G.R. ter Haar

Ultrasound focal beam surgery

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.

Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU)

Acoustic cavitation has been shown to play a key role in a wide array of novel therapeutic ultrasound applications. This paper presents a brief discussion of the physics of thermally relevant acoustic cavitation in the context of high-intensity focussed ultrasound (HIFU). Models for how different types of cavitation activity can serve to accelerate tissue heating are presented, and results suggest that the bulk of the enhanced heating effect can be attributed to the absorption of broadband acoustic emissions generated by inertial cavitation. Such emissions can be readily monitored using a passive cavitation detection (PCD) scheme and could provide a means for real-time treatment monitoring. It is also shown that the appearance of hyperechoic regions (or bright-ups) on B-mode ultrasound images constitutes neither a necessary nor a sufficient condition for inertial cavitation activity to have occurred during HIFU exposure. Once instigated at relatively large HIFU excitation amplitudes, bubble activity tends to grow unstable and to migrate toward the source transducer, causing potentially undesirable pre-focal damage. Potential means of controlling inertial cavitation activity using pulsed excitation so as to confine it to the focal region are presented, with the intention of harnessing cavitation-enhanced heating for optimal HIFU treatment delivery. The role of temperature elevation in mitigating bubble-enhanced heating effects is also discussed, along with other bubble-field effects such as multiple scattering and shielding.

Effect of blood perfusion on the ablation of liver parenchyma with high-intensity focused ultrasound

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.

LESION DEVELOPMENT IN FOCUSED ULTRASOUND SURGERY: A GENERAL MODEL

An analytical model has been constructed for the process of formation of thermal lesions in tissue, resulting from exposure to intense, highly focused ultrasound beams such as may be used in minimally invasive surgery. The model assumes a Gaussian approximation to beam shape in the focal region and predicts, for any such focal beam, the time delay to initiation of a lesion and the subsequent time course of growth of that lesion in lateral and axial dimensions, taking into account the effects of thermal diffusion and blood perfusion. The necessary approximations and assumptions of the model are considered. Comparison of predictions with experimentally measured data on excised pig liver indicate generally good agreement. Comparisons are also made of this theory with previously published data on exposure-time dependence of lesioning threshold intensity. Deficiencies are identified in existing practice for measuring and reporting acoustic exposures for focused ultrasound surgery, and the proposal is therefore made that a quantity that would be more satisfactory, from the viewpoints both of metrology and biophysical relevance, is the intensity spatially averaged over the area enclosed by the half-pressure-maximum contour in the focal plane, as determined under linear conditions, provisionally denoted as ISAL.

Acoustic properties of lesions generated with an ultrasound therapy system

Methods for quantitative imaging of ultrasound propagation properties were applied to the examination of the acoustic appearance of lesions generated by high intensity focused ultrasound in excised pig livers. Single lesions, about 10 mm maximum diameter by 30 mm long, were created in each of six liver specimens. Two dimensional images (32 by 32 points) of sound speed, mean attenuation coefficient (as a function of frequency in the range 3 to 8.5 MHz) and mean backscattering coefficient (5 to 8 MHz) were obtained in 7 mm thick sections of tissue, cut to include a cross-section through the lesion. Images of these properties, presented alongside surface photographs of the samples, provided a qualitative demonstration that attenuation coefficient was the most useful and backscattering coefficient was the least useful acoustic parameter for visualizing such lesions. Quantitatively the data demonstrated significant increases in attenuation coefficient and sound speed in lesioned liver relative to normal, whereas backscattering was shown not to change in a significant manner except when undissolved gas is the mechanism for increased acoustic scattering. Samples where gas was not fully removed following lesion production gave significant increases in backscattering at the lesion centre, but the shape and size of regions of high backscattering coefficient corresponded poorly with the shape and size of the lesions, unlike attenuation and sound speed for which such correspondence was good.

The intensity dependence of the site of maximal energy deposition in focused ultrasound surgery

The relationship between spatial peak intensity and the position of ultrasound induced tissue damage was studied in in vitro tissue models, using a 1.69 MHz spherical bowl transducer. The models corresponded to the transabdominal route to the bladder and prostate, which are potential target sites for focused ultrasound surgery. The results confirm that there is a relationship between lesion position and intensity, with lesions forming, under some exposure conditions, ahead of the geometric focus. Forward growth of lesions appears to be due to changes in the absorption characteristics of the tissue in the beam path. Using a computer model, we have demonstrated that the absorption coefficient of the tissue must increase significantly in front of the focus to enable lesions to form ahead of the predicted position. A possible mechanism for this is bubble formation as a result of acoustic cavitation. The effect of nonlinear propagation in the tissue, at the intensities studied, is shown to be relatively small.

Evidence for ultrasonically induced cavitation in vivo

The possibility of stable bubbles being produced during ultrasonic irradiation of a guinea-pig hind limb, has been examined using a pulse echo ultrasonic imaging technique, that can visualise, within a cross-section of the limb, both moving and stationary bubbles of diameters down to 10 mu m (Beck et al. 1978). The observations reported clearly show that acoustic cavitation, leading to stable bubble production, occurs in vivo in mammalian tissue as a result of irradiation with ultrasound above 80 mW cm-2 intensity. However, before the biological consequences of such bubble formation can be assessed, further studies must be carried out to define more fully the intensity threshold as a function of the time or irradiation, and to establish the time course for re-absorption of these stable bubbles in the absence of a sound field.

Preliminary results of a phase I dose escalation clinical trial using focused ultrasound in the treatment of localised tumours

OBJECTIVE The primary aim of this phase I trial was to assess the tolerance of cancer patients to focused ultrasound (FUS) treatment in a variety of different sites and to document any associated acute or delayed toxicity. This would appear to be the first time that treatment has been given without sedation or anaesthesia. METHODS Patients with advanced and/or metastatic disease were eligible for entry into this study. Previous work has established that an in situ ablative intensity (AI) of 1500 W/cm2 Isp for 1 s achieves coagulative necrosis at the focal spot. Ultrasonic exposures of 25-100% of AI for 1 s were delivered to preselected tissue volumes. Pain questionnaires recording any side effects were completed by the patient and the investigator separately. Ultrasound images of the target volume were taken before, immediately after, and 1 week after treatment. RESULTS A total of 14 patients have been entered into this study to date. Seven patients were treated at their primary site and seven received treatment to one of their metastases. No treatment needed to be stopped because of pain. Eight of the 14 patients did not complain of any side effect during or after the treatment. One patient complained of mild, and two of moderate pain during the week following treatment. One patient developed an asymptomatic blister on the skin. CONCLUSION Focused ultrasound is a safe, well-tolerated and non-invasive method of delivering ablative thermal energy to selected tumours. More clinical trials are needed to assess the role of this modality in the treatment of cancer.

Temperature rise recorded during lesion formation by high-intensity focused ultrasound

Temperature rise was observed as a function of time in liver and dog prostate tissue ex vivo during heating with high-intensity focused ultrasound. The temperature rise was measured using a needle thermocouple placed at the focus. The temperature vs. time behaviour closely followed the predictions of a model based on bulk and surface heating. When the tissue temperature was raised above 50 degrees C, an increase in heating rate was seen. At higher temperatures, a point was reached at which a marked, irreversible change of tissue properties was observed, consistent with protein denaturation. The change was sometimes accompanied by a sudden further rise in temperature followed by an equally sudden fall. On dissection, regions of tissue damage (lesions) were seen, sometimes containing bubbles consistent with acoustic cavitation or vaporisation.

Ablation of tissue volumes using high intensity focused ultrasound

Successful application of high intensity focused ultrasound to cancer treatment requires complete ablation of tissue volumes. In order to destroy an entire tumour it is necessary to place a contiguous array of touching lesions throughout it. In a study of how best to achieve this, exposures were selected to give single lesions that were thermal in origin, while avoiding effects due to tissue water boiling and acoustic cavitation. Arrays were formed in excised bovine liver. Under some exposure conditions, lesions were found to merge in front of the focal point, and failed to cover the desired volume. Using fine wire manganin-constantan thermocouples, temperature studies revealed a substantial rise in the temperature of surrounding untreated tissue. Cooling curves showed that it was necessary to allow surrounding tissue to cool for up to 2 min before ambient temperature was reached. By allowing the tissue to cool between exposures it was possible to form arrays of overlapping lesions thus successfully ablating the complete target region.