Real-time Ultrasound Image Guidance Research Articles

A combination of PD-L1-targeted IL-15 mRNA nanotherapy and ultrasound-targeted microbubble destruction for tumor immunotherapy

PD-1/PD-L1-based immune checkpoint blockade therapy has shown limited benefits in tumor patients, partially attributed to the inadequate infiltration of immune effector cells within tumors. Here, we established a nanoplatform named DPPA/IL-15 NPs to target PD-L1 for the tumor delivery of IL-15 messenger RNA (mRNA). DPPA/IL-15 NPs were endowed with ultrasound responsiveness and contrast-enhanced ultrasound (CEUS) imaging performance. They effectively protected IL-15 mRNA from degradation and specifically transfected it into tumor cells through the utilization of ultrasound-targeted microbubble destruction (UTMD). This resulted in the activation of IL-15-related immune effector cells while blocking the PD-1/PD-L1 pathway. In addition, UTMD could generate reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress-driven immunogenic cell death (ICD), initiating anti-tumor immunity. In vitro and in vivo studies revealed that this combination therapy could induce a robust systemic immune response and enhance anti-tumor efficacy. Thus, this combination therapy has the potential for clinical translation through enhanced immunotherapy and provides real-time ultrasound imaging guidance.

Contrast-Enhanced Imaging of Histotripsy Bubble Clouds Using Chirp-Coded Excitation and Volterra Filtering.

Histotripsy is a focused ultrasound therapy that ablates tissue via bubble cloud activity. Real-time ultrasound image guidance is used to ensure safe and effective treatment. Plane-wave imaging enables tracking of histotripsy bubble clouds at a high frame rate but lacks adequate contrast. Furthermore, bubble cloud hyperechogenicity is reduced in abdominal targets, making the development of contrast-specific sequences for deep-seated targets an active area of research. Chirp-coded subharmonic imaging was reported previously to enhance histotripsy bubble cloud detection by a modest 4-6 dB compared to the conventional sequence. Incorporating additional steps into the signal processing pipeline could enhance bubble cloud detection and tracking. In this study, we evaluated the feasibility of combining chirp-coded subharmonic imaging with Volterra filtering for enhancing bubble cloud detection in vitro. Chirped imaging pulses were used to track bubble clouds generated in scattering phantoms at a 1-kHz frame rate. Fundamental and subharmonic matched filters were applied to the received radio frequency signals, followed by a tuned Volterra filter to extract bubble-specific signatures. For subharmonic imaging, the application of the quadratic Volterra filter improved the contrast-to-tissue ratio from 5.18 ± 1.29 to 10.90 ± 3.76 dB, relative to the application of the subharmonic matched filter. These findings demonstrate the utility of the Volterra filter for histotripsy image guidance.

Safety considerations for treating the parotid and submandibular glands with neuromodulators for facial slimming.

Neuromodulators have predominantly been used for the treatment of upper facial lines, but their use has expanded to include lower face and neck treatments. However, the injection sites for these treatments are based on skin surface landmarks, which may pose risks to nearby structures and result in undesired outcomes. To investigate the spatial relationship between the FDA-approved skin surface landmarks for neuromodulator injections in the parotid and submandibular glands and the topographical anatomy of critical facial structures such as the facial artery, facial vein, external carotid artery, and retromandibular vein. A cross-sectional retrospective analysis was conducted on contrast-enhanced cranial CT scans. The scans were analyzed for the morphology and location of the parotid and submandibular glands. Measurements were taken for gland volume, craniocaudal extent, anterior-posterior extent, and distances between the skin surface and gland capsule or nearby structures such as arteries. The study sample consisted of 53 subjects, including 7 males and 46 females, with a mean age of 36.91 years and a mean BMI of 23.28 kg/m2 . The mean volume of the parotid gland was 31.9 ± 3.0 cc in males and 28.5 ± 3.6 cc in females with p < 0.001, while the mean volume of the submandibular gland was 18.2 ± 2.0 cc in males and 14.5 ± 3.4 cc in females with p < 0.001. The mean distances between skin surface and the gland capsule were 5.98 ± 2.2 and 8.84 ± 4.0 mm for the parotid and submandibular gland, respectively. This distance increased with higher age and higher BMI values in a statistically significant manner with p < 0.001. The distances between FDA-approved skin surface landmarks and the parotid and submandibular glands varied significantly depending on gender, age, and BMI. Optimal injection depth and location for neuromodulator treatments cannot be generalized based on these landmarks alone, emphasizing the need for real-time ultrasound imaging guidance.

Histotripsy Ablation of Spontaneously Occurring Canine Bone Tumors In Vivo.

Osteosarcoma (OS) is a devastating primary bone tumor in dogs and humans with limited non-surgical treatment options. As the first completely non-invasive and non-thermal ablation technique, histotripsy has the potential to significantly improve the standard of care for patients with primary bone tumors. Standard of care treatment for primary appendicular OS involves surgical resection via either limb amputation or limb-salvage surgery for suitable candidates. Biological similarities between canine and human OS make the dog an informative comparative oncology research model to advance treatment options for primary OS. Evaluating histotripsy for ablating spontaneous canine primary OS will build a foundation upon which histotripsy can be translated clinically into a standard of care therapy for canine and human OS. Five dogs with suspected spontaneous OS were treated with a 500 kHz histotripsy system guided by real-time ultrasound image guidance. Spherical ablation volumes within each tumor (1.25-3 cm in diameter) were treated with single cycle histotripsy pulses applied at a pulse repetition frequency of 500 Hz and a dose of 500 pulses/point. Tumor ablation was successfully identified grossly and histologically within the targeted treatment regions of all subjects. Histotripsy treatments were well-tolerated amongst all patients with no significant clinical adverse effects. Conclusion & Significance: Histotripsy safely and effectively ablated the targeted treatment volumes in all subjects, demonstrating its potential to serve as a non-invasive treatment modality for primary bone tumors.

Modified Biopsy Assessment for Endobronchial Ultrasound in Diagnosis of Peripheral Lung Neoplasms

Background. Diagnosis and treatment of malignant lung neoplasms are pressing issues. Peripheral lung cancer verification rate with endobronchial ultrasound varies within 30–85 %.Aim. To advance endobronchial ultrasound precision, a modified biopsy technique has been developed and introduced into clinical practice at the Chelyabinsk Regional Clinical Centre for Oncology and Nuclear Medicine. The modification comprises real-time ultrasound image guidance of the biopsy forceps alignment and opening. The technique patent for invention is RU 2719666 C1.Materials and methods. Modified endobronchial ultrasound has been performed in 66 patients with suspected peripheral lung malignancy at the Centre’s Department of Endoscopy within 2019–2021. Bioptic material was delivered for histological and, when necessary, immunohistochemical examination.Results. Malignancy diagnosis was verified in 78.8 % cases. The modified technique is relatively safe, with complications detected in two patients (3.8 % cases) and managed conservatively with success. Discussion. The standard biopsy technique provided for a lung malignancy verification rate of 57.7 % over 2019–2021. Thus, the rate improvement by modified technique is 21.1 %. The modified technique is relatively safe, with complications reported in two patients (3.8 % cases) and managed conservatively with success. Modified endobronchial ultrasound was adequately tolerated, with no increase in patient examination time. The technique can supersede more invasive diagnostic procedures.Conclusion. We believe that the modified technique will improve the power of endobronchial ultrasound, reduce examination time and expedite prescription of special therapies.

Advantages of real-time transabdominal ultrasound guidance in combined interstitial/intracavitary cervical brachytherapy: a case-based review.

Sub-optimal placement of both intracavitary devices and interstitial needles is a relatively common occurrence in cervical brachytherapy, which may reduce the accuracy of dose distribution and contribute to adverse toxicities. To mitigate complications, improve target dose coverage, and verify proper device placement, implants may be placed under real-time image guidance. Traditionally, transrectal ultrasound has been used for needle guidance. However, we have utilized transabdominal ultrasound (TA-US) in our brachytherapy center. The purpose of this pictorial essay was to provide a pictorial description of TA-US technique, present a retrospective review of our preliminary outcomes adopting TA-US into routine practice, and to discuss the advantages of real-time ultrasound image guidance for placement of intrauterine tandem and interstitial needles.

Development of Acoustically Active Nanocones Using the Host-Guest Interaction as a New Histotripsy Agent.

Histotripsy is a noninvasive and nonthermal ultrasound ablation technique, which mechanically ablates the tissues using very short, focused, high-pressured ultrasound pulses to generate dense cavitating bubble cloud. Histotripsy requires large negative pressures (≥28 MPa) to generate cavitation in the target tissue, guided by real-time ultrasound imaging guidance. The high cavitation threshold and reliance on real-time image guidance are potential limitations of histotripsy, particularly for the treatment of multifocal or metastatic cancers. To address these potential limitations, we have recently developed nanoparticle-mediated histotripsy (NMH) where perfluorocarbon (PFC)-filled nanodroplets (NDs) with the size of ∼200 nm were used as cavitation nuclei for histotripsy, as they are able to significantly lower the cavitation threshold. However, although NDs were shown to be an effective histotripsy agent, they pose several issues. Their generation requires multistep synthesis, they lack long-term stability, and determination of PFC concentration in the treatment dose is not possible. In this study, PFC-filled nanocones (NCs) were developed as a new generation of histotripsy agents to address the mentioned limitations of NDs. The developed NCs represent an inclusion complex of methylated β-cyclodextrin as a water-soluble analog of β-cyclodextrin and perfluorohexane (PFH) as more effective PFC derivatives for histotripsy. Results showed that NCs are easy to produce, biocompatible, have a size <50 nm, and have a quantitative complexation that allows us to directly calculate the PFH amount in the used NC dose. Results further demonstrated that NCs embedded into tissue-mimicking phantoms generated histotripsy cavitation “bubble clouds” at a significantly lower transducer amplitude compared to control phantoms, demonstrating the ability of NCs to function as effective histotripsy agents for NMH.

Design and Experiments of Ultrasound Image-Guided Multi-DOF Robot System for Brachytherapy

To implant radioactive seeds through a needle precisely and safely, a novel multi-DOF surgical robotic system is presented in this paper for percutaneous prostate intervention through the patient’s perineum under real-time ultrasound image guidance. The proposed robot, which is designed with 9-DOF, consists of a 3-DOF automatic location platform for position adjustment, 2-DOF for automatic ultrasonic probe adjustment mounted with electromagnetic trackers, and 4-DOF for manually adjusting the guided template. Meanwhile, a new registration method based on the quaternion algorithm and least square method is developed, and the needle insertion is performed under the real-time guidance of a navigation system. Furthermore, the robot system has undergone some preliminary experiments with a laser tracker to evaluate the repeatability and accuracy of the robot system. The location error of the puncture needle tip can be controlled under 0.7 mm in air for the whole robotic system. The acquired results endorse the precision of the robot system for prostate seed implantation brachytherapy.

An improved tracking framework for ultrasound probe localization in image-guided radiosurgery

Abstract Real-time target localization with ultrasound holds high potential for image guidance and motion compensation in radiosurgery due to its non-invasive image acquisition free from ionizing radiation. However, a two-step localization has to be performed when integrating ultrasound into the existing radiosurgery workflow. In addition to target localization inside the ultrasound volume, the probe itself has to be localized in order to transform the target position into treatment room coordinates. By adapting existing camera calibration tools, we have developed a method to extend the stereoscopic X-ray tracking system of a radiosurgery platform in order to locate objects such as marker geometries with six degrees of freedom. The calibration was performed with 0.1 mm reprojection error. By using the full area of the flat-panel detectors without pre-processing the extended software increased the tracking volume and resolution by up to 80%, substantially improving patient localization and marker detectability. Furthermore, marker-tracking showed sub-millimeter accuracy and rotational errors below 0.1°. This demonstrates that the developed extension framework can accurately localize marker geometries using an integrated X-ray system, establishing the link for the integration of real-time ultrasound image guidance into the existing system.

Monte Carlo modeling of ultrasound probes for image guided radiotherapy.

To build Monte Carlo (MC) models of two ultrasound (US) probes and to quantify the effect of beam attenuation due to the US probes for radiation therapy delivered under real-time US image guidance. MC models of two Philips US probes, an X6-1 matrix-array transducer and a C5-2 curved-array transducer, were built based on their megavoltage (MV) CT images acquired in a Tomotherapy machine with a 3.5 MV beam in the EGSnrc, BEAMnrc, and DOSXYZnrc codes. Mass densities in the probes were assigned based on an electron density calibration phantom consisting of cylinders with mass densities between 0.2 and 8.0 g/cm(3). Beam attenuation due to the US probes in horizontal (for both probes) and vertical (for the X6-1 probe) orientation was measured in a solid water phantom for 6 and 15 MV (15 × 15) cm(2) beams with a 2D ionization chamber array and radiographic films at 5 cm depth. The MC models of the US probes were validated by comparison of the measured dose distributions and dose distributions predicted by MC. Attenuation of depth dose in the (15 × 15) cm(2) beams and small circular beams due to the presence of the probes was assessed by means of MC simulations. The 3.5 MV CT number to mass density calibration curve was found to be linear with R(2) > 0.99. The maximum mass densities in the X6-1 and C5-2 probes were found to be 4.8 and 5.2 g/cm(3), respectively. Dose profile differences between MC simulations and measurements of less than 3% for US probes in horizontal orientation were found, with the exception of the penumbra region. The largest 6% dose difference was observed in dose profiles of the X6-1 probe placed in vertical orientation, which was attributed to inadequate modeling of the probe cable. Gamma analysis of the simulated and measured doses showed that over 96% of measurement points passed the 3%/3 mm criteria for both probes placed in horizontal orientation and for the X6-1 probe in vertical orientation. The X6-1 probe in vertical orientation caused the highest attenuation of the 6 and 15 MV beams, which at 10 cm depth accounted for 33% and 43% decrease compared to the respective (15 × 15) cm(2) open fields. The C5-2 probe in horizontal orientation, on the other hand, caused a dose increase of 10% and 53% for the 6 and 15 MV beams, respectively, in the buildup region at 0.5 cm depth. For the X6-1 probe in vertical orientation, the dose at 5 cm depth for the 3-cm diameter 6 MV and 5-cm diameter 15 MV beams was attenuated compared to the corresponding open fields to a greater degree by 65% and 43%, respectively. MC models of two US probes used for real-time image guidance during radiotherapy have been built. Due to the high beam attenuation of the US probes, the authors generally recommend avoiding delivery of treatment beams that intersect the probe. However, the presented MC models can be effectively integrated into US-guided radiotherapy treatment planning in cases for which beam avoidance is not practical due to anatomy geometry.

Real Time Target Tracking in a Phantom Using Ultrasonic Imaging

In this paper we present a real-time ultrasound image guidance method suitable for tracking the motion of tumors. A 2D ultrasound based motion tracking system was evaluated. A robot was used to control the focused ultrasound and position it at the target that has been segmented from a real-time ultrasound video. Tracking accuracy and precision were investigated using a lesion mimicking phantom. Experiments have been conducted and results show sufficient efficiency of the image guidance algorithm. This work could be developed as the foundation for combining the real time ultrasound imaging tracking and MRI thermometry monitoring non-invasive surgery.

Prostate CT segmentation method based on nonrigid registration in ultrasound-guided CT-based HDR prostate brachytherapy.

The technological advances in real-time ultrasound image guidance for high-dose-rate (HDR) prostate brachytherapy have placed this treatment modality at the forefront of innovation in cancer radiotherapy. Prostate HDR treatment often involves placing the HDR catheters (needles) into the prostate gland under the transrectal ultrasound (TRUS) guidance, then generating a radiation treatment plan based on CT prostate images, and subsequently delivering high dose of radiation through these catheters. The main challenge for this HDR procedure is to accurately segment the prostate volume in the CT images for the radiation treatment planning. In this study, the authors propose a novel approach that integrates the prostate volume from 3D TRUS images into the treatment planning CT images to provide an accurate prostate delineation for prostate HDR treatment. The authors' approach requires acquisition of 3D TRUS prostate images in the operating room right after the HDR catheters are inserted, which takes 1-3 min. These TRUS images are used to create prostate contours. The HDR catheters are reconstructed from the intraoperative TRUS and postoperative CT images, and subsequently used as landmarks for the TRUS-CT image fusion. After TRUS-CT fusion, the TRUS-based prostate volume is deformed to the CT images for treatment planning. This method was first validated with a prostate-phantom study. In addition, a pilot study of ten patients undergoing HDR prostate brachytherapy was conducted to test its clinical feasibility. The accuracy of their approach was assessed through the locations of three implanted fiducial (gold) markers, as well as T2-weighted MR prostate images of patients. For the phantom study, the target registration error (TRE) of gold-markers was 0.41 ± 0.11 mm. For the ten patients, the TRE of gold markers was 1.18 ± 0.26 mm; the prostate volume difference between the authors' approach and the MRI-based volume was 7.28% ± 0.86%, and the prostate volume Dice overlap coefficient was 91.89% ± 1.19%. The authors have developed a novel approach to improve prostate contour utilizing intraoperative TRUS-based prostate volume in the CT-based prostate HDR treatment planning, demonstrated its clinical feasibility, and validated its accuracy with MRIs. The proposed segmentation method would improve prostate delineations, enable accurate dose planning and treatment delivery, and potentially enhance the treatment outcome of prostate HDR brachytherapy.

Intraoperative Registered Transrectal Ultrasound Guidance for Robot-Assisted Laparoscopic Radical Prostatectomy

To provide unencumbered real-time ultrasound image guidance during robot-assisted laparoscopic radical prostatectomy, we developed a robotic transrectal ultrasound system that tracks the da Vinci® Surgical System instruments. We describe our initial clinical experience with this system. After an evaluation in a canine model, 20 patients were enrolled in the study. During each procedure the transrectal ultrasound transducer was manually positioned using a brachytherapy stabilizer to provide good imaging of the prostate. Then the transrectal ultrasound was registered to the da Vinci robot by a previously validated procedure. Finally, automatic rotation of the transrectal ultrasound was enabled such that the transrectal ultrasound imaging plane safely tracked the tip of the da Vinci instrument controlled by the surgeon, while real-time transrectal ultrasound images were relayed to the surgeon at the da Vinci console. Tracking was activated during all critical stages of the surgery. The transrectal ultrasound robot was easy to set up and use, adding 7 minutes (range 5 to 14) to the procedure. It did not require an assistant or additional control devices. Qualitative feedback was acquired from the surgeons, who found transrectal ultrasound useful in identifying the urethra while passing the dorsal venous complex suture, defining the prostate-bladder interface during bladder neck dissection, identifying the seminal vesicles and their location with respect to the rectal wall, and identifying the distal prostate boundary at the apex. Real-time, registered robotic transrectal ultrasound guidance with automatic instrument tracking during robot-assisted laparoscopic radical prostatectomy is feasible and potentially useful. The results justify further studies to establish whether the approach can improve procedure outcomes.

High dose rate prostate brachytherapy: an overview of the rationale, experience and emerging applications in the treatment of prostate cancer

The technological advances in real-time ultrasound image guidance for high dose rate (HDR) prostate brachytherapy places this treatment modality at the forefront of innovation in radiotherapy. This review article will explore the rationale for HDR brachytherapy as a highly conformal method of dose delivery and safe dose escalation to the prostate, in addition to the particular radiobiological advantages it has over low dose rate and external beam radiotherapy. The encouraging outcome data and favourable toxicity profile will be discussed before looking at emerging applications for the future and how this procedure will feature alongside stereotactic radiosurgery.

High-intensity focused ultrasound as a treatment for colorectal liver metastasis in difficult position

High-intensity focused ultrasound as a treatment for colorectal liver metastasis in difficult position

Sa1458 Clinical Impact of EUS-Guided Fine Needle Aspiration Biopsy in the Diagnosis of Lymphoma

Sa1458 Clinical Impact of EUS-Guided Fine Needle Aspiration Biopsy in the Diagnosis of Lymphoma

Clinical Impact of Endoscopic Ultrasound-Guided Fine Needle Aspiration Biopsy In the Diagnosis of Patients with Lymphoma Who Have No Superficial Lymphadenopathies

AbstractAbstract 5083 Background:In patients with mediastinal and intra-abdominal lymphoma who do not have superficial lymphadenopathies, the diagnosis is usually made by surgical sampling with open thoracic surgery, laparotomy, mediastinoscopy, thoracoscopy, or laparoscopy. However, these surgical procedures are cumbersome and invasive; therefore, the treatment is often delayed, and doctors often hesitate to attempt the procedures for patients in poor performance status (PS). Recently, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been used for the diagnosis of unknown mediastinal and abdominal lymphadenopathies or masses. With this procedure, pathological materials can be obtained through the gastrointestinal tract under real-time ultrasound imaging guidance. It is regarded as a minimally invasive, safe, and relatively accurate procedure. However, only a small amount of material can be sampled with this technique. Immunohistochemical, flow cytometric, and chromosomal analyses are essential for the diagnosis of lymphoma, but it is not clear whether these analyses can be assessed on samples obtained by EUS-FNA. Aim:To evaluate the yield of EUS-FNA for the diagnosis of lymphoma. Patients and Methods:Between June 2005 and December 2009, a total of 224 consecutive patients who were suspected to have lymphoma underwent EUS-FNA with a 19-gauge needle at our hospital. We reviewed the baseline characteristics of the patients; the histological diagnosis including immunohistochemical stainings, flow cytometric analysis (FCM), and chromosomal analysis (by the G-banding method) of the FNA samples; and the final diagnosis. EUS-FNA was performed in 241 lesions in the 224 patients. One hundred and forty-three patients (63.8%) underwent the procedure as outpatients. Ten in 224 patients had a poor PS (grade 4). Results:The locations of the lesions were mediastinal in 99 and intra-abdominal in 142 (inclusive of 9 splenic, 5 left adrenal, 2 pancreatic, and 1 right renal lesions). After all, 142 in 224 patients were finally diagnosed as having lymphoma. Among them, 138 in 142 patients (97.2%) were diagnosed by EUS-FNA, and detailed classification in accordance with the WHO system was also possible in 125 in 142 patients (88.0%) on the basis of comprehensive findings including immunohistochemical staining, FCM, FISH method, and chromosomal analysis. While, remaining 82 in 224 patients were diagnosed as having inflammatory diseases such as sarcoidosis, necrotizing lymphadenitis, tuberculosis, or other cancers. No serious complications occurred with the procedure. Conclusions:EUS-FNA is a safe and convenient procedure with high diagnostic value for the diagnosis of lymphoma. Therefore, this procedure should be initially considered to attempt for patients with mediastinal and intra-abdomnal lymphadenopathy or mass who do have no superficial lesions. Disclosures:No relevant conflicts of interest to declare.

This Month in Anesthesiology

This Month in Anesthesiology

Needle steering for 3D TRUS-guided robot-aided brachytherapy

To provide unencumbered real-time ultrasound image guidance during robot-assisted laparoscopic radical prostatectomy, we developed a robotic transrectal ultrasound system that tracks the da Vinci® Surgical System instruments. We describe our initial clinical experience with this system.After an evaluation in a canine model, 20 patients were enrolled in the study. During each procedure the transrectal ultrasound transducer was manually positioned using a brachytherapy stabilizer to provide good imaging of the prostate. Then the transrectal ultrasound was registered to the da Vinci robot by a previously validated procedure. Finally, automatic rotation of the transrectal ultrasound was enabled such that the transrectal ultrasound imaging plane safely tracked the tip of the da Vinci instrument controlled by the surgeon, while real-time transrectal ultrasound images were relayed to the surgeon at the da Vinci console. Tracking was activated during all critical stages of the surgery.The transrectal ultrasound robot was easy to set up and use, adding 7 minutes (range 5 to 14) to the procedure. It did not require an assistant or additional control devices. Qualitative feedback was acquired from the surgeons, who found transrectal ultrasound useful in identifying the urethra while passing the dorsal venous complex suture, defining the prostate-bladder interface during bladder neck dissection, identifying the seminal vesicles and their location with respect to the rectal wall, and identifying the distal prostate boundary at the apex.Real-time, registered robotic transrectal ultrasound guidance with automatic instrument tracking during robot-assisted laparoscopic radical prostatectomy is feasible and potentially useful. The results justify further studies to establish whether the approach can improve procedure outcomes.

Ultrasound imaging-guided noninvasive ultrasound thrombolysis: preclinical results.

Catheter-based therapeutic ultrasound thrombolysis was recently shown to be effective and safe. The purpose of this work was to study the safety and efficacy of external high-intensity focused ultrasound thrombolysis guided by ultrasound imaging in experimental settings. A therapeutic transducer was constructed from an acoustic lens and integrated with an ultrasound imaging transducer. In vitro clots were inserted into bovine arterial segments and sonicated under real-time ultrasound imaging guidance in a water tank. With pulsed-wave (PW) ultrasound, the total sonication time correlated with thrombolysis efficiency (r(2)=0.7666). A thrombolysis efficiency of 91% was achieved with optimal PW parameters (1:25 duty cycle, 200-micros pulse length) at an intensity (I(spta)) of >35+/-5 W/cm(2). Ultrasound imaging during sonication showed the cavitation field as a spherical cloud of echo-dense material. Within <2 minutes, the vessel lumen evidenced neither residual clot nor damage to the arterial wall. On serial filtration, 93+/-1% of the lysed clot became subcapillary in size (<8 microm). In vitro safety studies, however, showed arterial damage when an I(spta) of 45 W/cm(2) was used for periods of >/=300 seconds. External high-intensity focused ultrasound thrombolysis using optimal PW parameters for periods of </=300 seconds appears to be a safe and effective method to induce thrombolysis. The procedure can be guided by ultrasound imaging, thereby allowing the monitoring of therapy.