Real-Time Monitoring of High-Intensity Focused Ultrasound Thermal Therapy Using the Manifold Learning Method

High-intensity focused ultrasound (HIFU) induces thermal lesions by increasing the tissue temperature in a tight focal region. The main ultrasound imaging techniques currently used to monitor HIFU treatment are standard pulse-echo B-mode ultrasound imaging, ultrasound temperature estimation and elastography-based methods. The present study was carried out on ex vivo animal tissue samples, in which backscattered radiofrequency (RF) signals were acquired in real time at time instances before, during and after HIFU treatment. The manifold learning algorithm, a non-linear dimensionality reduction method, was applied to RF signals which construct B-mode images to detect the HIFU-induced changes among the image frames obtained during HIFU treatment. In this approach, the embedded non-linear information in the region of interest of sequential images is represented in a 2-D manifold with the Isomap algorithm, and each image is depicted as a point on the reconstructed manifold. Four distinct regions are chosen in the manifold corresponding to the four phases of HIFU treatment (before HIFU treatment, during HIFU treatment, immediately after HIFU treatment and 10-min after HIFU treatment). It was found that disorganization of the points is achieved by increasing the acoustic power, and if the thermal lesion has been formed, the regions of points related to pre- and post-HIFU significantly differ. Moreover, the manifold embedding was repeated on 2-D moving windows in RF data envelopes related to pre- and post-HIFU exposure data frames. It was concluded that if mean values of the points related to pre- and post-exposure frames in the reconstructed manifold are estimated, and if the Euclidean distance between these two mean values is calculated and the sliding window is moved and this procedure is repeated for the whole image, a new image based on the Euclidean distance can be formed in which the HIFU thermal lesion is detectable.     

Calibration of Ultrasound Backscatter Temperature Imaging for High-Intensity Focused Ultrasound Treatment Planning

High-intensity focused ultrasound (HIFU) is rapidly gaining acceptance as a non-invasive method for soft tissue tumor ablation, but improvements in the methods of treatment delivery, planning and monitoring are still required. Backscatter temperature imaging (BTI) uses ultrasound to visualize heating-induced echo strain and may be used to indicate the position of the HIFU focal region using low-power “sub-lesioning” exposure. The technique may also provide a quantitative tool for assessing the efficacy of treatment delivery if apparent strain measurements can be related to the underlying temperature rise. To obtain temperature estimates from strain measurements, the relationship between these variables has to be either measured or otherwise assumed from previous calibrations in similar tissues. This article describes experimental measurements aimed at deriving the relationship between temperature rise and apparent strain in the laboratory environment using both ex vivo bovine liver tissue samples and normothermically perfused porcine livers. A BTI algorithm was applied to radiofrequency ultrasound echo data acquired from a clinical ultrasound scanner (Z.One, Zonare Medical Systems, Mountain View, CA, USA) where the imaging probe was aligned with the focal region of a HIFU transducer. Temperature measurements were obtained using needle thermocouples implanted in the liver tissue. A series of “non-ablative” HIFU exposures giving peak temperatures below 10°C were made in three separate ex vivo bovine livers, yielding an average strain/temperature coefficient of 0.126 ± 0.088 percentage strain per degree Celsius. In the perfused porcine livers at a starting temperature of 38°C (normal body temperature) the strain/temperature coefficients were found to be 0.040 ± 0.029 percentage strain per degree Celsius. The uncertainty in these results is directly linked to the precision of the strain measurement, as well as the naturally occurring variance between different tissue samples, indicating that BTI may lack the accuracy required to be implemented successfully in practice as a quantitative treatment planning technique at a sub-lesioning exposure level. This is because, to be of use in treatment planning, temperature-rise estimates may require an accuracy greater (<10%) than that offered by BTI measurement. BTI may, however, still play a role in ensuring the correct positioning of the focal region and as a treatment monitoring modality capable of detecting an increased rate of heating in tissue after HIFU ablation.     

Non-invasive Magnetic Resonance Imaging Follow-up of Sono-sensitive Liposome Tumor Delivery and Controlled Release After High-Intensity Focused Ultrasound

This work examines the use of lanthanide-based contrast agents and magnetic resonance imaging in monitoring liposomal behavior in vivo. Dysprosium (Dy) and gadolinium (Gd) chelates, Dy-diethylenetriaminepentaacetic acid bismethylamide (Dy-DTPA-BMA) and Gd-DTPA-BMA, were encapsulated in pegylated distearoylphosphatidylethanolamine-based (saturated) liposomes, and then intravenously injected into Copenhagen rats with subcutaneous Dunning AT2 xenografts. Liposome-encapsulated Dy chelate shortens transverse relaxation times (T₂ and T₂*) of tissue; thus, liposomal accumulation in the tumor can be monitored by observing the decrease in T₂* relaxation time over time. The tumor was treated at the time of maximum liposomal accumulation (48 h) with confocal, cavitating high-intensity focused ultrasound to induce liposomal payload release. Using liposome-encapsulated Gd chelate at high enough concentrations and saturated liposomal phospholipids induces an exchange-limited longitudinal (T₁) relaxation when the liposomes are intact; when the liposomes are released, exchange limitation is relieved, thus allowing in vivo observation of payload release as a decrease in tumor T₁.     

Real-Time Spatiotemporal Control of High-Intensity Focused Ultrasound Thermal Ablation Using Echo Decorrelation Imaging in ex Vivo Bovine Liver

The ability to control high-intensity focused ultrasound (HIFU) thermal ablation using echo decorrelation imaging feedback was evaluated in ex vivo bovine liver. Sonications were automatically ceased when the minimum cumulative echo decorrelation within the region of interest exceeded an ablation control threshold, determined from preliminary experiments as ?2.7 (log-scaled decorrelation per millisecond), corresponding to 90% specificity for local ablation prediction. Controlled HIFU thermal ablation experiments were compared with uncontrolled experiments employing two, five or nine sonication cycles. Means and standard errors of the lesion width, area and depth, as well as receiver operating characteristic curves testing ablation prediction performance, were computed for each group. Controlled trials exhibited significantly smaller average lesion area, width and treatment time than five-cycle or nine-cycle uncontrolled trials and also had significantly greater prediction capability than two-cycle uncontrolled trials. These results suggest echo decorrelation imaging is an effective approach to real-time HIFU ablation control.     

Multiple-Exposure Drug Release from Stable Nanodroplets by High-Intensity Focused Ultrasound for a Potential Degenerative Disc Disease Treatment

The combination of simvastatin and CF680 dye encapsulated by stable nanodroplets has been developed as a drug delivery carrier. Simvastatin has previously been found to be a potential degenerative disc disease treatment. Multiple exposures of the nanodroplets to high-intensity focused ultrasound induced release of simvastatin. Each ultrasound exposure yielded a consistent concentration of the drug and dye released. B-mode ultrasound image analysis data and cavitation data clearly indicated the release mechanism is phase transition of the liquid nanodroplets into gas bubbles. The nanodroplets were stably stored in ex vivo rabbit spinal discs for at least 14 days, and the contents responded to ultrasound exposure on demand. Lastly, nucleus pulposus cells harvested from rabbit spine discs and exposed to media with nanodroplets exhibited a decrease in cell viability (85%) relative to the cells only (96.7%) at 24 h, but no difference at 48 h. Thus, the system may be a potential degenerative disc disease treatment.     

Experimental Studies and Clinical Experiences on Treatment of Secondary Hypersplenism with Extracorporeal High-Intensity Focused Ultrasound

The aim of this study is to investigate the efficacy and safety of extracorporeal high-intensity focused ultrasound (HIFU) in treatment of hypersplenism. Fifteen adult dogs, weighing 13–18 kg were divided into three groups: sham group, SVL group undergoing splenic vein ligation (SVL) after laparotomy, and SVL + HIFU group receiving SVL followed by extracorporeal HIFU. Pathologic and hematologic analyses were performed. We also reviewed the clinical data of 19 patients with secondary hypersplenism caused by liver cirrhosis or hepatocellular carcinoma who underwent extracorporeal HIFU. Extracorporeal HIFU significantly diminished the volume of the spleen of animals, coupled with occurrence of coagulation necrosis and fibrosis in the target area. Both platelet and red blood cell counts were significantly restored by HIFU intervention. Similarly, HIFU treatment improved the hematologic parameters in patients with hypersplenism, and no major complications were encountered. Extracorporeal HIFU intervention is effective and safe in managing secondary hypersplenism.     

Synergistic Ablation of Liver Tissue and Liver Cancer Cells with High-Intensity Focused Ultrasound and Ethanol

We investigated the combined effect of ethanol and high-intensity focused ultrasound (HIFU), first, on heating and cavitation bubble activity in tissue-mimicking phantoms and porcine liver tissues and, second, on the viability of HepG2 liver cancer cells. Phantoms or porcine tissues were injected with ethanol and then subjected to HIFU at acoustic power ranging from 1.2 to 20.5 W (HIFU levels 1–7). Cavitation events and the temperature around the focal zone were measured with a passive cavitation detector and embedded type K thermocouples, respectively. HepG2 cells were subjected to 4% ethanol solution in growth medium (v/v) just before the cells were exposed to HIFU at 2.7, 8.7 or 12.0 W for 30 s. Cell viability was measured 2, 24 and 72 h post-treatment. The results indicate that ethanol and HIFU have a synergistic effect on liver cancer ablation as manifested by greater temperature rise and lesion volume in liver tissues and reduced viability of liver cancer cells. This effect is likely caused by reduction of the cavitation threshold in the presence of ethanol and the increased rate of ethanol diffusion through the cell membrane caused by HIFU-induced streaming, sonoporation and heating.     

High-Intensity Focused Ultrasound Treatment of Late-Stage Pancreatic Body Carcinoma: Optimal Tumor Depth for Safe Ablation

Objective criteria are currently not available for assessing the extent of ablation by high-intensity focused ultrasound (HIFU). A retrospective review was conducted in Chinese patients with late-stage pancreatic body carcinoma treated with 1 h/d intermittent HIFU at a single center. Clinical and procedure-related characteristics were examined in relation to tumor posterior depth. Clinically, tumor ablation was negatively correlated with posterior tumor depth, with a 1-cm increase in depth decreasing ablation by 30.7%. At a computed tomography (CT)-determined 7-cm posterior tumor depth (considered the critical value for the procedure), ablation sensitivity and specificity were 77.8% and 72.7%, respectively. Tumor ablation >30% in patients with a CT-determined posterior tumor depth ≤7 cm was 9.333 times better than that in patients with a CT-determined posterior tumor depth >7 cm. Adverse effects did not affect the efficacy of HIFU. Tumors with posterior depths <7 cm may effectively be treated with HIFU-induced ablation with minimal adverse events.     

Gel Phantom Study with High-Intensity Focused Ultrasound: Influence of Metallic Stent Containing Either Air or Fluid

We aimed to investigate whether a cylindrical structure containing either air or fluid and with or without a metallic stent affects the volume and density of cavitation produced by high-intensity focused ultrasound via a gel phantom study. Sixteen tissue-mimicking phantoms based on a polyacrylamide gel mixed with bovine serum albumin with a cylindrical hole 1 cm in diameter and 7.5 cm in length were divided into four groups of four phantoms with air in the holes (group 1), four phantoms with fluid in the holes (group 2), four phantoms with air-containing metallic stents (group 3) and four phantoms with fluid-containing metallic stents (group 4). A pulsed high-intensity focused ultrasound beam (50% duty cycle, 40-Hz pulse repetition frequency) at 75 W of acoustic power was directed perpendicularly to the longitudinal axis of the hole, with its focus at the posterior wall of the hole. The size of the cavitation on the x-, y-, and z-axes was measured, and the volumes of cavitation and coagulation were calculated using the formula for the volume of an elliptical cone. The density of cavitation was measured in the tissue phantom anterior to the hole with a 1 × 1-cm square region of interest. For statistical analysis, the Kruskal–Wallis test and Mann–Whitney U-test were used. The phantoms with air-containing holes (groups 1 and 3) developed larger and denser cavitations anterior to the focus, without unnecessary coagulation posterior to the focus, compared with the phantoms with fluid-containing holes (groups 2 and 4), regardless of the presence of stents. All of the axes and volumes of the anterior cavitations were significantly larger than those of the posterior cavitations in groups 1 and 3 (all p-values <0.05). The results of this study might be applied to maximize cavitation to enhance drug delivery into tumors.     

Influence of Skin and Subcutaneous Tissue on High-Intensity Focused Ultrasound Beam: Experimental Quantification and Numerical Modeling

High-intensity focused ultrasound (HIFU) enables the non-invasive thermal ablation of tumors. However, numerical simulations of the treatment remain complex and difficult to validate in clinically relevant situations. In this context, needle hydrophone measurements of the acoustic field downstream of seven rabbit tissue layers comprising skin, subcutaneous fat and muscle were performed in different geometrical configurations. Increasing curvature and thickness of the sample were found to decrease the focusing of the beam: typically, a curvature of 0.05 mm⁻¹ decreased the maximum pressure by 45% and doubled the focal area. A numerical model based on k-Wave Toolbox was found to be in very good agreement with the reported measurements. It was used to extrapolate the effect of the superficial tissues on peak positive and peak negative pressure at focus, which affects both cavitation and target heating. The shape of the interface was found to have a strong influence on the values, and it is therefore an important parameter to monitor or to control in the clinical practice. This also highlights the importance of modeling realistic configurations when designing treatment procedures.     

Effects of Non-Focused Microbubble-Enhanced and High-Intensity Focused Ultrasound on Hemostasis in a Rabbit Model of Liver Trauma

Uncontrolled hemorrhage after trauma to the liver can lead to death. The present study compared the effects of non-focused microbubble-enhanced ultrasound and high-intensity focused ultrasound on hepatic hemostasis in the injured liver. Blood perfusion level, serum liver enzyme levels and the aspartate transaminase/alanine transaminase ratio differed between the two types of treatment (all p values < 0.05). Hepatic cells in the microbubble-enhanced ultrasound group exhibited edema and compressed the hepatic sinus and blood vessels in the portal area. Coagulation and necrosis, inflammatory cell infiltration, and fibrous tissue encapsulation were observed in the high-intensity focused ultrasound group at later stages. The groups also differed in degree of ultrastructural damage and recovery time. Thus, microbubble-enhanced ultrasound has less of an impact on blood reperfusion and surrounding normal tissue than high-intensity focused ultrasound and is a better choice for the treatment of liver trauma.     

Cesarean Scar Pregnancy: Comparing the Efficacy and Tolerability of Treatment with High-Intensity Focused Ultrasound and Uterine Artery Embolization

The aim of this study was to investigate the clinical efficacy of high-intensity focused ultrasound (HIFU) for the treatment of a cesarean scar pregnancy compared with uterine artery embolization (UAE) and intra-arterial methotrexate infusion combined with uterine curettage. In this retrospective cohort study, 31 patients were treated with HIFU (HIFU group), and 45 patients were treated with UAE (UAE group). We compared the treatment and recovery of the patients, including follow-up. After UAE treatment, serum levels of the β subunit of human chorionic gonadotropin declined significantly on the first day, and the residual lesions disappeared in 3–17 wk. One patient underwent hysterectomy; intrauterine adhesions were found by hysteroscopic examination after 6 mo in 2 patients, whose menstrual function did not return to normal. The remainder of the 42 patients recovered normal menstrual functioning during the 3- to 18-wk follow-up. In the patients who underwent HIFU treatment, serum β-HCG levels did not decline rapidly; serum β-HCG levels increased in many patients and then declined to normal steadily within 2–12 wk. Lesions detached in 3–14 wk in all patients, and menstrual functioning was recovered in 3–9 wk without uterine curettage. Compared with the UAE group, the HIFU group had less pain and fewer complications; the patients in the HIFU group were not hospitalized or anesthetized and had lower costs. HIFU is an efficient, tolerable and non-invasive treatment.     

高强度聚焦超声肝脏生物学焦域及超声监控

目的探讨在相同声强作用下,高强度聚焦超声经体外辐照肝脏形成的生物学焦域体积大小与辐照深度和辐照时间的关系.同时探讨超声显像法实时监控生物学焦域的图像变化规律.方法采用重庆医科大学医学超声工程研究所自主研制的JC-A型HIFU肿瘤治疗系统(1MHz,5500W*cm-2),对18只山羊的肝脏组织进行体外定点脉冲辐照,辐照深度为距皮肤3cm和4cm,辐照时间为5s、10s、15s和20s.辐照过程中系列测量靶区超声灰度和强回声区面积的变化.辐照后3～5天处死动物,剖腹观察并测量所形成的肝脏HIFU生物学焦域的体积.结果肝脏经体外HIFU辐照后即刻,靶区内出现明显的回声增强并随观测时间延长而逐渐降低.强回声区面积随辐照时间增加而增大.辐照时间为5s、10s、15s和20s,辐照深度为3cm时,形成的生物学焦域体积分别为(85±28.0)mm3、(274±55.0)mm3、(410±90.0)mm3和(694±131.0)mm3;而辐照深度为4cm时,肝脏HIFU生物学焦域体积则分别为(63±7.0)mm3、(167±25.0)mm3、(273±56.0)mm3和(472±104.0)mm3.结论在相同辐照声强作用下,肝脏HIFU生物学焦域体积随辐照时间的增加而增加,随辐照深度的增加而减小.     

Performance Evaluation of Methods for Two-Dimensional Displacement and Strain Estimation Using Ultrasound Radio Frequency Data

In elastography, several methods for 2-D strain imaging have been introduced, based on both raw frequency (RF) data and speckle-tracking. Although the precision and lesion detectability of axial strain imaging in terms of elastographic signal-to-noise ratio (SNRe) and elastographic contrast-to-noise ratio (CNRe) have been reported extensively, analysis of lateral precision is still lacking. In this paper, the performance of different 2-D correlation RF- and envelope-based strain estimation methods was evaluated using simulation data and phantom experiments. Besides window size and interpolation methods for subsample displacement estimation, the influence of recorrelation techniques was examined. Precision and contrast of the measured displacements and strains were assessed using the difference between modeled and measured displacements, SNRe and CNRe. In general, a 2-D coarse-to-fine displacement estimation method is favored, using envelope data for window sizes exceeding the theoretical upper bound for strain estimation. Using 2-D windows of RF data resulted in better displacement estimates for both the axial and lateral direction than 1-D RF-based or envelope-based techniques. Obtaining subsample lateral displacement estimates by fitting a predefined shape through the cross-correlation function (CCF) yielded results similar to those obtained with up-sampling of RF data in the lateral direction. Using a CCF model was favored because of the decreased computation time. Local aligning and stretching of the windows (recorrelation) resulted in an increase of 2–17 and 6–7 dB in SNRe for axial and lateral strain estimates, respectively, over a range of strains (0.5 to 5.0%). For a simulated inhomogeneous phantom (2.0% applied strain), the measured axial and lateral SNRes were 29.2 and 20.2 dB, whereas the CNRes were 50.2 dB and 31.5 dB, respectively. For the experimental data, lower SNRe (axial: 28.5 dB; lateral: 17.5 dB) and CNRe (axial: 39.3 dB; lateral: 31 dB) were found. In conclusion, a coarse-to-fine approach is favored using RF data on a fine scale. The use of 2D parabolic interpolation is favored to obtain subsample displacement estimates. Recorrelation techniques, such as local aligning and stretching, increase SNRe and CNRe in both directions. (E-mail: r.lopata@cukz.umcn.nl)