A Study of Bubble Activity Generated in Ex Vivo Tissue by High Intensity Focused Ultrasound

Cancer treatment by extracorporeal high-intensity focused ultrasound (HIFU) is constrained by the time required to ablate clinically relevant tumour volumes. Although cavitation may be used to optimize HIFU treatments, its role during lesion formation is ambiguous. Clear differentiation is required between acoustic cavitation (noninertial and inertial) effects and bubble formation arising from two thermally-driven effects (the vapourization of liquid into vapour, and the exsolution of formerly dissolved permanent gas out of the liquid and into gas spaces). This study uses clinically relevant HIFU exposures in degassed water and ex vivo bovine liver to test a suite of cavitation detection techniques that exploit passive and active acoustics, audible emissions and the electrical drive power fluctuations. Exposure regimes for different cavitation activities (none, acoustic cavitation and, for ex vivo tissue only, acoustic cavitation plus thermally-driven gas space formation) were identified both in degassed water and in ex vivo liver using the detectable characteristic acoustic emissions. The detection system proved effective in both degassed water and tissue, but requires optimization for future clinical application. (E-mail: jmclaughlan7@gmail.com)     

Real-time monitoring of high-intensity focused ultrasound lesion formation using acousto-optic sensing

High-intensity focused ultrasound (HIFU) is a promising modality that is used to noninvasively ablate soft tissue tumors. Nevertheless, real-time treatment monitoring with diagnostic ultrasound still poses a significant challenge since tissue necrosis, in the absence of cavitation or boiling, provides little acoustic contrast with normal tissue. In comparison, the optical properties of tissue are significantly altered accompanying lesion formation. A photorefractive crystal-based acousto-optic (AO) sensing system that uses a single HIFU transducer to simultaneously generate tissue necrosis and pump the AO interaction is used to monitor the real-time optical changes associated with thermal lesions induced in chicken breast ex vivo. It is found that the normalized change in AO response increases proportionally with the volume of necrosis. This study demonstrates AO sensing can identify the onset and growth of lesion formation in real time and, when used as feedback to guide exposures, results in more predictable lesion formation. (E-mails: laipuxiang@gmail.com or ronroy@bu.edu)     

Real-time passive acoustic monitoring of HIFU-induced tissue damage

Thermal ablation by high-intensity focused ultrasound (HIFU) shows great promise as a noninvasive cancer therapy. This work proposes a novel method of real-time HIFU treatment monitoring that uses the passively monitored acoustic signal emanating from the focus during HIFU exposure. We performed 212 exposures in seven freshly excised ox livers using 1.067-MHz HIFU at a 95% duty cycle for a range of insonation durations and acoustic intensities. Acoustic emissions were recorded using a 15-MHz passive detector aligned confocally and coaxially with the HIFU transducer. Lesion presence and size were ascertained by slicing the tissue in the transverse and axial focal planes post exposure. Our results demonstrate that successful formation of HIFU lesions in ex vivo ox liver is highly correlated with the presence of pronounced dips in the magnitude of the received signal at integer harmonics of the insonation frequency. A detector based on this observation predicted lesioning with >80% accuracy in regimes that were very likely to create lesions (≥60 J of energy) and had an error rate of <6% for exposures that were too short to cause lesioning (≤1 s long). The overall sensitivity and specificity of the detector were 75.6% and 74.2%, respectively. The proposed detector could therefore provide a low-cost means of effectively monitoring clinical HIFU treatments passively and in real time.     

Tumor vessel destruction resulting from high-intensity focused ultrasound in patients with solid malignancies

The purpose of this study was to explore the sequential imaging and histologic alterations of tumor blood vessels in the patient with solid malignancies after extracorporeal treatment of high-intensity focused ultrasound (HIFU). A total of 164 patients underwent extracorporeal HIFU ablation of malignant solid tumors. After HIFU treatment, enhanced magnetic resonance imaging (MRI), color Doppler ultrasound (US) imaging, dynamic radionuclide scanning, digital subtraction angiography, and histologic study were performed to monitor the response of tumor vessels to HIFU ablation. Compared with tumor images in the patients before HIFU, clinical images showed an abrupt interruption, followed by the cessation of blood flow within the tumor vessels after HIFU treatment. The histologic examination indicated that not only the treated tumor cells showed coagulative necrosis, but also small tumor vessels were severely damaged by the HIFU treatment. The results strongly imply that the damaged tumor vessels might play a critical role in secondary tumor cell death, and then indirectly strengthen the destructive force of focused US beams on tumor tissue. It is concluded that tumor vessel damage can be induced by HIFU, which may be a promising strategy in the treatment of patients with solid malignancies.     

Thermal Fixation of Swine Liver Tissue after Magnetic Resonance-Guided High-Intensity Focused Ultrasound Ablation

The aim of this study was to investigate experimental conditions for efficient and controlled in vivo liver tissue ablation by magnetic resonance (MR)-guided high-intensity focused ultrasound (HIFU) in a swine model, with the ultimate goal of improving clinical treatment outcome. Histological changes were examined both acutely (four animals) and 1 wk after treatment (five animals). Effects of acoustic power and multiple sonication cycles were investigated. There was good correlation between target size and observed ablation size by thermal dose calculation, post-procedural MR imaging and histopathology, when temperature at the focal point was kept below 90°C. Structural histopathology investigations revealed tissue thermal fixation in ablated regions. In the presence of cavitation, mechanical tissue destruction occurred, resulting in an ablation larger than the target. Complete extra-corporeal MR-guided HIFU ablation in the liver is feasible using high acoustic power. Nearby large vessels were preserved, which makes MR-guided HIFU promising for the ablation of liver tumors adjacent to large veins.     

Feasibility of High-Intensity Focused Ultrasound for Hepatocellular Carcinoma after Stereotactic Body Radiation Therapy: Initial Experience

The purpose of this initial clinical observation was to investigate the safety and effect of high-intensity focused ultrasound (HIFU) for patients with hepatocellular carcinoma (HCC) after stereotactic body radiation therapy (SBRT). Twenty patients who had been treated with SBRT, with 24 local residuals, received HIFU ablation. The changes of periphery blood cell count and serum biochemistry were observed before HIFU and 1 week after. Contrast-enhanced magnetic resonance imaging before HIFU and 2 weeks after was performed to assess the effect of HIFU. All patients received follow-up. The mean ± standard deviation follow-up time was 19.3 ± 18.0 mo. The median survival time and 1-y survival rate were 21 mo and 76.2%. Seventeen residual lesions (70.8%) received complete ablation and seven received partial ablation, with a mean ablation ratio of 75.8% ± 18.2%. No significant differences were found in periphery blood cell counts or serum biochemistry 1 week after HIFU compared with before HIFU. No severe adverse reactions related to HIFU were observed. Thus, we believe that HIFU can safely and effectively ablate residual HCC after SBRT, which may be a feasible option for patients with HCC who have local residuals after SBRT.     

Pathological changes in human malignant carcinoma treated with high-intensity focused ultrasound

The purpose of this study was to investigate the pathologic changes of extracorporeal ablation of human malignant tumors with high-intensity focused ultrasound (HIFU). HIFU treatment was performed in the 164 patients with liver cancer, breast cancer, malignant bone tumor, soft tissue sarcoma and other malignant tumors at focal peak intensities from 5000 W x cm(-2) to 20,000 W x cm(-2), with operating frequencies of 0.8 to 3.2 MHz. To explore the pathologic impact of extracorporeal HIFU, 30 patients with malignant carcinoma underwent surgical removal after HIFU treatment. Pathologic findings showed that the treated tissues demonstrated homogeneous coagulative necrosis with an irreversible tumor cell death and severe damage to tumor blood vessels at the level of microsvasculature within the HIFU-targeted region. Thermolesions to intervening tissue were never observed. The treated region had a sharp border comprising only several cell layers between the treated and untreated areas. The repair of lesions had the processes of necrotic tissue absorption and granulation tissue replacement. It is concluded that extracorporeal treatment of human solid malignancies with HIFU could be safe, effective and feasible. As a noninvasive therapy, HIFU would be used clinically to treat patients with solid malignancies.     

高强度聚焦超声治疗中晚期胰腺癌的临床研究

目的 初步评价高强度聚焦超声(HIFU)治疗胰腺癌的止痛作用和有效性.方法 29例不能手术的胰腺癌患者进行了HIFU治疗,通过症状、实验室检查和影像学变化等观察HIFU的治疗效果,同时比较全麻与镇静镇痛2种方式下HIFU治疗的剂量强度和效率的不同.结果 治疗后68.2%(15/22)患者血清肿瘤标志物(Ca19-9)下降,疼痛缓解有效率为69.2%(18/26),影像学显示HIFU辐照靶区内组织呈凝固性坏死表现,1年生存率为23.1%,中位生存期为8.5个月.而全麻与镇静镇痛2种方式下HIFU治疗的剂量强度是一致的(P>0.05),但镇静镇痛方式下治疗的效率均要高于全麻方式(P<0.05).结论 HIFU 治疗能够有效地消融胰腺肿瘤和缓解疼痛,HIFU治疗胰腺癌更适合使用镇静镇痛方式.     

Neoadjuvant HIFU treatment for malignant fibrous histiocytoma: report of a case

High-intensity focused ultrasound (HIFU) is an innovative, noninvasive, extracorporeal technique that induces coagulative necrosis of tumor tissue by thermal effects and cavitation. In published studies, HIFU has usually been used as an alternative to surgery, with or without other treatment modalities, to achieve curative tumor ablation or palliative tumor cytoreduction. Neoadjuvant HIFU treatment for primary inoperable malignant fibrous histiocytoma has never been reported, and neoadjuvant radiotherapy, chemoradiation, or chemotherapy is routinely under consideration. This is the first case in which HIFU ablation contributed as a neoadjuvant therapy to facilitate function-sparing resection, not as a replacement for surgery. It suggests that HIFU ablation may have some unique major advantages for treating inoperable huge soft-tissue sarcomas as a neoadjuvant local treatment modality, especially for patients for whom neoadjuvant chemotherapy or radiotherapy is not indicated.     

Miniaturized ultrasound arrays for interstitial ablation and imaging

A potential alternative to extracorporeal, noninvasive HIFU therapy is minimally invasive intense ultrasound ablation that can be performed laparoscopically or percutaneously. An approach to minimally invasive ablation of soft tissue using miniaturized linear ultrasound arrays is presented here. Recently developed 32-element arrays with aperture 2.3 x 49 mm, therapy frequency 3.1 MHz, pulse-echo bandwidths >42% and surface acoustic energy density >80 W/cm2, are described. These arrays are integrated into a probe assembly, including a coupling balloon and piercing tip, suitable for interstitial ablation. An integrated electronic control system allows therapy planning and automated treatment guided by real-time interstitial B-scan imaging. Image quality, challenging because of limited probe dimensions and channel count, is aided by signal processing techniques that improve image definition and contrast, resulting in image quality comparable to typical transabdominal ultrasound imaging. Ablation results from ex vivo and in vivo experiments on mammalian liver tissue show that this approach is capable of ablation rates and volumes relevant to clinical applications of soft tissue ablation such as treatment of liver cancer.     

高强度聚焦超声辐照猪胰腺实验研究

目的探讨改善胰腺HIFU辐照超声通道的方法,并了解不同能量HIFU辐照对猪胰腺组织的损伤及对胃肠道的影响。方法以2头新鲜离体猪胰腺和16头在体猪胰腺体部为靶目标,活体实验中,HIFU辐照前在12头猪胃内放置球囊并注入800~1200ml脱气水,分别以高、中、低能量HIFU进行辐照,4头猪未放置球囊并以中等能量辐照,通过光镜和电镜检查观察胰腺病理损伤程度,并观察副损伤发生情况。结果胃内放置水囊后高能量组4头猪胰腺凝固性坏死程度最重,1头发生皮肤烧伤,2头结肠坏死或穿孔,4头胃黏膜损伤;中等能量组4头猪胰腺凝固性坏死程度较轻,1头发生结肠坏死;低能量组胰腺组织凝固性坏死不明显,但电镜下可见细胞器损伤,1周后出现胰腺坏死现象,未发生皮肤、胃及结肠损伤;未放置水囊组4头猪中只有1头光镜下见胰腺点状坏死,皮肤、胃及结肠的损伤较放置水囊组明显加重。结论通过胃内放置水囊的方法可有效改善猪胰腺HIFU超声通道,高能量HIFU辐照猪胰腺更易发生凝固性坏死,但对胃、结肠的损伤较重;中低能量HIFU可引起猪胰腺发生多种形式损伤或坏死,损伤程度相对较轻,但相对安全。     

An ex Vivo Human Lung Model for Ultrasound-Guided High-Intensity Focused Ultrasound Therapy Using Lung Flooding

The usability of an ex vivo human lung model for ablation of lung cancer tissue with high-intensity focused ultrasound (HIFU) is described. Lung lobes were flooded with saline, with no gas remaining after complete atelectasis. The tumor was delineated sono-morphologically. Speed of sound, tissue density and ultrasound attenuation were measured for flooded lung and different pulmonary cancer tissues. The acoustic impedance of lung cancer tissue (1.6–1.9 mega-Rayleighs) was higher than that of water, as was its attenuation coefficient (0.31–0.44 dB/cm/MHz) compared with that of the flooded lung (0.12 dB/cm/MHz). After application of HIFU, the temperature in centrally located lung cancer surrounded by the flooded lung increased as high as 80°C, which is sufficient for treatment. On the basis of these preliminary results, ultrasound-guided HIFU ablation of lung cancer, by lung flooding with saline, appears feasible and should be explored in future clinical studies.     

HIFU体外块"切除"动物肝脏、肾脏和肌肉的剂量研究

目的　用能效因子( energy- efficiency factor,EEF)作为高强度聚焦超声( high intensity focused ultrasound,HIFU)治疗剂量学评价指标来研究HIFU切除组织块的治疗剂量。方法　按照由束损伤→片损伤→块损伤的治疗原则,使用声强为70 0 0～2 770 0 W/ cm2 ,扫描线长3 0 mm,扫描速度3 mm/ s,束损伤的空间间距5～1 0 mm,片损伤的空间间距5 mm,在山羊肝脏、肾脏和肌肉中形成一个凝固性坏死块。并把形成单位体积凝固性坏死所需的超声能量叫做HIFU治疗的EEF,用EEF作为HIFU治疗剂量学评价指标。结果　按照束损伤→片损伤→块损伤的组合方式能在山羊肝脏、肾脏、肌肉中形成一个完整的凝固性坏死块,且中间没有正常组织残留。在山羊肾脏中形成一个凝固性坏死块的EEF明显大于在山羊肝脏中形成一个凝固性坏死块的EEF,而相比于肾脏和肝脏,在山羊肌肉中形成一个凝固性坏死块的EEF最小。结论　本研究表明同一超声能量在不同的靶组织中所产生的凝固性坏死体积不同,组织的结构、功能状态对HIFU治疗肿瘤的效果具有较大的影响,HIFU治疗剂量学的研究有望为临床治疗肿瘤提供剂量学指导     

晚期胰体癌HIFU消融效果与CT靶皮距的相关性

目的探讨晚期胰体癌HIFU消融效果与CT靶皮距的相关性。方法将HIFU消融体积比>30%定为A组,即存在与HIFU相关的消融;≤30%定为B组,即不明确存在与HIFU相关的消融。根据上述分组,对20例晚期胰体癌肿物消融效果与CT靶皮距的相关性进行分析。结果 A组与B组之间CT靶皮距差异有统计学意义(P<0.05),且CT靶皮距每增加1cm,消融效果降低0.31倍;ROC曲线显示,当CT靶皮距为7.15cm时,其预测消融效果的敏感度为80.00%,特异度为70.00%,曲线下面积为0.81(P=0.02)。结合临床,将7cm作为CT靶皮距的分界值,预测消融效果的敏感度和特异度分别为77.80%和72.70%,OR值为9.33。结论晚期胰体癌HIFU消融效果与CT靶皮距呈负相关;CT靶皮距等于7cm可作为胰体癌HIFU治疗的适应证选择界值。     

Performance assessment of HIFU lesion detection by harmonic motion imaging for focused ultrasound (HMIFU): a 3-D finite-element-based framework with experimental validation

Harmonic motion imaging for focused ultrasound (HMIFU) is a novel high-intensity focused ultrasound (HIFU) therapy monitoring method with feasibilities demonstrated in vitro, ex vivo and in vivo. Its principle is based on amplitude-modulated (AM) - harmonic motion imaging (HMI), an oscillatory radiation force used for imaging the tissue mechanical response during thermal ablation. In this study, a theoretical framework of HMIFU is presented, comprising a customized nonlinear wave propagation model, a finite-element (FE) analysis module and an image-formation model. The objective of this study is to develop such a framework to (1) assess the fundamental performance of HMIFU in detecting HIFU lesions based on the change in tissue apparent elasticity, i.e., the increasing Young’s modulus, and the HIFU lesion size with respect to the HIFU exposure time and (2) validate the simulation findings ex vivo. The same HMI and HMIFU parameters as in the experimental studies were used, i.e., 4.5-MHz HIFU frequency and 25 Hz AM frequency. For a lesion-to-background Young’s modulus ratio of 3, 6 and 9, the FE and estimated HMI displacement ratios were equal to 1.83, 3.69 and 5.39 and 1.65, 3.19 and 4.59, respectively. In experiments, the HMI displacement followed a similar increasing trend of 1.19, 1.28 and 1.78 at 10-s, 20-s and 30-s HIFU exposure, respectively. In addition, moderate agreement in lesion size growth was found in both simulations (16.2, 73.1 and 334.7 mm²) and experiments (26.2, 94.2 and 206.2 mm²). Therefore, the feasibility of HMIFU for HIFU lesion detection based on the underlying tissue elasticity changes was verified through the developed theoretical framework, i.e., validation of the fundamental performance of the HMIFU system for lesion detection, localization and quantification, was demonstrated both theoretically and ex vivo.     

High-intensity focused ultrasound ablation of ex vivo bovine achilles tendon

Small tears in tendons are a common occurrence in athletes and others involved in strenuous physical activity. Natural healing in damaged tendons can result in disordered regrowth of the underlying collagen matrix of the tendon. These disordered regions are weaker than surrounding ordered regions of normal tendon and are prone to re-injury. Multiple cycles of injury and repair can lead to chronic tendinosis. Current treatment options either are invasive or are relatively ineffective in tendinosis without calcifications. High-intensity focused ultrasound (HIFU) has the potential to treat tendinosis noninvasively. HIFU ablation of tendons is based on a currently-used surgical analog, viz., needle tenotomy. This study tested the ability of HIFU beams to ablate bovine tendons ex vivo. Two ex vivo animal models were employed: a bare bovine Achilles tendon (deep digital flexor) on an acoustically absorbent rubber pad, and a layered model (chicken breast proximal, bovine Achilles tendon central and a glass plate distal to the transducer). The bare-tendon model enables examination of lesion formation under simple, ideal conditions; the layered model enables detection of possible damage to intervening soft tissue and consideration of the possibly confounding effects of distal bone. In both models, the tissues were degassed in normal phosphate-buffered saline. The bare tendon was brought to 23 degrees C or 37 degrees C before insonification; the layered model was brought to 37 degrees C before insonification. The annular array therapy transducer had an outer diameter of 33 mm, a focal length of 35 mm and a 14-mm diameter central hole to admit a confocal diagnostic transducer. The therapy transducer was excited with a continuous sinusoidal wave at 5.25 MHz to produce nominal in situ intensities from 0.23-2.6 kW/cm(2). Insonification times varied from 2-10 s. The focus was set over the range from the proximal tendon surface to 7 mm deep. The angle of incidence ranged from 0 degrees (normal to the tissue surface) to 15 degrees . After insonification, tendons were dissected and photographed, and the dimensions of the lesions were measured. Transmission electron micrographs were obtained from treated and untreated tissue regions. Insonification produced lesions that mimicked the shape of the focal region. When lesions were produced below the proximal tendon surface, no apparent damage to overlying soft tissue was apparent. The low intensities and short durations required for consistent lesion formation, and the relative insensitivity of ablation to small variations in the angle of incidence, highlight the potential of HIFU as a noninvasive treatment option for chronic tendinosis.     

A Preclinical In Vivo Investigation of High-Intensity Focused Ultrasound Combined with Radiotherapy

This study aims to perform an in vivo investigation evaluating the injury to the pancreas and adjacent tissue of swine resulting with high-intensity focused ultrasound (HIFU) combined with radiotherapy (RT). The protocol was approved by the animal ethics committee at the Peking University First Hospital. A total of 12 domestic swine were divided into four groups: control, HIFU only, RT only and HIFU + RT. The injury to the pancreas, adjacent tissue and tissue within the acoustic path of the HIFU beam was assessed based on gross and histologic findings. For the targeted region of the pancreas, the score of the combined group was higher than that of the HIFU group and there was significant difference. For the acoustic path tissue, there was no significant difference except between the control group and the other groups. HIFU combined with RT increased the injury to the targeted pancreas, without increased injury to tissue outside of the targeted region. (E-mail: xsgao777@hotmail.com)     

HIFU联合脂质纳米氟碳液滴消融兔肝的实验研究

目的 探讨脂质纳米氟碳液滴增效HIFU消融兔肝脏的空化活动及术后病理学变化。方法 首先制备全氟戊烷脂质纳米氟碳液滴(L-PFP);然后将24只正常新西兰兔随机分为对照组(单纯HIFU组)和L-PFP组;在 B 超引导下进行HIFU定点消融兔肝脏(超声能量：900 J);通过被动空化检测系统(PCD)监控空化活动;分别将消融即刻、1d、3d、7d的兔肝脏标本取出进行H E染色,观察消融灶转归过程中的病理学变化。结果 经耳缘静脉注射L-PFP后HIFU 辐照兔肝脏所产生的空化泡群更明显,其灰度变化值为对照组的1.93倍,累积瞬态空化剂量为对照组的6.3倍,空化活动表现强烈;大体病理及H E结果显示L-PFP组造成的组织损伤严重,细胞变性更为彻底,炎性反应更为强烈;单纯HIFU组消融灶7d修复为正常组织,转归所需时间显著短于L-PFP组。结论 脂质纳米氟碳液滴通过增强空化效应有效提高HIFU消融效果,延长消融灶转归所需时间。     

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.     

Selective reduction of multifetal pregnancy using high-intensity focused ultrasound in the rabbit model.

OBJECTIVE: High-order multifetal pregnancies carry a significant risk of obstetric complications and poor pregnancy outcome. Selective reduction has traditionally been performed using transabdominal and transvaginal ultrasound-guided intracardiac injection of potassium chloride. We have previously shown that high-intensity focused ultrasound (HIFU) can create a coagulative tissue necrosis in the sheep fetus. The objective of this study was to investigate the feasibility of non-invasive selective fetal reduction using HIFU in a rabbit model. METHODS: A protocol for HIFU-induced tissue coagulation was developed in the rabbit model. The fetal heart was targeted with ultrasound-guided tissue ablation by a HIFU beam. Five time-mated does between 20-29 days' gestation underwent transabdominal fetal cardiac ablation in a total of 11 fetuses. The HIFU system consisted of a 7-MHz high-power transducer, operated at 2000 W/cm2. The fetal heart rate was observed using real-time ultrasound with Doppler flow velocimetry. All lesions were assessed macroscopically and by histological analysis. RESULTS: Severe bradycardia leading to asystole was observed in all targeted fetuses with ultrasound examination. Dissection of fetuses demonstrated a necrotic intrathoracic lesion similar in size to the HIFU focus (approximately 1 x 9 mm). None of the surrounding fetuses was found to have bradycardia during the procedure or a macroscopic lesion on dissection. CONCLUSION: In this pilot study HIFU seems promising to ablate even highly vascularized tissue in the fetus.