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.     

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.     

高能聚焦超声治疗子宫肌瘤疗效的Meta分析

目的 系统评价高能聚焦超声（HIFU）治疗子宫肌瘤的疗效与安全性。 方法 计算机检索PubMed、EMbase、Web of Science、The Cochrane Library（2012年第10期）、CBM、CNKI和WanFang Data中有关HIFU治疗子宫肌瘤疗效的随机对照试验（RCT）,检索时限均为建库至2012年11月。根据纳入与排除标准选择试验、提取资料,并评估纳入研究的方法学质量后,采用RevMan 5.0软件进行Meta分析,然后采用GRADE pro 3.2软件对结果进行证据质量分级。 结果 最终纳入6个RCT,共643例患者。Meta分析结果显示：与外科手术相比,HIFU治疗肌瘤的完全或部分消融率、肌瘤复发率差异无统计学意义;与射频相比,HIFU治疗肌瘤的完全或部分消融率之间差异有统计学意义;与米非司酮相比,HIFU治疗肌瘤的完全消融率差异有统计学意义。 结论 HIFU是一种可供选择的、无创的、有效的治疗子宫肌瘤的方法。     

High-Intensity Focused Ultrasound– and Radiation Therapy–Induced Immuno-Modulation: Comparison and Potential Opportunities

In recent years, high-intensity focused ultrasound (HIFU) has emerged as a new and promising non-invasive and non-ionizing ablative technique for the treatment of localized solid tumors. Extensive pre-clinical and clinical studies have evidenced that, in addition to direct destruction of the primary tumor, HIFU-thermoablation may elicit long-term systemic host anti-tumor immunity. In particular, an important consequence of HIFU treatment includes the release of tumor-associated antigens (TAAs), the secretion of immuno-suppressing factors by cancer cells and the induction of cytotoxic T lymphocyte (CTL) activity. Radiation therapy (RT) is the main treatment modality used for many types of tumors and about 50% of all cancer patients receive RT, often used in combination with surgery and chemotherapy. It is well known that RT can modulate anti-tumor immune responses, modifying micro-environment and stimulating inflammatory factors that can greatly affect cell invasion, bystander effects, radiation tissue complications (such as fibrosis), genomic instability and thus, intrinsic cellular radio-sensitivity. To date, various combined therapeutic strategies (such as immuno-therapy) have been performed in order to enhance RT success in treating locally advanced and recurrent tumors. Recent works suggested the combined use of HIFU and RT treatments to increase the tumor cell radio-sensitivity, in order to synergize the effects reaching the maximum results with minimal doses of ionizing radiation (IR). Here, we highlight the opposite immuno-modulation roles of RT and HIFU, providing scientific reasons to test, by experimental approaches, the use of HIFU immune-stimulatory capacity to improve tumor radio-sensitivity, to reduce the RT induced inflammatory response and to decrease the dose-correlated side effects in normal tissues.     

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.     

Preclinical in vivo Evaluation of an Extracorporeal HIFU Device for Ablation of Pancreatic Tumors

Extracorporeal high-intensity focused ultrasound (HIFU) can be used to ablate tissue noninvasively by delivering focused ultrasound energy from an external source. HIFU for clinical treatment of pancreatic cancer has been reported; however, systematic evaluation of the safety and efficacy of pancreatic ablation with HIFU has not been performed. The objectives of this in vivo study are as follows: (1) assess the safety and feasibility of targeting and ablating pancreatic tissue using the FEP-BY02 HIFU system (Yuande Bio-Medical Engineering, Beijing, China); (2) evaluate a method for estimating in situ acoustic treatment energy in an in vivo setting; and (3) identify the optimal treatment parameters that result in safe and effective ablation of the pancreas. The pancreata of 12 common swine were treated in vivo. Prior to therapy, blood was drawn for laboratory analysis. Animals were then treated with extracorporeal HIFU at three different acoustic treatment energies (750, 1000 and 1250 J). Endoscopy was performed prior to and immediately following HIFU therapy to assess for gastric injury. Blood was drawn after completion of the treatment and on days 2 and 7 following treatment to assess for biochemical evidence of pancreatitis. Animals were then euthanized 7 d following treatment and a necropsy was performed to assess for unintended injury and to obtain pancreatic tissue for histology to assess efficacy of HIFU ablation. Histologic scoring of pancreatic tissue changes was performed by a pathologist blinded to the treatment energy delivered. The degree of ablation identified on histology correlated with the treatment energy. No collateral tissue damage was seen at treatment energies of 750 and 1000 J. At 1250 J, thermal injury to the abdominal muscles and gastric ulcers were observed. There were no premature deaths, serious illnesses, skin burns or evidence of pancreatitis on biochemical analysis. HIFU treatment of the pancreas is feasible, safe and can be used to ablate tissue noninvasively. A clinical trial in humans examining the use of extracorporeal HIFU for palliation of pain related to pancreatic cancer is planned. (E-mail: jooha@u.washington.edu)     

高强度聚焦超声增效的方法学研究进展

高强度聚焦超声（HIFU）已运用于临床十余年,其三维适形扫描组合模式已成熟运用,但仍存在诸多问题,如治疗时间过长、辐照剂量大,临床风险和医疗成本增高等。为此,提高HIFU治疗效率的方法受到越来越多的关注。本文就HIFU方法学研究进展进行综述。     

超声造影评价高强度聚焦超声和射频消融治疗不同大小子宫肌瘤疗效及比较

目的采用超声造影技术评价高强度聚焦超声(HIFU)和射频消融治疗子宫肌瘤的疗效,并比较两者对不同大小子宫肌瘤疗效的差异。方法 100例子宫肌瘤患者共138个肌瘤,随机分为2组,每组各50例,分别接受HIFU及射频消融治疗。HIFU组16例患者24个肌瘤直径2.0～4.0cm,26例患者32个肌瘤直径4.0～6.0cm,8例患者12个肌瘤直径6.0～8.0cm;射频消融组14例患者22个肌瘤直径2.0～4.0cm,27例患者35个肌瘤直径4.0～6.0cm,9例患者13个肌瘤直径6.0～8.0cm。所有患者均于治疗前、后1周内行超声造影。采用Chi-squareχ2检验比较HIFU、射频消融治疗不同大小子宫肌瘤完全消融率、术后并发症发生率。结果 HIFU组、射频消融组直径2.0～4.0cm子宫肌瘤完全消融率分别为91.7%(2/24)和95.5%(1/22),差异无统计学意义(χ2=0.270,P>0.05);HIFU组、射频消融组直径4.0～6.0cm子宫肌瘤完全消融率分别为56.3%(18/32)和94.3%(33/35),HIFU组完全消融率低于射频消融组,且差异有统计学意义(χ2=13.304,P<0.05);HIFU组、射频消融组直径6.0～8.0cm子宫肌瘤完全消融率分别为16.7%(2/12)和76.9%(10/13),HIFU组与射频消融组的完全消融率均降低,但射频消融组的完全消融率仍高于HIFU组,且差异有统计学意义(χ2=10.711,P<0.05)。术后并发症包括发热、下腹部疼痛、盆腔积液、阴道排液及单侧下肢麻木。HIFU组并发症发生率为16.0%(8/50),低于射频消融组的36.0%(18/50),差异有统计学意义(χ2=4.917,P<0.05)。结论 HIFU和射频消融对于直径4.0cm以下子宫肌瘤疗效显著。对于直径6.0cm以上的子宫肌瘤,射频消融可取得较好疗效。HIFU作为一种无创治疗手段,可作为小肌瘤非手术治疗的首选方法。     

Changes in circulating immunosuppressive cytokine levels of cancer patients after high intensity focused ultrasound treatment

Immunosuppression in a patient with malignant tumor is a major obstacle in cancer treatment. In this study, we investigated changes in the circulating level of all measured immunosuppressive cytokines in patients with malignancy before and after high intensity focused ultrasound (HIFU) treatment. Fifteen patients with solid malignancy were enrolled in this study and an enzyme-linked immunoabsorbent assay (ELISA) method was used to measure serum level of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), transforming growth factor-beta2 (TGF-beta2), interleukin 6 (IL-6) and interleukin 10 (IL-10), respectively before and 1 wk after HIFU treatment. Among them, seven patients had distant metastasis and the remaining eight had no metastasis. All patients received one-session HIFU treatment for primary cancer, including complete ablation in eight patients without metastasis, and partial ablation in seven patients with metastases. The results showed that serum immunosuppressive cytokine levels decreased after HIFU treatment, and there were significant decreases of VEGF, TGF-beta1, and TGF-beta2 before and after HIFU treatment. Compared with the values in the metastatic patients, serum levels of immunosuppressive cytokines were significantly lower in the nonmetastatic patients after HIFU treatment. It is concluded that HIFU can decrease tumor-secreted immunosuppressive cytokine production in addition to its direct tumor destruction. This change may lessen tumor-induced immunosuppression and renew antitumor immunity after HIFU in cancer patients.     

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.     

高强度聚焦超声联合碘油栓塞损伤肝脏的病理转归及肝、肾功能的变化

目的探讨肝脏局部碘油栓塞联合高强度聚焦超声(HIFU)热切除术后,坏死组织的病理转归及肝、肾功能的变化,阐明联合治疗的安全性。方法10只山羊,肝左叶动脉碘油栓塞和局部HIFU热切除后,分为A、B二组,各5只。A组动物定期观察坏死组织的动态病理变化,而B组则动态观察术后的肝、肾功能变化。结果肝脏碘油栓塞和HIFU治疗后可形成明显的凝固性坏死灶并引起肝、肾功能的明显变化。但随着时间延长,坏死灶逐渐溶解吸收、纤维化,肝肾功能也逐渐恢复正常。结论局部肝脏碘油栓塞联合高强度聚焦超声热切除术是安全的。     

Confocal dual‐frequency enhances the damaging effect of high‐intensity focused ultrasound in tissue‐mimicking phantom

The volume of the lesions created by conventional single‐frequency high‐intensity focused ultrasound (HIFU) is small, which leads to long treatment duration in patients who are undergoing tumor ablation. In this study, the lesions induced by confocal dual‐frequency HIFU in an optically transparent tissue‐mimicking phantom were investigated and compared with the lesions created by conventional single‐frequency HIFU. The results show that using different exposure times resulted in lesions of different sizes in both dual‐frequency and single‐frequency HIFU modes at the same spatially averaged intensity level (ISAL = 4900?W?cm^?2), but the lesion dimensions made in dual‐frequency mode were significantly larger than those made in single‐frequency mode. Difference frequency acoustic fields that exist in the confocal region of dual‐frequency HIFU may be the reason for the enlargement of the lesions' dimensions. The dual‐frequency HIFU mode may represent a new technique to improve the ablation efficiency of HIFU. The total time for the ablation of a tumor can be reduced, thus requiring less therapy time and reducing possible patient complications.     

High-intensity focused ultrasound treatment for intra-abdominal desmoid tumors: a report of four cases

Desmoid tumors are rare clonal fibroblastic proliferations that can arise at abdominal or extra-abdominal sites. Complete surgical resection is the primary treatment for resectable desmoid tumors, but a high rate of local recurrence has been reported even after complete resection. For patients with a recurrent tumor, the goals of treatment are to control the recurrence, maintain quality of life, and prolong survival. Radiofrequency ablation, radiotherapy, chemotherapy, and other medical therapies can be used as alternative methods, but there are considerable controversies over the roles of these methods in the management of desmoid tumors. High-intensity focused ultrasound (HIFU) is a minimally invasive and effective method for treatment of solid tumors. We used HIFU to treat four patients with intra-abdominal desmoid tumors from June 2011 to September 2013. Post-procedural pain was seen in all patients. One patient had an intra-abdominal abscess and another suffered a slight injury to the femoral nerve. The patients were followed up for 19–46 months (mean 34 months) until April 2015. The tumor in one patient disappeared, and no tumor progression was observed in the other patients.     

治疗性超声技术的临床应用进展

超声可作为能量的载体,通过组织媒介进行传播。超声治疗是一种安全、经济且发展迅速的治疗方法,磁共振或超声引导的HIFU一直被用于实体瘤的消融。此外,超声技术在心脏起搏和止血过程中有很大潜力,而低能量超声可以介导药物或基因的传递以及溶栓治疗。本文将超声在临床治疗方面的应用进行简要综述。     

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。     

超声用于评价高强度聚焦超声联合射频治疗大肝癌的研究

目的探讨超声图像监控在高强度聚焦超声（HIFU）联合射频（RFA）治疗大肝癌（直径〉5cm）肿瘤时的作用。方法利用HIFU联合RFA治疗大肝癌患者76例,观察肝癌组织术中、术后超声图像的变化,并对照手术前后腹部MRI结果进行对比分析。结果HIFU及RFA治疗时,可见超声灰阶增强,术后随访癌灶血流减少或消失,术后MRI显示治疗靶区坏死明显,坏死区与超声定位治疗靶区相一致,提示超声定位及监控准确,周围邻近脏器未见损伤。结论超声是目前HIFU及RFA治疗大肝癌时较好的定位及治疗监控手段。     

Radiofrequency tumor ablation: principles and techniques.

Radiofrequency (RF) tumor ablation has been demonstrated as a reliable method for creating thermally induced coagulation necrosis using either a percutaneous approach with image-guidance or direct surgical placement of thin electrodes into tissues to be treated. Early clinical trials with this technology have studied the treatment of hepatic, cerebral, and bony malignancies. However, more recently this technology has been used to treat a host of malignant processes throughout the body. This article will discuss the principles and technical considerations of RF ablation with the goal of defining optimal parameters for the therapy of focal lesions. This includes technologic innovations that permit large volume tumor ablation (i.e., hooked and internally cooled electrodes), as well as methods and adjuvant therapies that can modulate tumor biophysiology to permit improved tumor destruction (i.e, altered tissue conductivity and blood flow). Potential biophysical limitations to RF induced coagulation, such as perfusion mediated tissue cooling (vascular flow) will likewise be discussed. Lastly, the principles governing safe usage of the system, such as proper grounding pad placement, will be adressed.     

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.     

超声弹性成像对高强度聚焦超声肿瘤治疗的疗效评价

高强度聚焦超声(HIFU)是一种非侵入性肿瘤治疗技术,具有良好疗效。超声弹性成像能够得到关于组织弹性的信息,以评价HIFU肿瘤治疗的疗效。本文就静压弹性成像、谐波运动成像和声辐射力脉冲成像的特点以及用于HIFU肿瘤治疗疗效评价的研究概况做一综述。