Intervention and therapy.
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Biomedical subjects
Publications and source records attributed to G ter Haar.
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The purpose of this investigation was to study the tissue damage (including blood vessels) on both normal and tumor-bearing experimental livers and the course of liver repair after focused ultrasound (FUS) treatment using histological evaluation. A series of experiments were carried out in vivo. Tissue was treated using arrays of ultrasound exposures with a frequency of 1.7 MHz, in situ spatially averaged focal intensity (I(SAL) in situ) of 212-266 W/cm2 (corresponding to in situ spatial peak intensity of 382-479 W/cm2), 5-10 s exposure duration and 1.5-3.0 mm exposure separation. Tissue specimens were examined using both light and electron microscopy. The damage to the blood vessel walls was studied. The results showed the existence of indirect tissue damage in both normal and tumor tissue that is outside of the treatment volume, due to disruption of the major blood vessels supplying the adjacent area. Evidence for liver regeneration was found 2 months after FUS treatment.
Therapeutic ultrasound has been in use for many years. Early applications were those for which tissue heating was the goal, and so it was used for soft tissue injuries such as may be incurred during sport. More recently, attention has been drawn both to high intensity focused beams that may be used for thermal ablation of selected regions, and also to low intensity fields that appear to be able to stimulate physiological processes, such as tissue repair, without biologically significant temperature rises. Ultrasonic tools are used for therapeutic effect in dentistry and are being investigated for use in thrombolysis. This paper reviews the various therapeutic applications of ultrasound.
This article reports treatment of implanted liver tumors (HSN fibrosarcoma) with focused ultrasound (FUS). Experiments were carried out on implanted liver tumors in vivo. In order to determine the optimum treatment conditions, various combinations of exposure parameters were investigated. The results showed that it is possible to achieve total destruction of tumor cells in the treatment volume using an FUS system with a frequency of 1.7 MHz, with in situ ISAL of 261 W/cm2, 5-s exposure duration, and 1.5-mm exposure separation, with an in situ ISAL of 266 W/cm2, 10-s duration, and 2-mm separation, or with in situ ISAL of 213 W/cm2, 8-s duration, and 1.5-mm separation. Fifteen selected tumors were treated with these experimentally determined "optimum" exposure conditions. All the tumors were destroyed completely. Assessment of tumor viability in the treated volume was performed using both histologic and tissue culture methods. The mechanism of tumor damage, the limitations of the tumor model, and the effect of exposure parameters and liver blood flow on the treatment are discussed.
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Ventricular size increases during growth, but often due to cardiac disease. This study aims to describe left ventricular dimension interrelations using a representation that is applicable to patients with cardiac disease, and subsequently to statistically study possible age and gender influences in a large population. In retrospect we analyzed echocardiographically obtained diameters of the left ventricle in 442 dogs of various breeds with congenital or acquired heart disease. Also, we compared our findings with published data on humans and other animals. Multivariate regression analysis was applied to assess possible influences of age and gender. A high correlation was found for end-systolic diameter (ESD) versus end-diastolic diameter (EDD): ESD (cm) = -1.01 cm + 0.93 x EDD (cm) with r = 0.94, p < .00001. Next, these patients were categorized into three age groups (divisions at 3 and 7 years). We detected a slight age dependent effect: the regression coefficients for the younger group differed from the two older groups. No significant gender-related influence was detected. The observation of a high correlation for the ESD versus EDD relationship could be confirmed by reanalysis of published data on normal individuals and human patients. The newly described relationship between ESD and EDD applies in particular to cardiac patients. This is a relevant finding, because clinically important indices of ventricular performance generally depend on ESD, EDD or both. Thus, ESD versus EDD offers a convenient framework for studies on cardiac volume regulation and performance in the cardiopathological spectrum, while permitting incorporation of modulating effects related to age.
In order to ablate tumours using high-intensity focused ultrasound (HIFU) it is necessary to irradiate the tumour with a confluent array of single ultrasound exposures. We have identified a phenomenon that we term lesion-to-lesion interaction, which occurs when the spatial separation of individual exposures is such that an existing lesions appears to affect the formation of a subsequent lesion. This article investigates the implications of this phenomenon for strategies to ablate large tissue volumes in the treatment of hepatic metastases. Experiments on pig and rat livers have been carried out using a focused ultrasound system with a frequency of 1.7 MHz, an in situ spatially averaged focal intensity (ISAL) of 133-658 W cm-2 (ISP of 239-1185 W cm-2) and an exposure duration of 5-15 s. The results show that there is interaction between lesions that spatial exposure separations that depend on the intensities and exposure durations used. As a result, either subsequent lesions form closer to the ultrasound source (if the focal peak of the ultrasound beam is placed deep inside the liver tissue) or their length is reduced (if the focal peak is near the liver surface). An explanation is suggested for this effect and a strategy for its avoidance during in vivo HIFU treatment is discussed.
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High intensity beams of ultrasound may be focused at depth within the body, thereby producing selective damage within the focal volume, with no harm to overlying or surrounding tissues. The technique is thus noninvasive, insofar as the source of ultrasound energy is situated outside the body. The mechanism for cell killing is predominantly thermal, although acoustic cavitation may also occur. Ultrasound focal surgery was first conceived in the 1940s as a possible tool for creating selective damage in the brain for neurosurgical research; its potential for more widespread clinical use was not exploited at that time, probably because of the lack of facilities for providing precise visualisation and localisation of the damage. The availability of modern imaging techniques has encouraged a revival of clinical interest, and applications in ophthalmology, urology and oncology are currently being developed.
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This paper reports the histological changes found in rat liver tumours treated with high-intensity focused ultrasound. HSN fibrosarcoma, implanted subcapsularly in the livers of CBH rats, were treated using an array of ultrasound exposures. At predetermined times following treatment, the rats were sacrificed and tissue specimens were examined histologically. Evident tissue damage was confined to regions that had been given high ultrasound exposures. Within these regions ("lesions") there was no evidence of intact cells whereas in the sharply demarcated surrounding tissue there was no evidence of cell damage. Where individual ultrasound lesions had been placed in sufficiently close proximity, there was correspondingly continuous and complete cell destruction. There is suggestive evidence that tissue damage may arise through two different mechanisms: direct, primarily thermal, damage and indirect damage resulting from compromised blood supply. Under the same exposure conditions, normal liver cells appear to lose their morphological structure more readily than do tumour cells.
This paper discusses the effect of blood perfusion on the ablation of rat liver tissue with high-intensity focused ultrasound (HIFU). For this study a practical method has been developed, in which the liver blood flow can be reduced by ligation of the hepatic artery and portal vein. During the treatment the rat liver was mobilized out of the abdomen and the blood flow was measured using both the radioactive microsphere method and a laser Doppler blood-flow monitor. The results show that the hepatic blood flow was about 23 ml/100 g min-1 via the hepatic artery and about 227 ml/100 g min-1 via the portal vein. The total liver blood flow was reduced by 98% when both the hepatic artery and portal vein were ligated. Comparative lesions were made on the same liver lobes of rats with both normal and reduced blood flow using a focused ultrasound beam of 1.7 MHz, 67-425 W cm-2 spatially averaged focal intensity ISAL and 2-20 s exposure duration. A marked difference has been found between the lesion dimensions obtained with normal blood flow and that with reduced blood flow. For exposures at 169 W cm-2 the lesion diameter with normal blood flow was reduced by 14% for 3 s exposure duration compared to that obtained with both hepatic artery and portal vein ligated, while the reduction was more than 20% for longer durations.
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Hyperthermia is now established as a successful therapy for some tumours. It has been found that, for some tumours, the combination of heat and ionizing radiation is more effective than either type of treatment on its own. Ultrasound is commonly used to produce hyperthermia. We have therefore studied the effect of combined heat, ultrasound and 60Co gamma irradiation treatments on suspension cultures of V79 Chinese hamster lung fibroblasts. Cells were exposed to 43 degrees C hyperthermia with or without simultaneous continuous wave ultrasound (2.6 MHz, 2.3 W cm-2) either before or after 60Co gamma exposure (428 c Gy). It was found that when the two types of exposure followed one immediately after the other, then the ultrasound exposure increased the amount of cell killing produced by the combination of heat and ionizing radiation, whether the heat or the ionizing radiation came first. If an interval for repair of 72 minutes was left between the heat and ionizing radiation, then this enhancement was lost. The increase in cell killing produced by the ultrasound is shown to be caused by a mechanism that is nonthermal in origin.
Discrete implanted liver tumours in the rat have been exposed to arrays of 1.7 MHz ultrasound lesions. Focal peak intensities in the range 1.4-3.5 k Wcm-2 were used for an exposure time of 10 s. It has been demonstrated that where the whole tumour volume was exposed to the focused ultrasound beam, no evidence of tumour growth could be detected histologically. Where the ultrasonic lesion array was not contiguous, regrowth occurred. Preliminary histological studies confirmed this finding.
The effect of continuous wave ultrasound exposures on the cytotoxicity of adriamycin has been studied. It has been found that 2.6 MHz, 2.3 Wcm-2 (spatial average) ultrasound can enhance the cell killing potential of adriamycin both in suspensions of single V79 chinese hamster fibroblast cells and in spheroids formed from these cells. The ratio of the slopes of the survival curves for single cell suspensions is 1.5. For spheroids, the growth delay is increased by 1.3 days by simultaneous ultrasound exposure. Flow cytometric studies of the intracellular concentration of adriamycin following ultrasound exposure reveals that this is increased when compared with that measured when the cells are only exposed to adriamycin. Evidence is presented to suggest that this is a non-thermal effect of ultrasound.
No significant differences were found when the obstetric outcome of 515 rural adolescents aged 16 years and younger was compared with that of an equal number of matched young adult rural women aged 20-29 years in respect of booking status, postpartum haemoglobin content, operative/instrumental delivery, mean neonatal birth mass and the incidence of infants weighing under 2,500 g. These results support the conclusions of recent studies in Australia and the USA that adolescence per se confers no increased obstetric risk. On the other hand, unwed motherhood (among all age groups) constitutes a most disturbing social trend in black rural society and this, rather than teenage pregnancy as such, ought to be the focus of concern for social workers and the medical profession.
The use of diagnostic ultrasound can be justified if it can be shown to provide only negligible or small risk while giving good benefit to the patient. In the absence of biological evidence, one way of assessing a new (or existing) piece of diagnostic equipment would be to predict the biophysical changes (i.e. heat and cavitation) that may be produced by its ultrasonic fields in tissue. An assessment of risk may then be made from our knowledge of thermal and cavitational biology. To this end, this study has sought to measure temperature rise, bubble formation, sonoluminescence and acoustic streaming arising from clinical transducers that have been carefully calibrated using a Beam Calibrator, and to determine whether there is good correlation between measured acoustic parameters in water and any of these biophysical characteristics. The results are inconclusive.