Modeling of heat transfer in whole-body hyperthermia

The therapeutic application of whole-body hyperthermia, whereby the body temperature is for a short time raised to 43–44°C is currently considered quite promising. However, body temperature above 42°C also raises the risks associated with hemodynamic instability and arrhythmia. A model of heat transfer is built to improve the efficacy and safety of the immersion-convection technique of whole-body hyperthermia. The model takes into account the changes in skin blood flow and the dynamics of heart rate depending on body temperature. It adequately reflects the processes of heating in the organism and can be used to calculate the heat distribution in the body.     

Modeling of processes of heat transfer in whole-body hyperthermia

The method of whole-body hyperthermia in which the body temperature for a short time reaches values up to 43-44 degrees C holds currently much promise. However, at body temperatures above 42 degrees C, the risks associated with the hemodynamic instability and the appearance of arrhythmia in the patient increase. A model of heat transfer has been created to increase the efficiency and safety of the immersion-convectional method of whole-body hyperthermia. This model takes into account changes in the skin blood flow and the dynamics of pulse rate depending on body temperature. The model of heat transfer adequately reflects processes of heating of the organism and can form a basis for the calculation of distribution of heat inside the organism.     

Modification of radiation damage in the canine kidney by hyperthermia: a histologic and functional study

The purpose of this study was to evaluate the effect of hyperthermia on the histologic and functional response of the canine kidney, a late-responding normal tissue, to irradiation. Both kidneys were irradiated. Radiation was delivered in single doses of 0, 10, or 15 Gy. Whole-body hyperthermia was used to produce renal kidney temperatures approximating 42.0 degrees C for 60 min. Thirty-six beagles were placed randomly in the following six treatment groups: control, whole-body hyperthermia alone, 10 Gy alone, 10 Gy + whole-body hyperthermia, 15 Gy alone, and 15 Gy + whole-body hyperthermia. Renal histologic and functional changes were assessed at 1 to 9 months after therapy. No changes were seen in glomerular filtration rate or renal tissue volumes in control or hyperthermia alone groups. Renal vascular and glomerular volumes were not affected significantly by any combination of hyperthermia and/or radiation. In all groups receiving radiation, glomerular filtration rate decreased, percentage renal tubular volume decreased, and interstitial volume increased significantly after therapy. The magnitude of these changes in the functional and histologic response of the kidney and the latent period before expression of this damage were dependent on radiation dose. However, hyperthermia did not modify expression of radiation damage in the kidney based on glomerular filtration rate and histologic quantification of renal tissue components.     

A semi-empirical model for cell kill kinetics during hyperthermia

A three-parameter mathematical model is developed which describes the available data on cell-kill kinetics during hyperthermia. The sub-exponential behaviour of the kinetics suggests that the cell-kill is not a one-step process.     

Mathematical model of a simultaneous combined effect of ionizing radiation and hyperthermia

A mathematical model has been proposed suggesting that the synergistic action of a combination of ionizing radiation and hyperthermia is conditioned by additional lethal damages arising from the interaction of "sub-lesions" induced by both agents. The model describes quantitatively the synergism of the combined action of the agents used and predicts the maximal value of the synergistic effect and conditions in which it can be achieved.     

Clinical Effects of Whole-body Hyperthermia in Advanced Malignancy

Fifty-one patients in the terminal stages of cancer have been treated with whole-body hyperthermia either alone (38 cases) or in combination with chemotherapy (13 cases). Altogether 227 treatment sessions were held averaging four hours each. The most sensitive tumours were those of the gastrointestinal tract and sarcomas. Breast and genitourinary tumours did not respond, and lung tumours and melanomas were only partially responsive. Major complications were remarkably few.     

A mathematical model of life-threatening hyperthermia during infancy.

A mathematical model was created to test the hypothesis that a partially covered febrile infant may develop potentially lethal temperature elevation. Infants may be at special risk to develop hyperthermia because, unlike older children, infants may not be able to remove blankets in response to temperature elevation. The model compared heat production (MTsk) with heat loss (Qtot). The difference between these terms is the excess energy (E): MTsk - Qtot = E. In most situations the simulated infant transfers heat to the environment as rapidly as it is produced (E less than 0), so hyperthermia does not result. In some situations, heat production exceeds heat loss (E greater than 0), causing progressive warming. The time was calculated for the simulated infant to progress from 41 to 43.4 degrees C (defined as a lethal end point). In certain circumstances, this may occur in less than 90 min. An infant at high risk of hyperthermia may not appear to be covered by a conspicuous excess of insulation (less than or equal to 3.5 cm may be sufficient). In many situations, heat loss is more closely determined by exposed body surface area than by blanket thickness. These findings have important implications for understanding the antecedents of hyperthermia in infants and may help in understanding the role of hyperthermia in certain pediatric illnesses.     

A study on thermal damage during hyperthermia treatment based on DPL model for multilayer tissues using finite element Legendre wavelet Galerkin approach

Hyperthermia is a process that uses heat from the spatial heat source to kill cancerous cells without damaging the surrounding healthy tissues. Efficacy of hyperthermia technique is related to achieve temperature at the infected cells during the treatment process. A mathematical model on heat transfer in multilayer tissues in finite domain is proposed to predict the control temperature profile at hyperthermia position. The treatment technique uses dual-phase-lag model of heat transfer in multilayer tissues with modified Gaussian distribution heat source subjected to the most generalized boundary condition and interface at the adjacent layers. The complete dual-phase-lag model of bioheat transfer is solved using finite element Legendre wavelet Galerkin approach. The present solution has been verified with exact solution in a specific case and provides a good accuracy. The effect of the variability of different parameters such as lagging times, external heat source, metabolic heat source and the most generalized boundary condition on temperature profile in multilayer tissues is analyzed and also discussed the effective approach of hyperthermia treatment. Furthermore, we studied the modified thermal damage model with regeneration of healthy tissues as well. For viewpoint of thermal damage, the least thermal damage has been observed in boundary condition of second kind. The article concludes with a discussion of better opportunities for future clinical application of hyperthermia treatment.     

An animal model of life-threatening hyperthermia during infancy.

A mathematical model of heat balance in human infants suggests that it may be possible for severe hyperthermia to develop if an infant is unable to remove his blankets in response to overheating (thermal entrapment). This hypothesis was tested in an animal model of weanling piglets. Ten piglets were warmed in a radiant heater to rectal temperature of 41 degrees C to simulate a fever. Animals in the experimental and control groups were removed from the heater and covered with ordinary infant blankets (to a thickness of approximately 3 cm). Endogenously produced heat caused the animals to warm to 42 degrees C. At this point, the control animals were uncovered. They rapidly cooled to normal body temperature. Animals in the experimental group remained covered until they expired from hyperthermia at 43.9 +/- 0.7 degrees C (SD) after 96 +/- 43 (SD) min. These data show that lethal hyperthermia may result from thermal entrapment. This finding may help clarify the role that hyperthermia may play in illnesses such as hemorrhagic shock and encephalopathy syndrome and some cases of sudden infant death syndrome.     

Mathematical modeling of the synergistic effects of sequential thermoradiation action on mammalian cells

In order to estimate the dependence of the synergistic enhancement ratio on the damage level induced by ionizing radiation and hyperthermia, data obtained by other authors for mammalian cells treated with sequential thermoradiation were used. The experimental results were described and interpreted by means of the mathematical model of synergism, according to which synergism is determined by additional lethal damage arising from the interaction of nonlethal sublesions induced by individual damaging agents.     

Effects of hyperthermia on spectrin expression patterns of murine lymphocytes

In this study the influence of whole-body hyperthermia on the distribution of spectrin in murine lymphocytes isolated from various lymphoid tissues is examined. Lymphocytes normally vary in terms of the pattern of spectrin distribution within the cell. In certain populations of lymphocytes, spectrin is distributed into a dense submembranous aggregate that can be easily identified by immunofluorescence microscopy. In these lymphocytes, little or no spectrin is seen at the plasma membrane region in the rest of the cell. Other lymphocytes have no such cytoplasmic aggregates, and the protein is seen at the region of the plasma membrane. Following whole-body hyperthermia (40.5 degrees C for 90 min) there is a 100% increase in cells exhibiting polar spectrin aggregates in the spleen, while lymphocytes from the thymus show no alteration in the number of cells showing such aggregates. The increase in the percentage of splenic cells that express aggregated spectrin is a result of increases occurring in both T- and B-cell subsets. This increase gradually returns to control levels by 48 h post-heating. During recovery to control levels this phenomenon is resistant to additional changes when a second heat treatment is applied. The effects described above are not observed when the experiments are performed in vitro; therefore, it is likely that the in vivo heat-induced alteration in the splenic lymphocyte population reflects the physiological response of lymphocytes to stimuli during a natural fever. The role that spectrin may play in the modulation of lymphocyte membrane properties is discussed.     

Sensitivity of mice to systemic hyperthermia: effect of ascites tumor cell transplants

The effect of a transplantation of mastocytoma cells in the abdominal cavity on the sensitivity of mice to a systemic hyperthermia was studied. The systemic hyperthermia was induced by exposing whole-body of animals to 2,450 MHz waves under anesthesia. Core body temperature was raised up to 42.0 +/- 0.2 degrees C in 15 min and maintained constant at the temperature for variable length of time. Thermosensitivity of animal was expressed with LD50, 42 degrees which was the length of heating time at the temperature of 42 degrees C lethal for 50% of the animals examined. The transplants were mastocytoma FMA3 cells. They were transplanted at a dose of 10(5) cells per mouse. The LD50, 42 degrees observed 3, 12 hrs, 1, 2, 3 and 6 days after the transplantation was 33, 23, 17, 24 and 35 min, respectively. In mice without tumor it was 43 min.     

Spatial analysis of cell death and Hsp70 induction in brain, thymus, and bone marrow of the hyperthermic rat

Heat shock response and programmed cell death are cellular reactions to stressful stimuli. Previous studies have not correlated these responses in vivo at the spatial level in mammalian tissues. This study uses a dual procedure involving immunocytochemistry for Hsp70 localization and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end-labeling (TUNEL) assay for cell death to correlate the pattern of stress-inducible Hsp70 and cell death at the cellular level. After whole-body hyperthermia in the rat, an increase in Hsp70-positive cells and TUNEL-positive cells was noted in brain, thymus, and bone marrow. However, 2 populations of cells were apparent in the tissues examined, those inducing Hsp70 and those triggered into programmed cell death. Cells that were both Hsp70 positive and TUNEL positive were rarely detected. In tissues of the intact mammal, cells that induce Hsp70 after whole-body hyperthermia were not triggered into programmed cell death.     

Mathematical modeling of synergistic interaction of sequential thermoradiation action on mammalian cells

Data obtained by other authors for mammalian cells treated by sequential action of ionizing radiation and hyperthermia were used to estimate the dependence of synergistic enhancement ratio on the ratio of damages induced by these agents. Experimental results were described and interpreted by means of the mathematical model of synergism in accordance with which the synergism is expected to result from the additional lethal damage arising from the interaction of sublesions induced by both agents.     

Tumor cell apoptosis,lymphocyte recruitment and tumor vascular changes are induced by low temperature,long duration (fever-like) whole body hyperthermia

A single treatment of low-temperature, long-duration, whole-body hyperthermia of either severe combined immunodeficient (SCID) mice bearing human breast tumor xenografts or Balb/c mice bearing syngeneic tumors for 6–8 hr can cause a temporary reduction of tumor volume and/or a growth delay. In both animal model systems, this inhibition is correlated with the appearance of large numbers of apoptotic tumor cells. Because this type of mild heat exposure, comparable to a common fever, is not itself directly cytotoxic, other explanations for the observed tumor cell death were considered. Our data support the hypothesis that this hyperthermia protocol stimulates some component(s) of the immune response, which results in increased antitumor activity. In support of this hypothesis, increased numbers of lymphocyte-like cells, macrophages, and granulocytes are observed in the tumor vasculature and in the tumor stroma immediately following this mild hyperthermia exposure. In Balb/c mice, an infiltrate persists in the tumor for at least 2 weeks. Using the SCID mouse/human tumor system, we found that both host natural killer (NK) cells and injected human NK cells were increased at the site of tumor following hyperthermia treatment. Experiments using anti-asialo-GM1 antibodies indicate that the tumor cell apoptosis seen in the SCID mouse appears to be due largely to the activity of NK cells, although additional roles for other immunoeffector cells and cytokines appear likely in the immunologically complete Balb/c model. Another interrelated hypothesis is that immunoeffector cells may have greater access to the interior of the tumor because we have observed that this treatment causes an obvious expansion in the diameter of blood vessels within the tumor and an increase in nucleated blood cells within the vessels, which persists as long as 2 weeks after treatment. Further study of the mechanisms by which mild hyperthermia exerts antitumor activity could result in this treatment protocol being used as an effective, nontoxic adjuvant to immunotherapy and/or other cancer therapies. J. Cell. Physiol. 177:137–147, 1998. © 1998 Wiley-Liss, Inc.     

Influence of repeated hyperthermia on the early development of carcinogen-induced rat mammary cancers; Refinement of a technique for hyperthermia research

• 1.1.|Hyperthermia (c. 41°C) occurs in mammals (e.g. humans) during normal life-history events such as fever and vigorous exercise. The effects of such episodic hyperthermia on early developmental stages of cancer are of potential importance, yet have been investigated hardly at all.
• 2.2.|We injected female Sprague-Dawley rats with the mammary-gland carcinogen 7,12-dimethylbenzathracene and, over a 4-week period before cancer onset, subjected them to 20 1-h episodes of whole-body hyperthermia (41.2°C colonic) to determine effects on subsequent appearance of carcinomas.
• 3.3.|Hyperthermia did not have significant effects on the development of clinical disease in this system, indicating that precancerous or incipient cancerous cells are not susceptible to damage by the levels of hyperthermia associated with normal life-history events.
• 4.4.|For repeated induction of hyperthermia with minimal confounding effects of stress, we refined a technique in which hyperthermia-treated animals, as well as controls, were anesthetized with sodium pentabarbital during thermal treatments, thus suppressing thermoregulation and higher brain functions.

     

Regional hyperthermia by magnetic induction in a beagle dog model: analysis of thermal dosimetry

We have investigated magnetic induction heating techniques for achieving normal tissue hyperthermia in a beagle dog model to clarify the physics and physiology of "regional heating," to develop an animal model of regional heating in humans, and to develop a method of rapid regional heating in dogs for a normal visceral tissue toxicity study. Heating was done with a concentric coil or a coaxial pair of coils applied to the abdominal region, and with or without surface cooling blankets in each case. Thermometers were placed at multiple visceral and subcutaneous sites including an intraarterial thermocouple at the aortic arch level. With either electrode arrangement and no surface cooling, whole-body hyperthermia ( WBH ) at 42 degrees C was produced within 30 to 55 min with 250 W applied power; the 42 degrees C state could be maintained with 40 to 60 W of power. Thermal gradients in these cases reflected nonuniform power deposition superimposed upon arterial temperature elevation. With surface cooling blankets added, systemic heating was significantly reduced, and temperature gradients again reflected the nonuniform power deposition. Regional heating in a dog produces WBH unless sufficient surface cooling is used to provide a heat dissipation rate balancing the heat absorption rate; this latter case best models the use of inductive techniques in humans. The coaxial pair of coils, without surface cooling, produced rapid WBH and the visceral temperature maximum and minimum were within Tesoph + 0.21 degrees C and Tesoph - 0.07 degrees C, respectively (95% confidence index; Tesoph = esophageal temperature). This is an appropriate technique for the proposed toxicity study.