Purpose: We evaluated magnetic resonance imaging controlled transurethral ultrasound therapy as a treatment for magnetic resonance imaging defined focal prostate cancer using subsequent prostatectomy and histology as the reference standard.Materials and Methods: Five men completed this pilot study, which was approved by the institutional review board. Prior to radical prostatectomy focal tumors identified by magnetic resonance imaging were treated by coagulating targeted subtotal 3-dimensional volumes of prostate tissue using magnetic resonance imaging controlled transurethral focused ultrasound. Treatment was performed with a 3 Tesla clinical magnetic resonance imaging unit combined with modified clinical planning software for high intensity focused ultrasound therapy. After prostatectomy whole mount histological sections parallel to the magnetic resonance imaging treatment planes were used to compare magnetic resonance imaging measurements with thermal damage at the cellular level and, thus, evaluate treatment and target accuracy.Results: Three-dimensional target volumes of 4 to 20 cc and with radii up to 35 mm from the urethra were treated successfully. Mean +/- SD temperature control accuracy at the target boundary was -1.6 +/- 4.8C and the mean spatial targeting accuracy achieved was -1.5 +/- 2.8 mm. Mean treatment accuracy with respect to histology was -0.4 +/- 1.7 mm with all index tumors falling inside the histological outer limit of thermal injury.

PURPOSE Magnetic resonance imaging (MRI) is capable of providing valuable real-time feedback during medical procedures, partly due to the excellent soft-tissue contrast available. Several technical hurdles still exist to seamless integration of medical devices with MRI due to incompatibility of most conventional devices with this imaging modality. In this study, the effect of local perturbations in the magnetic field caused by the magnetization of medical devices was examined using finite element analysis modeling. As an example, the influence of the geometric and material characteristics of a transurethral high-intensity ultrasound applicator on temperature measurements using proton resonance frequency (PRF)-shift thermometry was investigated. METHODS The effect of local perturbations in the magnetic field, caused by the magnetization of medical device components, was examined using finite element analysis modeling. The thermometry artifact generated by a transurethral ultrasound applicator was simulated, and these results were validated against analytic models and scans of an applicator in a phantom. Several parameters were then varied to identify which most strongly impacted the level of simulated thermometry artifact, which varies as the applicator moves over the course of an ablative high-intensity ultrasound treatment. RESULTS Key design parameters identified as having a strong influence on the magnitude of thermometry artifact included the susceptibility of materials and their volume. The location of components was also important, particularly when positioned to maximize symmetry of the device. Finally, the location of component edges and the inclination of the device relative to the magnetic field were also found to be important factors. CONCLUSIONS Previous design strategies to minimize thermometry artifact were validated, and novel design strategies were identified that substantially reduce PRF-shift thermometry artifacts for a variety of device orientations. These new strategies are being incorporated into the next generation of applicators. The general strategy described in this study can be applied to the design of other interventional devices intended for use with MRI.

PurposeTo investigate the spatial, temporal, and temperature resolution of a segmented gradient echo echo‐planar imaging (EPI) technique as applied to proton resonance frequency (PRF) shift thermometry at 3 T in the human prostate gland, and to determine appropriate sequence parameters for magnetic resonance imaging (MRI)‐controlled transurethral ultrasound thermal therapy.Materials and MethodsEleven healthy volunteers (age range 23–58) were scanned at 3 T with a 16‐channel torso coil to study the behavior of a gradient echo EPI thermometry sequence. The temperature stability and geometric distortion were assessed for 11 different parameter sets. In a further five volunteers, the prostate T2* was measured.ResultsFor all scan parameters investigated, the temperature standard deviation within the prostate was less than 1°C, while the distortion was less than 1 mm. Temperature stability was best with higher TE values (up to 25 msec), larger voxel sizes and lower EPI factors, but this had to be balanced against requirements for good spatial and temporal resolution. Prostate T2* values ranged from 30–50 msec.ConclusionA good balance between temperature stability and temporal/spatial resolution is obtained with TE = 15 msec, voxel size = 1.14 mm, and EPI factor = 9, resulting in a dynamic scan time of 7.2 seconds for the nine slices. J. Magn. Reson. Imaging 2013;38:1564–1571. © 2013 Wiley Periodicals, Inc.

PURPOSE:To evaluate the feasibility and safety of magnetic resonance (MR) imaging-controlled transurethral ultrasound therapy for prostate cancer in humans.MATERIALS AND METHODS:This pilot study was approved by the institutional review board and was performed in eight men (mean age, 60 years; range, 49-70 years) with localized prostate cancer (Gleason score≤7, prostate-specific antigen level #15 μg/L) immediately before radical prostatectomy. All patients provided written informed consent. This phase 0 feasibility and safety study is the first evaluation in humans. Transurethral ultrasound therapy was performed with the patient under spinal anesthesia by using a clinical 1.5-T MR unit. Patients then underwent radical prostatectomy, and the resected gland was sliced in the plane of treatment to compare the MR imaging measurements with the pattern of thermal damage. The overall procedure time and coagulation rate were measured. In addition, the spatial targeting accuracy was evaluated, as was the thermal history along the thermal damage boundaries in the gland.RESULTS:The average procedure time was 3 hours, with 2 or fewer hours spent in the MR unit. The treatment was well tolerated by all patients, and a temperature uncertainty of less than 2°C was observed in the treatments. The mean temperature and thermal dose measured along the boundary of thermal coagulation were 52.3°C±2.1 and 3457 (cumulative equivalent minutes at 43°C)±5580, respectively. The mean treatment rate was 0.5 mL/min, and a spatial targeting accuracy of -1.0 mm±2.6 was achieved.CONCLUSION:MR imaging-controlled transurethral ultrasound therapy is feasible, safe, and well tolerated. This technology could be an attractive approach for whole-gland or focal therapy.

The recent emergence at the clinical level of minimally-invasive focal therapy such as laser-induced thermal therapy (LITT) has demonstrated promise in the management of brain metastasis [1], although control over the spatial pattern of heating is limited. Delivery of HIFU from minimally-invasive applicators enables high spatial control of the heat deposition in biological tissues, large treatment volumes and high treatment rate in well chosen conditions [2,3]. In this study, the feasibility of MRI-guided interstitial ultrasound therapy in brain was studies in-vivo in a porcine model. A prototype system originally developed for transurethral ultrasound therapy [4,5,6] was used in this study. Two burr holes of 12 mm in diameter were created in the animal's skull to allow the insertion of the therapeutic ultrasound applicator (probe) into the brain at two locations (right and left frontal lobe). A 4-element linear ultrasound transducer (f = 8 MHz) was mounted at the tip of a 25-cm linear probe (6 mm in diameter). The target boundary was traced to cover in 2D a surface compatible with the treatment of a 2 cm brain tumor. Acoustic power of each element and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control to optimize heat deposition at the target boundary [2,4,5]. Two MRT-controlled ultrasound brain treatments per animal have been performed using a maximal surface acoustic power of 10W. cm-2. In all cases, it was possible to increase accurately the temperature of the brain tissues in the targeted region over the 55 degrees C threshold necessary for the creation of irreversible thermal lesion. Tissue changes were visible on T1w contrast-enhanced images immediately after treatment. These changes were also evident on T2w FSE images taken 2 hours after the 1st treatment and correlated well with the temperature image. On average, the targeted volume was 4.7 +/- 2.3 cm3 and the 55 degrees C treated volume was 6.7 +/- 4.4 cm3. The volumetric undertreatment and overtreatment were respectively 0.1 +/- 0.1 cm3 and 0.7 +/- 0.6 cm3. The radial targeting accuracy was on average 1 +/- 3 mm. Treatments were completed within 7 +/- 3 min, that is an treatment rate of 0.9 +/- 0.7 cm3/min. MRI-controlled interstitial ultrasound therapy of brain tissue is feasible. This minimally-invasive approach avoids the need to propagate ultrasound through the skull and allows spatially controlled heating which could be used for tissue ablation or drug delivery.

Transurethral ultrasound therapy uses real-time magnetic resonance (MR) temperature feedback to enable the 3D control of thermal therapy accurately in a region within the prostate. Previous canine studies showed the feasibility of this method in vivo. The aim of this study was to reduce the procedure time, while maintaining targeting accuracy, by investigating new combinations of treatment parameters. Simulations and validation experiments in gel phantoms were used, with a collection of nine 3D realistic target prostate boundaries obtained from previous preclinical studies, where multi-slice MR images were acquired with the transurethral device in place. Acoustic power and rotation rate were varied based on temperature feedback at the prostate boundary. Maximum acoustic power and rotation rate were optimised interdependently, as a function of prostate radius and transducer operating frequency. The concept of dual frequency transducers was studied, using the fundamental frequency or the third harmonic component depending on the prostate radius. Numerical modelling enabled assessment of the effects of several acoustic parameters on treatment outcomes. The range of treatable prostate radii extended with increasing power, and tended to narrow with decreasing frequency. Reducing the frequency from 8MHz to 4MHz or increasing the surface acoustic power from 10 to 20 W/cm(2) led to treatment times shorter by up to 50% under appropriate conditions. A dual frequency configuration of 4/12MHz with 20 W/cm(2) ultrasound intensity exposure can treat entire prostates up to 40 cm(3) in volume within 30 min. The interdependence between power and frequency may, however, require integrating multi-parametric functions in the controller for future optimisations.

Ultrasound thermal therapy of localized prostate cancer offers a minimally-invasive non-ionizing alternative [1-3] to surgery and radiotherapy. MRI-controlled transurethral ultrasound prostate therapy [4-6] has previously been investigated in a pilot human feasibility study [7], by treating a small sub-volume of prostate tissue. In this study, the feasibility of transurethral dual-frequency ultrasound focal therapy has been investigated in gel phantom. A database of pelvic anatomical models of human prostate cancer patients have been created using MR clinical images. The largest prostate boundary (47 cm3) was used to fabricate an anatomical gel phantom which included various MR characteristics to mimic prostate tissues, 4 localized tumors and surrounding prostate tissues. A 9-element transurethral ultrasound applicator working in dual-frequency mode (f = 4.6/14.5 MHz) was evaluated to heat: (i) the entire prostate volume (Full prostate treatment strategy), (ii) a prostate region restricted to tumors (Focal therapy). Acoustic power of each element and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control (nine thermal slices updated every 6.2s). Experiments have been performed using dual-frequency ultrasound exposures (surface Pmax: 20W. cm-2). (i) For full prostate heating, 7 elements of the device were used to cover the entire prostate length. The heating process was completed within 35 min. Ultrasound exposures at the fundamental frequency allowed full heating of the largest prostate radii (>18 mm), while exposures at the 3rd harmonic ensured homogeneous treatment of the smallest radii. Undertreated and overtreated regions represented respectively 2% and 17% of the prostate volume. (ii) For focal therapy, the target region was optimized to maintain safe regions in the prostate and to cover all tumor-mimics. Only 5 ultrasound elements were used to treat successfully all tumor-mimics within 26 min. Undertreated and overtreated regions each represented 7% of the prostate volume. MRI-guided transurethral ultrasound procedure enables full treatment and focal therapy in human prostate geometry. Prostate volume heating was fast compared to standard HIFU prostate treatments. Dual-frequency ultrasound exposures allowed optimal heat deposition in all prostate regions. The focal therapy strategy is promising as regard to safety and could contribute to enhance the post-treatment autonomy of the patient.

PURPOSEThe feasibility and safety of magnetic resonance imaging (MRI)-controlled transurethral ultrasound therapy were demonstrated recently in a preliminary human study in which a small subvolume of prostate tissue was treated prior to radical prostatectomy. Translation of this technology to full clinical use, however, requires the capability to generate thermal coagulation in a volume up to that of the prostate gland itself. The aim of this study was to investigate the parameters required to treat a full 3D human prostate accurately with a multi-element transurethral applicator and multiplanar MR temperature control.METHODSThe approach was a combination of simulations (to select appropriate parameters) followed by experimental confirmation in tissue-mimicking phantoms. A ten-channel, MRI-compatible transurethral ultrasound therapy system was evaluated using six human prostate models (average volume: 36 cm(3)) obtained from the preliminary human feasibility study. Real-time multiplanar MR thermometry at 3 T was used to control the spatial heating pattern in up to nine planes simultaneously. Treatment strategies incorporated both single (4.6 or 8.1 MHz) and dual (4.6 and 14.4 MHz) frequencies, as well as maximum acoustic surface powers of 10 or 20 W cm(-2).RESULTSTreatments at 4.6 MHz were capable of coagulating a volume equivalent to 97% of the prostate. Increasing power from 10 to 20 W cm(-2) reduced treatment times by approximately 50% with full treatments taking 26 ± 3 min at a coagulation rate of 1.8 ± 0.4 cm(3) min(-1). A dual-frequency 4.6∕14.4 MHz treatment strategy was shown to be the most effective configuration for achieving full human prostate treatment while maintaining good treatment accuracy for small treatment radii. The dual-frequency approach reduced overtreatment close to the prostate base and apex, confirming the simulations.CONCLUSIONSThis study reinforces the capability of MRI-controlled transurethral ultrasound therapy to treat full prostate volumes in a short treatment time with good spatial targeting accuracy and provides key parameters necessary for the next clinical trial.

William Apoutou N'DJIN, Mathieu BURTNYK, Nir LIPSMAN, Michael BRONSKILL, Michael SCHWARTZ, Walter KUCHARCZYK, and Rajiv CHOPRA Imaging Research, Sunnybrook Research Institute, Toronto, ON, Canada, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, Department of Medical Imaging, University Health Network and the University of Toronto, Toronto, ON, Canada, Division of Neurosurgery, University of Toronto, Toronto, ON, Canada

Introduction Standard treatments for localized prostate cancer such as radical prostatectomy and radiotherapy treat disease effectively but are associated with significant long-term complications with respect to urinary, sexual and bowel function. For low-risk patients (85% of the diagnosed patients), the after cancer life quality and maintenance of autonomy is essential to assess real treatment benefits. Ultrasound thermal therapy of localized prostate cancer offers a minimally-invasive non-ionizing alternative [1-3] that could be better suited for patients with low-risk localized disease. MRI-controlled transurethral ultrasound prostate therapy [4-6] has recently been investigated in a pilot human feasibility study [7]; however, only a small sub-volume of prostate tissue was treated to ensure safety to study participants. In this study, the feasibility of transurethral dual-frequency ultrasound focal therapy has been investigated experimentally in gel phantom.

MRI-guided transurethral ultrasound therapy uses a linear array of transducer elements and active temperature feedback to create volumes of thermal coagulation shaped to predefined prostate geometries in 3-D. Numerical simulations have been used to determine robust feedback control algorithms, optimal transducer designs, effects of various tissue and imaging parameters, as well as to evaluate potential treatment accuracy and safety in patient-specific anatomical models. The goal of this work is to evaluate quantitatively the accuracy with which these numerical simulations predict the extent, shape and temperature pattern of 3-D heating produced in tissue-mimicking Zerdine* gel phantoms. Methods. Eleven experiments were performed in a 1.5T MRI scanner. Temperature feedback was used to control the rotation rate and ultrasound power of a transurethral device with five 3.5x5mm transducer elements. Heating patterns shaped to 23 and 11 cc human prostate geometries were generated using devices operating at 4.7 and 8.0 MHz, respectively, and 10W/cm(2) surface acoustic intensity. Transducer surface velocity measurements were acquired using a vibrometer and used to calculate the resulting acoustic pressure distribution in gel. Temperature dynamics were determined according to a FDTD solution to Pennes' BHTE. Results. The numerical simulations predicted the extent and shape of the coagulation boundary produced in gel to within (mean +/- stdev [min, max]): 0.1 +/- 0.4 [-1.4, 1.7] and 0.0 +/- 0.3 [-1.0, 1.5] mm for the treatments at 4.7 and 8.0 MHz, respectively. The temperatures across all MRI thermometry images were predicted to within 10%, and the treatment time (similar to 20 mm) to within 20%. The simulations showed excellent agreement in regions of sharp temperature gradients, near the transurethral and endorectal devices. Conclusion. Heating patterns predicted by the numerical simulations correspond closely to those produced experimentally in gel. This work quantifies the accuracy and demonstrates the validity of using numerical simulations to model MRI-guided transurethral ultrasound prostate therapy.

Previous work from our group has shown that transurethral ultrasound therapy, with a single ultrasound transducer guided by temperature feedback from a single MRI plane (slice), can be used to treat a targeted region accurately in the prostate gland. We have extended this approach to a larger, 3D, targeted volume within the prostate, using a multi-clement transducer controlled concurrently by temperature feedback from multiple imaging planes. Animals were placed supine in a 1.5T clinical MRI, and the transurethral heating device was positioned with image guidance. A four-element transducer (each element was 5mm long, operating at similar to 8 MHz) was rotated to treat a targeted volume around the device. Temperature maps transverse to each element were acquired during heating and used to control the acoustic power of each clement and the rate of rotation of the device. 12-weighted and contrast-enhanced (CE) MR images were obtained pre- and post-heating. Following the treatment, prostates were removed and fixed, axially sliced, stained with H&E, and digitally imaged at high-resolution to outline boundaries of cell death. Slice alignment and image registration techniques were developed to enable quantitative comparison of the axial MRI images and matching histological sections. Prostate sections showed clear regions of coagulative necrosis, extending similar to 20mm along the urethra, which correlated well with CE MRI data and transducer length. After registration, the outer border of coagulative necrosis on H&E conformed well to the target isotherm, similar to results from our previous (single clement) acute studies. These results confirm that our previous analysis techniques for a single transducer can be extended to multiple elements, and that a large volumetric ablation of the prostate gland is feasible with a high degree of accuracy.

OBJECTIVE To confirm the correlation between planning and thermal injury of the prostate as determined by magnetic resonance imaging (MRI) and histology in canine and humans treated with transurethral ultrasound.MATERIAL AND METHODS Canine studies: 2 sets of in vivo studies were performed under general anesthesia in 1.5 T clinical MRI. Nine dogs were treated using single transducer; 8 dogs were treated using urethral applicator with multiple transducers. Rectal cooling was maintained. After initial imaging, a target boundary was selected and high-intensity ultrasound energy delivered. The spatial temperature distribution was measured continuously every 5 seconds with MR thermometry using the proton-resonant frequency shift method. The goal was to achieve 55 degrees C at the target boundary. After treatment, the prostate was harvested and fixed with adjoining tissue, including rectum. Temperature maps, anatomical images, and histologic sections were registered to each other and compared. Human studies: To date, 5 patients with localized prostate cancer have been treated immediately before radical prostatectomy. Approximately 30% of the gland volume was targeted.RESULTS A continuous pattern of thermal coagulation was successfully achieved within the target region, with an average spatial precision of 1-2 mm. Radical prostatectomy was routine, with an uncomplicated postoperative course in all patients. The correlation between anatomical, thermal, and histologic images was <= 3 mm. Treatment time was <30 minutes. No thermal damage to rectal tissue was observed.CONCLUSIONS Thermal ablation within the prescribed target of the prostate has been successfully demonstrated in canine studies. The treatment is also feasible in humans. UROLOGY 76: 1506-1511, 2010. (C) 2010 Elsevier Inc.

MRI-controlled transurethral ultrasound therapy uses a linear array of transducer elements and active temperature feedback to create volumes of thermal coagulation shaped to predefined prostate geometries in 3D. The specific aims of this work were to demonstrate the accuracy and repeatability of producing large volumes of thermal coagulation (>10 cc) that conform to 3D human prostate shapes in a tissue-mimicking gel phantom, and to evaluate quantitatively the accuracy with which numerical simulations predict these 3D heating volumes under carefully controlled conditions. Eleven conformal 3D experiments were performed in a tissue-mimicking phantom within a 1.5T MR imager to obtain non-invasive temperature measurements during heating. Temperature feedback was used to control the rotation rate and ultrasound power of transurethral devices with up to five 3.5 × 5 mm active transducer elements. Heating patterns shaped to human prostate geometries were generated using devices operating at 4.7 or 8.0 MHz with surface acoustic intensities of up to 10 W cm−2. Simulations were informed by transducer surface velocity measurements acquired with a scanning laser vibrometer enabling improved calculations of the acoustic pressure distribution in a gel phantom. Temperature dynamics were determined according to a FDTD solution to Pennes' BHTE. The 3D heating patterns produced in vitro were shaped very accurately to the prostate target volumes, within the spatial resolution of the MRI thermometry images. The volume of the treatment difference falling outside ±1 mm of the target boundary was, on average, 0.21 cc or 1.5% of the prostate volume. The numerical simulations predicted the extent and shape of the coagulation boundary produced in gel to within (mean ± stdev [min, max]): 0.5 ± 0.4 [−1.0, 2.1] and −0.05 ± 0.4 [−1.2, 1.4] mm for the treatments at 4.7 and 8.0 MHz, respectively. The temperatures across all MRI thermometry images were predicted within −0.3 ± 1.6 °C and 0.1 ± 0.6 °C, inside and outside the prostate respectively, and the treatment time to within 6.8 min. The simulations also showed excellent agreement in regions of sharp temperature gradients near the transurethral and endorectal cooling devices. Conformal 3D volumes of thermal coagulation can be precisely matched to prostate shapes with transurethral ultrasound devices and active MRI temperature feedback. The accuracy of numerical simulations for MRI-controlled transurethral ultrasound prostate therapy was validated experimentally, reinforcing their utility as an effective treatment planning tool.

Minimally invasive treatments for localised prostate cancer are being developed with the aim of achieving effective disease control with low morbidity. High-temperature thermal therapy aimed at producing irreversible thermal coagulation of the prostate gland is attractive because of the rapid onset of thermal injury, and the immediate visualisation of tissue response using medical imaging. High-intensity ultrasound therapy has been shown to be an effective means of achieving thermal coagulation of prostate tissue using minimally invasive devices inserted into the rectum, urethra, or directly into the gland itself. The focus of this review is to describe the work done in our group on the development of MRI-controlled transurethral ultrasound therapy. This technology utilises high intensity ultrasound energy delivered from a transurethral device to achieve thermal coagulation of prostate tissue. Control over the spatial pattern of thermal damage is achieved through closed-loop temperature feedback using quantitative MR thermometry during treatment. The technology, temperature feedback algorithms, and results from numerical modelling, along with experimental results obtained in animal and human studies are described. Our experience suggests that this form of treatment is technically feasible, and compatible with existing MR imaging systems. Temperature feedback control algorithms using MR thermometry can achieve spatial treatment accuracy of a few millimetres in vivo. Patient-specific simulations predict that surrounding tissues can be spared from thermal damage if appropriate measures are taken into account during treatment planning. Recent human experience has been encouraging and motivates further evaluation of this technology as a potential treatment for localised prostate cancer.

and other risk factors that are associated with variations in breast density, and the biological plausibility of the associations with risk of breast cancer. We also discuss the potential for improved risk prediction that might be achieved by using alternative breast imaging methods, such as magnetic resonance or ultrasound. After adjustment for other risk factors, breast density is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer. Breast density is associated with risk of all of the proliferative lesions that are thought to be precursors of breast cancer. Studies of twins have shown that breast density is a highly heritable quantitative trait. Associations between breast density and variations in breast histology, risk of proliferative breast lesions, and risk of breast cancer may be the result of exposures of breast tissue to both mitogens and mutagens. Characterization of breast density by mammography has several limitations, and the uses of breast density in risk prediction and breast cancer prevention may be improved by other methods of imaging, such as magnetic resonance or ultrasound tomography.