 30 or 60 minutes (0 hr D1-D2). In the tumor studies using systemic heating, the kinetic pattern of the induced tolerance was similar to that observed after local heating. In the leg studies, 41.0 degrees for 30 minutes increased the time at 45 degrees C necessary to induce a specified level of tissue damage (mean score of 7) by a maximum of 1.8 times (24 hr D1-D2). The kinetic pattern was similar to that for the tumors. In the ear studies, 41.0 degrees C for 30 minutes increased the time at 45 degrees C necessary to induce ear necrosis in 50% of animals by a maximum of 3.5 times (48 hr D1-D2). The peak tolerance level occurred later for the ears, which have a lower normal temperature of 28-30 degrees C, than for the tumors or legs. These results indicate that: thermotolerance can begin to appear in tumors during treatment if hyperthermia sessions involve initial low thermal exposures (near 41 degrees C) for 15 minutes or longer; thermotolerance can develop in tumors after systemic heating and occurs with a kinetic pattern similar to that following local heating; and normal tissues also can develop high levels of thermotolerance after similar thermal exposures.