Search

OBJECTIVES To report the 3-year follow-up of a Phase I study of magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA) in 30 men with localised prostate cancer. Favourable 12-month safety and ablation precision were previously described. PATIENTS AND METHODS As a mandated safety criterion, TULSA was delivered as near whole-gland ablation, applying 3-mm margins sparing 10% of peripheral prostate tissue in 30 men. After 12-month biopsy and MRI, biannual follow-up included prostate-specific antigen (PSA), adverse events (AEs), and functional quality-of-life assessment, with repeat systematic biopsy at 3 years. RESULTS A 3-year follow-up was completed by 22 patients. Between 1 and 3 years, there were no new serious or severe AEs. Urinary and bowel function remained stable. Erectile function recovered by 1 year and was stable at 3 years. The PSA level decreased 95% to a median (interquartile range) nadir of 0.33 (0.1-0.4) ng/mL, stable to 0.8 (0.4-1.6) ng/mL at 3 years. Serial biopsies identified clinically significant disease in 10/29 men (34%) and any cancer in 17/29 (59%). By 3 years, seven men had recurrence (four histological, three biochemical) and had undergone salvage therapy without complications (including six prostatectomies). At 3 years, three of 22 men refused biopsy, and two of the 22 (9%) had clinically significant disease (one new, one persistent). Predictors of salvage therapy requirement included less extensive ablation coverage and higher PSA nadir. CONCLUSION With 3-year Phase I follow-up, TULSA demonstrates safe and precise ablation for men with localised prostate cancer, providing predictable PSA and biopsy outcomes, without affecting functional abilities or precluding salvage therapy.

ObjectivesTo assess differences in 24-month oncologic and functional outcomes in men with low to intermediate-risk prostate cancer treated with MRI-guided transurethral ultrasound ablation (TULSA) using intentionally conservative versus intensified treatment parameters.Patients and MethodsPatients from a single center involved in two multicenter trials were included in this analysis. This included 14 of 30 patients with Gleason 3 + 3 from a Phase I study using intentionally conservative treatment parameters, and 15 of 115 patients with Gleason ≤ 3 + 4 from a pivotal study using intensified parameters. Follow-up data compared across these cohorts included 12-month biopsy and MRI for all patients, and 24-month PSA, micturition and quality of life (IIEF, IPSS, IPSS-QOL). The prognostic value of baseline parameters and PSA kinetics on 12-month histological recurrence was evaluated by logistic regression.Results12-month biopsy revealed clinically significant residual disease in 4 (29%) and 2 (14%) patients from the Phase I and pivotal studies, respectively. PSA nadir was 0.7 ng/ml for Phase I and 0.5 ng/ml for pivotal study patients. Patient age at diagnosis, use of MRI fusion/systematic prostate biopsy, number of obtained cores at initial biopsy, PSA course, and PSA nadir were identified as prognostic factors for treatment success. All but one patient from each cohort maintained erection firmness sufficient for penetration. No cases of pad use were reported at 24 months. There were no Grade 4 or higher adverse events, and no late toxicity related to the procedure.ConclusionTwo-year follow-up demonstrated the efficacy of TULSA for the treatment of localized prostate cancer, and the durability of PSA and functional outcomes. Intensifying treatment parameters in the pivotal trial had no impact on safety or functional outcomes through 24 months, while reducing the recurrence rate for clinically significant disease. Careful patient selection by MRI fusion/systematic prostate biopsy and adequate follow-up through routine 12-month biopsy are recommended.

Purpose: Magnetic resonance imaging-guided transurethral ultrasound ablation uses directional thermal ultrasound under magnetic resonance imaging thermometry feedback control for prostatic ablation. We report 12-month outcomes from a prospective multicenter trial (TACT). Materials and methods: A total of 115 men with favorable to intermediate risk prostate cancer across 13 centers were treated with whole gland ablation sparing the urethra and apical sphincter. The co-primary 12-month endpoints were safety and efficacy. Results: In all, 72 (63%) had grade group 2 and 77 (67%) had NCCN® intermediate risk disease. Median treatment delivery time was 51 minutes with 98% (IQR 95-99) thermal coverage of target volume and spatial ablation precision of ±1.4 mm on magnetic resonance imaging thermometry. Grade 3 adverse events occurred in 9 (8%) men. The primary endpoint (U.S. Food and Drug Administration mandated) of prostate specific antigen reduction ≥75% was achieved in 110 of 115 (96%) with median prostate specific antigen reduction of 95% and nadir of 0.34 ng/ml. Median prostate volume decreased from 37 to 3 cc. Among 68 men with pretreatment grade group 2 disease, 52 (79%) were free of grade group 2 disease on 12-month biopsy. Of 111 men with 12-month biopsy data, 72 (65%) had no evidence of cancer. Erections (International Index of Erectile Function question 2 score 2 or greater) were maintained/regained in 69 of 92 (75%). Multivariate predictors of persistent grade group 2 at 12 months included intraprostatic calcifications at screening, suboptimal magnetic resonance imaging thermal coverage of target volume and a PI-RADS™ 3 or greater lesion at 12-month magnetic resonance imaging (p

INTRODUCTION AND OBJECTIVE:MRI-guided transurethral ultrasound ablation (TULSA) is a minimally-invasive procedure for customized ablation of benign and malignant prostate tissue. We report five-yea...

To quantitatively assess 12-month prostate volume (PV) reduction based on T2-weighted MRI and immediate post-treatment contrast-enhanced MRI non-perfused volume (NPV), and to compare measurements with predictions of acute and delayed ablation volumes based on MR-thermometry (MR-t), in a central radiology review of the Phase I clinical trial of MRI-guided transurethral ultrasound ablation (TULSA) in patients with localized prostate cancer. Treatment day MRI and 12-month follow-up MRI and biopsy were available for central radiology review in 29 of 30 patients from the published institutional review board-approved, prospective, multi-centre, single-arm Phase I clinical trial of TULSA. Viable PV at 12 months was measured as the remaining PV on T2-weighted MRI, less 12-month NPV, scaled by the fraction of fibrosis in 12-month biopsy cores. Reduction of viable PV was compared to predictions based on the fraction of the prostate covered by the MR-t derived acute thermal ablation volume (ATAV, 55°C isotherm), delayed thermal ablation volume (DTAV, 240 cumulative equivalent minutes at 43°C thermal dose isocontour) and treatment-day NPV. We also report linear and volumetric comparisons between metrics. After TULSA, the median 12-month reduction in viable PV was 88%. DTAV predicted a reduction of 90%. Treatment day NPV predicted only 53% volume reduction, and underestimated ATAV and DTAV by 36% and 51%. Quantitative volumetry of the TULSA phase I MR and biopsy data identifies DTAV (240 CEM43 thermal dose boundary) as a useful predictor of viable prostate tissue reduction at 12 months. Immediate post-treatment NPV underestimates tissue ablation. • MRI-guided transurethral ultrasound ablation (TULSA) achieved an 88% reduction of viable prostate tissue volume at 12 months, in excellent agreement with expectation from thermal dose calculations. • Non-perfused volume on immediate post-treatment contrast-enhanced MRI represents only 64% of the acute thermal ablation volume (ATAV), and reports only 60% (53% instead of 88% achieved) of the reduction in viable prostate tissue volume at 12 months. • MR-thermometry-based predictions of 12-month prostate volume reduction based on 240 cumulative equivalent minute thermal dose volume are in excellent agreement with reduction in viable prostate tissue volume measured on pre- and 12-month post-treatment T2w-MRI.

This report details a single-center experience of using magnetic resonance imaging-guided transurethral ultrasound ablation (TULSA) for whole-gland prostate treatment. Nine men with organ-confined low-to-intermediate-risk prostate cancer underwent the TULSA procedure. The primary endpoint of reduction of more than 75% was achieved in 8 of 9 patients, and all patients demonstrated a histologic benefit at 12-month biopsy. No major urinary or gastrointestinal side effects were observed, and there were no postprocedural changes in erectile firmness. These findings suggest that TULSA is potentially safe and efficacious for patients with low-to-intermediate-risk disease.

INTRODUCTION AND OBJECTIVES:MRI-guided transurethral ultrasound ablation (TULSA) is a novel minimally-invasive procedure for customized prostate ablation. We report one-year outcomes from the TULSA...

We determine the safety and feasibility of magnetic resonance image guided transurethral ultrasound prostate ablation using active temperature feedback control in a preclinical canine model with 28-day followup.After a long acclimatization period we performed ultrasound treatment in 8 subjects using the magnetic resonance image guided TULSA-PRO™ transurethral ultrasound prostate ablation system. Comprehensive examinations and observations were done before and throughout the 28-day followup, including assessment of clinically significant treatment related adverse events. In addition to gross pathology evaluation, extensive histopathological analysis was done to assess cell kill inside and outside the prostate. We evaluated prostate conformal heating by comparing the spatial difference between the treatment plan and the 55C isotherm measured on magnetic resonance imaging thermometry acquired during treatment. These findings were confirmed on contrast enhanced magnetic resonance imaging immediately after treatment and at 28 days.Clinically there were no adverse events in any of the 8 subjects throughout the 28-day followup. All subjects had normal urinary and bowel function. Gross necropsy and histology confirmed that the intended thermal cell kill was confined to the prostate. No surrounding tissue was damaged, including the rectum and the external urinary sphincter. Conformal heating was achieved with an average -0.9 mm accuracy and 0.9 mm precision. Contrast enhanced magnetic resonance imaging and histological analysis confirmed tissue ablation in targeted areas of the prostate. Urethral tissue was spared from thermal damage.Magnetic resonance image guided transurethral ultrasound is a safe, feasible procedure for accurate and precise conformal thermal ablation of prostate tissue, as demonstrated in a preclinical model with 28-day followup.

RRP radical retropubic prostatectomy, HDR high dose rate brachytherapy, Cryo cryoablation, HIFU high-intensity focused ultrasound, TURP transurethral resection of the prostate, OIU optic internal urethrotomy, SD standard deviation, IIEF-5 5-item version of the international index of erectile function, IPSS international prostate symptom score, QoL quality of life *Erectile dysfunction and Mean scores for IIEF-5 were restricted to those men who reported IIEF-5 17 at baseline Vol. 195, No. 4S, Supplement, Friday, May 6, 2016 THE JOURNAL OF UROLOGY e201

To evaluate the feasibility and safety of magnetic resonance (MR) imaging-controlled transurethral ultrasound therapy for prostate cancer in humans.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.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.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.

Purpose: The 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. Methods: The 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 cm3) 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. Results: Treatments 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 cm3 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. Conclusions: This 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.

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.

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.

Purpose: MRI-guided transurethral ultrasound therapy can generate highly accurate volumes of thermal coagulation conforming to 3D human prostate geometries. This work simulated, quantified, and evaluated the thermal impact of these treatments on the rectum, pelvic bone, neurovascular bundles (NVBs), and urinary sphincters because damage to these structures can lead to complications. Methods: Twenty 3D anatomical models of prostate cancer patients were used with detailed bioacoustic simulations incorporating an active feedback algorithm which controlled a rotating, planar ultrasound transducer (17, 4 × 3 mm 2 elements, 10 W acoustic / cm 2 ). Heating of the adjacent surrounding anatomy was evaluated at 4.7, 9.7, and 14.2 MHz using thermal tolerances reported in literature. Results: Heating of the rectum posed the most important safety concern, influenced largely by the water temperature of an endorectal cooling device (ECD); depending on anatomy, temperatures of 7 – 37 ° C were required to limit potential damage to less than 10 mm 3 on the outer 1 mm layer of the rectal wall. Heating of the pelvic bone could be important at 4.7 MHz. A smaller sized ECD or a higher ultrasound frequency in sectors where the bone was less than 10 mm from the prostate reduced heating in all cases below the threshold for irreversible damage. Heating of the NVB was significant in 75% of the patient models in the absence of treatment planning; this proportion was reduced to 5% by increasing treatment margins up to 4 mm. To avoid damaging the urinary sphincters, the transducer should be positioned at least 2–4 mm from the sphincters, depending on the transurethral cooling temperature. Conclusions: Simulations show that MRI-guided transurethral therapy can treat the prostate accurately, but in the absence of treatment planning, some thermal impact can be predicted on the surrounding anatomy. Treatment planning strategies have been developed, which reduce thermal injury to the surrounding anatomy.

A new MRI-guided therapy is being developed as a minimally invasive treatment for localized prostate cancer utilizing high-intensity ultrasound energy to generate a precise region of thermal coagulation within the prostate gland. The purpose of this study was to evaluate in vivo the capability to produce a spatial heating pattern in the prostate that accurately matched the shape of a target region using transurethral ultrasound heating and active MR temperature feedback. Experiments were performed in a canine model (n = 9) in a 1.5 T MR imager using a prototype device comprising a single planar transducer operated under rotational control. The spatial temperature distribution, measured every 5 s with MR thermometry, was used to adjust the acoustic power and rotation rate in order to achieve a temperature of 55 degrees C along the outer boundary of the target region. The results demonstrated the capability to produce accurate spatial heating patterns within the prostate gland. An average temperature of 56.2 +/- 0.6 degrees C was measured along the outer boundary of the target region across all experiments in this study. The average spatial error between the target boundary and the 55 degrees C isotherm was 0.8 +/- 0.7 mm (-0.2 to 3.2 mm), and the overall treatment time was < or =20 min for all experiments. Excellent spatial agreement was observed between the temperature information acquired with MRI and the pattern of thermal damage measured on H&E-stained tissue sections. This study demonstrates the benefit of adaptive energy delivery using active MR temperature feedback, and an excellent capability to treat precise regions within the prostate gland with this technology.

Background Magnetic resonance imaging–guided transurethral ultrasound ablation (MRI-TULSA) is a novel minimally invasive technology for ablating prostate tissue, potentially offering good disease control of localized cancer and low morbidity. Objective To determine the clinical safety and feasibility of MRI-TULSA for whole-gland prostate ablation in a primary treatment setting of localized prostate cancer (PCa). Design, setting, and participants A single-arm prospective phase 1 study was performed at three tertiary referral centers in Canada, Germany, and the United States. Thirty patients (median age: 69 yr; interquartile range [IQR]: 67–71 yr) with biopsy-proven low-risk (80%) and intermediate-risk (20%) PCa were treated and followed for 12 mo. Intervention MRI-TULSA treatment was delivered with the therapeutic intent of conservative whole-gland ablation including 3-mm safety margins and 10% residual viable prostate expected around the capsule. Outcome measurements and statistical analysis Primary end points were safety (adverse events) and feasibility (technical accuracy and precision of conformal thermal ablation). Exploratory outcomes included quality of life, prostate-specific antigen (PSA), and biopsy at 12 mo. Results and limitations Median treatment time was 36min (IQR: 26–44) and prostate volume was 44ml (IQR: 38–48). Spatial control of thermal ablation was ±1.3mm on MRI thermometry. Common Terminology Criteria for Adverse Events included hematuria (43% grade [G] 1; 6.7% G2), urinary tract infections (33% G2), acute urinary retention (10% G1; 17% G2), and epididymitis (3.3% G3). There were no rectal injuries. Median pretreatment International Prostate Symptom Score 8 (IQR: 5–13) returned to 6 (IQR: 4–10) at 3 mo (mean change: −2; 95% confidence interval [CI], −4 to 1). Median pretreatment International Index of Erectile Function 13 (IQR: 6–28) recovered to 13 (IQR: 5–25) at 12 mo (mean change: −1; 95% CI, −5 to 3). Median PSA decreased 87% at 1 mo and was stable at 0.8 ng/ml (IQR: 0.6–1.1) to 12 mo. Positive biopsies showed 61% reduction in total cancer length, clinically significant disease in 9 of 29 patients (31%; 95% CI, 15–51), and any disease in 16 of 29 patients (55%; 95% CI, 36–74). Conclusions MRI-TULSA was feasible, safe, and technically precise for whole-gland prostate ablation in patients with localized PCa. Phase 1 data are sufficiently compelling to study MRI-TULSA further in a larger prospective trial with reduced safety margins. Patient summary We used magnetic resonance imaging–guided transurethral ultrasound to heat and ablate the prostate in men with prostate cancer. We showed that the treatment can be targeted within a narrow range (1mm) and has a well-tolerated side effect profile. A larger study is under way. Trial registration NCT01686958, DRKS00005311.

The feasibility of using MR thermometry for temperature feedback to control a transurethral ultrasound heating applicator with planar transducers was investigated. The sensitivity of a temperature-based feedback algorithm to spatial (control point area, slice thickness, angular alignment) and non-spatial (imaging time, temperature uncertainty) parameters was evaluated through numerical simulations. The angular alignment of the control point with the ultrasound beam was an important parameter affecting the average spatial error in heat delivery. The other spatial parameters were less influential, thus providing an opportunity to reduce spatial resolution for increased SNR in the MR imaging. The update time was the most important non-spatial parameter determining the performance of the control algorithm. Combined non-spatial and spatial parameters achieved acceptable performance with a voxel size of 3 mm x 3 mm, a 10 mm slice thickness and a 5 s update time. Temperature uncertainty of up to 2 degrees C had little effect on the performance of the control algorithm but did reduce the average error slightly due to a systematic, noise-induced overestimation of the boundary temperature. These simulations imply that MR thermometry performed on clinical 1.5 T imaging systems is of sufficient quality for use as thermal feedback for conformal prostate thermal therapy with transurethral ultrasound heating applicators incorporating planar transducers.

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 8 MHz to 4 MHz 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 4/12 MHz 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.

MRI-guided transurethral ultrasound therapy has previously been evaluated in human volunteers by treating a prostate subvolume, prior to radical prostatectomy. Extension of this technique to full clinical use requires validation of the technique for coagulating a volume of tissue equivalent to the entire gland. This in-vitro study evaluates approaches for treating the whole prostate gland by comparing various treatment strategies. An 8-element ultrasound therapy system was evaluated in gel phantoms using 6 human prostate profiles segmented from MR clinical images (average volume: 36 cm3). Real-time MR-thermometry feedback was performed over nine slices covering the entire prostate. Decisions on acoustic power, frequency, and device rotation rate were made based on prostate target radii and temperature maps updated every 7s. Low and high power treatment approaches (10, 20 W/cm2) were tested as well as single-and dual-frequency strategies (8.1, 4.6/14.4 MHz). Decreasing frequency to 4.6 MHz enabled treati...

High-intensity contact ultrasound therapy can generate precise volumes of thermal damage in deep-seated tissue using interstitial or intracavitary devices. Multi-element, dual-frequency transducers offer increased spatial control of the heating pattern by enabling modulation of ultrasound power and frequency along the device. The performance and acoustic coupling between elements of simple, multi-element, dual-frequency transducers was measured. Transducer arrays were fabricated by cutting halfway through a rectangular plate of PZT, creating individual 4 × 5 mm segments with fundamental frequency (4.1 MHz) and third harmonic (13.3 MHz). Coupling between elements was investigated using a scanning laser vibrometer to measure transducer surface displacements at each frequency and different acoustic powers (0, 10, 20 W/cm2). The measured acoustic power was proportional to the input electrical power with no hysteresis and efficiencies >50% at both frequencies. Maximum transducer surface displacements were obse...

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°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°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.

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 3.5×5 mm transducer elements. Heating patterns shaped to 23 and 11 cc human prostate geometries were generated using devices operating at 4.7 ...

Previous numerical simulations have shown that MRI‐guided transurethral ultrasound therapy can generate highly accurate volumes of thermal coagulation conforming to 3‐D human prostate geometries. The goal of this work is to simulate, quantify and evaluate the thermal impact of these treatments on the rectum, pelvic bone, neurovascular bundles (NVB) and urinary sphincters. This study used twenty 3‐D anatomical models of prostate cancer patients and detailed bio‐acoustic simulations incorporating an active feedback algorithm which controlled a rotating, planar ultrasound transducer (17–4×3 mm elements, 4.7/9.7 MHz, 10 Wac/cm2). Heating of the adjacent surrounding anatomy was evaluated using thermal tolerances reported in the literature. Heating of the rectum poses the most important safety concern and is influenced largely by the water temperature flowing through an endorectal cooling device; temperatures of 7–37° C are required to limit potential damage to less than 10 mm3 on the outer 1 mm layer of rectum...

Development of non‐invasive techniques for prostate cancer treatment requires implementation of quantitative measures for evaluation of the treatment results. In this paper. we introduce measures that estimate spatial targeting accuracy and potential thermal damage to the structures surrounding the prostate. The measures were developed for the technique of treating prostate cancer with a transurethral ultrasound heating applicators guided by active MR temperature feedback. Variations of ultrasound element length and related MR imaging parameters such as MR slice thickness and update time were investigated by performing numerical simulations of the treatment on a database of ten patient prostate geometries segmented from clinical MR images. Susceptibility of each parameter configuration to uncertainty in MR temperature measurements was studied by adding noise to the temperature measurements. Gaussian noise with zero mean and standard deviation of 0, 1, 3 and 5° C was used to model different levels of uncer...

Purpose: The capability of MRI-guided transurethral ultrasound therapy to produce continuous regions of thermal coagulation that conform to human prostate geometries was evaluated using 3-D anatomical models of prostate cancer patients. Methods: Numerical simulations incorporating acoustic and biothermal modeling and a novel temperature control feedback algorithm were used to evaluate treatment accuracy of a rotating dual-frequency multi-element transducer. Treatments were simulated on twenty anatomical models obtained from the manual segmentation of the prostate and surrounding structures on MR images of prostate cancer patients obtained prior to radical prostatectomy. Results: Regions of thermal coagulation could be accurately shaped to predefined volumes within 1 mm across the vast majority of the prostates. Over- and under-treated volumes remained smaller than 4% of the corresponding prostate volumes which ranged from 14 to 60 cc. Treatment times were typically 30 min and remained below 60 min even for large 60 cc prostates. Heating of the rectal wall remained below 30 min43� C in half of the patient models with only minor, superficial heating in the other cases. The simulated feedback control algorithm adjusted the ultrasound transducer parameters such that high treatment accuracy was maintained despite variable blood perfusion, changing tissue ultrasound attenuation, and practical temperature measurement noise and sampling rate. Conclusions: Numerical simulations predict that MRI-guided transurethral ultrasound therapy is capable of producing highly accurate volumes of thermal coagulation that conform to human prostate glands.

MRI‐guided transurethral ultrasound therapy is a promising new approach for the treatment of localized prostate cancer. Several studies have demonstrated the feasibility of producing large regions of thermal coagulation adequate for prostate therapy; however, the quantitative assessment of shaping these regions to complex 3‐D human prostate geometries has not been fully explored. This study used numerical simulations and twenty manually‐segmented pelvic anatomical models derived from high‐quality MR images of prostate cancer patients to evaluate the treatment accuracy and safety of 3‐D conformal MRI‐guided transurethral ultrasound therapy. The simulations incorporated a rotating multi‐element planar dual‐frequency ultrasound transducer (seventeen 4×3 mm elements) operating at 4.7/9.7 MHz and 10 W/cm2 maximum acoustic power. Results using a novel feedback control algorithm which modulated the ultrasound frequency, power and device rate of rotation showed that regions of thermal coagulation could be shaped ...

High intensity ultrasound delivered transurethrally is a promising approach for the treatment of localized prostate cancer. The use of multiple planar ultrasound transducers mounted on an MR‐compatible applicator with rotational capability can provide precise control over the spatial deposition of energy within the gland. Using MR thermometry for adaptive temperature feedback, accurately shaped three‐dimensional heating patterns can potentially be achieved. The goal of this study was to evaluate the feasibility of simultaneously controlling multiple elements with real‐time MR temperature feedback in gel phantoms in a 1.5T MR imager. Numerical simulations were used initially to determine treatment delivery strategies and appropriate tuning of the temperature feedback control algorithm. Two typical prostate shapes were then treated in tissue‐mimicking polyacrylamide gel phantoms using a prototype system to demonstrate conformity of the thermal damage patterns to the target boundaries. Five planar gradient‐e...

The capability of MRI to measure spatial heating patterns during therapy delivery with ultrasound makes adaptive thermal therapy possible. Active feedback provided by MR thermometry enables on‐line adjustment of the treatment to compensate for tissue/perfusion changes during heating. The feasibility of performing 3‐D conformal thermal therapy of the entire prostate gland with a multi‐element transurethral ultrasound heating applicator was considered in this study. The major challenge was using MR temperature feedback to adjust simultaneously the device’s rate of rotation and the power and frequency of multiple independent ultrasound transducers, to shape the region of thermal damage to the prostate gland in all spatial dimensions while sparing surrounding tissues from damage. The 3‐D Bioheat Transfer Equation was used to model the ultrasound therapy using manually segmented MRI prostate geometries from 20 prostate cancer patients. Average prostate dimensions (±SD) were: length: 37.8±7.2 mm, width: 47.1±5....

A method for conformal prostate thermal therapy using transurethral ultrasound heating applicators incorporating planar transducers is described. The capability to shape heating patterns to the geometry of the prostate gland from a single element in a multi-element heating applicator was evaluated using Bioheat transfer modelling. Eleven prostate geometries were obtained from patients who underwent MR imaging of the prostate gland prior to radical prostatectomy. Results indicate that ultrasound heating applicators incorporating multi-frequency planar transducers (4 x 20 mm, f = 4.7 MHz, 9.7 MHz) are capable of shaping thermal damage patterns to the geometry of individual prostates. A temperature feedback control algorithm has been developed to control the frequency, rotation rate and applied power level from transurethral heating applicators based on measurements of the boundary temperature during heating. The discrepancy between the thermal damage boundary and the target boundary was less than 5 mm, and the transition distance between coagulation and normal tissue was less than 1 cm. Treatment times for large prostate volumes were less than 50 min, and perfusion did not have significant impact on the control algorithm. Rectal cooling will play an important role in reducing undesired heating near the rectal wall. Experimental validation of the simulations in a tissue-mimicking gel phantom demonstrated good agreement between the predicted and generated patterns of thermal damage.

Purpose: The recent clinical emergence of minimally invasive image-guided therapy has demonstrated promise in the management of brain metastasis, although control over the spatial pattern of heating currently remains limited. Based on experience in other organs, the delivery of high-intensity contact ultrasound energy from minimally invasive applicators can enable accurate spatial control of energy deposition, large treatment volumes, and high treatment rate. In this acute study, the feasibility of active MR-Temperature feedback control of dynamic ultrasound heat deposition for interstitial thermal ablation in brain was evaluatedin vivo. Methods: A four-element linear ultrasound transducer (f = 8.2 MHz) originally developed for transurethral ultrasound therapy was used in a porcine model for generating thermal ablations in brain interstitially. First, the feasibility of treating and retreating preciselyin vivo brain tissues using stationary (non-rotating device) ultrasound exposures was studied in two pigs. Experimental results were compared to numerical simulations for maximum surface acoustic intensities ranging from 5 to 20 W cm−2. Second, active MRT feedback-controlled ultrasound treatments were performed in three pigs with a rotating device to coagulate target volumes of various shapes. The acoustic power 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. Modeling of in vivo treatments were performed and compared to observed experimental results. Results: Overall, the time-space evolution of the temperature profiles observedin vivo could be well estimated from numerical simulations for both stationary and dynamic interstitial ultrasound exposures. Dynamic exposures performed under closed-loop temperature control enabled accurate elevation of the brain tissues within the targeted region above the 55 °C threshold necessary for the creation of irreversible thermal damage. Treatment volumes ranging from 1 to 9 cm3 were completed within 8 ± 3 min with a radial targeting error

MRI-guided transurethral ultrasound therapy is a minimally-invasive treatment for localized prostate cancer that provides local control with a low side-effect profile which would have a major impact in improving disease management. High-intensity ultrasound energy from a device inserted into the prostatic urethra generates an accurate region of thermal coagulation in the gland under MR-temperature control. The purpose of this study was to characterize the acoustic, electrical and spatial properties of multi-element ultrasound transducers designed for MRI-guided transurethral ultrasound therapy. The transducer design is described, along with characterization of the electrical and acoustic properties of the device. Transmission spectrum and power output are shown for a single element illustrating their high acoustic efficiencies and power stability at fundamental and third harmonic frequencies. These results provide insight into the heating characteristics of this ultrasound device and its suitability for treating localized prostate cancer.

Current radical treatments for prostate cancer can have numerous, permanent side effects including incontinence, sexual dysfunction and bowel dysfunction. The development of an effective, minimally invasive treatment with fewer side effects would enhance treatment options, particularly for younger men with low‐risk disease. MRI‐guided transurethral high intensity ultrasound therapy has been shown to have a high degree of accuracy in coagulating tissue. A real‐time feedback system in conjunction with continuous MR thermometry gives the system control over heat deposition, as demonstrated in both gel and preclincal animal models. A subvolume treatment of the gland was performed on six men with low grade prostate cancer who volunteered for the procedure prior to their scheduled radical prostatectomy. Histological measurements were performed on the surgically removed prostate to asses the accuracy of the ultrasound therapy. A spinal anaesthetic was given to the patient to limit discomfort and movement during treatment. A transurethral device fitted with four 5‐mm planar transducers operating at 8MHz delivered the treatment in a 1.5T clinical MRIsystem. A volume within the prostate was targeted, based on MR images, usually involving a 180° rotation of the device. Temperature uncertainty of ∼1C° was obtained and the coagulation boundary from histology agreed with the target boundary with an accuracy of 1mm ± 1.5mm. This presentation describes a preliminary study of safety and feasibility in human beings.

A control algorithm has been developed for MRI-guided conformal thermal therapy of the prostate gland with transurethral ultrasound heating applicators. The ability of the algorithm to produce conformal thermal damage patterns was evaluated using prostate boundaries obtained from clinical MR images and bioheat transfer simulations of the heating process. The algorithm enabled the generation of conformal thermal damage patterns with an error of less than 3 mm across eleven prostates. Treatment times ranged from 12-45 minutes depending on prostate size. Rectal cooling may be important in protecting the rectal wall from unwanted thermal damage.

A control system has been developed to perform MRI-guided interstitial ultrasound heating in a closed-bore MR scanner. A prototype delivery system capable of positioning, rotating, and delivering RF power to a heating applicator has been built and algorithms for using temperature information as a source of feedback for the control system have been tested. Heating experiments indicate that the system is capable of producing repeatable thermal lesions. Simulations of heating with the control algorithm enable the automatic selection of parameters to achieve a conformal region of thermal coagulation.

MRI-guided transurethral ultrasound ablation (TULSA) is a new minimally-invasive modality for the treatment of prostate cancer, which aims to provide local disease control with low morbidity. A transurethral ultrasound device generates a continuous volume of thermal coagulation that is shaped precisely to the prostate using real-time MR thermometry and active temperature feedback control. The aim of this multi-center, prospective Phase I clinical study is to determine the safety and feasibility of MRI-guided TULSA, and to assess initial efficacy for treatment of localized prostate cancer.