HIFU Exposure Research Articles

Novel treatment system using endoscopic ultrasound-guided high-intensity focused ultrasound: A proof-of-concept study

AimHigh-intensity focused ultrasound (HIFU) is a novel minimally invasive local treatment of solid tumors. Endoscopic ultrasound-guided HIFU (EUS-HIFU) using mechanical effects would have potential benefits, including precise detection of target lesions and enhance drug delivery. The aim of this study is to develop EUS-HIFU device and to prove our concept in porcine model using a locally injected phase change nano droplet (PCND) as the sensitizer. MethodA phospholipid PCND contained volatile perfluoro-carbon liquids. The prototype HIFU apparatus comprised a small (20 × 20 mm) transducer with center frequency of 2.1 MHz, attachable to a linear EUS transducer. Under general anesthetic, a single porcine received EUS-guided injection of PCND. The HIFU transducer was placed laparotomically in the stomach, and the liver was ablated through the gastric wall. ResultsPCND was injected successfully and a distinct lesion was generated at the HIFU transducer focus only in injected areas that received HIFU exposure at 4.7 kW/cm2 at a duty cycle of 5 % (mean temporal intensity, 0.245 kW/cm2) for 30 s. The generated lesions were mechanically fractionated in macroscopic view. ConclusionThe concept of transluminal HIFU ablation using novel EUS-HIFU system was proved in a porcine animal model. This novel treatment system has great potential for future cancer treatment although further investigation in more animals and different organs are warranted.

Stability testing of gadoteridol and gadobenate dimeglumine formulations under exposure to high-intensity focused ultrasound.

Contrast-enhanced MRI could be useful to guide high-intensity focused ultrasound treatment (HIFU), but the effects of HIFU on gadolinium-based agents is not known. Here, we tested in vitro the stability of gadoteridol and gadobenate dimeglumine, two widely used MR contrast agents, after exposure to HIFU at power levels typically applied in the clinical practice. 0.5 M (gadoteridol and gadobenate dimeglumine) and diluted formulations (1:10 gadoteridol in saline) were exposed to different HIFU sequences. Unexposed and exposed solutions were characterized by high-performance liquid chromatography in terms of concentration of gadolinium complex, free gadolinium and free ligand. Gadoteridol formulation after treatment showed concentrations of the complex not significantly different from control. Free Gd and/or free ligand concentrations in the order of 0.002/0.004% w/w, were observed occasionally without significant correlation with intensity and duration of exposure to HIFU. Gadobenate dimeglumine formulation after treatment showed complex assay content values, by-products (0.24-0.26%) and free BOPTA levels (0.07%) comparable to control sample within the experimental error. In the range of conditions explored, HIFU exposure did not induce significant dissociations of gadoteridol and gadobenate dimeglumine, nor a detectable increase in the concentration of free species. Our study strengthens the hypothesis that gadolinium-based contrast agents are stable during HIFU treatment for body applications (e.g. thermal ablation of uterine fibroids).

PRELIMINARY EVALUATION OF THE EFFECTIVENESS OF HIFU-THERAPY IN PATIENTS WITH PANCREATIC CANCER

Purpose: to conduct a preliminary analysis of the safety and effectiveness of hifu-therapy with a lowenergy hifu-2001 device (shenzhen Huikang Medical apparatus Co., ltd) performed concurrently with chemotherapy in pancreatic cancer patients who are not suitable for surgery or chemoradiotherapy.Material and Method. The study included 24 pancreatic cancer patients who were treated at the Hertsen Moscow Oncology Research institute in the period from 2016 to 2019. There were 17 (71 %) women and 7 (29 %) men. The percentage of patients in the elderly group was 79 %. Stage iia pancreatic cancer was diagnosed in 3 (12.5 %) patients, stage ii in 5 (21 %) patients, stage iii in 9 (37.5 %) patients, and stage iv in 7 (29 %) patients. All patients received combination therapy, including systemic chemotherapy and hifu-therapy. Results. The most frequent adverse events of treatment were skin burns (n=6), with third-degree burns occurring in 2 (8.3 %) patients. Local sclerosis of subcutaneous adipose tissue was observed in 4 (17 %) patients; development of asymptomatic pancreatic pseudocysts in the area of hifu exposure was observed in 1 (4 %) patient. Pain control was achieved in 17 (85 %) patients, and local tumor control was achieved in 19 (79.2 %) patients. The follow-up time ranged from 5 to 30 months with a median time of 14.5 months. The median total life expectancy of patients was 16 months, and the median time to progression was 9 months. The overall 6-month survival rate was 100 %. The 1- and 1.5-year survival rates were 75.0 % and 41.7 %, respectively. The 2-year survival rate was 17.2 %. The 6-month and 1-year disease-free survival rates were 62.5 % and 12.5 %, respectively. Conclusion. The short- and long-term outcomes were consistent with those described in other studies, which indicated that a combination of systemic drug therapy and hifu-therapy is an appropriate approach for the treatment of patients with pancreatic cancer.

Evidence of the formation of the shock scattering induced violent cavitation cluster during boiling histotripsy insonation: A numerical case study

Boiling histotripsy is a promising noninvasive ultrasonic technique that can be used to mechanically destroy solid tumours. In boiling histotripsy, the formations and dynamics of a boiling vapour bubble and cavitation clouds contribute towards mechanical tissue fractionation. Whilst a number of numerical and experimental studies have been performed to examine and understand the evolution of a boiling bubble at the HIFU focus in a viscoelastic medium, little is known about the subsequent generation of cavitation clouds that form in between the boiling bubble and the HIFU transducer during boiling histotripsy insonation. Previous experimental observations suggest that the shock scattering by a boiling bubble may play a significant role in producing cavitation clouds. The main objective of the present study is, therefore, to investigate the relationship between the shock scattering phenomenon and the occurrence of cavitation clouds through (a) performing a numerical simulation of nonlinear wave propagation with the presence of a bubble at the HIFU focus and (b) comparing with the previous high speed camera observations of a cavitation cluster formation. The size of a bubble (i.e., 95.7, 128.1 and 258 μm in diameter) as well as the HIFU exposure conditions (i.e., a driving frequency of 1.1 MHz, peak positive and negative pressures of 68.4 MPa and −13.9 MPa) used in the simulations were obtained from the previous boiling histotripsy experiments conducted with a tissue gel phantom. The numerical results presented in this study clearly demonstrate that the shock scattering is the main cause of the creation of a cavitation cluster in boiling histotripsy.

Experimental investigation of effect of ultrasonic duty cycle on generation of reactive oxygen species for highly efficient sonodynamic treatment

Sonodynamic treatment (SDT) is a non-invasive treatment of cancer, combining ultrasound, reactive oxygen species (ROS), and sonosensitizer. When cavitation bubbles generated by ultrasound oscillate and collapse, ROS are generated due to the high temperature and high pressure inside the bubble. By generating cavitation bubbles in a target tissue, it can be treated by the cytotoxicity of ROS, which can be further enhanced by a sonosensitizer. In SDT, the small treatment region by a single shot of HIFU results in a long treatment time, which needs to be reduced by improving the efficiency of ROS generation. ROS can be visualized by the sonochemiluminescence of luminol. In this study, a polyacrylamide gel soaked with luminol solution is used as a target of ultrasonic exposure. The effect of the duty cycle of HIFU exposure on ROS generation was investigated by capturing sonochemiluminescent light emission, and high-speed photography of cavitation bubbles.

Toroidal intra-operative high intensity focused ultrasound transducer for treating liver metastases under ultrasound imaging guidance: Clinical results of Phase II study

The aim of this study was to assess the feasibility, safety, and accuracy of HIFU ablation in patients with liver metastases in a prospective phase II trial. The transducer has a toroidal shape (diameter: 70 mm, radius of curvature: 70 mm) and was divided into 32 ring-shaped emitters operating at 2.5 MHz. Thirty-one patients were included. HIFU ablations were created to ablate metastases (up to 30 mm in diameter) with safety margins in all directions. The use of a toroidal transducer enables an ablation rate (10 cc min-1) significantly higher than spherical transducers. Therefore, using electronic focusing of the beam, it was possible to treat all metastases with safety margin without the need to displace the device between HIFU exposures. The exposure time varied from 40 s to 370 s according to the diameter of the metastases to be treated. The dimensions of these HIFU ablations were a diameter of 48 ± 4.9 mm and a long axis of 45 ± 3.4 mm. No damage occurred to neighboring tissues. This study is the first clinical use of intra-operative HIFU in patients with liver metastases.

HIFU-induced changes in optical scattering and absorption of tissue over nine orders of thermal dose

The optical properties of tissue change during thermal ablation. Multi-modal methods such as acousto-optic (AO) and photo-acoustic (PA) imaging may provide a real-time, direct measure of lesion formation. Baseline changes in optical properties have been previously measured over limited ranges of thermal dose for tissues exposed to a temperature-controlled water bath, however, there is scant data for optical properties of lesions created by HIFU. In this work, the optical scattering and absorption coefficients from 400–1300 nm of excised chicken breast exposed to HIFU were measured using an integrating sphere spectrophotometric technique. HIFU-induced spatiotemporal temperature elevations were measured using an infrared camera and used to calculate the thermal dose delivered to a localized region of tissue. Results obtained over a range of thermal dose spanning 9 orders of magnitude show that the reduced scattering coefficient increases for HIFU exposures exceeding a threshold thermal dose of CEM43 = 600 ± 81 cumulative equivalent minutes. HIFU-induced thermal damage results in changes in scattering over all optical wavelengths, with a 2.5-fold increase for thermal lesions exceeding 70 °C. The tissue absorption coefficient was also found to increase for thermally lesioned tissue, however, the magnitude was strongly dependent on the optical wavelength and there was substantial sample-to-sample variability, such that the existence of a threshold thermal dose could not be determined. Therapeutic windows, where the optical penetration depth is expected to be greatest, were identified in the near infrared regime centered near 900 nm and 1100 nm. These data motivate further research to improve the real-time AO and PA sensing of lesion formation during HIFU therapy as an alternative to thermometry.

Macrophage response and surface analysis of dental cementum after treatment with high intensity focused ultrasound

ObjectiveTo investigate effects of HIFU on macrophage phenotype, surface micro-topography and nano-scale surface mechanical properties of dental cementum. Materials and methodsRoot discs (2 mm thickness) were cut apical to CEJ and sectioned into quadrants. HIFU setup with bowl-shaped piezo ceramic transducer submerged in a water tank was used for exposure on each specimen for 15 s, 30 s or 60 s. The specimens of the control group were left without any HIFU exposure. HIFU was generated with a continuous sinusoidal wave of 120Vpp amplitude, 250 KHZ resonance-frequency and highest ultrasonic pressure of ∼10 bar at the focus. Specimens for SEM were viewed, and micro-topography characterization performed, using AFM and Ra parameter and surface area (SA) calculated by specialized SPM surface analysis software. For nano-indentation testing, experiments were carried out using AFM. Macrophage cell isolation and culturing was performed on cementum to receive the HIFU treatment at different time periods. Raman spectroscopy were scanned to create spectra perpendicular to the cementum substrate to analyze generation of standard spectra for Raman intensity ratio of hydroxyapatite normalized to the peaks ν1 960 cm−1. Data was expressed as means ± standard deviations and analyzed by one-way ANOVA in term of Ra, SA, H and Er. Different points for fluorescence intensity ratio were analyzed by Raman using Wilcoxon rank sum test. ResultsHIFU exposure at 60 s removed the smear layer and most of cementum appeared smoothened. AFM characterisation, showed a slight decrease in the irregularity of the surface as exposure time increased. Intact macrophages can be identified in control and all experimental HIFU groups. The level of fluorescence for the control and HIFU 15 and 30 s were low as compared to HIFU 60 s. ConclusionIf HIFU can be successfully implemented, it may be a possible alternative to current methods used in periodontal therapy to achieve smooth root surfaces.

Bubble dynamics in boiling histotripsy

Boiling histotripsy is a non-invasive, cavitation-based ultrasonic technique which uses a number of millisecond pulses to mechanically fractionate tissue. Though a number of studies have demonstrated the efficacy of boiling histotripsy for fractionation of solid tumours, treatment monitoring by cavitation measurement is not well studied because of the limited understanding of the dynamics of bubbles induced by boiling histotripsy. The main objectives of this work are to (a) extract qualitative and quantitative features of bubbles excited by shockwaves and (b) distinguish between the different types of cavitation activity for either a thermally or a mechanically induced lesion in the liver. A numerical bubble model based on the Gilmore equation accounting for heat and mass transfer (gas and water vapour) was developed to investigate the dynamics of a single bubble in tissue exposed to different High Intensity Focused Ultrasound fields as a function of temperature variation in the fluid. Furthermore, ex vivo liver experiments were performed with a passive cavitation detection system to obtain acoustic emissions. The numerical simulations showed that the asymmetry in a shockwave and water vapour transport are the key parameters which lead the bubble to undergo rectified growth at a boiling temperature of 100°C. The onset of rectified radial bubble motion manifested itself as (a) an increase in the radiated pressure and (b) the sudden appearance of higher order multiple harmonics in the corresponding spectrogram. Examining the frequency spectra produced by the thermal ablation and the boiling histotripsy exposures, it was observed that higher order multiple harmonics as well as higher levels of broadband emissions occurred during the boiling histotripsy insonation. These unique features in the emitted acoustic signals were consistent with the experimental measurements. These features can, therefore, be used to monitor (a) the different types of acoustic cavitation activity for either a thermal ablation or a mechanical fractionation process and (b) the onset of the formation of a boiling bubble at the focus in the course of HIFU exposure.

Nakagami-m parametric imaging for characterization of thermal coagulation and cavitation erosion induced by HIFU

Nowadays, both thermal and mechanical ablation techniques of HIFU associated with cavitation have been developed for noninvasive treatment. A specific challenge for the successful clinical implementation of HIFU is to achieve real-time imaging for the evaluation and determination of therapy outcomes such as necrosis or homogenization. Ultrasound Nakagami-m parametric imaging highlights the degrading shadowing effects of bubbles and can be used for tissue characterization. The aim of this study is to investigate the performance of Nakagami-m parametric imaging for evaluating and differentiating thermal coagulation and cavitation erosion induced by HIFU. Lesions were induced in basic bovine serum albumin (BSA) phantoms and ex vivo porcine livers using a 1.6 MHz single-element transducer. Thermal and mechanical lesions induced by two types of HIFU sequences respectively were evaluated using Nakagami-m parametric imaging and ultrasound B-mode imaging. The lesion sizes estimated using Nakagami-m parametric imaging technique were all closer to the actual sizes than those of B-mode imaging. The p-value obtained from the t-test between the mean m values of thermal coagulation and cavitation erosion was smaller than 0.05, demonstrating that the m values of thermal lesions were significantly different from that of mechanical lesions, which was confirmed by ex vivo experiments and histologic examination showed that different changes result from HIFU exposure, one of tissue dehydration resulting from the thermal effect, and the other of tissue homogenate resulting from mechanical effect. This study demonstrated that Nakagami-m parametric imaging is a potential real-time imaging technique for evaluating and differentiating thermal coagulation and cavitation erosion.

Effects of Subatmospheric Pressure and Dissolved Oxygen Content on Lesions in Ex Vivo Bovine Livers Induced by High Intensity Focused Ultrasound

This study was aim at investigating the effects of subatmospheric pressure and dissolved oxygen content(DOC) on cavitation in tissue. This experiment put ex vivo bovine liver tissues which were degassed for 60 minutes into three different DOC degassed water, 1.0 mg/L, 1.5 mg/L and 2.0 mg/L, respectively. 1 MHz US with Isp equal to 11700 W/cm2 was used to exposure the degassed bovine livers under two ambient hydrostatic pressure(Pstat), atmospheric pressure(Pstat=1 bar) and subatmospheric pressure(Pstat=0.1 bar), with exposure time of 2 s, exposure depth of 2 cm. The hyperecho in focus before and after HIFU exposure were monitored by B mode ultrasound. The acoustic cavitaion signal was detected by passive cavitation detector (PCD) during the process of exposure. The results showed that the broadband noise under atmospheric pressure were all higher than that under subatmospheric pressure when keep DOC the same. Under atmospheric pressure, evident signals of broadband noise were appeared during HIFU exposure under three DOC condition, meanwhile the hyperecho was found in focus after exposing. Moreover, the intensity of broadband noise signal increased with the increase of DOC. Under subatmospheric pressure, cavitation just occurred under DOC of 2.0 mg/L, and only under DOC of 1.0 mg/L did not found hyperehco in focus. Results also demonstrated that lesions induced by HIFU increased with DOC under two Pstat, but the volume of lesions under atmospheric pressure were all larger than that under subatmospheric pressure when keep DOC the same. 1. The volume of lesion decrease with the decrease of DOC when keep Pstat constant. 2. Subatmospheric pressure would suppress cavitation in biological tissue during HIFU exposure. 3. The homogeneity of lesions in tissue was changed by cavitation.

High intensity focused ultrasound enhances anti-tumor immunity by inhibiting the negative regulatory effect of miR-134 on CD86 in a murine melanoma model

HIFU has been demonstrated to enhance anti-tumor immunity, however, the mechanism of which has not been well elucidated. Emerging evidence indicates that miRNAs play important roles in immune response. In this study, we used the B16F10 melanoma allograft mouse model to investigate the role of miRNAs in HIFU-enhanced anti-tumor immunity. We found that HIFU treatment decreased circulating B16F10 cells and pulmonary metastasis nodules while increased IFN-γ and TNF-α in the peripheral blood and cumulative mouse survival, which was associated with inhibition of miR-134 expression and activation of CD86 expression in tumor tissues. Further, we determined that miR-134 directly binds to the 3'UTR of CD86 mRNA to suppress its expression in B16F10 cells. When B16F10 cells transfected with miR-134 were co-cultured with normal splenic lymphocytes, the secretion of IFN-γ and TNF-α from lymphocytes was reduced and B16F10 cell survival was increased. HIFU exposure efficiently decreased miR-134 while increased CD86 expression in B16F10 cells in vitro. CD86 knockdown with siRNA markedly rescued the viability of HIFU-treated B16F10 cells that co-cultured with lymphocytes. Altogether, our results suggest that HIFU down-regulates miR-134 to release the inhibition of miR-134 on CD86 in melanoma cells, thereby enhancing anti-tumor immune response.

Dual echo gradient echo imaging for simultaneous thermal mapping in cortical bone and soft tissue

MRI-guided high-intensity focused ultrasound (MR-HIFU) therapy can relieve pain associated with metastatic and benign bone tumours in patients who fail to respond to conventional radiation therapy. However, since existing MR-thermometry techniques do not provide temperature information within the bone, HIFU exposures in bone are currently monitored using temperature changes in adjacent soft tissues. In this study, a standard dual echo spoiled gradient echo (SPGR) sequence is proposed to monitor thermal effects in both bone and soft tissue simultaneously. Magnitude signal changes at the shorter TE (~1ms) reflect thermal changes in cortical bone, while phase changes at the longer TE (~10ms) allow conventional PRF thermometry in surrounding tissues.

An instrumented bone/soft tissue phantom designed to mimic HIFU treatments of bone

Clinically, HIFU exposures of bone are used to palliate pain from primary or secondary bone tumours. Such tumours weaken bone structure and render the patient susceptible to bone fracture. Ultrasound metrology for bone exposures is extremely challenging. The ultrasound beam is strongly reflected at the bone surface, with rapid surface absorption of sound entering the cortex. Pain relief is obtained when the HIFU induced temperature increase ablates the peri-osteal nerves. Standard PRF based MR thermometry, used for treatment monitoring, is inappropriate for bone. Thus, a method of determining the temperature distribution in a clinical environment is needed.

Ultrasound-induced fractionation of the intervertebral disk

Current surgical treatments for lower back pain, which is strongly associated with degeneration of the intervertebral disk, are highly invasive and have low long-term success rates. The present work thus aims to develop a novel, minimally invasive therapy for disk replacement without the need for surgical incision. Using ex vivo bovine coccygeal spinal segments as an experimental model, two confocally aligned 0.5 MHz HIFU transducers were positioned with their focus inside the disc and used to generate peak rarefactional pressures in the range of 1–12 MPa. Cavitation activity was monitored, characterized, and localized in real time using both a single-element passive cavitation detector and a 2D Passive Acoustic Mapping array. The inertial cavitation threshold in the central portion of the disk, the nucleus pulposus (NP), was first determined both in the absence and in the presence of externally injected cavitation nuclei. HIFU exposure parameters were subsequently optimized to maximize sustained inertial cavitation over 10 min and achieve fractionation of the NP. Following sectioning of treated disks, staining of live and dead cells as well as microscopy under polarized light were used to assess the impact of the treatment on cell viability and collagen structure within the NP, inner annulus and outer annulus.

Passive Cavitation Detection during Pulsed HIFU Exposures of Ex Vivo Tissues and In Vivo Mouse Pancreatic Tumors

Pulsed high-intensity focused ultrasound (pHIFU) has been shown to enhance vascular permeability, disrupt tumor barriers and enhance drug penetration into tumor tissue through acoustic cavitation. Monitoring of cavitation activity during pHIFU treatments and knowing the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue are therefore very important. Here, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitation detection were introduced: cavitation probability, cavitation persistence and the level of the broadband acoustic emissions. These metrics were used to characterize cavitation activity in several ex vivo tissue types (bovine tongue and liver and porcine adipose tissue and kidney) and gel phantoms (polyacrylamide and agarose) at varying peak-rare factional focal pressures (1–12 MPa) during the following pHIFU protocol: frequency 1.1 MHz, pulse duration 1 ms and pulse repetition frequency 1 Hz. To evaluate the relevance of the measurements in ex vivo tissue, cavitation metrics were also investigated and compared in the ex vivo and in vivo murine pancreatic tumors that develop spontaneously in transgenic KrasLSL.G12 D/+; p53 R172 H/+; PdxCretg/+ (KPC) mice and closely re-capitulate human disease in their morphology. The cavitation threshold, defined at 50% cavitation probability, was found to vary broadly among the investigated tissues (within 2.5–10 MPa), depending mostly on the water-lipid ratio that characterizes the tissue composition. Cavitation persistence and the intensity of broadband emissions depended both on tissue structure and lipid concentration. Both the cavitation threshold and broadband noise emission level were similar between ex vivo and in vivo pancreatic tumor tissue. The largest difference between in vivo and ex vivo settings was found in the pattern of cavitation occurrence throughout pHIFU exposure: it was sporadic in vivo, but it decreased rapidly and stopped over the first few pulses ex vivo. Cavitation activity depended on the interplay between the destruction and circulation of cavitation nuclei, which are not only used up by HIFU treatment but also replenished or carried away by circulation in vivo. These findings are important for treatment planning and optimization in pHIFU-induced drug delivery, in particular for pancreatic tumors.

Non-invasive estimation of temperature using diagnostic ultrasound during high intensity focused ultrasound therapy

The use of HIFU for thermal ablation of human tissues requires safe real-time monitoring of the lesion formation during the treatment to avoid damage of the surrounding healthy tissues and to control temperature rise. Besides MR imaging, several methods have been proposed for temperature imaging using diagnostic ultrasound, and echoshift estimation (using speckle tracking) is the most promising technique. It is based on the thermal dependence of the ultrasound echo that accounts for two different physical phenomena: local change in speed of sound and thermal expansion of the propagating medium due to changes in temperature. In our experiments we have used two separate transducers: HIFU exposure was performed using a 1.06 MHz single element focusing transducer of 64 mm aperture and 63.2mm focal length; the ultrasound diagnostic probe of 11 MHz operated in B-mode for image guidance. The temperature measurements were performed in an agar-based tissue-mimicking phantom complying with the specification given in IEC60601-2-5. To verify the obtained results, the numerical modeling of the acoustic and temperature fields was carried out using KZK and Pennes Bioheat equations. The comparison of the results simulated and measured, as well as measured with thermocouples, shows a rather good coincidence.

Twinkling artifact of Doppler imaging for cavitation detection during high-intensity focused ultrasound therapy: Sensitivity and resolution

The mechanism of the twinkling artifact (TA) during Doppler imaging of kidney stones is well-known and is hypothesized to stem from the irregular scattering of Doppler ensemble pulses from fluctuating microbubbles trapped in crevices of the kidney stone. We have previously demonstrated that the TA can be used to detect and image microbubbles in soft tissue during pulsed HIFU treatment. In this work, the characteristics of the method—the sensitivity to small bubbles and the spatial resolution—were investigated experimentally and compared to other passive and active cavitation imaging methods such as pulse inversion. An approach was proposed for quantification of the cavitation images provided by the method, and the resulting metric was compared to the inertial cavitation dose. The experiments were performed using pulsed 1-MHz HIFU exposures of transparent gel phantoms, ex vivo tissue and in vivo mouse model of pancreatic cancer. [Work supported by RFBR and NIH (EB007643, 1K01EB015745, and R01CA154451).]

Imaging and monitoring non‐cavitating focused ultrasound lesions using light and sound.

Acoustically imaging non‐cavitating HIFU lesions is challenging due to the relatively weak contrast between normal and necrosed tissues. However, thermal lesions posses optical scattering and absorption characteristics that can differ significantly from surrounding tissue. Acousto‐optic (AO) sensing refers to the detection of phase modulated photons generated by the nonlinear interaction of diffuse laser light (532 and 1064 nm) and a focused ultrasound beam. AO sensing in excised chicken breast exposed to HIFU (1.1 MHz) is used to sense the onset and spatial extent of lesion formation in real time and to image an existing lesion after HIFU exposure. We also demonstrate that the AO signal can be used to provide real‐time feedback in order to more effectively control the duration of the HIFU exposure. [Work supported by the Center for Subsurface Sensing and Imaging Systems (NSF ERC Award No. EEC‐9986821).]

Abstract 3981: Characterization of high intensity focused Ultrasound induced vascular damage using histology, MR, and Ultrasound Imaging

Abstract Background High intensity focused ultrasound (HIFU) has considerable clinical potential for noninvasive ablation of solid tumors. HIFU is based on tightly focusing high energy ultrasound at a target, causing a lethal temperature rise which induces thermal coagulative necrosis. Studies have shown that HIFU can also be used for induction of vascular occlusion. Selective occlusion of tumor feeder vessels in conjunction with anti-angiogenic drugs may be a way of treating cancer either by de-bulking a tumor prior to surgery or as a palliative growth retardation therapy. The aim of this work was to characterize the vascular disruption caused by HIFU exposure, including the evolution of any changes, using Magnetic Resonance Imaging (MRI), Ultrasound (US) Imaging and histology. Methods An in-vivo rat liver model was used and four HIFU exposures each at one of 3 different free-field spatial peak intensities (1106 ± 91 W/cm2 for 10s; 1751 ± 119 W/cm2 for 6s; or 2753 ± 192 W/cm2 for 4s) were placed in a row at 4-6 mm separation. Livers (n=4 per time point) were harvested for histology (paraffin based) at 0, 1.5, 3, 6, 12, 24, 48 hrs, 3 and 7 days. Stains used included Haematoxylin and Eosin (H&E), Picrosirius Millers (collagen and Elastin), cleaved Caspase 3 (apoptosis), CD68 (macrophages), Hif1 alpha (hypoxia), Ki67 (proliferation), thrombin and Factor XIIIa (clotting). Some animals were injected with Hoechst (perfusion indicator) and Pimanidazole (hypoxia probe) and the liver was frozen for histological assessment. Some of the animals underwent MRI (7 T) and targeted (VEGF) contrast agent imaging with a high resolution US system (Visual Sonics) to obtain quantitative vessel size and perfusion data. Finally additional three-dimensional quantitative information from vascular casting will be described Results and Conclusions Hoechst data acquired immediately after HIFU showed a lack of perfusion within, and downstream of, the exposed regions. This demonstrated that vessels were occluded. Although H&E images obtained immediately after HIFU showed no distinct cellular changes in the non-ablated unperfused regions, from 6 hours onwards changes indicative of ischemic damage were apparent, confirming vascular occlusion. Apoptosis was also evident in these regions. A band of macrophages observed as early as 1.5 hrs after occlusion was found to gradually infiltrate the center of ischemic damage. Two days after exposure, Ki67 (proliferation) stain showed no positive staining within regions of ischemic damage. The results of the ongoing imaging studies will be presented. This study concludes that HIFU can be used for vessel occlusion in order to nutrient deprive a region significantly larger than the ablated volume. The perfusion poor region then undergoes controlled cell death and phagocytic activity, suggesting the potential use of this technique to inhibit tumor growth. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3981.