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.     

声通道上的肋骨对高强度聚焦超声在羊肝内形成凝固性坏死的影响

目的从有效性、安全性和剂量学的角度探讨声通道上的肋骨对高强度聚焦超声（HIFU）损伤山羊肝的影响。方法HIFU分别辐照声通道上有肋骨（对照组）和声通道上肋骨被手术切除（实验组）的羊肝。辐照结束后2d处死动物，观察靶区凝固性坏死形成情况，测量凝固性坏死的体积并计算能效因子（energy efficiency factor，EEF）。结果实验组的凝固性坏死形成率明显高于对照组，EEF远远小于对照组。结论声通道上的肋骨明显影响凝固性坏死的形成率和EEF，提高HIFU治疗受肋骨阻挡的肝癌的治疗效率非常重要。     

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.     

Utility of a tumor-mimic model for the evaluation of the accuracy of HIFU treatments. results of in vitro experiments in the liver

Presented in this article is a tumor-mimic model that allows the evaluation, before clinical trials, of the targeting accuracy of a high intensity focused ultrasound (HIFU) device for the treatment of the liver. The tumor-mimic models are made by injecting a warm solution that polymerizes in hepatic tissue and forms a 1 cm discrete lesion that is detectable by ultrasound imaging and gross pathology. First, the acoustical characteristics of the tumor-mimics model were measured in order to determine if this model could be used as a target for the evaluation of the accuracy of HIFU treatments without modifying HIFU lesions in terms of size, shape and homogeneity. On average (n = 10), the attenuation was 0.39 +/- 0.05 dB.cm(-1) at 1 MHz, the ultrasound propagation velocity was 1523 +/- 1 m.s(-1) and the acoustic impedance was 1.84 +/- 0.00 MRayls. Next, the tumor-mimic models were used in vitro in order to verify, at a preclinical stage, that lesions created by HIFU devices guided by ultrasound imaging are properly positioned in tissues. The HIFU device used in this study is a 256-element phased-array toroid transducer working at a frequency of 3 MHz with an integrated ultrasound imaging probe working at a frequency of 7.5 MHz. An initial series of in vitro experiments has shown that there is no significant difference in the dimensions of the HIFU lesions created in the liver with or without tumor-mimic models (p = 0.3049 and p = 0.8796 for the diameter and depth, respectively). A second in vitro study showed that HIFU treatments performed on five tumor-mimics with safety margins of at least 1 mm were properly positioned. The margins obtained were on average 9.3 +/- 2.7 mm (min. 3.0 - max. 20.0 mm). This article presents in vitro evidence that these tumor-mimics are identifiable by ultrasound imaging, they do not modify the geometry of HIFU lesions and, thus, they constitute a viable model of tumor-mimics indicated for HIFU therapy.     

高强度聚焦超声定位损伤小型香猪肝脏组织的影像学检查

目的：观察超声在监测高强度聚焦超声（ＨＩＦＵ）损伤肝组织的动态影像学特征,旨在探讨彩超检测ＨＩＦＵ疗效的可行性。方法：采用重庆医科大学医学超声工程研究所自行研制的ＨＩＦＵ治疗样机（１．６ＭＨｚ,１３１５３Ｗ／ｃｍ２）,对２８只小型香猪肝脏组织致超声损伤。于损伤前１天、损伤后即刻、１天、３天、７天、１４天、２１天、２８天分别行彩超观察及解剖活检。结果：ＨＩＦＵ损伤即刻损伤区回声明显增强,３～７天,损伤区回声仍增强,边界更清晰。７～１４天,回声强弱不均,２８天损伤区与正常组织区无明显差异,这些改变与病理检查相一致。结论：超声在监测ＨＩ－ＦＵ疗效方面有重要的应用价值     

超声造影剂对高强度聚集超声治疗兔肝VX2肿瘤的影响

目的探讨高强度聚焦超声（HIFU）联合超声造影剂治疗兔肝VX2肿瘤时，不同剂量的超声造影剂对治疗效应的影响。方法45只荷瘤兔随机分为三组：A组，单纯HIFU辐照组；B组和C组，均为联合辐照组，超声造影剂剂量分别为0．03ml／kg和0．05ml／kg。结果超声造影剂能够增强HIFU治疗效率，且超声造影剂的剂量越高，HIFU治疗效率提高越明显（P〈0．05）。结论超声造影剂可以提高HIFU治疗效率，而且超声造影剂剂量越高则HIFU的治疗效率越高。     

Treatment of rabbit liver cancer in vivo using miniaturized image-ablate ultrasound arrays

In the preclinical studies reported here, VX2 cancer within rabbit liver has been treated by bulk ultrasound ablation employing miniaturized image-ablate arrays. Array probes were constructed with 32 elements in a 2.3 × 20 mm² aperture, packaged within a 3.1 mm stainless steel tube with a cooling and coupling balloon for in vivo use. The probes were measured capable of 50% fractional bandwidth for pulse-echo imaging (center frequency 4.4 MHz) with >110 W/cm² surface intensity available at sonication frequencies 3.5 and 4.8 MHz. B-scan imaging performance of the arrays was measured to be comparable to larger diagnostic linear arrays, although nearfield image quality was reduced by ringdown artifacts. A series of in vivo ablation procedures was performed using an unfocused 32-element aperture firing at 4.8 MHz with exposure durations 20–70.5 s and in situ spatial average, temporal average intensities 22.4–38.5 W/cm². Ablation of a complete tumor cross-section was confirmed by vital staining in seven of 12 exposures, with four exposures ablating an additional margin >1 mm beyond the tumor in all directions. Analysis suggests a threshold ablation effect, with complete ablation of tumor cross-sections for exposures with delivery of >838 J acoustic energy. The results show feasibility for in vivo liver cancer ablation using miniaturized image-ablate arrays suitable for interstitial deployment.     

高强度聚焦超声破坏深部组织超声图像变化

为阐明高强度聚焦超声(HIFU)对体内肝组织的生物学效应,本研究用超声图像定量分析方法观察小型香猪肝脏受损组织的形态学变化.用超声定位的HIFU体外断层切除肝脏靶区.并用定量分析系统检测靶区,发现HIFU治疗前后超声图像有明显差异.结果提示:超声图像定量分析可用于监测HIFU治疗后受损组织的形态学变化.     

Echo Decorrelation Imaging of Rabbit Liver and VX2 Tumor during In Vivo Ultrasound Ablation

In open surgical procedures, image-ablate ultrasound arrays performed thermal ablation and imaging on rabbit liver lobes with implanted VX2 tumor. Treatments included unfocused (bulk ultrasound ablation, N = 10) and focused (high-intensity focused ultrasound ablation, N = 13) exposure conditions. Echo decorrelation and integrated backscatter images were formed from pulse-echo data recorded during rest periods after each therapy pulse. Echo decorrelation images were corrected for artifacts using decorrelation measured prior to ablation. Ablation prediction performance was assessed using receiver operating characteristic curves. Results revealed significantly increased echo decorrelation and integrated backscatter in both ablated liver and ablated tumor relative to unablated tissue, with larger differences observed in liver than in tumor. For receiver operating characteristic curves computed from all ablation exposures, both echo decorrelation and integrated backscatter predicted liver and tumor ablation with statistically significant success, and echo decorrelation was significantly better as a predictor of liver ablation. These results indicate echo decorrelation imaging is a successful predictor of local thermal ablation in both normal liver and tumor tissue, with potential for real-time therapy monitoring.     

Characterization of extracorporeal ablation of normal and tumor-bearing liver tissue by high intensity focused ultrasound

Treatment parameters of extracorporeal high intensity focused ultrasound (HIFU) were analysed in normal and tumor-bearing rabbit liver. HIFU was generated with a 1 MHz transducer and energy was provided by a 7.5 kW power amplifier. In vivo experiments were conducted on 74 New Zealand rabbits. Normal rabbits and rabbits bearing an intrahepatic VX2 tumor were used. In group 1, spatial peak temporal peak (SPTP) intensities ranging from 1470 to 5500 W cm⁻² and exposure times from 0.5 to 5 s were tested at a constant depth in the liver; in group 2, the output power was adjusted as a function of the target depth in order to keep constant the focal in situ intensity in the liver; in group 3 (liver tumors), the focal in situ intensity was 1365 W cm⁻² in eight rabbits and 500 W cm⁻² in nine. In groups 1, 2 and 3, rabbits were sacrificed 48 h after the treatment. Groups 4 and 5 were designated for analysis of the lesion in the normal liver 4 weeks after treatment at 1000 W cm⁻² and 3000 W cm⁻² SPTP intensities, respectively. In normal rabbits, the lesion volume increased with exposure time at constant intensity; there was a negative correlation between intensity and exposure time (group 1). When the output power was adjusted as a function of the path length, the lesion size was nearly constant (group 2). In VX2 rabbits, tumor destruction rates were significantly higher in rabbits treated at 500 W cm⁻² than in rabbits treated at 1365 W cm⁻² (p < 0.05; group 3). As in the normal liver, the lesion volume increased with the exposure time at constant intensity. HIFU lesions treated at 1000 W cm⁻² (SPTP) healed as thin fibrous scars, and no severe complication occurred (group 4); at 3000 W cm⁻² (SPTP), scars were larger and perforation of a neighboring organ was seen in 7 of 11 rabbits (group 5).     

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.     

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.     

高能聚焦超声治疗兔VX2肝癌后磁共振灌注加权成像特征初探

目的：探讨兔VX2肝癌经高能聚焦超声（HIFU）治疗后的磁共振灌注加权成像（PWI）的基本成像特点。方法：新西兰大白兔20只,采用组织块种植的方法制成20只兔VX2肝癌模型,使用1.5T MR扫描仪行常规扫描后,采用EPI-SE序列、SENSE技术,于治疗前、后14d对肿瘤行PWI,选取病灶与周围正常肝组织的感兴趣区（ROI）,分别测量血流灌注值,进行统计学分析。PWI采用信号强度-时间曲线的最大信号下降斜率（SRSmax）作为定量指标,分析不同ROI的SRSmax变化规律。结果：治疗前、后兔肝VX2瘤中央区及周边区之间的SRSmax的差异有统计学意义（P＜0.05）;瘤旁肝实质之间的SRSmax的差异无统计学意义（P＞0.05）。结论：利用1.5T MR扫描仪进行兔肝VX2瘤灌注成像研究是可行的,PWI可用于评价HIFU治疗后肝脏肿瘤的血管生成、破坏状况;不同ROI的SRSmax变化程度及规律也不同,其PWI表现与肿瘤的坏死程度、范围基本相符。     

自制脂膜氟烷超声造影剂对实验性肾肿瘤显影效果的研究

目的　探讨自制脂膜氟烷超声造影剂“脂氟显”对兔肾VX2 肿瘤的显影效果。方法　对 16只肾肿瘤模型经兔耳缘静脉团注“脂氟显”0 .0 2ml/kg进行超声造影 ,并与增强CT、病理对照研究。结果　 16只兔肾病理检查共有5 1个肿瘤 ,超声造影后检出 46个 ,检出率 90 .1% ,增强螺旋CT检出 45个 ,检出率 88.2 %。超声造影和增强CT对模型兔肾肿瘤的检出率无统计学差异 (P >0 .0 5 ) ,两者漏诊的肿瘤直径均小于 0 .3 2cm。造影前超声假阳性 5个 ,假阳性率13 .8% ,CT平扫无假阳性。结论　超声造影剂“脂氟显”能有效增强兔肾肿瘤的显像 ,提高肾脏肿瘤的检出率和特异性 ,其诊断价值与增强螺旋CT相当     

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.     

高功率聚焦超声高温破坏肝肿瘤的影像学检测

本文报告彩超、ＣＴ和ＭＲＩ观察高功率聚焦超声（ＨＩＦＵ）破坏兔肝肿瘤前、后影像特征变化，旨在探讨这三种影像学技术检测ＨＩＦＵ疗效的可行性。１０只兔肝肿瘤模型由肝内注射Ｆｒｅｕｎｄ完全佐剂，一周后形成炎性假瘤结节制成。ＨＩＦＵ治疗参数采用频率１．１ＭＨｚ，功率５００Ｗ／ｃｍ２，连续超声波照射时间２０秒。结果显示：彩超能有效检测ＨＩＦＵ破坏肝肿瘤疗效。经ＨＩＦＵ照射后，表现为强回声病灶变为低回声，且Ｄｏｐｐｌｅｒ血流消失，２４ｈ后病灶边缘出现强回声带。这些特征性变化与病理改变相一致。而ＣＴ和ＭＲＩ在本实验中未能检测到ＨＩＦＵ破坏肿瘤的特征性改变     

Dual-Focus Therapeutic Ultrasound Transducer for Production of Broad Tissue Lesions

In noninvasive high-intensity focused ultrasound (HIFU) treatment, formation of a large tissue lesion per sonication is desirable for reducing the overall treatment time. The goal of this study is to show the feasibility of enlarging tissue lesion size with a dual-focus therapeutic ultrasound transducer (DFTUT) by increasing the depth-of-focus (DOF). The proposed transducer consists of a disc- and an annular-type element of different radii of curvatures to produce two focal zones. To increase focal depth and to maintain uniform beamwidth of the elongated DOF, each element transmits ultrasound of a different center frequency: the inner element at a higher frequency for near field focusing and the outer element at a lower frequency for far field focusing. By activating two elements at the same time with a single transmitter capable of generating a dual-frequency mixed signal, the overall DOF of the proposed transducer may be extended considerably. A prototype transducer composed of a 4.1 MHz inner element and a 2.7 MHz outer element was fabricated to obtain preliminary experimental results. The feasibility the proposed technique was demonstrated through sound field, temperature and thermal dose simulations. The performance of the prototype transducer was verified by hydrophone measurements and tissue ablation experiments on a beef liver specimen. When several factors affecting the length and the uniformity of elongated DOF of the DFTUT are optimized, the proposed therapeutic ultrasound transducer design may increase the size of ablated tissues in the axial direction and, thus, decreasing the treatment time for a large volume of malignant tissues especially deep-seated targets. (E-mail: jongsjeo@usc.edu)     

The role of contrast-enhanced sonography for radiofrequency ablation of liver tumors.

OBJECTIVE: To assess the feasibility and usefulness of contrast-enhanced sonography for tumor detection and guidance of liver VX2 tumor ablation and to evaluate post radiofrequency ablation effectiveness. METHODS: VX2 tumors were implanted into the livers of 6 rabbits. Both conventional and harmonic gray scale and power Doppler imaging were performed with a commercially available scanner to evaluate the liver tumors before and after intravenous injection of a sonographic contrast agent before and after radiofrequency ablation. Contrast-enhanced imaging was used to detect the tumors before ablation, to guide needle insertion, and to measure the ablation sites after radiofrequency ablation. Pathologic examination was performed for comparison. RESULTS: Three tumors were seen without contrast enhancement, whereas 10 tumors (<1 cm) were detected with contrast enhancement. Intentionally, 2 tumors were completely ablated and 5 tumors were partially ablated. In 3 cases, incompletely ablated tumors could only be identified on contrast-enhanced Doppler imaging by enhancing the detection of residual tumor vascularity. There was excellent concordance between sonographic imaging and gross pathologic findings. CONCLUSIONS: Contrast-enhanced sonographic imaging appears useful for detection of liver tumors and for guiding and monitoring tumor ablation therapies.     

Safety and Efficacy of Ultrasound-Guided High-Intensity Focused Ultrasound Treatment for Uterine Fibroids and Adenomyosis

The objective of this study was to assess the tolerability and efficacy of ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation using a Haifu JC Focused Ultrasound Tumor Therapeutic System (operating transducer frequency: 0.8 MHz, 300–400 W/cm²) under real-time ultrasound guidance (2.5- to 5.0-MHz imaging probe) for uterine fibroids and adenomyosis in 1807 patients (928 with fibroids and 889 with adenomyosis). Volume change and clinical symptom improvement after treatment were evaluated based on symptom severity scores and health-related quality of life scores using the Uterine Fibroid Symptom and Quality of Life questionnaires. At 3, 6 and 12 mo after treatment, symptom severity scores and health-related quality of life scores and reductions in volumes of uterine adenomyosis and fibroids all revealed good effects. The complication rate was 4.6% (84/1807). With supportive care, all complications resolved without any permanent adverse effects. Thus, USgHIFU is an effective, non-invasive modality for treating uterine fibroids and adenomyosis with manageable complications.     

高强度聚焦超声治疗恶性骨肿瘤的实验研究

目的 探讨高强度聚焦超声（HIFU）治疗恶性骨肿瘤的可行性。方法 12只VX2移植性骨肿瘤兔接受HIFU治疗,采用超声检查、组织病理学方法观察HIFU治疗后移植性骨肿瘤的变化。结果 HIFU治疗后骨内、外肿瘤组织的回声增强,肿瘤组织凝固性坏死。结论 HIFU治疗兔移植性VX2骨肿瘤是可行的。