Combining radiation with hyperthermia: a multiscale model informed by in vitro experiments.

Combined radiotherapy and hyperthermia offer great potential for the successful treatment of radio-resistant tumours through thermo-radiosensitization. Tumour response heterogeneity, due to intrinsic, or micro-environmentally induced factors, may greatly influence treatment outcome, but is difficult to account for using traditional treatment planning approaches. Systems oncology simulation, using mathematical models designed to predict tumour growth and treatment response, provides a powerful tool for analysis and optimization of combined treatments. We present a framework that simulates such combination treatments on a cellular level. This multiscale hybrid cellular automaton simulates large cell populations (up to 107 cells) in vitro, while allowing individual cell-cycle progression, and treatment response by modelling radiation-induced mitotic cell death, and immediate cell kill in response to heating. Based on a calibration using a number of experimental growth, cell cycle and survival datasets for HCT116 cells, model predictions agreed well (R2 > 0.95) with experimental data within the range of (thermal and radiation) doses tested (0-40 CEM43, 0-5 Gy). The proposed framework offers flexibility for modelling multimodality treatment combinations in different scenarios. It may therefore provide an important step towards the modelling of personalized therapies using a virtual patient tumour.

Pathophysiological mechanisms of high-intensity focused ultrasound-mediated vascular occlusion and relevance to non-invasive fetal surgery.

High-intensity focused ultrasound (HIFU) is a non-invasive technology, which can be used occlude blood vessels in the body. Both the theory underlying and practical process of blood vessel occlusion are still under development and relatively sparse in vivo experimental and therapeutic data exist. HIFU would however provide an alternative to surgery, particularly in circumstances where serious complications inherent to surgery outweigh the potential benefits. Accordingly, the HIFU technique would be of particular utility for fetal and placental interventions, where open or endoscopic surgery is fraught with difficulty and likelihood of complications including premature delivery. This assumes that HIFU could be shown to safely and effectively occlude blood vessels in utero. To understand these mechanisms more fully, we present a review of relevant cross-specialty literature on the topic of vascular HIFU and suggest an integrative mechanism taking into account clinical, physical and engineering considerations through which HIFU may produce vascular occlusion. This model may aid in the design of HIFU protocols to further develop this area, and might be adapted to provide a non-invasive therapy for conditions in fetal medicine where vascular occlusion is beneficial.

High-intensity focused ultrasound in obstetrics and gynecology: the birth of a new era of noninvasive surgery?

Although ultrasound is an essential investigative modality in obstetrics and gynecology, the potential for therapeutic high-intensity focused ultrasound (HIFU) (also referred to as focused ultrasound surgery, FUS) to offer an alternative to invasive surgery is less well known. The ability of HIFU to create discrete regions of tissue necrosis only in precisely targeted positions by careful placement of the focus, without the need for any surgical intervention, has made HIFU of interest to those seeking noninvasive alternatives to conventional abdominal surgery. This article reviews the current experimental and clinical experience with HIFU in obstetrics and gynecology, and outlines potential future applications in fetal medicine and the challenges faced in their development.

Measurement of thermal and ultrasonic properties of some biological tissues.

The measurement of thermal and ultrasonic properties of biological tissues is essential for the assessment of the temperature rise induced in vivo by diagnostic ultrasound. In this paper, we present measurements of thermal conductivity, thermal diffusivity, speed of sound and ultrasonic attenuation of fresh ex vivo porcine tissue, namely 'muscle' (from abdomen and leg), 'skin with subcutaneous fat' (from abdomen and leg), 'abdominal fat' and 'bone'. The measurements of the thermal properties of biological tissue samples are based on a transient method. Thermal property measurements show that subcutaneous fat has the lowest thermal conductivity (0.23 W m(-1) K(-1)), while muscle gives the highest values (0.46 W m(-1) K(-1)). Thermal diffusivity of muscle tissue recorded the highest value among the studied tissues (0.16 mm(2) s(-1)) while that of skin with subcutaneous fat gave the lowest value (0.11 mm(2) s(-1)). A scanning acoustic macroscope was used to measure attenuation coefficient and speed of sound for the tissue samples. The results for the speed of sound are broadly similar to those reported in the literature. The power law dependence of the attenuation coefficient of the form eta = a f (b) as a function of frequency was found to be more appropriate than the linear fit in this study.

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.

Sliding window dual gradient echo (SW-dGRE): T1 and proton resonance frequency (PRF) calibration for temperature imaging in polyacrylamide gel.

The aim of the work is to evaluate a magnetic resonance imaging (MRI) thermometry sequence suitable for targeting of focused ultrasound (FUS) when used in vascular occlusion studies. A sliding window dual gradient echo (SW-dGRE) sequence was used. This sequence has the capability of monitoring both T1 relaxation and phase changes, which vary with temperature. Preliminary work involved quantification of the changes in T1 relaxation time with temperature and obtaining the PRF shift coefficient in polyacrylamide gel as it underwent an exothermic reaction during polymerization (avoiding the use of an external heat source). Temperature changes were visualized using thermal maps acquired with the sequence. For FUS guidance a thermal imaging technique is required with a temporal resolution <5 s, a spatial resolution of approximately 1 mm and a temperature resolution of approximately 5 degrees C. The sequence was optimized to improve the CNR (contrast to noise ratio) and SNR (signal to noise ratio) in the phase and magnitude images respectively. The PRF coefficient obtained for the polyacrylamide gel was -9.98 +/- 0.24 ppb degrees C(-1), whilst deltaT1 and temperature change were related by a proportionality factor, the T1 temperature coefficient, of 102.3 +/- 2.9 ms degrees C(-1). The sequence produces an image at every 1.4 s interval. In both magnitude and phase data, the in-plane resolution is +/- 1.2 mm and the temperature resolution is approximately 2 degrees C. The advantage of this sequence is that the temperature obtained from the magnitude data can be confirmed independently using the phase data and vice versa. Thus the sequence can essentially be crosschecked.

Preclinical development of noninvasive vascular occlusion with focused ultrasonic surgery for fetal therapy.

OBJECTIVE: This study was undertaken to investigate the ability of focused ultrasonic surgery to occlude blood flow in vivo. STUDY DESIGN: A 5-mm linear track exposure of 1.7-MHz focused ultrasound was applied across the femoral vessels for 5 seconds. Free field spatial peak intensities in the range of 1,000 to 4,660 W x cm(-2) were used. Vascular occlusion was confirmed after demonstration of an absent distal arterial pulse and an absent flow signal on magnetic resonance angiography and subtracted (after minus before) contrast-enhanced dual-echo steady-state sequences. RESULTS: The minimum intensity for consistent vascular occlusion was 1,690 W x cm(-2) at a focal depth of 5 mm when the transducer was moved at 1 mm x s(-1) orthogonal to the direction of blood flow. CONCLUSIONS: This study demonstrates that focused ultrasonic surgery can achieve reproducible vascular occlusion in vivo. Potential obstetric applications include noninvasive ultrasonographically guided occlusion of placental vessels mediating interfetal transfusion in monochorionic twins.

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.

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.

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 pig's 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.

High-intensity focused ultrasound ablation of the kidney in a large animal model.

The purpose of this study was to establish the feasibility of noninvasive treatment of small renal tumors with high-intensity focused ultrasound (HIFU). A 1.69-MHz extracorporeal HIFU transducer of 150-mm focal length was used. In vitro experiments with excised porcine kidneys allowed determination of suitable exposure parameters to be tested in vivo. For short exposure times (< 2 seconds), the minimum energy required to produce acute thermal damage was 500 +/- 100 Wcm-2 per second. Porcine kidneys (N = 18) were treated in vivo at a depth of 40 mm from the skin surface, with acute damage detected in 13. Damage was macroscopically and histologically discrete and confined to the target area within the kidney. Skin induration was observed after treatment in nine cases, and there was one skin burn. Transducer developments to prevent this morbidity and to improve energy deposition within the target are discussed.

MRI study of hepatic tumours following high intensity focused ultrasound surgery.

High intensity, focused ultrasound has considerable potential as a non-invasive surgical technique, with applications which include the treatment of benign prostatic hyperplasia and the elimination of metastatic disease in the liver. In this study, the use of MRI for treatment planning and subsequent monitoring of ultrasound therapy in the liver has been evaluated. In an experimental model both tumour bearing and normal liver lobes were treated invasively with high intensity focused beam ultrasound surgery. Subsequent changes in the tissue properties were investigated using MRI, in combination with the intravenous contrast agent, Gd-DTPA. The repair of ultrasound damaged tissue was followed until 8 weeks after treatment. The appearance of the MR images was compared with histological sections prepared from parallel experiments. Imaging and histology results showed excellent agreement, illustrating that MRI is well suited to the non-invasive observation of the effects of high intensity focused ultrasound therapy on tissue. Thus, as the clinical potential of ultrasound surgery is realized, MRI, together with the use of contrast agents, will be invaluable both in treatment planning and in monitoring the progress of a treated tumour.

A feasibility study for the non-invasive treatment of superficial bladder tumours with focused ultrasound.

OBJECTIVE: To determine whether high-intensity focused ultrasound can be used to ablate bladder wall tissue using a transabdominal approach in a large animal model, and whether it can be developed as a non-invasive treatment for superficial bladder tumours. MATERIALS AND METHODS: The bladder wall of 25 large white pigs was treated with a 1.7 MHz extracorporeal focused-bowl ultrasonic transducer. Animals were killed either 2 h, 3 days or 4 weeks after treatment and the bladder wall examined macroscopically and histologically. RESULTS: Acute bladder wall damage was detected in 15 of 16 animals at 2 h and in all six animals examined after 3 days. Areas of healing were seen in 10 of 12 animals at 4 weeks. Histological analysis of the treated areas revealed that the urothelium was denuded within 2 h and was associated with an acute inflammatory response in the bladder wall. At 4 weeks, the urothelium had regenerated over a maturing scar. CONCLUSIONS: Focused ultrasound can be used successfully to destroy regions of the bladder wall in a large animal model in vivo.

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.

Absolute 99Tcm-DMSA renal uptake in children: a study of 321 kidneys.

Absolute 99Tcm-dimercaptosuccinic acid (DMSA) uptake was measured in 160 children ranging in age from 3 months to 15 years. In total, 108 pairs of kidneys were normal and the mean uptake for the left and right kidneys was 24.0 and 23.4%, respectively. The mean summed uptake for the left and right kidneys was 47.3%. A method of calculation based on the geometric mean of the anterior and posterior views was used to allow for radiation attenuation. DMSA uptake did not vary significantly with the age of the child. The value of the method in the assessment of abnormal kidneys is presented. The effect of using a supine or prone position for the anterior view was also investigated.

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.

Histological changes in rat liver tumours treated with high-intensity focused ultrasound.

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.

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.

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.

High intensity focused ultrasound--a surgical technique for the treatment of discrete liver tumours.

The treatment of discrete liver tumours is often a difficult clinical problem. High intensity, focused ultrasound may provide one form of therapy for such disease. The ability to focus ultrasound precisely on a predetermined volume allows the possibility of selective tissue destruction at this position without damage to intervening tissues. We have investigated this both in vivo and in excised liver samples in vitro. Quantitative and qualitative studies have been carried out on the relationship between the ultrasonic exposure and the lesion shape, position and volume. In addition, the highly echogenic nature of the ultrasonic lesion has been studied, in an attempt to determine whether 'real time' observation of the extent of tissue damage is feasible.