Estimation of tissue blood flow from hyperthermia treatment data

During hyperthermia treatment of patients the delivered heat and the temperatures at several points in the tissue are often measured and recorded. These data contain information about thermal tissue parameters. A method for extracting this information, i.e. estimating the tissue parameters—in particular the blood perfusion rate—is described. The method applies a system identification technique, adjusting the unknown parameters in a thermal tissue model, until the predicted model output (temperature) coincides well with the measured temperature. Data from a number of patient treatments have been used to test the method, and although the accuracy of the method remains to be established conclusively it appears to give a good estimate of the model parameter representing blood flow. The obvious advantage of the method is that it requires no special transducers or experiments. The weak aspect is that it depends on the correctness of a thermal model of the perfused tissue.     

Estimation of tissue blood flow from hyperthermia treatment data

During hyperthermia treatment of patients the delivered heat and the temperatures at several points in the tissue are often measured and recorded. These data contain information about thermal tissue parameters. A method for extracting this information, i.e. estimating the tissue parameters--in particular the blood perfusion rate--is described. The method applies a system identification technique, adjusting the unknown parameters in a thermal tissue model, until the predicted model output (temperature) coincides well with the measured temperature. Data from a number of patient treatments have been used to test the method, and although the accuracy of the method remains to be established conclusively it appears to give a good estimate of the model parameter representing blood flow. The obvious advantage of the method is that it requires no special transducers or experiments. The weak aspect is that it depends on the correctness of a thermal model of the perfused tissue.     

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 °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°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°C in tumour and 27.6–41.8°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 > 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.     

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.     

Timing of cancer chemotherapy based on circadian variations in tumor tissue blood flow

Blood flows of normal tissues (subcutis, liver, kidney cortex, bone marrow) and tumor tissues (SLC) were measured during a daytime period (3–9 HALO) and a nighttime period (15–21 HALO) by the hydrogen clearance technique. Rats were subjected to an artificial light-dark cycle with light from 7 A.M. to 7 P.M. In all normal tissues, there were no significant differences between average tissue blood flows in 2 different time zones, while tumor tissue blood flow increased significantly in the nighttime. Based on this functional characteristic of tumor microcirculation, anti-tumor effects were compared between a group in which ADM was administered at 4 HALO and a group in which it was administered at 16 HALO. The therapeutic effect of ADM on rats administered at 16 HALO was significantly greater, particularly in large tumors, than that on rats administered at 4 HALO. The main reason for this therapeutic improvement may be due to the selective increase in delivery of anti-cancer drugs to tumor tissues brought about by a circadian increase in tumor tissue blood flow. © 1996 Wiley-Liss, Inc.     

Pharmacokinetics of vinblastine in rat blood plasma and tumour tissue determined by a biological method using flow cytofluorimetry

For the optimal use of vinblastine as an antineoplastic agent, knowledge of the pharmacokinetic distribution in blood plasma and tumour tissue is necessary. A method is presented for the determination of mitotic inhibitory activity of vinblastine and its metabolites, extracted from tissue samples. With this method concentrations as low as0.005 mg/l which are biologically active can be reproducibly determined.The method has been applied to follow the concentration of vinblastine in blood plasma and tumour tissue after injection of1.5 mg of vinblastine/kg body weight in WAG/Rij rats with aR-1, M tumour of0.3–1.0 g growing in the flank. The high concentration in plasma immediately after i.v. injection decreases quickly within24 hr to the minimal detectable concentration in plasma of0.01 mg/l. Although after i.p. injection the concentration in plasma is lower initially, at24 hr it tends to be higher than after i.v. injection. In tumour tissue the maximal concentration is reached at6 hr after i.v. injection (3.0 mg/kg) and at12 hr after i.p. injection (0.6 mg/kg). From12 hr after i.p. injection the concentration remains constant during2–3 days while after i.v. injection a slow decrease is observed. These pharmacokinetic data are compared with the changes of cell proliferation kinetics in the tumour induced by vinblastine. The finding that after i.v. injection the maximal concentration in tumour tissue is higher and is reached earlier than after i.p. injection correlates well with the higher degree of accumulation of cells in mitosis.     

Modified thermal clearance technique for determination of blood flow during local hyperthermia

The thermal clearance method utilizes the rate of temperature decay after the applied power is turned off to estimate the local blood flow. A limitation of this method has been its inability to account for the contribution of thermal conduction to the rate of temperature decay. As a result, the blood flow is generally overestimated. A modification of the thermal clearance method is described in this paper which enables the conduction component to be determined. Profiles of the tissue temperature are obtained in three mutually orthogonal directions about the point where thermal clearance is measured. The Laplacian of the temperature is evaluated from these profiles by the method of finite differences. The tissue thermal conductivity is estimated from literature values. The greatest source of error is the uncertainty in the location of the washout point in each catheter. Strict thermometry requirements must be adopted to reduce the localization error to ± 0.25 cm. The thermometry catheters should be orthogonal to within ± 10° and all three catheters should be in contact at the washout point. The methodology was tested in a phantom, studied by use of a computer model, and implemented in the clinic. The experimental error in the conduction component is typically 50%. The resulting error in the blood flow depends on the relative rates of energy removal by blood flow and thermal conduction. When perfusion is the dominant mode of energy removal, the resulting uncertainty in the blood flow is typically in the range 20–30%.     

Modified thermal clearance technique for determination of blood flow during local hyperthermia

The thermal clearance method utilizes the rate of temperature decay after the applied power is turned off to estimate the local blood flow. A limitation of this method has been its inability to account for the contribution of thermal conduction to the rate of temperature decay. As a result, the blood flow is generally overestimated. A modification of the thermal clearance method is described in this paper which enables the conduction component to be determined. Profiles of the tissue temperature are obtained in three mutually orthogonal directions about the point where thermal clearance is measured. The Laplacian of the temperature is evaluated from these profiles by the method of finite differences. The tissue thermal conductivity is estimated from literature values. The greatest source of error is the uncertainty in the location of the washout point in each catheter. Strict thermometry requirements must be adopted to reduce the localization error to +/- 0.25 cm. The thermometry catheters should be orthogonal to within +/- 10 degrees and all three catheters should be in contact at the washout point. The methodology was tested in a phantom, studied by use of a computer model, and implemented in the clinic. The experimental error in the conduction component is typically 50%. The resulting error in the blood flow depends on the relative rates of energy removal by blood flow and thermal conduction. When perfusion is the dominant mode of energy removal, the resulting uncertainty in the blood flow is typically in the range 20-30%.     

Changes in human skin blood flow by hyperthermia

The heat-induced changes in blood circulation in human forearm skin were studied. With the use of laser Doppler flowmetry, it was possible to noninvasively monitor the velocity and volume of red cells, and thus the flow rate of red cells or blood flow in the human skin. When the skin surface was heated at 35 degrees -43 degrees C for 60 min, the laser Doppler flow (LDF) changed dynamically, indicating that the blood flow in human forearm skin could increase as much as 15-20 times during heating at 43 degrees C. Such an increase in laser Doppler flow resulted from dilation of arterioles and recruitment of capillaries, and also to a lesser extent, from an increase in the velocity of red cell flux. The increase in the velocity of red cell flux implies that arteriovenous anastomoses exist in the human forearm skin, in contradiction to the common view that human forearm skin is devoid of arteriovenous anastomosis.     

Continuous, simultaneous and instantaneous tissue gas and blood flow measurements using the mass spectrometer

Using a membrane permeable to gases it has been demonstrated in our laboratory that partial pressures of O₂, CO₂ and N₂ can be monitored continuously, simultaneously and instantaneously employing a mass spectrometer. Physiologic studies in experimental animals have been carried out recording tissue gases from kidney, liver, skin and brain. Responses in these organs to changes in blood flow, blood gases, surgical trauma, and isolated perfusion have been conducted. Blood flow can be calculated by adding an inert gas (Argon) to the ventilation mixture, and recording its washout time. Simultaneous pO₂, pCO₂ and PAr permits focal metabolic studies previously impossible to record.     

Pharmacokinetics and tissue distribution of larotaxel in rats: comparison of larotaxel-loaded microsphere with larotaxel-solution

Purpose

Larotaxel is a new taxane compound with poor solubility. The aim of this study is to develop a new formulation to locate the poorly soluble drug and compare the pharmacokinetics and tissue distribution of larotaxel-loaded microsphere (LTX-LM) with the solution form larotaxel-solution (LTX-solution).

Methods

A sensitive and efficient UPLC-MS/MS method was developed and validated for determination of larotaxel in rat plasma and tissues and applied to assess the plasma protein binding, pharmacokinetics, and tissue distribution.

Results

Pharmacokinetic study indicated that larotaxel plasma disposition was triphasic, and LTX-LM group had markedly higher AUC, smaller clearance, and lower apparent volume of distribution than the LTX-solution group. The tissue distribution exhibited significant lower uptake of LTX-LM in lung, kidney, heart, muscle, and brain among all the tissues, indicating the advantage of LTX-LM over the solution form in reducing drug precipitation in vivo and toxicity in cardiovascular system and central nervous system.

Conclusions

These results suggest that lipid microsphere could be an effective parenteral carrier for LTX delivery in cancer treatment.     

上消化道多原发癌特征及诊治新进展

我国多原发癌中消化道多原发癌所占比例最大,相对于单发病灶,多原发癌一旦漏诊或误诊,将直接影响患者手术术式、治疗方法的选择及预后情况。近年来随着影像学检查技术的发展以及对该病认识的提高,相关研究逐渐增多,相较于日本等地,我国报道的上消化道多原发癌检出率差异较大。本文总结近期国内外相关文献,对其诊断、临床特点、治疗、预后及发病机制等方面的研究情况进行综述,以提高临床医生对上消化道多原发癌的认识。