2D ultrasound thermometry during thermal ablation with high-intensity focused ultrasound.

The clinical use of high intensity focused ultrasound (HIFU) therapy for noninvasive tissue ablation has recently gained momentum. Guidance is provided by either magnetic resonance imaging (MRI) or conventional B-mode ultrasound imaging, each with its own advantages and disadvantages. The main limitation of ultrasound imaging is its inability to provide temperature measurements over the ranges corresponding to the target temperatures during ablative thermal therapies (between 55 °C and 70 °C). Here, variations in ultrasound backscattered energy (ΔBSE) were used to monitor temperature increases in liver tissue up to an absolute value of 90 °C during and after HIFU treatment. In vitro experimental measurements were performed in 47 bovine liver samples using a toroidal HIFU transducer operating at 2.5 MHz to increase the temperature of tissues. An ultrasound imaging probe working at 7.5 MHz was placed in the center of the HIFU transducer to monitor the backscattered signals. The free-field acoustic power was set to 9 W, 12 W or 16 W in the different experiments. HIFU sonications were performed for 240 s using a duty cycle of 83 % to allow ultrasound imaging and raw radiofrequency data acquisition during exposures. Measurements showed a linear relationship between ΔBSE (in dB) and temperature (r = 0.94, p < 0.001) over a temperature range from 37 °C to 90 °C, with a high reliability of temperature measurements below 75 °C. Monitoring can be performed at the frame rate of ultrasound imaging scanners with an accuracy within an acceptable threshold of 5 °C, given the temperatures targeted during thermal ablations. If the maximum temperature reached is below 70 °C, ΔBSE is also a reliable approach for estimating the temperature during cooling. Histological analysis shown the impact of the treatment on the spatial arrangement of cells that can explain the observed variation of ΔBSE. These results demonstrate the ability of ΔBSE measurements to estimate temperature in ultrasound images within an effective therapeutic range. This method can be implemented clinically and potentially applied to other thermal-based therapies.

In vivo exposure of the bladder using a non-invasive high intensity focused ultrasound toroidal transducer.

A toroidal high-intensity focused ultrasound (HIFU) transducer was used to expose normal bladder wall tissues non-invasively in vivo in a porcine model in order to investigate the potential to treat bladder tumors. The transducer was divided into 32 concentric rings with equal surface areas, operating at 2.5 MHz. Eight animals were split into two groups of 4. In the first group, post-mortem evaluation was performed immediately after ultrasound exposure. In the second group, animals survived for up to seven days before post-mortem evaluation. The ultrasound imaging guided HIFU device was hand-held during the procedure using optical tracking to ensure correct targeting. One thermal lesion in each animal was created using a 40 s exposure at 80 acoustic Watts (free-field) in the trigone region of the bladder wall. The average (±Standard Deviation) abdominal wall and bladder wall thicknesses were 10.3 ± 1.4 mm and 1.1 ± 0.4 mm respectively. The longest and shortest axes of the HIFU ablations were 7.7 ± 2.9 mm and 6.0 ± 1.8 mm, respectively, resulting in an ablation of the whole thickness of the bladder wall in most cases. Ablation were performed at an average depth (distance from the skin surface to the centre of the HIFU lesion) of 42.5 ± 3.8 mm and extended throughout the thickness of the bladder. There were two cases of injury to tissues immediately adjacent to the bladder wall but without signs of perforation, as confirmed by histological analysis. Non-invasive HIFU ablation using a hand-held toroidal transducer was successfully performed to destroy regions of the bladder wall in vivo.

Non-invasive High-Intensity Focused Ultrasound Treatment of Liver Tissues in an In Vivo Porcine Model: Fast, Large and Safe Ablations Using a Toroidal Transducer.

A toroidal high-intensity focused ultrasound (HIFU) transducer was used to non-invasively treat liver tissues in vivo in a pig model. The transducer was divided into 32 concentric rings with equal surface areas operating at 2.5 MHz. First, attenuation of skin, fat, muscle and liver tissues was measured in fresh animal samples to adjust the energy delivered to the focal zone. Then, 8 animals were included in the present protocol and placed in a dorsal decubitus proclive position at an angle of 15°. The device was held by hand, and sonications were performed during apnea. Two thermal HIFU lesions were created in 40 s in each animal. The average abdominal wall thickness was 14.8 ± 1.3 mm (12.5-17.6 mm). The longest and shortest axes of the HIFU ablations were 20.9 ± 6.3 mm (14.0-33.7 mm) and 14.2 ± 5.5 mm (7.0-22.0 mm), respectively. All HIFU lesions were visible on sonograms. The correlation between the dimensions of the HIFU lesions observed on sonograms and those obtained during gross examination was r = 0.84. Creating large and fast ablations with reliable ultrasound imaging guidance in the liver using this handheld device may represent a new therapeutic option for patients with liver tumors.

Quantitative ultrasound techniques for assessing thermal ablation: Measurement of the backscatter coefficient from ex vivo human liver.

BACKGROUND: Understanding the changes occurring in biological tissue during thermal ablation is at the heart of many current challenges in both therapy and medical imaging research. PURPOSE: The objective of this work is to quantitatively interpret the scattering response of human liver samples, before and after thermal ablation. We report acoustic measurements performed involving n = 21 human liver samples. Thermal ablation is achieved at temperatures between 45 and 80°C and quantification of the irreversible changes in acoustic attenuation and Backscattering Coefficient (BSC) is reported, with a particular attention to the latter. METHODS: Both attenuation coefficient and BSCs were measured in the frequency range from 10 to 52 MHz. Scans were performed before heating and after cooling down. Attenuation coefficients were calculated using spectral difference method and BSC estimated using the reference phantom method. RESULTS: Strong increases of attenuation coefficients and BSCs with heating temperature were observed. Quantitative ultrasonic parameters obtained with the polydisperse structure factor model (poly-SFM)are compared to histological observations and seen to be close to hepatocyte mean diameter (HMD). CONCLUSIONS: The results presented in this study provide a description of the impact of thermal ablation in human liver tissue on acoustic attenuation and the BSC. For the first time, quantitative agreement between the Effective Scatterer Diameter (ESD) estimated from BSC and HMD was shown, highlighting the important role of cellular network in the scattering response of the medium. This core result is an important step toward the determination of the nature of scattering sources in biological tissues.

Intra-operative High-Intensity Focused Ultrasound in Patients With Colorectal Liver Metastases: A Prospective Ablate-and-Resect Study.

OBJECTIVE: High-intensity focused ultrasound (HIFU) is a recent, non-ionizing and non-invasive technology of focal destruction. Independence from the heat-sink effect of blood flow makes HIFU an interesting technique for focal ablation of liver tumors. Current available technology is based on extracorporeal treatment that limits use of HIFU for the treatment of liver tumors, as elementary ablations are small and must be juxtaposed to treat tumors, resulting in long-duration treatment. We developed an HIFU probe with toroidal technology, which increases the volume of ablation, for intra-operative use, and we assessed the feasibility and efficacy of this device in patients with colorectal liver metastasis (CLM) measuring less than 30 mm. METHODS: This study was an ablate-and-resect, prospective, single-center, phase II study. All ablations were performed in the area of liver scheduled for liver resection to avoid loss of chance of recovery. The primary objective was to ablate CLM with safety margins (>5 mm). RESULTS: Between May 2014 and July 2020, 15 patients were enrolled and 24 CLM were targeted. The HIFU ablation time was 370 s. In total, 23 of 24 CLM were successfully treated (95.8%). No damage occurred to extrahepatic tissues. HIFU ablations were oblate shaped with an average long axis of 44.3 ± 6.1 mm and an average shortest axis of 35.9 ± 6.7 mm. On pathological examination, the average diameter of the treated metastasis was 12.2 ± 4.8 mm. CONCLUSION: Intra-operative HIFU can safely and accurately produce large ablations in 6 min with real-time guidance (ClinicalTrials.gov identifier: NCT01489787).

High-intensity focused ultrasound (HIFU)-assisted hepatic resection in an animal model.

BACKGROUND: Bleeding is the main cause of postoperative complications of hepatic surgery. To minimize intraoperative bleeding during hepatectomy, resections are generally carried out under hepatic vascular control despite the risk of liver dysfunction in patients with chronic liver disease. This study evaluates the feasibility and safety of high-intensity focused ultrasound (HIFU)-assisted hepatic resection during an open procedure in an animal model. METHODS: Three groups of 12-14-week-old Landrace pigs (n = 7/group) were used to evaluate HIFU-assisted liver resection (group A) vs liver resection with or without portal triad clamping (groups B and C). In each pig, liver resection was performed on the right and left paramedian lobes. The following were evaluated and compared in the 3 groups: total blood loss, blood loss/cm(2) of resection area, clip density, procedure duration, morbidity, and mortality. RESULTS: Median blood loss was significantly lower in group A than in group B (P = .02), and group C (P = .007). Median blood loss/cm(2) of resection area was 4.77 mL/cm² in group A, 11.35 mL/cm² in group B, 12.22 mL/cm² in Group C. Precoagulation resulted in sealing blood vessels <5 mm; therefore, median clip density during liver transection was 0.78 clip/cm² in group A, 1.61 clip/cm(2) in group B, and 1.57 clip/cm(2) in group C. Median duration of the surgical procedure was 12 min in group A, 21 min in group B, and 19 min in group C. CONCLUSIONS: HIFU-assisted hepatic resection during an open procedure in an animal model is safe, reduces bleeding, and allows real-time ultrasound guidance.

Pancreatic Ductal Adenocarcinoma: Current and Emerging Therapeutic Uses of Focused Ultrasound.

Pancreatic ductal adenocarcinoma (PDAC) diagnosis accompanies a somber prognosis for the patient, with dismal survival odds: 5% at 5 years. Despite extensive research, PDAC is expected to become the second leading cause of mortality by cancer by 2030. Ultrasound (US) has been used successfully in treating other types of cancer and evidence is flourishing that it could benefit PDAC patients. High-intensity focused US (HIFU) is currently used for pain management in palliative care. In addition, clinical work is being performed to use US to downstage borderline resectable tumors and increase the proportion of patients eligible for surgical ablation. Focused US (FUS) can also induce mechanical effects, which may elicit an anti-tumor response through disruption of the stroma and can be used for targeted drug delivery. More recently, sonodynamic therapy (akin to photodynamic therapy) and immunomodulation have brought new perspectives in treating PDAC. The aim of this review is to summarize the current state of those techniques and share our opinion on their future and challenges.

Intraoperative HIFU Ablation of the Pancreas Using a Toroidal Transducer in a Porcine Model. The First Step towards a Clinical Treatment of Locally Advanced Pancreatic Cancer.

Apart from palliative chemotherapy, no other therapy has been proven effective for the treatment of locally advanced pancreatic tumors. In this study, an intraoperative high-intensity focused ultrasound (HIFU) device was tested in vivo to demonstrate the feasibility of treating the pancreatic parenchyma and tissues surrounding the superior mesenteric vessels prior to clinical translation of this technique. Twenty pigs were included and treated using a HIFU device equipped with a toroidal transducer and an integrated ultrasound imaging probe. Treatments were performed with energy escalation (from 30 kJ to 52 kJ). All treatments resulted in visible (macroscopically and in ultrasound images) homogeneous thermal damage, which was confirmed by histology. The dimensions of thermal lesions measured in ultrasound images and those measured macroscopically were correlated (r = 0.82, p < 0.05). No arterial spasms or occlusion were observed at the lowest energy setting. Temporary spasm of the peripancreatic artery was observed when using an energy setting greater than 30 kJ. The possibility of treating the pancreas and tissues around mesenteric vessels without vascular thrombosis holds great promise for the treatment of locally advanced pancreatic cancers. If clinically successful, chemotherapy followed by HIFU treatment could rapidly become a novel treatment option for locally advanced pancreatic cancer.

Evaluation of Ultrasonic Attenuation in Primary and Secondary Human Liver Tumors and Its Potential Effect on High-Intensity Focused Ultrasound Treatment.

Primary and secondary liver tumors are completely different diseases but are usually treated similarly using high-intensity focused ultrasound (HIFU). However, the acoustic parameters of these tissues are not well documented. In this study, attenuation coefficients were evaluated in fresh primary (N = 8) and secondary (N = 13) human liver tumor samples recovered by hepatectomy. The average attenuation coefficients of the primary and secondary liver tumors were 0.10 ± 0.03 and 0.20 ± 0.04 Np/cm/MHz, respectively. The average attenuation coefficients of the liver tissue surrounding the primary and secondary tumors were 0.16 ± 0.07 and 0.07 ± 0.02 Np/cm/MHz, respectively. Numerical simulations performed using these values revealed that completely different HIFU ablation patterns were created in primary and secondary liver tumors using the same exposure parameters. The dimensions of a typical HIFU lesion were two times larger in secondary liver tumors than in primary tumors. HIFU treatment parameters should be set properly according to the acoustic properties of the diseased liver tissue.

Imaging of Thermal Effects during High-Intensity Ultrasound Treatment in Liver by Passive Elastography: A Preliminary Feasibility in Vitro Study.

High-intensity focused ultrasound is a non-invasive modality for thermal ablation of tissues through locally increased temperature. Thermal lesions can be monitored by elastography, following the changes in the elastic properties of the tissue as reflected by the shear-wave velocity. Most studies on ultrasound elastography use shear waves created by acoustic radiation force. However, in the human body, the natural noise resulting from cardiac activity or arterial pulsatility can be used to characterize elasticity through noise-correlation techniques, in the method known as passive elastography. The objective of this study was to investigate the feasibility of monitoring high-intensity ultrasound treatments of liver tissue using passive elastography. Bovine livers were heated to 80°C using a high-intensity planar transducer and imaged with a high-frame-rate ultrasound imaging device. The dynamics of lesion formation are captured through tissue stiffening and lesion expansion.

Fast and Selective Ablation of Liver Tumors by High-Intensity Focused Ultrasound Using a Toroidal Transducer Guided by Ultrasound Imaging: The Results of Animal Experiments.

This study demonstrated that high-intensity focused ultrasound (HIFU) produced with an intra-operative toroidal-shaped transducer causes fast, selective liver tumor ablations in an animal model. The HIFU device is composed of 256 emitters working at 3 MHz. A 7.5 MHz ultrasound imaging probe centered on the HIFU transducer guided treatment. VX2 tumor segments (25 mg) were implanted into the right lateral liver lobes of 45 New Zealand rabbits. The animals were evenly divided into groups 1 (toroidal HIFU ablation), 2 (surgical resection) and 3 (untreated control). Therapeutic responses were evaluated with gross pathology and histology 11 d post-treatment. Toroidal transducer-produced HIFU ablation (average ablation rate 10.5 cc/min) allowed fast and homogeneous tumor treatment. Sonograms showed all ablations. VX2 tumors were completely coagulated and surrounded by safety margins without surrounding-organ secondary HIFU lesions. HIFU group tumor volumes at autopsy (39 mm3) were significantly lower than control group volumes (2610 mm3, p < 0.0001). HIFU group tumor metastasis (27%) was lower than resected (33%) and control (67%) group metastasis. Ultrasound imaging, gross pathology and histology results supported these outcomes. HIFU procedures had no complications. Rabbit liver tumor ablation using a toroidal HIFU transducer under ultrasound imaging guidance might therefore be an effective intra-operative treatment for localized liver metastases.

High-intensity focused ultrasound ablation for the treatment of colorectal liver metastases during an open procedure: study on the pig.

OBJECTIVE: To demonstrate in a porcine model that high-intensity focused ultrasound (HIFU) with toroid-shaped emitters may have a role in treating unresectable colorectal liver metastases. SUMMARY BACKGROUND DATA: Surgical resection is the only curative option for colorectal hepatic metastases. Only 20% of patients are suitable for surgery. Many ablative techniques have been assessed but several limitations have been documented: traumatic puncture of the parenchyma, limited size of lesions, and inability to monitor the treatment in real time. METHODS: A HIFU device with 256 toroid-shaped emitters and integrated ultrasound imaging probe was used. Single lesions, induced in 40 seconds, and juxtaposition of 6 single lesions were created under ultrasound guidance on 13 pigs. The lesions were studied on sonograms, macroscopically and microscopically up to 30 days after the treatment. RESULTS: Ninety percent of the HIFU lesions were immediately hypoechoic on ultrasound imaging. The average coagulated volume obtained from a 40 seconds total exposure in the liver was 7.0 +/- 2.5 cm (1.5-20.0), average diameter: 19.5 +/- 3.8 mm (10.0-29.0). Using the real-time visualization of the treated region, single lesions were easily juxtaposed to produce larger lesions up to 6 cm in diameter without any major complication. CONCLUSIONS: This toroid HIFU device allows short treatment times, noninvasiveness regarding the liver and real time ultrasound guidance. It seems to be simpler and more reliable to use than current ablative methods. Additionally, lesions through large vessels (up to 5 mm) being feasible, treatment of some juxta-vascular metastases should be possible.

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases.

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% of patients. Surgery has been widely used in association with radiofrequency, cryotherapy, or microwaves to expand the number of treatments performed with a curative intent. Nevertheless, several limitations have been documented when using these techniques (i.e., a traumatic puncture of the parenchyma, a limited size of lesions, and an inability to monitor the treatment in real-time).High-intensity focused ultrasound (HIFU) technology can achieve precise ablations of biological tissues without incisions or radiation. Current HIFU devices are based on an extracorporeal approach with limited access to the liver. We have developed a HIFU device designed for intraoperative use. The use of a toroidal transducer enables an ablation rate (10 cm3·min-1) higher than any other treatment and is independent of perfusion. The feasibility, safety, and accuracy of intraoperative HIFU ablation were evaluated during an ablate-and-resect prospective study. This clinical phase I and IIa study was performed in patients undergoing hepatectomy for liver metastases. The HIFU treatment was performed on healthy tissue scheduled for resection.Liver metastases measuring less than 20 mm will be targeted during phase IIb (currently ongoing). This set-up allows the real-time evaluation of HIFU ablation while protecting participating patients from any adverse effects related to this new technique. Fifteen patients were included in phase I-IIa and 30 HIFU ablations were safely created within 40 s and with a precision of 1-2 mm. The average dimensions of the HIFU ablations were 27.5 x 21.0 mm2, corresponding to a volume of approximately 7.5 cm3. The aim of the ongoing phase IIb is to ablate metastases of less than 20 mm in diameter with a 5 mm margin.

Treatment of esophageal tumors using high intensity intraluminal ultrasound: first clinical results.

BACKGROUND: Esophageal tumors generally bear a poor prognosis. Radical surgery is generally the only curative method available but is not feasible in the majority of patients; palliative therapy with stent placement is generally performed. It has been demonstrated that High Intensity Ultrasound can induce rapid, complete and well-defined coagulation necrosis. Thus, for the treatment of esophageal tumors, we have designed an ultrasound applicator that uses an intraluminal approach to fill up this therapeutic gap. METHODS: Thermal ablation is performed with water-cooled ultrasound transducers operating at a frequency of 10 MHz. Single lesions extend from the transducer surface up to 10 mm in depth when applying an intensity of 14 W/cm2 for 10s. A lumen inside the therapy applicator provides path for an endoscopic ultrasound imaging probe operating at a frequency of 12 MHz. The mechanical rotation of the applicator around its axis enables treatment of sectorial or cylindrical volumes. This method is thus particularly suitable for esophageal tumors that may develop only on a portion of the esophageal circumference. Previous experiments were conducted from bench to in vivo studies on pig esophagi. RESULTS: Here we report clinical results obtained on four patients included in a pilot study. The treatment of esophageal tumors was performed under fluoroscopic guidance and ultrasound imaging. Objective tumor response was obtained in all cases and a complete necrosis of a tumor was obtained in one case. All patients recovered uneventfully and dysphagia improved significantly within 15 days, allowing for resuming a solid diet in three cases. CONCLUSION: This clinical work demonstrated the efficacy of intraluminal high intensity ultrasound therapy for local tumor destruction in the esophagus.

Transient elastography using impulsive ultrasound radiation force: a preliminary comparison with surface palpation elastography.

The use of impulsive acoustic radiation force for transient strain imaging was investigated and compared with conventional elastography. A series of experiments were performed to evaluate the performances of the technique on gelatine phantoms containing inclusions and to determine a range of applications where radiation force elastography may be useful compared with static elastography. Slip boundaries and cylindrical inclusions of varying elastic modulus were placed in background materials. A focused ultrasound transducer was used to apply localised radiation force to a small volume of tissue mimic (100 mm3) for durations of 8 ms. A conventional real-time ultrasound imaging probe was used to obtain radio- frequency echo signals. The resulting strains were mapped using ultrasound correlation-based methods. The instantaneous strain immediately following cessation of the radiation force was observed at depth within homogeneous gels and within stiff inclusions. The highly localised and transient strain that is produced at depth permits the sensing of variations in tissue elastic properties that are difficult to detect with conventional elastography, due to greater independence from boundary conditions. In particular, radiation force elastograms were more homogeneous in the background and within the inclusions and displayed a superior contrast-transfer-efficiency, particularly for regions that had negative modulus contrast or that were disconnected from the background or the anterior medium by a low friction boundary.

Thermal Ablation of the Pancreas With Intraoperative High-Intensity Focused Ultrasound: Safety and Efficacy in a Porcine Model.

OBJECTIVE: New focal destruction technologies such as high-intensity focused ultrasound (HIFU) may improve the prognosis of pancreatic ductal adenocarcinoma. Our objectives were to demonstrate the safety and efficacy of intraoperative pancreatic HIFU ablation in a porcine model. METHODS: In a porcine model (N = 12), a single HIFU ablation was performed in either the body or tail of the pancreas, distant to superior mesenteric vessels. All animals were sacrificed on the eighth day. The primary objective was to obtain an HIFU ablation measuring at least 1 cm without premature death. RESULTS: In total, 12 HIFU ablations were carried out. These ablations were performed within 160 seconds and on average measured 20 (15-27) × 16 (8-26) mm. The primary objective was fulfilled in all but 1 pig. There were no premature deaths or severe complications. High-intensity focused ultrasound treatment was associated with a transitory increase in amylase and lipase levels, and pseudocysts were observed in half of the pigs without being clinically apparent. All ablations were well delimited at both gross and histological examinations. CONCLUSIONS: Intraoperative thermal destruction of porcine pancreas with HIFU is feasible. Reproducibility and safety have to be confirmed when applied close to mesenteric vessels and in long-term preclinical studies.

Efficacy of high-intensity focused ultrasound-assisted hepatic resection (HIFU-AR) on blood loss reduction in patients with liver metastases requiring hepatectomy: study protocol for a randomized controlled trial.

BACKGROUND: Liver resection is the only potentially curative treatment for colorectal liver metastases (LM). It is considered a safe procedure, but is often associated with blood loss during liver transection. Blood transfusions are frequently needed, but they are associated with increased morbidity and risk of recurrence. Many surgical devices have been developed to decrease blood loss. However, none of them has proven superior to the standard crushing technique. We developed a new, powerful intra-operative high-intensity focused ultrasound (HIFU) transducer which destroys tissue by coagulative necrosis. We aim to evaluate whether HIFU-assisted liver resection (HIFU-AR) results in reduced blood loss. METHODS: This is a prospective, single-centre, randomized (1:1 ratio), comparative, open-label phase II study. Patients with LM requiring a hepatectomy for ≥ 2 segments will be included. Patients with cirrhosis or sinusoidal obstruction syndrome with portal hypertension will be excluded. The primary endpoint is normalized blood loss in millilitres per square centimetre of liver section plane. Secondary endpoints are: total blood loss, transection time, transection time per square centimetre of liver area, haemostasis time, clip density on the liver section area, rate and duration of the Pringle manœuvre, rate of patients needing a blood transfusion, length of hospital stay, morbidity, patients with positive resection margin, and local recurrence. Assuming a blood loss of 7.6 ± 3.7 mL/cm2 among controls, the study will have 85% power to detect a twofold decrease of blood loss in the experimental arm, using a Wilcoxon (Mann-Whitney) rank-sum test with a 0.05 two-sided significance level. Twenty-one randomized patients per arm are required. Considering the risk of contraindications at surgery, up to eight patients may be enrolled in addition to the 42 planned, with an enrolment period of 24 months. Randomization will be stratified by surgeon. DISCUSSION: We previously demonstrated the safety and efficacy of intra-operative HIFU in patients operated on for LM. We also demonstrated the efficacy of HIFU-AR in a preclinical study. Participants in the HIFU-AR group of this randomized trial can expect to benefit from reduced blood loss and decreased ischemia of liver parenchyma. TRIAL REGISTRATION: Clinicaltrial.gov, NCT02728167 . Registered on 22 March 2016.

Elastography for breast cancer diagnosis using radiation force: system development and performance evaluation.

The use of impulsive acoustic radiation force for strain imaging was investigated. A focused ultrasound transducer was used to apply localized radiation force to a small volume of tissue mimic (100 mm3) for durations of 8 ms. A conventional real-time ultrasound imaging probe was used to obtain echo signals. The resulting strains were mapped using ultrasound correlation-based methods. The instantaneous strain immediately following cessation of the radiation force was observed at depth within homogeneous gels and within stiff inclusions, and was seen to vary approximately linearly with Young's modulus of the material. The highly localized and transient strain that is produced may permit the sensing of variations in tissue elastic properties that are difficult to detect with conventional elastography because of greater independence from boundary conditions. For example, the characteristic, bi-directional, high strain artefacts attributable to stress concentration, often seen with static elastography at tissue-inclusion interfaces, do not appear using the transient radiation force strain imaging technique.

An Ultrasound Image-Based Dynamic Fusion Modeling Method for Predicting the Quantitative Impact of In Vivo Liver Motion on Intraoperative HIFU Therapies: Investigations in a Porcine Model.

Organ motion is a key component in the treatment of abdominal tumors by High Intensity Focused Ultrasound (HIFU), since it may influence the safety, efficacy and treatment time. Here we report the development in a porcine model of an Ultrasound (US) image-based dynamic fusion modeling method for predicting the effect of in vivo motion on intraoperative HIFU treatments performed in the liver in conjunction with surgery. A speckle tracking method was used on US images to quantify in vivo liver motions occurring intraoperatively during breathing and apnea. A fusion modeling of HIFU treatments was implemented by merging dynamic in vivo motion data in a numerical modeling of HIFU treatments. Two HIFU strategies were studied: a spherical focusing delivering 49 juxtapositions of 5-second HIFU exposures and a toroidal focusing using 1 single 40-second HIFU exposure. Liver motions during breathing were spatially homogenous and could be approximated to a rigid motion mainly encountered in the cranial-caudal direction (f = 0.20 Hz, magnitude > 13 mm). Elastic liver motions due to cardiovascular activity, although negligible, were detectable near millimeter-wide sus-hepatic veins (f = 0.96 Hz, magnitude < 1 mm). The fusion modeling quantified the deleterious effects of respiratory motions on the size and homogeneity of a standard "cigar-shaped" millimetric lesion usually predicted after a 5-second single spherical HIFU exposure in stationary tissues (Dice Similarity Coefficient: DSC < 45%). This method assessed the ability to enlarge HIFU ablations during respiration, either by juxtaposing "cigar-shaped" lesions with spherical HIFU exposures, or by generating one large single lesion with toroidal HIFU exposures (DSC > 75%). Fusion modeling predictions were preliminarily validated in vivo and showed the potential of using a long-duration toroidal HIFU exposure to accelerate the ablation process during breathing (from 0.5 to 6 cm3 · min(-1)). To improve HIFU treatment control, dynamic fusion modeling may be interesting for assessing numerically focusing strategies and motion compensation techniques in more realistic conditions.

Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer.

Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailability for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors.