Assessing high-intensity focused ultrasound treatment of prostate cancer with hyperpolarized 13 C dual-agent imaging of metabolism and perfusion.

The goal of the study was to establish early hyperpolarized (HP) 13 C MRI metabolic and perfusion changes that predict effective high-intensity focused ultrasound (HIFU) ablation and lead to improved adjuvant treatment of partially treated regions. To accomplish this a combined HP dual-agent (13 C pyruvate and 13 C urea) 13 C MRI/multiparametric 1 H MRI approach was used to measure prostate cancer metabolism and perfusion 3-4 h, 1 d, and 5 d after exposure to ablative and sub-lethal doses of HIFU within adenocarcinoma of mouse prostate tumors using a focused ultrasound applicator designed for murine studies. Pathologic and immunohistochemical analysis of the ablated tumor demonstrated fragmented, non-viable cells and vasculature consistent with coagulative necrosis, and a mixture of destroyed tissue and highly proliferative, poorly differentiated tumor cells in tumor tissues exposed to sub-lethal heat doses in the ablative margin. In ablated regions, the intensity of HP 13 C lactate or HP 13 C urea and dynamic contrast-enhanced (DCE) MRI area under the curve images were reduced to the level of background noise by 3-4 h after treatment with no recovery by the 5 d time point in either case. In the tissues that received sub-lethal heat dose, there was a significant 60% ± 12.4% drop in HP 13 C lactate production and a significant 30 ± 13.7% drop in urea perfusion 3-4 h after treatment, followed by recovery to baseline by 5 d after treatment. DCE MRI Ktrans showed a similar trend to HP 13 C urea, demonstrating a complete loss of perfusion with no recovery in the ablated region, while having a 40%-50% decrease 3-4 h after treatment followed by recovery to baseline values by 5 d in the margin region. The utility of the HP 13 C MR measures of perfusion and metabolism in optimizing focal HIFU, either alone or in combination with adjuvant therapy, deserves further testing in future studies.

Thermal therapy of pancreatic tumours using endoluminal ultrasound: Parametric and patient-specific modelling.

PURPOSE: The aim of this study is to investigate endoluminal ultrasound applicator configurations for volumetric thermal ablation and hyperthermia of pancreatic tumours using 3D acoustic and biothermal finite element models. MATERIALS AND METHODS: Parametric studies compared endoluminal heating performance for varying applicator transducer configurations (planar, curvilinear-focused, or radial-diverging), frequencies (1-5 MHz), and anatomical conditions. Patient-specific pancreatic head and body tumour models were used to evaluate feasibility of generating hyperthermia and thermal ablation using an applicator positioned in the duodenal or stomach lumen. Temperature and thermal dose were calculated to define ablation (> 240 EM(43 °C)) and moderate hyperthermia (40-45 °C) boundaries, and to assess sparing of sensitive tissues. Proportional-integral control was incorporated to regulate maximum temperature to 70-80 °C for ablation and 45 °C for hyperthermia in target regions. RESULTS: Parametric studies indicated that 1-3 MHz planar transducers are the most suitable for volumetric ablation, producing 5-8 cm(3) lesion volumes for a stationary 5-min sonication. Curvilinear-focused geometries produce more localised ablation to 20-45 mm depth from the GI tract and enhance thermal sparing (T(max) < 42 °C) of the luminal wall. Patient anatomy simulations show feasibility in ablating 60.1-92.9% of head/body tumour volumes (4.3-37.2 cm(3)) with dose < 15 EM(43 °C) in the luminal wall for 18-48 min treatment durations, using 1-3 applicator placements in GI lumen. For hyperthermia, planar and radial-diverging transducers could maintain up to 8 cm(3) and 15 cm(3) of tissue, respectively, between 40-45 °C for a single applicator placement. CONCLUSIONS: Modelling studies indicate the feasibility of endoluminal ultrasound for volumetric thermal ablation or hyperthermia treatment of pancreatic tumour tissue.

Quantifying temperature-dependent T1 changes in cortical bone using ultrashort echo-time MRI.

PURPOSE: To demonstrate the feasibility of using ultrashort echo-time MRI to quantify T1 changes in cortical bone due to heating. METHODS: Variable flip-angle T1 mapping combined with 3D ultrashort echo-time imaging was used to measure T1 in cortical bone. A calibration experiment was performed to detect T1 changes with temperature in ex vivo cortical bone samples from a bovine femur. Ultrasound heating experiments were performed using an interstitial applicator in ex vivo bovine femur specimens, and heat-induced T1 changes were quantified. RESULTS: The calibration experiment demonstrated that T1 increases with temperature in cortical bone. We observed a linear relationship between temperature and T1 with a linear coefficient between 0.67 and 0.84 ms/°C over a range of 25-70°C. The ultrasound heating experiments showed increased T1 changes in the heated regions, and the relationship between the temperature changes and T1 changes was similar to that of the calibration. CONCLUSION: We demonstrated a temperature dependence of T1 in ex vivo cortical bone using a variable flip-angle ultrashort echo-time T1 mapping method.

Catheter-based ultrasound technology for image-guided thermal therapy: current technology and applications.

Catheter-based ultrasound (CBUS) is applied to deliver minimally invasive thermal therapy to solid cancer tumours, benign tissue growth, vascular disease, and tissue remodelling. Compared to other energy modalities used in catheter-based surgical interventions, unique features of ultrasound result in conformable and precise energy delivery with high selectivity, fast treatment times, and larger treatment volumes. We present a concise review of CBUS technology being currently utilized in animal and clinical studies or being developed for future applications. CBUS devices have been categorised into interstitial, endoluminal and endovascular/cardiac applications. Basic applicator designs, site-specific evaluations and possible treatment applications have been discussed in brief. Particular emphasis has been given to ablation studies that incorporate image guidance for applicator placement, therapy monitoring, feedback control, and post-procedure assessment. Examples of devices included here span the entire spectrum of the development cycle from preliminary simulation-based design studies to implementation in clinical investigations. The use of CBUS under image guidance has the potential for significantly improving precision and applicability of thermal therapy delivery.

Modelling of endoluminal and interstitial ultrasound hyperthermia and thermal ablation: applications for device design, feedback control and treatment planning.

Endoluminal and catheter-based ultrasound applicators are currently under development and are in clinical use for minimally invasive hyperthermia and thermal ablation of various tissue targets. Computational models play a critical role in device design and optimisation, assessment of therapeutic feasibility and safety, devising treatment monitoring and feedback control strategies, and performing patient-specific treatment planning with this technology. The critical aspects of theoretical modelling, applied specifically to endoluminal and interstitial ultrasound thermotherapy, are reviewed. Principles and practical techniques for modeling acoustic energy deposition, bioheat transfer, thermal tissue damage, and dynamic changes in the physical and physiological state of tissue are reviewed. The integration of these models and applications of simulation techniques in identification of device design parameters, development of real time feedback-control platforms, assessing the quality and safety of treatment delivery strategies, and optimisation of inverse treatment plans are presented.

Multiple applicator hepatic ablation with interstitial ultrasound devices: theoretical and experimental investigation.

PURPOSE: To evaluate multiple applicator implant configurations of interstitial ultrasound devices for large volume ablation of liver tumors. METHODS: A 3D bioacoustic-thermal model using the finite element method was implemented to assess multiple applicator implant configurations for thermal ablation with interstitial ultrasound energy. Interstitial applicators consist of linear arrays of up to four 10 mm-long tubular ultrasound transducers, each under separate and dynamic power control, enclosed within a water-cooled delivery catheter (2.4 mm OD). The authors considered parallel implants with two and three applicators (clustered configuration), spaced 2-3 cm apart, to simulate open surgical placement. In addition, the authors considered two applicator implants with applicators converging and diverging at angles of ∼20°, 30°, and 45° to simulate percutaneous placement. Heating experiments (10-15 min) were performed and compared against simulations employing the same experimental parameters. To estimate the performance of parallel, multiple applicator configurations in an in vivo setting, simulations were performed taking into account a range of blood perfusion levels (0, 5, 12, and 15 kg m(-3) s(-1)) that may occur in tumors of varying vascularity. The impact of tailoring the power supplied to individual transducer elements along the length of applicators is explored for applicators inserted in non-parallel (converging and diverging) configurations. Thermal dose (t(43) > 240 min) and temperature thresholds (T > 52 °C) were used to define the ablation zones, with dynamic changes to tissue acoustic and thermal properties incorporated within the model. RESULTS: Experiments in ex vivo bovine liver yielded ablation zones ranging between 4.0-5.6 cm × 3.2-4.9 cm, in cross section. Ablation zone dimensions predicted by simulations with similar parameters to the experiments were in close agreement (within 5 mm). Simulations of in vivo heating showed that 15 min heating and interapplicator spacing less than 3 cm are required to obtain contiguous, complete ablation zones. The ability to create complete ablation zone profiles for nonparallel implants was illustrated by tailoring applied power levels along the length of applicators. CONCLUSIONS: Parallel implants consisting of three interstitial ultrasound applicators in a triangular configuration yield complete ablation zones measuring up to 6.2 cm × 5.7 cm after 15 min heating. At larger interapplicator spacing, the level of blood perfusion in the tumor may yield indentations along the periphery of the ablation zone. Tailoring applied power along the length of the applicator can accommodate for nonparallel implants, without compromising safety.

Temperature superposition for fast computation of 3D temperature distributions during optimization and planning of interstitial ultrasound hyperthermia treatments.

PURPOSE: A temperature superposition method has been developed for fast optimisation and planning of interstitial hyperthermia treatments with convectively cooled multi-transducer ultrasound applicators integrated within high dose rate (HDR) brachytherapy catheters. METHODS: Steady-state temperature distributions produced by individual tubular transducers capable of directional heating were pre-computed using finite element models (FEM) methods. The composite temperature distributions generated by multi-applicator implants were approximated as superposition sums of the pre-computed temperature profiles. Composite temperature distributions produced by the multi-applicator implants were also computed using accurate but computationally expensive FEM methods (considered here as the validation standard). Both methods were used for temperature calculation on a range of test implant geometries and representative patient cases (HDR implants in prostate (n = 13) and cervix (n = 2)), with optimised treatment plans created for the latter. RESULTS: Difference between temperatures calculated by the superposition and FEM methods was below 0.37°C (95% confidence interval) in test implants at clinically relevant acoustic intensities (0.3-2.0 W/cm²) and blood perfusion (2 kg/m³/s). Difference in 41°C isothermal volumes was below 8.3%. Superposition-based optimisations followed by FEM forward calculations (hybrid plans) were completed 4-7 times faster than FEM-only plans (FEM optimisation + FEM forward). Mean T90, T50 and T10 values from both plans were within 0.3°C, 0.4°C and 0.45°C respectively, and the mean acoustic intensities were within 0.23 W/cm². CONCLUSIONS: Temperature superposition provides a fast technique for forward or optimised planning of interstitial ultrasound hyperthermia treatments with calculations comparable to more accurate but time consuming FEM methods.

Catheter Ablation Lesion Visualization With Intracardiac Strain Imaging in Canines and Humans.

Catheter ablation is a common treatment for arrhythmia, but can fail if lesion lines are noncontiguous. Identification of gaps and nontransmural lesions can reduce the likelihood of treatment failure and recurrent arrhythmia. Intracardiac myocardial elastography (IME) is a strain imaging technique that provides visualization of the lesion line. Estimation of lesion size and gap resolution were evaluated in an open-chest canine model ( n = 3 ), and clinical feasibility was investigated in patients undergoing ablation to treat typical cavotricuspid isthmus (CTI) atrial flutter ( n = 5 ). A lesion line consisting of three lesions and two gaps was generated on the canine left ventricle via epicardial ablation. One lesion was generated in one canine right ventricle. Average lesion and gap areas were measured with high agreement (33 ± 14 and 30 ± 15 mm2, respectively) when compared against gross pathology (34 ± 19 and 26 ± 11 mm2, respectively). Gaps as small as 11 mm2 (3.6 mm on epicardial surface) were identifiable. Absolute error and relative error in estimated lesion area were 9.3 ± 8.4 mm2 and 31% ± 34%; error in estimated gap area was 11 ± 9.0 mm2 and 40% ± 29%. Flutter patients were imaged throughout the procedure. Strain was shown to be capable of differentiating between baseline and after ablation completion as confirmed by conduction block. In all patients, strain decreased in the CTI after ablation (mean paired difference of -17% ± 11%, ). IME could potentially become a useful ablation monitoring tool in health facilities.

Passive cavitation imaging with ultrasound arrays.

A method is presented for passive imaging of cavitational acoustic emissions using an ultrasound array, with potential application in real-time monitoring of ultrasound ablation. To create such images, microbubble emissions were passively sensed by an imaging array and dynamically focused at multiple depths. In this paper, an analytic expression for a passive image is obtained by solving the Rayleigh-Sommerfield integral, under the Fresnel approximation, and passive images were simulated. A 192-element array was used to create passive images, in real time, from 520-kHz ultrasound scattered by a 1-mm steel wire. Azimuthal positions of this target were accurately estimated from the passive images. Next, stable and inertial cavitation was passively imaged in saline solution sonicated at 520 kHz. Bubble clusters formed in the saline samples were consistently located on both passive images and B-scans. Passive images were also created using broadband emissions from bovine liver sonicated at 2.2 MHz. Agreement was found between the images and source beam shape, indicating an ability to map therapeutic ultrasound beams in situ. The relation between these broadband emissions, sonication amplitude, and exposure conditions are discussed.

Acoustic emissions during 3.1 MHz ultrasound bulk ablation in vitro.

Acoustic emissions associated with cavitation and other bubble activity have previously been observed during ultrasound (US) ablation experiments. Because detectable bubble activity may be related to temperature, tissue state and sonication characteristics, these acoustic emissions are potentially useful for monitoring and control of US ablation. To investigate these relationships, US ablation experiments were performed with simultaneous measurements of acoustic emissions, tissue echogenicity and tissue temperature on fresh bovine liver. Ex vivo tissue was exposed to 0.9-3.3-s bursts of unfocused, continuous-wave, 3.10-MHz US from a miniaturized 32-element array, which performed B-scan imaging with the same piezoelectric elements during brief quiescent periods. Exposures used pressure amplitudes of 0.8-1.4 MPa for exposure times of 6-20 min, sufficient to achieve significant thermal coagulation in all cases. Acoustic emissions received by a 1-MHz, unfocused passive cavitation detector, beamformed A-line signals acquired by the array, and tissue temperature detected by a needle thermocouple were sampled 0.3-1.1 times per second. Tissue echogenicity was quantified by the backscattered echo energy from a fixed region-of-interest within the treated zone. Acoustic emission levels were quantified from the spectra of signals measured by the passive cavitation detector, including subharmonic signal components at 1.55 MHz, broadband signal components within the band 0.3-1.1 MHz and low-frequency components within the band 10-30 kHz. Tissue ablation rates, defined as the thermally ablated volumes per unit time, were assessed by quantitative analysis of digitally imaged, macroscopic tissue sections. Correlation analysis was performed among the averaged and time-dependent acoustic emissions in each band considered, B-mode tissue echogenicity, tissue temperature and ablation rate. Ablation rate correlated significantly with broadband and low-frequency emissions, but was uncorrelated with subharmonic emissions. Subharmonic emissions were found to depend strongly on temperature in a nonlinear manner, with significant emissions occurring within different temperature ranges for each sonication amplitude. These results suggest potential roles for passive detection of acoustic emissions in guidance and control of bulk US ablation treatments.

MR thermometry-guided ultrasound hyperthermia of user-defined regions using the ExAblate prostate ablation array.

BACKGROUND: Hyperthermia therapy (HT) has shown to be an effective adjuvant to radiation, chemotherapy, and immunotherapy. In order to be safe and effective, delivery of HT requires maintenance of target tissue temperature within a narrow range (40-44 °C) for 30-60 min, which necessitates conformal heat delivery and accurate temperature monitoring. The goal of this project was to develop an MR thermometry-guided hyperthermia delivery platform based upon the ExAblate prostate array that would achieve uniform stable heating over large volumes within the prostate, while allowing the user to precisely control the power deposition patterns and shape of the region of treatment (ROT). METHODS: The HT platform incorporates an accelerated multi-slice real time MR thermometry pulse sequence and reconstruction pipeline. Temperature uniformity over a large contiguous area was achieved by multi-point temperature sampling with multi-focal feedback power control. The hyperthermia delivery system was based on an InSightec ExAblate 2100 prostate focused ultrasound ablation system, and HeartVista's RTHawk real-time MRI system integrated with a 3 T MRI scanner. The integrated system was evaluated in experiments with a tissue-mimicking phantom for prolonged exposures with a target temperature increase of 7 °C from baseline. RESULTS: Five various shapes of the region of treatment, defined on a 5 × 5 grid (35 × 35 mm, 11-25 focal spots per shape), were implemented to evaluate the performance of the system. MR temperature images, acquired after steady state was reached, showed different patterns of heating that closely matched the prescribed regions. Temperature uncertainty of the thermometry acquisition was 0.5 °C. The time to reach the target temperature (2:58-7:44 min) depended on the chosen ROT shape and on the distance from transducer to focal plane. Pre-cooling with circulating water helped to reduce near-field heating. CONCLUSIONS: We have implemented a real-time MR thermometry-guided system for hyperthermia delivery within user-defined regions with the ExAblate prostate array and evaluated it in phantom experiments for different shapes and focal depths. Our results demonstrate the feasibility of using a commercially available endorectal FUS transducer to perform spatially-conformal hyperthermia therapy and could lead to a new set of exciting applications for these devices.

880 kHz ultrasound treatment for drug delivery to the vitreous humor.

Clinical management of many chronic ophthalmological disorders requires direct delivery of drugs into the vitreous. There is an important need to investigate novel needle-less alternatives to deliver drugs to the vitreous. The purpose of this study is to assess the effects of a needle-less system using ultrasound to enhance vitreal delivery of small molecules through the sclera in an ex vivo model and to evaluate whether changes in permeability are mainly due to the heat generated by sonication. An eye cup containing 1 mL of sodium fluorescein 0.1% was placed on top of the sclera of cadaveric rabbit eyes. Treated eyes were sonicated for 10 minutes, and left in contact with the fluorescein solution for an additional 50 minutes. Control eyes received the same exposure to fluorescein solution (60 minutes) in the eye cup without ultrasound treatment. Vitreous humor was collected and analyzed using a fluorescence spectrophotometer to calculate the concentration of fluorescein that diffused into the vitreous humor. An additional set of eyes was treated using a heating probe to evaluate whether changes in permeability were mainly due to heat. Vitreous samples from ultrasound-treated eyes showed a 44.6% higher concentration of fluorescein compared to control eyes. The concentration of fluorescein in the vitreous of heat-treated eyes did not show a significant difference when compared to control eyes. Thus, phonophoresis is a promising needle-less method for vitreal drug delivery, and local heating conducted to the surface of the sclera should be mitigated because it does not enhance the efficacy of the method.

Spectrophotometric quantification of bilirubin in hemorrhagic spinal fluid using an innovative algorithm.

Annually, approximately 30,000 people suffer from aneurysmal subarachnoid hemorrhage (SAH) in the United States. In an estimated 5% of these patients, the hemorrhage is difficult to diagnose using conventional methods. Clinicians must rely upon a combination of clinical history, Computerized Tomography (CT) scan evidence and lumbar puncture results to diagnose and differentiate SAH from a traumatic spinal tap (blood in the spinal fluid due to the procedure). Here we describe an algorithm based development of an analytic methodology using visible spectroscopy to reliably quantify bilirubin in hemorrhagic spinal fluid. The analysis, which may be useful for diagnoses concerning hemorrhagic stroke, is based on the detection of bilirubin, and concomitant blood products produced within the Cerebral Spinal Fluid (CSF) following SAH. The algorithm quantifies bilirubin (0.3 to 10 mg/dL) from the resultant absorption spectrum. A model is developed from standard visible spectroscopic absorption curves of bilirubin and hemoglobin by applying traditional Beer's Law principles. The model is coupled to a modified partial least square analysis and control theory concept where the bilirubin is the "signal" and is masked by hemoglobin "noise." This paper describes the computational methods, sensitivity and utility of a system to quantify bilirubin in CSF like solutions containing hemoglobin and bilirubin over 0.5 g/dL-10 g/dL of hemoglobin concentrations.

Integration of deployable fluid lenses and reflectors with endoluminal therapeutic ultrasound applicators: Preliminary investigations of enhanced penetration depth and focal gain.

PURPOSE: Catheter-based ultrasound applicators can generate thermal ablation of tissues adjacent to body lumens, but have limited focusing and penetration capabilities due to the small profile of integrated transducers required for the applicator to traverse anatomical passages. This study investigates a design for an endoluminal or laparoscopic ultrasound applicator with deployable acoustic reflector and fluid lens components, which can be expanded after device delivery to increase the effective acoustic aperture and allow for deeper and dynamically adjustable target depths. Acoustic and biothermal theoretical studies, along with benchtop proof-of-concept measurements, were performed to investigate the proposed design. METHODS: The design schema consists of an array of tubular transducer(s) situated at the end of a catheter assembly, surrounded by an expandable water-filled conical balloon with a secondary reflective compartment that redirects acoustic energy distally through a plano-convex fluid lens. By controlling the lens fluid volume, the convex surface can be altered to adjust the focal length or collapsed for device insertion or removal. Acoustic output of the expanded applicator assembly was modeled using the rectangular radiator method and secondary sources, accounting for reflection and refraction at interfaces. Parametric studies of transducer radius (1-5 mm), height (3-25 mm), frequency (1.5-3 MHz), expanded balloon diameter (10-50 mm), lens focal length (10-100 mm), lens fluid (silicone oil, perfluorocarbon), and tissue attenuation (0-10 Np/m/MHz) on beam distributions and focal gain were performed. A proof-of-concept applicator assembly was fabricated and characterized using hydrophone-based intensity profile measurements. Biothermal simulations of endoluminal ablation in liver and pancreatic tissue were performed for target depths between 2 and 10 cm. RESULTS: Simulations indicate that focal gain and penetration depth scale with the expanded reflector-lens balloon diameter, with greater achievable performance using perfluorocarbon lens fluid. Simulations of a 50 mm balloon OD, 10 mm transducer outer diameter (OD), 1.5 MHz assembly in water resulted in maximum intensity gain of ~170 (focal dimensions: ~12 mm length × 1.4 mm width) at ~5 cm focal depth and focal gains above 100 between 24 and 84 mm depths. A smaller (10 mm balloon OD, 4 mm transducer OD, 1.5 MHz) configuration produced a maximum gain of 6 at 9 mm depth. Compared to a conventional applicator with a fixed spherically focused transducer of 12 mm diameter, focal gain was enhanced at depths beyond 20 mm for assembly configurations with balloon diameters ≥ 20 mm. Hydrophone characterizations of the experimental assembly (31 mm reflector/lens diameter, 4.75 mm transducer radius, 1.7 MHz) illustrated focusing at variable depths between 10-70 mm with a maximum gain of ~60 and demonstrated agreement with theoretical simulations. Biothermal simulations (30 s sonication, 75 °C maximum) indicate that investigated applicator assembly configurations, at 30 mm and 50 mm balloon diameters, could create localized ellipsoidal thermal lesions increasing in size from 10 to 55 mm length × 3-6 mm width in liver tissue as target depth increased from 2 to 10 cm. CONCLUSIONS: Preliminary theoretical and experimental analysis demonstrates that combining endoluminal ultrasound with an expandable acoustic reflector and fluid lens assembly can significantly enhance acoustic focal gain and penetration from inherently smaller diameter catheter-based applicators.

Endoluminal ultrasound applicators for MR-guided thermal ablation of pancreatic tumors: Preliminary design and evaluation in a porcine pancreas model.

PURPOSE: Endoluminal ultrasound may serve as a minimally invasive option for delivering thermal ablation to pancreatic tumors adjacent to the stomach or duodenum. The objective of this study was to explore the basic feasibility of this treatment strategy through the design, characterization, and evaluation of proof-of-concept endoluminal ultrasound applicators capable of placement in the gastrointestinal (GI) lumen for volumetric pancreas ablation under MR guidance. METHODS: Two variants of the endoluminal applicator, each containing a distinct array of two independently powered transducers (10 × 10 mm 3.2 MHz planar; or 8 × 10 × 20 mm radius of curvature 3.3 MHz curvilinear geometries) at the distal end of a meter long flexible catheter assembly, were designed and fabricated. Transducers and circulatory water flow for acoustic coupling and luminal cooling were contained by a low-profile polyester balloon covering the transducer assembly fixture. Each applicator incorporated miniature spiral MR coils and mechanical features (guiding tips and hinges) to facilitate tracking and insertion through the GI tract under MRI guidance. Acoustic characterization of each device was performed using radiation force balance and hydrophone measurements. Device delivery into the upper GI tract, adjacent to the pancreas, and heating characteristics for treatment of pancreatic tissue were evaluated in MR-guided ex vivo and in vivo porcine experiments. MR guidance was utilized for anatomical target identification, tracking/positioning of the applicator, and MR temperature imaging (MRTI) for PRF-based multislice thermometry, implemented in the real-time RTHawk software environment. RESULTS: Force balance and hydrophone measurements indicated efficiencies of 48.8% and 47.8% and -3 dB intensity beam-widths of 3.2 and 1.2 mm for the planar and curvilinear transducers, respectively. Ex vivo studies on whole-porcine carcasses revealed capabilities of producing ablative temperature rise (ΔT > 15 °C) contours in pancreatic tissue 4-40 mm long and 4-28 mm wide for the planar transducer applicator (1-13 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Curvilinear transducers produced more selective heating, with a narrower ΔT > 15 °C contour length and width of up to 1-24 mm and 2-7 mm, respectively (1-7 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Active tracking of the miniature spiral coils was achieved using a Hadamard encoding tracking sequence, enabling real-time determination of each coil's coordinates and automated prescription of imaging planes for thermometry. In vivo MRTI-guided heating trials in three pigs demonstrated capability of ∼20 °C temperature elevation in pancreatic tissue at 2 cm depths from the applicator, with 5-7 W/cm(2) applied intensity and 6-16 min sonication duration. Dimensions of thermal lesions in the pancreas ranged from 12 to 28 mm, 3 to 10 mm, and 5 to 10 mm in length, width, and depth, respectively, as verified through histological analysis of tissue sections. Multiple-baseline reconstruction and respiratory-gated acquisition were demonstrated to be effective strategies in suppressing motion artifacts for clear evolution of temperature profiles during MRTI in the in vivo studies. CONCLUSIONS: This study demonstrates the technical feasibility of generating volumetric ablation in pancreatic tissue using endoluminal ultrasound applicators positioned in the stomach lumen. MR guidance facilitates target identification, device tracking/positioning, and treatment monitoring through real-time multislice PRF-based thermometry.

Using passive cavitation images to classify high-intensity focused ultrasound lesions.

Passive cavitation imaging provides spatially resolved monitoring of cavitation emissions. However, the diffraction limit of a linear imaging array results in relatively poor range resolution. Poor range resolution has limited prior analyses of the spatial specificity and sensitivity of passive cavitation imaging in predicting thermal lesion formation. In this study, this limitation is overcome by orienting a linear array orthogonal to the high-intensity focused ultrasound propagation direction and performing passive imaging. Fourteen lesions were formed in ex vivo bovine liver samples as a result of 1.1-MHz continuous-wave ultrasound exposure. The lesions were classified as focal, "tadpole" or pre-focal based on their shape and location. Passive cavitation images were beamformed from emissions at the fundamental, harmonic, ultraharmonic and inharmonic frequencies with an established algorithm. Using the area under a receiver operating characteristic curve (AUROC), fundamental, harmonic and ultraharmonic emissions were found to be significant predictors of lesion formation for all lesion types. For both harmonic and ultraharmonic emissions, pre-focal lesions were classified most successfully (AUROC values of 0.87 and 0.88, respectively), followed by tadpole lesions (AUROC values of 0.77 and 0.64, respectively) and focal lesions (AUROC values of 0.65 and 0.60, respectively).

Development of an endoluminal high-intensity ultrasound applicator for image-guided thermal therapy of pancreatic tumors.

An ultrasound applicator for endoluminal thermal therapy of pancreatic tumors has been introduced and evaluated through acoustic/biothermal simulations and ex vivo experimental investigations. Endoluminal therapeutic ultrasound constitutes a minimally invinvasive conformal therapy and is compatible with ultrasound or MR-based image guidance. The applicator would be placed in the stomach or duodenal lumen, and sonication would be performed through the luminal wall into the tumor, with concurrent water cooling of the wall tissue to prevent its thermal injury. A finite-element (FEM) 3D acoustic and biothermal model was implemented for theoretical analysis of the approach. Parametric studies over transducer geometries and frequencies revealed that operating frequencies within 1-3 MHz maximize penetration depth and lesion volume while sparing damage to the luminal wall. Patient-specific FEM models of pancreatic head tumors were generated and used to assess the feasibility of performing endoluminal ultrasound thermal ablation and hyperthermia of pancreatic tumors. Results indicated over 80% of the volume of small tumors (~2 cm diameter) within 35 mm of the duodenum could be safely ablated in under 30 minutes or elevated to hyperthermic temperatures at steady-state. Approximately 60% of a large tumor (~5 cm diameter) model could be safely ablated by considering multiple positions of the applicator along the length of the duodenum to increase coverage. Prototype applicators containing two 3.2 MHz planar transducers were fabricated and evaluated in ex vivo porcine carcass heating experiments under MR temperature imaging (MRTI) guidance. The applicator was positioned in the stomach adjacent to the pancreas, and sonications were performed for 10 min at 5 W/cm2 applied intensity. MRTI indicated over 40°C temperature rise in pancreatic tissue with heating penetration extending 3 cm from the luminal wall.

Model-based feasibility assessment and evaluation of prostate hyperthermia with a commercial MR-guided endorectal HIFU ablation array.

PURPOSE: Feasibility of targeted and volumetric hyperthermia (40-45 °C) delivery to the prostate with a commercial MR-guided endorectal ultrasound phased array system, designed specifically for thermal ablation and approved for ablation trials (ExAblate 2100, Insightec Ltd.), was assessed through computer simulations and tissue-equivalent phantom experiments with the intention of fast clinical translation for targeted hyperthermia in conjunction with radiotherapy and chemotherapy. METHODS: The simulations included a 3D finite element method based biothermal model, and acoustic field calculations for the ExAblate ERUS phased array (2.3 MHz, 2.3 × 4.0 cm(2), ∼1000 channels) using the rectangular radiator method. Array beamforming strategies were investigated to deliver protracted, continuous-wave hyperthermia to focal prostate cancer targets identified from representative patient cases. Constraints on power densities, sonication durations and switching speeds imposed by ExAblate hardware and software were incorporated in the models. Preliminary experiments included beamformed sonications in tissue mimicking phantoms under MR temperature monitoring at 3 T (GE Discovery MR750W). RESULTS: Acoustic intensities considered during simulation were limited to ensure mild hyperthermia (Tmax < 45 °C) and fail-safe operation of the ExAblate array (spatial and time averaged acoustic intensity ISATA < 3.4 W/cm(2)). Tissue volumes with therapeutic temperature levels (T > 41 °C) were estimated. Numerical simulations indicated that T > 41 °C was calculated in 13-23 cm(3) volumes for sonications with planar or diverging beam patterns at 0.9-1.2 W/cm(2), in 4.5-5.8 cm(3) volumes for simultaneous multipoint focus beam patterns at ∼0.7 W/cm(2), and in ∼6.0 cm(3) for curvilinear (cylindrical) beam patterns at 0.75 W/cm(2). Focused heating patterns may be practical for treating focal disease in a single posterior quadrant of the prostate and diffused heating patterns may be useful for heating quadrants, hemigland volumes or even bilateral targets. Treatable volumes may be limited by pubic bone heating. Therapeutic temperatures were estimated for a range of physiological parameters, sonication duty cycles and rectal cooling. Hyperthermia specific phasing patterns were implemented on the ExAblate prostate array and continuous-wave sonications (∼0.88 W/cm(2), 15 min) were performed in tissue-mimicking material with real-time MR-based temperature imaging (PRFS imaging at 3.0 T). Shapes of heating patterns observed during experiments were consistent with simulations. CONCLUSIONS: The ExAblate 2100, designed specifically for thermal ablation, can be controlled for delivering continuous hyperthermia in prostate while working within operational constraints.

Spatial specificity and sensitivity of passive cavitation imaging for monitoring high-intensity focused ultrasound thermal ablation in ex vivo bovine liver.

Passive cavitation images (PCIs) generated from scattered acoustic waves are a potential technique for monitoring lesion formation during high-intensity focused ultrasound (HIFU) thermal ablation. HIFU lesion prediction by PCIs was assessed in ex vivo bovine liver samples (N=14) during 30-s sonications with 1.1-MHz continuous-wave ultrasound (1989 W/cm^2 estimated spatial-peak intensity). Treated samples were sectioned, optically scanned, and the HIFU lesions segmented based on tissue discoloration. During each insonation, a 192-element, 7-MHz linear array (L7/Iris 2, Ardent Sound) passively recorded emissions from a plane containing the HIFU propagation axis oriented parallel to the image azimuth direction. PCIs were formed from beamformed A-lines filtered into fundamental, harmonic, ultraharmonic, and inharmonic frequency bands. Lesion prediction was tested using binary classification of local tissue ablation based on thresholded PCIs, with spatial specificity and sensitivity of lesion prediction quantified by the area under receiver operating characteristic curves (AUROC). Tadpole-shaped lesions were best predicted by harmonic emissions (AUROC=0.76), prefocal lesions were best predicted by harmonic or ultraharmonic emissions (AUROC=0.86), and cigar-type focal lesions were best predicted by fundamental and harmonic emissions (AUROC=0.65). These results demonstrate spatial specificity and sensitivity when predicting HIFU lesions with PCIs.

Ultrasound-enhanced penetration of topical riboflavin into the corneal stroma.

PURPOSE: To determine whether ultrasound treatment can promote the permeation of topical riboflavin into the corneal stroma. METHODS: Fresh cadaveric rabbit eyes with intact epithelium were left for 45 minutes in riboflavin 0.1% solution and divided in the following groups: A--untreated, epithelium-on; B--ultrasound-treated (1 W/cm(2) at 880 kHz for 6 minutes) with epithelium-on; and C--epithelium-off (no ultrasound). Eyes were removed from the riboflavin solution, corneas were excised, and group B was divided into B1 (with epithelium maintained) and B2 (epithelium removed for the fluorescence analysis). Confocal microscopy was performed to quantify the fluorescence intensity in the cornea according to the distance from the surface (with epithelium in groups A and B1; without epithelium in groups B2 and C). RESULTS: The average fluorescence intensity of riboflavin at a depth of 100, 150, 200, and 250 µm was 69.97, 58.83, 49.23, and 41.72 arbitrary units (A.U.) in group A, respectively; 255.26, 206.01, 159.81, 124.20 A.U. in group B1; 218.90, 177.90, 141.43, 110.45 A.U. in group B2; and 677.64, 420.10, 250.72 and 145.07 A.U. in group C. The difference in fluorescence was statistically significant between groups A and B1 (P = 0.001) and groups B2 and C (P < 0.0001). CONCLUSIONS: Ultrasound treatment increased the entry of topical riboflavin into the corneal stroma despite the presence of a previously intact epithelial barrier. This approach may offer a means of achieving clinically useful concentrations of riboflavin within the cornea with minimum epithelial damage, thereby improving the risk profile of corneal cross-linking procedures.