Ian Rivens

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.

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.

High intensity focused ultrasound for the treatment of rat tumours

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.

Vascular occlusion using focused ultrasound surgery for use in fetal medicine

OBJECTIVE Focused ultrasound surgery (FUS) is being developed clinically for the non-invasive treatment of soft tissue tumours of the prostate, bladder, liver, kidney, muscle and breast. In the work described in this paper, the application of FUS is extended to investigate the potential to induce vascular occlusion, with the aim of applying the technique to problems in fetal medicine and oncology. METHODS In this feasibility study the occlusion of femoral blood flow in vivo is demonstrated using an array of multiple single exposures of 1.7 MHz focused ultrasound. These were placed in two rows of four lesions at a focal depth of 5 mm. The 4660-W cm-2 (free field spatial peak intensity) 2-s exposures were placed 2 mm apart. Vascular patency was assessed using a Siemens Vision (1.5T) magnetic resonance (MR) imaging scanner with an extremity coil, and intravenous gadolinium contrast agent. FLASH and FISP MR sequences were used to obtain full 3D data sets providing information on soft tissue damage and perfusion. RESULTS AND CONCLUSION Total vascular occlusion was achieved in four of nine cases and significant vascular disruption in five of nine cases. Refinement of the FUS technique and long-term studies are now indicated prior to initial clinical application in fetal medicine.

Investigation of the viscous heating artefact arising from the use of thermocouples in a focused ultrasound field

Accurate temperature measurements in therapeutic ultrasound fields are necessary for understanding damage mechanisms, verification of thermal modelling and calibration of non-invasive clinical thermometry. However, artefactual heating, primarily due to viscous forces which result from motion relative to the surrounding tissue, occurs when metal thermocouples are used in an ultrasound field. The magnitude and time dependence of this artefact has been characterized by comparison with novel thin-film thermocouples (TFTs) at 1-2 cm focal depths in fresh degassed ex vivo bovine liver. High-intensity focused ultrasound exposures (1.7 MHz; free-field spatial-peak temporal-average intensities 40-600 W cm(-2)) were used. Subtraction of the TFT data from that obtained for other thermocouples yielded the time dependence of the viscous heating artefact. This was found to be intensity independent up to 600 W cm(-2) (below the threshold for cavitation and lesion formation) and remained significant at radial distances out to the first side lobe in the focal plane. The contribution of viscous heating to cooling was also found to be significant for at least 5 s after the end of insonation. The ratio of viscous artefact to absorptive heating after 5 s was: 1.76 +/- 0.07 for a fine-wire, 0.45 +/- 0.07 and 1.93 +/- 0.07 for two different sheathed-wires and 0.24 +/- 0.07 for a needle thermocouple.

A Study of Bubble Activity Generated in Ex Vivo Tissue by High Intensity Focused Ultrasound

Cancer treatment by extracorporeal high-intensity focused ultrasound (HIFU) is constrained by the time required to ablate clinically relevant tumour volumes. Although cavitation may be used to optimize HIFU treatments, its role during lesion formation is ambiguous. Clear differentiation is required between acoustic cavitation (noninertial and inertial) effects and bubble formation arising from two thermally-driven effects (the vapourization of liquid into vapour, and the exsolution of formerly dissolved permanent gas out of the liquid and into gas spaces). This study uses clinically relevant HIFU exposures in degassed water and ex vivo bovine liver to test a suite of cavitation detection techniques that exploit passive and active acoustics, audible emissions and the electrical drive power fluctuations. Exposure regimes for different cavitation activities (none, acoustic cavitation and, for ex vivo tissue only, acoustic cavitation plus thermally-driven gas space formation) were identified both in degassed water and in ex vivo liver using the detectable characteristic acoustic emissions. The detection system proved effective in both degassed water and tissue, but requires optimization for future clinical application.

Treatment monitoring and thermometry for therapeutic focused ultrasound

Therapeutic ultrasound is currently enjoying increasingly widespread clinical use especially for the treatment of cancer of the prostate, liver, kidney, breast, pancreas and bone, as well as for the treatment of uterine fibroids. The optimum method of treatment delivery varies between anatomical sites, but in all cases monitoring of the treatment is crucial if extensive clinical acceptance is to be achieved. Monitoring not only provides the operating clinician with information relating to the effectiveness of treatment, but can also provide an early alert to the onset of adverse effects in normal tissue. This paper reviews invasive and non-invasive monitoring methods that have been applied to assess the extent of treatment during the delivery of therapeutic ultrasound in the laboratory and clinic (follow-up after treatment is not reviewed in detail). The monitoring of temperature and, importantly, the way in which this measurement can be used to estimate the delivered thermal dose, is dealt with as a separate special case. Already therapeutic ultrasound has reached a stage of development where it is possible to attempt real-time feedback during exposure in order to optimize each and every delivery of ultrasound energy. To date, data from MR imaging have shown better agreement with the size of regions of damage than those from diagnostic ultrasound, but novel ultrasonic techniques may redress this balance. Whilst MR currently offers the best method for non-invasive temperature measurement, the ultrasound techniques under development, which could potentially offer more rapid visualisation of results, are discussed.

A 3-D finite-element model for computation of temperature profiles and regions of thermal damage during focused ultrasound surgery exposures

Although there have been numerous models implemented for modeling thermal diffusion effects during focused ultrasound surgery (FUS), most have limited themselves to representing simple situations for which analytical solutions and the use of cylindrical geometries sufficed. For modeling single lesion formation and the heating patterns from a single exposure, good results were achieved in comparison with experimental results for predicting lesion size, shape and location. However, these types of approaches are insufficient when considering the heating of multiple sites with FUS exposures when the time interval between exposures is short. In such cases, the heat dissipation patterns from initial exposures in the lesion array formation can play a significant role in the heating patterns for later exposures. Understanding the effects of adjacent lesion formation, such as this, requires a three-dimensional (3-D) representation of the bioheat equation. Thus, we have developed a 3-D finite-element representation for modeling the thermal diffusion effects during FUS exposures in clinically relevant tissue volumes. The strength of this approach over past methods is its ability to represent arbitrarily shaped 3-D situations. Initial simulations have allowed calculation of the temperature distribution as a function of time for adjacent FUS exposures in excised bovine liver, with the individually computed point temperatures comparing favorably with published measurements. In addition to modeling these temperature distributions, the model was implemented in conjunction with an algorithm for calculating the thermal dose as a way of predicting lesion shape. Although used extensively in conventional hyperthermia applications, this thermal dose criterion has only been applied in a limited number of simulations in FUS for comparison with experimental measurements. In this study, simulations were run for focal depths 2 and 3 cm below the surface of pigs liver, using multiple intensity levels and exposure times. The results also compare favorably to published in vitro experimental measurements, which bodes well for future application to more complex problems, such as the modeling of multiple lesion arrays within complex anatomical geometries.