Intratumour temperature distributions during hyperthermia

Temperature gradients as high as 2.2°C/cm were observed within Walker 256 mammary carcinoma in vivo, when the tumours were heated at one end by a diathermic lamp. When the blood supply to the tumour was interrupted, the temperature gradients increased as expected, due to lack of cooling effect caused by blood. A mathematical model described these data adequately.     

Esophageal and tympanic temperature responses to core blood temperature changes during hyperthermia

Esophageal, rectal, tympanic, and central blood temperature, i.e., pulmonary artery and aortic arch, were recorded in three patients during iatrogenic whole-body hyperthermia for the treatment of advanced malignant metastatic cancer. Aortic temperature closely followed changes in pulmonary arterial temperature, with an average delay time of 27 s. Esophageal temperature reflected quantitatively and more quickly (avg lag time, 80 s) the temperature changes in the pulmonary artery than tympanic membrane temperature. Tympanic temperature was consistently lower than the blood temperature of the heart during steady state. Therefore it is suggested that esophageal temperature is a preferable index of central blood temperature. Additionally, measurement of esophageal temperature can be made more easily and safely than tympanic membrane temperature.     

Pulsatile blood flow effects on temperature distribution and heat transfer in rigid vessels

The effect of blood velocity pulsations on bioheat transfer is studied. A simple model of a straight rigid blood vessel with unsteady periodic flow is considered. A numerical solution that considers the fully coupled Navier-Stokes and energy equations is used for the simulations. The influence of the pulsation rate on the temperature distribution and energy transport is studied for four typical vessel sizes: aorta, large arteries, terminal arterial branches, and arterioles. The results show that: the pulsating axial velocity produces a pulsating temperature distribution; reversal of flow occurs in the aorta and in large vessels, which produces significant time variation in the temperature profile. Change of the pulsation rate yields a change of the energy transport between the vessel wall and fluid for the large vessels. For the thermally important terminal arteries (0.04-1 mm), velocity pulsations have a small influence on temperature distribution and on the energy transport out of the vessels (8 percent for the Womersley number corresponding to a normal heart rate). Given that there is a small difference between the time-averaged unsteady heat flux due to a pulsating blood velocity and an assumed nonpulsating blood velocity, it is reasonable to assume a nonpulsating blood velocity for the purposes of estimating bioheat transfer.     

Temperature evolution in tissues embedded with large blood vessels during photo-thermal heating

During laser-assisted photo-thermal therapy, the temperature of the heated tissue region must rise to the therapeutic value (e.g., 43 °C) for complete ablation of the target cells. Large blood vessels (larger than 500 micron in diameter) at or near the irradiated tissues have a considerable impact on the transient temperature distribution in the tissue. In this study, the cooling effects of large blood vessels on temperature distribution in tissues during laser irradiation are predicted using finite element based simulation. A uniform flow is assumed at the entrance and three-dimensional conjugate heat transfer equations in the tissue region and the blood region are simultaneously solved for different vascular models. A volumetric heat source term based on Beer–Lambert law is introduced into the energy equation to account for laser heating. The heating pattern is taken to depend on the absorption and scattering coefficients of the tissue medium. Experiments are also conducted on tissue mimics in the presence and absence of simulated blood vessels to validate the numerical model. The coupled heat transfer between thermally significant blood vessels and their surrounding tissue for three different tissue-vascular networks are analyzed keeping the laser irradiation constant. A surface temperature map is obtained for different vascular models and for the bare tissue (without blood vessels). The transient temperature distribution is seen to differ according to the nature of the vascular network, blood vessel size, flow rate, laser spot size, laser power and tissue blood perfusion rate. The simulations suggest that the blood flow through large blood vessels in the vicinity of the photothermally heated tissue can lead to inefficient heating of the target.     

Effect of water temperature on cooling efficiency during hyperthermia in humans.

We evaluated the cooling rate of hyperthermic subjects, as measured by rectal temperature (T(re)), during immersion in a range of water temperatures. On 4 separate days, seven subjects (4 men, 3 women) exercised at 65% maximal oxygen consumption at an ambient temperature of 39 degrees C until T(re) increased to 40 degrees C (45.4 +/- 4.1 min). After exercise, the subjects were immersed in a circulated water bath controlled at 2, 8, 14, or 20 degrees C until T(re) returned to 37.5 degrees C. No difference in cooling rate was observed between the immersions at 8, 14, and 20 degrees C despite the differences in the skin surface-to-water temperature gradient, possibly because of the presence of shivering at 8 and 14 degrees C. Compared with the other conditions, however, the rate of cooling (0.35 +/- 0.14 degrees C/min) was significantly greater during the 2 degrees C water immersion, in which shivering was seldom observed. This rate was almost twice as much as the other conditions (P < 0.05). Our results suggest that 2 degrees C water is the most effective immersion treatment for exercise-induced hyperthermia.     

The effect of VEGF on blood vessels and blood cells during Xenopus development

Vascular endothelial growth factor (VEGF) is known to play an essential role in vascular development. We have overexpressed VEGF122 or VEGF170, which are equivalent to mouse VEGF120 and VEGF164, in developing Xenopus embryos. Overexpression of VEGF170 but not VEGF122 demonstrated an absence of expression of hematopoietic markers alpha-globin and GATA-1 but only in the posterior portion of the blood island. Interestingly, strong signals of endothelial markers, msr, fli-1, and tie-2, were detectable in those regions, instead of hematopoietic markers. These results suggested both that injection of VEGF170 resulted in disturbance of vasculogenesis in the posterior portion of the blood island, with excessive production of endothelial cells at the expense of blood cells, and that the anterior and posterior portions of the VBI may have distinct characteristics.     

Predicting effects of blood flow rate and size of vessels in a vasculature on hyperthermia treatments using computer simulation

Background

Pennes Bio Heat Transfer Equation (PBHTE) has been widely used to approximate the overall temperature distribution in tissue using a perfusion parameter term in the equation during hyperthermia treatment. In the similar modeling, effective thermal conductivity (K_eff) model uses thermal conductivity as a parameter to predict temperatures. However the equations do not describe the thermal contribution of blood vessels. A countercurrent vascular network model which represents a more fundamental approach to modeling temperatures in tissue than do the generally used approximate equations such as the Pennes BHTE or effective thermal conductivity equations was presented in 1996. This type of model is capable of calculating the blood temperature in vessels and describing a vasculature in the tissue regions.

Methods

In this paper, a countercurrent blood vessel network (CBVN) model for calculating tissue temperatures has been developed for studying hyperthermia cancer treatment. We use a systematic approach to reveal the impact of a vasculature of blood vessels against a single vessel which most studies have presented. A vasculature illustrates branching vessels at the periphery of the tumor volume. The general trends present in this vascular model are similar to those shown for physiological systems in Green and Whitmore. The 3-D temperature distributions are obtained by solving the conduction equation in the tissue and the convective energy equation with specified Nusselt number in the vessels.

Results

This paper investigates effects of size of blood vessels in the CBVN model on total absorbed power in the treated region and blood flow rates (or perfusion rate) in the CBVN on temperature distributions during hyperthermia cancer treatment. Also, the same optimized power distribution during hyperthermia treatment is used to illustrate the differences between PBHTE and CBVN models. K_eff (effective thermal conductivity model) delivers the same difference as compared to the CBVN model. The optimization used here is adjusting power based on the local temperature in the treated region in an attempt to reach the ideal therapeutic temperature of 43°C. The scheme can be used (or adapted) in a non-invasive power supply application such as high-intensity focused ultrasound (HIFU). Results show that, for low perfusion rates in CBVN model vessels, impacts on tissue temperature becomes insignificant. Uniform temperature in the treated region is obtained.

Conclusion

Therefore, any method that could decrease or prevent blood flow rates into the tumorous region is recommended as a pre-process to hyperthermia cancer treatment. Second, the size of vessels in vasculatures does not significantly affect on total power consumption during hyperthermia therapy when the total blood flow rate is constant. It is about 0.8% decreasing in total optimized absorbed power in the heated region as γ (the ratio of diameters of successive vessel generations) increases from 0.6 to 0.7, or from 0.7 to 0.8, or from 0.8 to 0.9. Last, in hyperthermia treatments, when the heated region consists of thermally significant vessels, much of absorbed power is required to heat the region and (provided that finer spatial power deposition exists) to heat vessels which could lead to higher blood temperatures than tissue temperatures when modeled them using PBHTE.     

The effects of hyperthermia and hypoxia on ventilation during low-intensity steady-state exercise

This study assessed whether the elevated sensitivity of ventilation to hypoxia during exercise is accounted for by an elevation of esophageal temperature (T(es)). Eleven males volunteered for two exercise sessions on an underwater, head-out cycle ergometer at a steady-state rate of oxygen consumption (V(.)(O(2))) of approximately 0.87 l/min (SD 0.07). In one exercise session, 31.5 degrees C (SD 1.4) water held T(es) at a normothermic level of approximately 37.1 degrees C, and in the other exercise session, water at 38.2 degrees C (SD 0.1) maintained a hyperthermic T(es) of approximately 38.5 degrees C. After a 30-min rest and 20-min warm-up, exercising participants inhaled air for 10 min [Euoxia 1 (E1)], an isocapnic hypoxic gas mixture with 12% O(2) in N(2) (H1) for the next 10 min and air again [Euoxia 2 (E2)] for the last 10 min. A significant increase in V(.)(E) during all hyperthermia conditions (0.01< P < 0.048) was evident; however, during hyperthermic hypoxia, there was a disproportionate and significant (P = 0.017) increase in V(.)(E) relative to normothermic hypoxia. This was the main explanation for a significant esophageal temperature and gas type interaction (P = 0.012) for V(.)(E). Significant effects of hyperthermia, isocapnic hypoxia, and their positive interaction remained evident after removing the influence of (V(.)(O(2))) on V(.)(E). Serum lactate and potassium concentrations, as well as hemoglobin oxygen saturation, were each not significantly different between normothermic and hyperthermic-hypoxic conditions. In conclusion, the elevated sensitivity of exercise ventilation to hypoxia during exertion appears to be modulated by elevations in esophageal temperature, potentially because of a temperature-mediated stimulation of the peripheral chemoreceptors.     

Determination of the 3D temperature distribution during ferromagnetic hyperthermia under the influence of blood flow

A numerical simulation of tissue heating during thermo-seed ferromagnetic hyperthermia was performed to determine the temperature distribution of treated tumor tissues under the influence of three large blood vessels at different locations. The effects of the blood velocity waveform, blood vessel size, Curie point of the thermo-seeds and the thermo-seed number on temperature distributions were analyzed. The results indicate that the existence of a blood vessel inside the tumor has a significant cooling effect on the temperature distribution in a treated tumor tissue, which is enhanced with an increase in blood velocity. However, the pulsatile blood flow does not have apparently different effects on the outcomes of uniformly heating target tissues in comparison with the steady blood flow during the hyperthermia process. It is also concluded that a higher Curie point temperature and an increase in the number of thermo-seeds can result in profound increases in the temperature variations of the tumor tissue. In addition, tissue-equivalent phantom experiments were conducted to confirm the cooling effects of the blood vessels, and to validate the effectiveness and accuracy of the proposed heat transfer model for the ferromagnetic hyperthermia.     

The effects of arginine-8 vasopressin on blood vessels supplying the cerebral cortex

A videocamera and a dissecting microscope have been used to record the effects of arginine-8 vasopressin (AVP) upon pial blood vessels in anaesthetised rats. Topical application of AVP caused a contraction of pial arteries, but had no measureable effect upon the diameter of veins. The smallest concentration of AVP that was effective in contracting arteries was 10(-7) mU/microliter. Stronger solutions (10(-5) to 2.0 mU/microliter) produced approximately the same (45%) reduction of external diameter. Contraction was maximal 0.25-1.0 min after application of the hormone, had almost recovered (10% contraction) after 10 min, and showed complete recovery by 30 min. Concentrations of AVP that were greater than 10(-3) mU/microliter produced tachyphylaxis, so that a second application of AVP 30 min later had considerably less effect. Concentrations less than 10(-3) mU/microliter produced no detectable tachyphylaxis. These results suggest that blood flow to the normal cerebral cortex may be partly under tonic control by the local concentration of AVP.     

The fine structure of cephalopod blood vessels II. The vessels of the nervous system

Summary Blood vessels of the perioesophageal nerve ganglia (brain) of Octopus vulgaris and the stellate ganglia of Sepia officinalis are described. The vessels have an incomplete endothelium, a complete basement membrane and a complete investment of pericytes. The pericytes are joined by specialised membrane junctions but these are not tight junctions. The main type of neuron/vessel arrangement is one where there is a collagen-filled space between the pericytes and the surrounding glial cells. Axons or neurons are sometimes applied directly to the vessel pericytes and in the neuropil, pericytes contact glial cells that ensheath bundles of axons. Blood spaces between neurons are also present.We would like thank Professor J. Z. Young and Dr. E. G. Gray for encouragement and advice, Mrs. Jane Astafiev for drawing Fig. 11, Mr. S. Waterman for photographic assistance and Miss Cheryl Martin for secretarial and other assistance.     

Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans.

The development of hyperthermia during prolonged exercise in humans is associated with various changes in the brain, but it is not known whether the cerebral metabolism or the global cerebral blood flow (gCBF) is affected. Eight endurance-trained subjects completed two exercise bouts on a cycle ergometer. The gCBF and cerebral metabolic rates of oxygen, glucose, and lactate were determined with the Kety-Schmidt technique after 15 min of exercise when core temperature was similar across trials, and at the end of exercise, either when subjects remained normothermic (core temperature = 37.9 degrees C; control) or when severe hyperthermia had developed (core temperature = 39.5 degrees C; hyperthermia). The gCBF was similar after 15 min in the two trials, and it remained stable throughout control. In contrast, during hyperthermia gCBF decreased by 18% and was therefore lower in hyperthermia compared with control at the end of exercise (43 +/- 4 vs. 51 +/- 4 ml. 100 g(-1). min(-1); P < 0.05). Concomitant with the reduction in gCBF, there was a proportionally larger increase in the arteriovenous differences for oxygen and glucose, and the cerebral metabolic rate was therefore higher at the end of the hyperthermic trial compared with control. The hyperthermia-induced lowering of gCBF did not alter cerebral lactate release. The hyperthermia-induced reduction in exercise cerebral blood flow seems to relate to a concomitant 18% lowering of arterial carbon dioxide tension, whereas the higher cerebral metabolic rate of oxygen may be ascribed to a Q(10) (temperature) effect and/or the level of cerebral neuronal activity associated with increased exertion.     

The effects of simulated microgravity on avian embryonic development.

Based on the few reports available, microgravity (MG) can have adverse effects on the early development of vascularised extra-embryonic membranes in avian eggs. Whether gravity or oxygen availability is the stimulus for development of the blood vessels in the chorioallantoic membranes (CAM) remains unclear. Under gravity the blastoderm forms on top of the yolk sac, closest to the oxygen rich region beneath the shell membranes, and from there the CAM buds from an abdominal extension subsequently to form a close contact with shell membranes. Then as the embryo develops it spreads beneath the eggshell surface to maximise the surface area of the CAM vascular bed available for O2 uptake. To investigate how simulated MG influences development of the CAM and embryo we conducted experiments on chicken embryos during incubation in a 3D-clinostat (control or continuous MG treatment at 5 rpm). Further, to determine if CAM angiogenesis is directed towards regions of high O2 tension or gravity we investigated the effects of wax treatment (50% shell surface area) on development in MG. We found that clinostat MG caused embryonic failure between day 0-5 by preventing normal development of CAM-shell membrane complex. Thereafter acute MG promoted increases in CAM mass, but did not affect embryo mass. Preliminary findings suggest that combined acute MG and wax treatment did not significantly affect embryonic growth in either MG or control groups, but retarded CAM growth in control embryos only. Finally, we will present evidence to show that acute and prolonged exposure to MG does not prevent normal growth and hatching, but might have more subtle effects on hatchling physiology, including reduced heart mass.     

Small-scale temperature fluctuations in perfused tissue during local hyperthermia

We develop analytical expressions (scaling laws) for the local temperature fluctuations near isolated and countercurrent blood vessels during hyperthermia. These scaling laws relate the magnitude of such fluctuations to the size of the heated region and to the thermal equilibration length of the vessels. A new equilibration length is identified for countercurrent vessels. Significant temperature differences are predicted between the vessels and the immediately adjacent tissue when the equilibration length is comparable to or longer than the size of the heated tissue region. Countercurrent vessels are shown to have shorter equilibration lengths and produce smaller temperature fluctuations than isolated vessels of the same size.     

Potassium and blood vessels.

Intraarterial infusion of potassium causes vasodilation whereas reduction of the potassium concentration in the inflowing blood causes vasoconstriction. These responses have always been puzzling since the predicted effects from the Nernst equation are just the reverse. Recent evidence suggests that they result form effects on the activity of sarcolemmal Na, K ATPase in the vascular smooth muscle cell which influence the electrogenic NaK pump. The possible relevance of these findings is discussed.     

The effects of thermal and mechanical material properties on tumorous tissue during hyperthermia treatment

Although there have been numerous reports in several articles about the viscoelastic properties of biological tissues, no effort has been made to investigate the combined thermal and mechanical behavior of the viscoelastic tissue. At present, the model of thermo-viscoelasticity theory with variable thermal conductivity and rheological properties of the volume is considered to investigate bio-thermo-mechanics behavior in living tissue within the context of the Lord-Shulman theory. The model is applied to a limited thickness, cancerous layer problem. The problem was solved analytically in the transformed domain using Laplace transform as a tool. The exact solution is obtained in the context of transformation Laplace. Numerical results are given and illustrated graphically for the distributions of temperature, displacement, and stress. Some correlations are produced with the results obtained for the absence of the thermal relaxation parameter. The effects of variable thermal and volume materials properties, blood perfusion rate on the behavior of various fields are examined.