4TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND
High‐Intensity Focused Ultrasound (HIFU) for the Treatment of Localized Prostate Cancer using Sonablate‐500754(2005); http://dx.doi.org/10.1063/1.1901586View Description Hide Description
We evaluated 181 patients with localized prostate cancer treated with high‐intensity focused ultrasound (HIFU) for biochemical disease‐free rate, safety, morbidity and predictors of biochemical outcome. A total of 181 patients underwent HIFU with the Sonablate‐500 and with at least 12 months of follow‐up. Biochemical failure was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology Consensus Panel. The biochemical disease‐free rates at 1, 3 and 5 years in all patients were 84%, 80% and 78%, respectively. The biochemical disease‐free rates at 3 years for patients with pretreatment PSA less than 10 ng/ml, 10.01 to 20.0 ng/ml and more than 20.0 ng/ml were 94%, 75% and 35%, respectively (p<0.0001). According to multivariate analysis preoperative PSA (p<0.0001) was a significant independent predictor of time to biochemical recurrence. HIFU therapy appears to be a safe and efficacious minimally invasive therapy for patients with localized prostate cancer, especially those with a pretreatment PSA level less than 20 ng/ml.
754(2005); http://dx.doi.org/10.1063/1.1901587View Description Hide Description
Forty nine patients with 63 tumours were treated with the Chongqing Haifu knife, as an adjunct to intra‐arterial chemoinfusion. Treatment targets included breast (20 lesions), liver (16), bone (8), lymph‐node (6), soft tissue (4), lung and pleura (4), pancreas (2), kidney (2) and adrenal gland (1). Follow‐up contrast MRI was performed at 3 weeks to assess the effects of HIFU ablation.
All cases completed the planned treatment. Of 25 lesions treated with the intention of complete tumour ablation, complete necrosis was obtained in 19 lesions (76%) including 4 secondary success cases. Among 32 lesions having partial and palliative treatment, tumour size was decreased in 6 lesions (21%), and good pain control was obtained in 6 out of 7 patients (86%). Skin injury was the most common complication after HIFU (16%), and was mostly a superficial dermal burn that did not necessitate any treatment. However, there was one patient with deep skin injury at an operation scar which resulted in skin perforation. Other adverse events included soft tissue swelling, prolonged fever, anorexia, persistent pain, shortness of the breath, sacroiliac joint fracture and prolonged diarrhoea.
In our limited experience, superficial lesions (e.g. breast cancer, bone, soft tissue, lymph‐node and pleural metastasis) appear to be good candidates for HIFU treatment. There appears to be a role for the HIFU knife in pain control for patients with bone metastasis and pancreatic cancer.
Preliminary Experience Using Extracorporeal High‐Intensity Focused Ultrasound For The Treatment Of Kidney And Liver Tumours754(2005); http://dx.doi.org/10.1063/1.1901588View Description Hide Description
High‐intensity focused ultrasound (HIFU) provides a potentially non‐invasive alternative to conventional therapies. We have been using the extracorporeal ultrasound‐guided Model‐JC Tumor Therapy System (HAIFU™ Technology Co, China) in clinical trials to evaluate the safety and feasibility of treating renal and liver tumours. 30 patients have been treated (22 liver and 8 kidney tumours), all of whom were available for adverse event reporting. Of the 22 liver tumours, 20 are evaluable for response to treatment; 14 were followed up with magnetic resonance imaging (MRI) alone, and 6 with both MRI and histological resection. Evidence of ablation was seen in 20/20 (100%) cases radiologically, and 6/6 (100%) cases histologically. Of the 8 kidney tumours treated, 7 are evaluable; 2 were followed up with MRI alone, and 5 with both MRI and histological resection. Evidence of ablation was seen in 4/7 (57%) radiologically and 1/5 (20%) histologically. Mild, moderate or severe transient pain was reported by 16 (53%), 7 (23%) and 1 (3%) patients, respectively. Superficial skin toxicity was seen in 7 patients (23%). Renal function was unaffected, and all patients were fit for discharge from hospital the day after treatment. Early results show that this technique is feasible, and carries a low morbidity.
Feedback control of temperature evolution in rabbit kidney in vivo using MRI guided focused ultrasound. Application to renal VX2 carcinoma ablation754(2005); http://dx.doi.org/10.1063/1.1901589View Description Hide Description
A significant number of patients with small renal tumours may get benefit from in situ thermo‐ablation techniques. Focused ultrasound is a non‐invasive approach which offers excellent flexibility. On the other hand, real time MR thermometry is a valuable tool for monitoring and controlling therapy. In this study, coupling of focused ultrasound with PRF‐based, respiratory‐gated MR thermometry was used to provide temperature feedback control for local hyperthermia in the rabbit kidney. Two heating protocols were initially used in healthy kidneys (medulla and cortex): 1. fixed focal point heating; 2. spiral trajectories of the focal point. Further, five VX2 renal carcinomas were treated with multiple focal point heating in each tumour. Post‐treatment MRI follow up and post mortem histology were performed. The shape and size of the lesions (MRI, histology) were compared to the calculated thermal dose map. The standard deviation of the MR thermometry ranged from 0.5°C to 1°C. The temperature controller matched the objective curve with approximately 1°C precision (fixed focal point mode). Several technical and physiological difficulties for spiral heating could not be overcome with the available setup. Thermal ablation with temperature feedback control in healthy and tumour bearing kidney was demonstrated to be feasible and effective, despite specific challenges (deep seated organ, respiratory motion, high blood perfusion).
The Detection and Exclusion of the Prostate Neuro‐Vascular Bundle (NVB) in Automated HIFU Treatment Planning Using a Pulsed‐Wave Doppler Ultrasound System754(2005); http://dx.doi.org/10.1063/1.1901590View Description Hide Description
Men with prostate cancer are likely to develop impotence after prostate cancer therapy if the treatment damages the neuro‐vascular bundles (NVB). The NVB are generally located at the periphery of the prostate gland. To preserve the NVB, a Doppler system is used to detect and localize the associated blood vessels. This information is used during the therapy planning procedure to avoid treatment surrounding the blood vessel areas. The Sonablate®500 (Focus Surgery, Inc.) image‐guided HIFU device is enhanced with a pulse‐wave multi‐gate Doppler system that uses the current imaging transducer and mechanical scanner to acquire Doppler data. Doppler detection is executed after the regular B‐mode images are acquired from the base to the apex of the prostate using parallel sector scans. The results are stored and rendered in 3‐D display, registered with additional models generated for the capsule, urethra, and rectal wall, and the B‐mode data and treatment plan itself. The display of the blood flow can be in 2‐D color overlaid on the B‐mode image or in 3‐D color structure. Based on this 3‐D model, the HIFU treatment planning can be executed in automated or manual mode by the physician to remove originally defined treatment zones that overlap with the NVB (for preservation of NVB). The results of the NVB detection in animal experiments, and the 3‐D modeling and data registration of the prostate will be presented.
754(2005); http://dx.doi.org/10.1063/1.1901591View Description Hide Description
For thermal treatment of soft tissue, an alternative to HIFU is bulk ablation using unfocused or weakly focused intense ultrasound fields. This approach offers faster ablation of large tissue volumes and can be performed in minimally invasive (e.g., laparoscopic or percutaneous) procedures. Here, methods for image‐guided ablation of large tissue volumes using compact dual‐modality (image and treat) ultrasound arrays are reported including tissue modification caused by the thermal therapy. The dual‐modality arrays developed have 16–64 elements spanning apertures of 2–8 mm in elevation and 24–48 mm in azimuth. These devices can provide both therapeutically significant power (e.g. source intensity > 80 W/cm2 at 3.1 MHz) and broad bandwidth (e.g. 50% with a center frequency of 3.5 MHz) for imaging. Imaging challenges associated with limited probe dimensions and channel count are met using signal processing techniques that improve definition and contrast, allowing high‐quality B‐scan images and useful monitoring information to be obtained during therapy planning and treatment. Using linear and rotational scanning methods, large tissue volumes (20–60 cc) can be treated. The approach can be applied for ablation of other soft tissue pathologies, e.g., kidney, heart, uterus, brain, GI tract, etc.
754(2005); http://dx.doi.org/10.1063/1.1901592View Description Hide Description
Spasticity, a major complication of disorders of the central nervous system (CNS) signified by uncontrollable muscle contractions, is difficult to treat effectively. We report on the use of image‐guided high‐intensity focused ultrasound (HIFU) to target and suppress the function of the sciatic nerve complex of rabbits in vivo as a possible treatment of spasticity and pain. In situ focal acoustic intensity of 1480–1850 W/cm2 was applied using a scanning method. HIFU treatment of 36 ± 14 s (mean ± standard deviation) was effective in achieving complete conduction block in 100% of the 22 nerves treated (11 rabbits). Histological examination indicated axonal demyelination as a probable mechanism of nerve block.
A System Integrating HIFU Exposure Capabilities with Multiple Modes of Synchronous Ultrasonic Monitoring754(2005); http://dx.doi.org/10.1063/1.1901593View Description Hide Description
A versatile biomedical ultrasound system has been developed and tested. The system controls and monitors high‐intensity focused ultrasound (HIFU) exposures designed to produce therapeutic tissue lesions primarily by thermal phenomena. The system is used with custom HIFU transducer arrays that contain central diagnostic transducer arrays. The diagnostic and visualization functions are performed using a subsystem that provides full digital control over high‐resolution diagnostic ultrasound arrays. Custom software controls all aspects of the imaging (e.g., electronic focusing and frame rates) with scripts and a graphical user interface. The HIFU transducer is excited using a 16‐channel power amplifier controlled by a digital subsystem and waveform synthesizers. Software operator control is also provided for desired HIFU exposure parameters (apodization, frequency, time duration, focal length, intensity) and a variety of synchronous excitation modes for the HIFU and diagnostic arrays.
754(2005); http://dx.doi.org/10.1063/1.1901594View Description Hide Description
This study is an investigation of interference and blooming artifacts in real‐time color Doppler imaging during High‐Intensity Focused Ultrasound (HIFU) therapy to improve the field of view (FOV) and distinguish blood vessels from the artifacts. It is hypothesized that the interference and blooming artifacts are caused by incoherent interference between HIFU and imaging signals and inertial cavitation/boiling, respectively. The incoherent interference shifts the tissue velocity estimates toward the Nyquist limits in standard autocorrelation‐based estimation. The interference artifact is removed by applying a threshold according to the acceleration in tissue velocity estimation. The effects of inertial cavitation and/or boiling (i.e., broadband spectrum and high amplitude) in the blooming artifact are analyzed by measuring the standard deviation of phase differences, the average difference between adjacent eigenvalues and the average power. From in vivo rabbit experiments, due to its broadband spectrum, while the standard deviation of phase differences in the blooming artifact (0.0959 ± 0.0368 PRF) is significantly increased compared to the normal blood vessels (0.0078 ± 0.0013 PRF), the average difference between adjacent eigenvalues in the blooming artifact (−35.0 ± 8.6 dB) is moderately changed compared to those in the normal blood vessels (i.e., −58.6 ± 4.6 dB). The average power in the blooming artifact (i.e., 48.0 ± 12.7) is also increased compared to the normal blood vessels (i.e., 6.2 ± 1.2). This broadband and high amplitude signature could be utilized to remove this blooming artifact by thresholding after further investigation to distinguish the target blood vessel from the artifact.
754(2005); http://dx.doi.org/10.1063/1.1901595View Description Hide Description
MRI (Magnetic Resonance Imaging) has proven to be an exact and safe method to guide FUS (Focused ultrasound surgery) therapy. Besides its excellent soft tissue contrast, important for a precise treatment planning, MRI allows fast and reliable measurement of temperature changes caused by FUS application. In this study we compare standard MR‐imaging parameters (relaxation times, spin density) with MR measured tissue elasticity in order to differentiate between FUS induced thermal lesions and normal tissue in vitro. In addition we tried to observe FUS induced shear waves by dynamic MRE. FUS was performed with an MRI compatible 1.7 MHz fixed focus transducer (NA 0.44; f′= 68 mm). With increasing acoustic power (30–70 W) the difference in relaxation times T1, T2 and spin density between normal and lesioned tissue also increased. We measured values in the range 5% to 24%. The difference in tissue strain had a value of 23% at 30 W and was nearly constant (52–61%) at higher FUS power. Compared with standard MRI parameters MRE showed a clearly higher sensitivity to detect FUS induced lesions. With our experimental setup it was possible to image FUS induced shear waves. The measured wave length at 400Hz repetition rate was 7 mm. However, further experiments are necessary to utilize the potential of MRE in practice.
754(2005); http://dx.doi.org/10.1063/1.1901596View Description Hide Description
High Intensity Focused Ultrasound (HIFU) treatment of soft tissues has been shown to result in a hyperechoic region in B‐mode ultrasound (US) images. This is believed to result from bubble activity at the HIFU focus. Here we report our in vivo results of detecting inertial and stable cavitation in correlation with the appearance of a hyperechoic region, along with in vitro confirmation of these results that included measurement of the temperature at the HIFU focus. The ultrasound system consisted of a HIFU transducer (3.3 MHz), a broadband A‐mode transducer for active and passive cavitation detection (ACD and PCD), and an US‐imaging probe that were all co‐focal and synchronized. HIFU, at in situ intensities of 220– 1,710 W/cm2, was applied for 10 s to pig muscles in vivo or polyacrylamide in vitro at a focal depth of 2 cm. A thermocouple placed at the HIFU focus was added to the above system during the in vitro portion of this study. ACD and PCD results showed a strong correlation between the onset of cavitation and the appearance of a hyperechoic region. In vivo PCD results showed that inertial cavitation typically occurred prior (within 0.5 s) to the appearance of a hyperechoic region. In vitro PCD results show that inertial cavitation occurred at or within 1–2 pulses prior to the appearance of a hyperechoic region and typically preceded rapid heating up to 110 °C at the HIFU focus within 1–2 pulses. The observed cavitation activity suggests that bubbles are present during the formation of a hyperechoic region at the HIFU focus and that boiling occurs rapidly after the onset of cavitation. Further investigation is needed to determine if the hyperechoic region in the US image originates from bubbles formed during cavitation alone or during cavitation‐induced boiling.
Real‐Time Ultrasound‐Guided High‐Intensity Focused Ultrasound Therapy with Enhanced Visualization and Reduced Treatment Time754(2005); http://dx.doi.org/10.1063/1.1901597View Description Hide Description
We present a novel technique for synchronizing diagnostic ultrasound imaging and High‐Intensity Focused Ultrasound (HIFU) therapy systems for real‐time image‐guided therapy that does not require any modification of a commercial imaging system. HIFU therapy with a duty cycle of 83% could be performed simultaneously with B‐mode imaging by combining 5 image frames to remove HIFU interference in the entire field of view, with an overall frame rate of 11 frames/s. In vivo experiments in rabbit thigh muscle showed that the volume of HIFU‐treated lesions increased by 342% (p<0.01) when the duty cycle was increased from 50% to 95% for the same HIFU treatment times. The HIFU treatment time required at 90% duty cycle was 64% less (p<0.05) than that required at a 50% duty cycle to create lesions of the same volume.
754(2005); http://dx.doi.org/10.1063/1.1901598View Description Hide Description
Our objective was to investigate whether High‐Intensity Focused Ultrasound (HIFU) hemostasis can be achieved faster in the presence of ultrasound contrast agents (UCA). Incisions (3 cm long and 0.5 cm deep) were made in surgically exposed rabbit liver. Optison at a concentration of 0.18 ml/kg was injected into the mesenteric vein, immediately before the incision was made. The HIFU applicator (frequency of 5.5 MHz, and intensity of 3,700 W/cm2) was scanned manually over the incision (at an approximate rate of 1 mm/s) until hemostasis was achieved. The times to complete hemostasis were measured and normalized with the initial blood loss. The hemostasis times were 59±23 s in the presence of Optison and 70±23 s without Optison. The presence of Optison produced a 37% reduction in the normalized hemostasis times (p<0.05). Optison also provided faster (by 34%) formation of the coagulum seal over the lesion. Gross observations showed that the lesion size did not change due to the presence of Optison. Histological analysis showed that lesions consisted of an area of coagulation necrosis in vicinity of the incision, occasionally surrounded by a congestion zone filled with blood. Our results suggest the potential utility of microbubble contrast agents for increasing efficiency of HIFU hemostasis of internal organ injuries.
754(2005); http://dx.doi.org/10.1063/1.1901599View Description Hide Description
Compared to other modalities that might be employed for molecular imaging, ultrasound has some unique features. It is portable; highly adapted to the surgical environment; can be used for cavitation, heating, and tissue ablation; and is exquisitely sensitive to microbubbles. Using microbubbles as a contrast agent, ultrasound imaging can detect a single microbubble. Ultrasound in concert with bubbles can be used in NanoInvasive™ therapy and drug delivery. An example of NanoInvasive therapy is sonothrombolysis with microbubbles, or SonoLysis™.
Neuroprotective effect of combined ultrasound and microbubbles in a rat model of middle cerebral artery infarction754(2005); http://dx.doi.org/10.1063/1.1901600View Description Hide Description
Ultrasound‐mediated microbubble thrombolysis (UMT) was performed in a middle cerebral artery occlusion model in rats to evaluate possible effects upon brain infarct volume, apoptosis, IL‐6 and TNF‐alpha levels, and disruption of the blood‐brain barrier (BBB). The results show that infarct volume was significantly reduced (p<0.04) in the microbubble + ultrasound (MB + US) group as compared to control animals. The levels of IL‐6 and TNF‐alpha concentrations, as markers of tissue damage, were not significantly different. In trypan blue treated animals, no additional BBB disruption was observed for the UMT group. Likewise, there was no increase in apoptotic cell death outside the infarction area in animals treated with MB + US. The results demonstrate that UMT does not have a harmful effect upon ischemic stroke in a middle cerebral artery occlusion model of the rat. The significant reduction in brain infarction following insonation with ultrasound and microbubbles suggests a novel neuroprotective effect in ischemic stroke.
754(2005); http://dx.doi.org/10.1063/1.1901601View Description Hide Description
High‐intensity focused ultrasound (HIFU) has been shown to effectively occlude blood vessels deep within tissue. The objective of the current study was to synchronize HIFU and color‐Doppler ultrasound (US) for the real‐time visualization of flow within blood vessels during HIFU treatment. The excitation of the HIFU was synchronized with the color‐Doppler imager by collecting the excitation pulses of one of the elements of either a curved array intracavitary (C 9‐5) or an intraoperative (CL 10‐5) imaging probe. The collected excitation pulse was converted into a TTL‐high pulse, which was delayed and gated to time the excitation duration and location of the HIFU pulse with respect to each imaging frame. The single pulse was used to drive a 3.2 MHz concave HIFU transducer (focal length of 3.5 cm, f‐number 1) while the US imager was not collecting RF signals from the treatment region of the US image. The feasibility of the system was demonstrated in vivo by the selective ablation of tissue adjacent to, or the occlusion of, large vessels (including the femoral artery) both transcutaneously and interoperatively in the rabbit and pig. For the occlusion of vessels, the HIFU focus was placed immediately distal (with respect to the transducer) to the vessel at a depth of 2–2.5 cm. HIFU was applied at in situ intensities of 1000–2000 W/cm2, at a duty cycle of 50–75%, and a HIFU pulse repetition frequency (set by the US image frame rate) of 6–18 Hz. During each HIFU exposure, the HIFU pulse resulted in color interference bands running vertically within the color‐Doppler window. Through the synchronization of the US imager with the HIFU excitation, the location and duration of the interference bands were set outside the treatment region within each image frame. This provided the operator with a clear view of the HIFU treatment site during therapy. Gross assessment showed necrosis of the tissue surrounding the HIFU treated vessel and occlusion of vessels up to 4 mm in diameter after a 30 s HIFU exposure. We have developed a method of synchronizing pulsed HIFU with color‐Doppler US imaging for the real‐time visualization of flow within blood vessels during HIFU therapy. This provides a means of guiding HIFU therapy for the detection and occlusion of deep vessels, or the selective ablation of tissue surrounding the vessels without vascular occlusion.
754(2005); http://dx.doi.org/10.1063/1.1901602View Description Hide Description
A pulsatile flow phantom for studying ultrasound image‐guided acoustic hemostasis in a controlled environment has been developed. An ex vivo porcine carotid artery was attached to the phantom and embedded in a visually and ultrasonically transparent gel. Heparinized porcine blood was pumped through the phantom. Power‐Doppler and B‐mode ultrasound were used to remotely target the HIFU focus to the site of a needle puncture. In nine trials, complete hemostasis was achieved after an average HIFU application of 55 +/− 34 seconds. The vessels remained patent after treatment. With this phantom, it will be possible to do controlled studies of ultrasound image‐guided acoustic hemostasis.
754(2005); http://dx.doi.org/10.1063/1.1901603View Description Hide Description
The objective was to investigate the long‐term efficacy of hemostasis and healing of arteries after HIFU application. The femoral arteries of 22 adult rabbits were surgically exposed. Fifteen arteries were punctured with a needle and treated with HIFU, and 7 arteries were sham‐treated (no puncture or HIFU was applied). The tip of the HIFU applicator was positioned on the bleeding site, and HIFU energy was applied until hemostasis was achieved. The focal intensity was approximately 3,000 W/cm2, at the resonant frequency of 9.6 MHz. Serial ultrasound images, blood and tissue samples were collected immediately and on days 1, 3, 7, 14, 28, and 60 after the treatment. Eleven of the arteries were patent after the treatment, and four arteries were occluded, as confirmed using Doppler imaging. One of the occluded arteries reopened at day 14. HIFU exposure time to achieve hemostasis was 27 ±17 seconds for patent arteries and 101±38 seconds for the occluded arteries. The blood flow velocities were not statistically different between HIFU‐treated patent vessels and sham‐treated vessels. The tunica adventitia and media, disrupted and coagulated immediately after the treatment, recovered to normal appearance within 28 days, with localized thinning of the tunica media observed up to day 60. Neo‐intimal hyperplasia was observed in the arteries at days 14 and 28. HIFU produced an effective and long‐term (up to 60 days) hemostasis of injured femoral arteries while preserving a normal blood flow and vessel wall structure in the majority of vessels.
754(2005); http://dx.doi.org/10.1063/1.1901604View Description Hide Description
The objective of this study is to show how therapeutically effective a combination of a drug delivery system (DDS) and ultrasound (US) is by introducing data from two related experiments. Fullerene (C60) was chemically modified by polyethylene glycol (PEG) for water‐solubilization and tumour targeting. When the PEG‐modified C60 was injected intravenously into tumour bearing mice, followed by US irradiation to the tumour site, a synergistic anti‐tumour effect was observed. Following the intravenous injection of interferon (IFN) conjugated with pullulan which has an inherent affinity for the liver, and subsequent US irradiation to the liver, the activity level of an IFN‐specific enzyme was significantly enhanced compared with that of the conjugate injection alone.