Novel, Noninvasive, Rapid Tumor Ablation Technology using Histotripsy

标题：使用组织摧毁术的新型无创快速肿瘤消融技术 摘要 我们的目标是开发一种非侵入性的消融技术，可以实现快速，均匀的肿瘤消融 有能力克服目前肿瘤干预的局限性。许多癌症患者不符合条件 物.现有的微创和非侵入性肿瘤干预具有显著的局限性， 阻止它们有效治疗大血管附近的肿瘤、大肿瘤（直径>3 cm），或 肿瘤有多个（>3个）结节。组织摧毁术是一种非侵入性超声消融技术，可产生 以毫米精度破坏目标组织。我们以前在正常组织中的体内研究 并且肿瘤模型已经显示：1）在靶向区域中均质的、完全的细胞破坏， 损伤覆盖组织，2）能够治疗邻近大血管的组织，3）能够治疗约5 cm 直径肿瘤在一小时内，4）实时治疗监测超声成像，和5）潜在的 肿瘤完全消融，无肿瘤残留、复发或新转移。此外，我们最近的研究结果 显示组织碎石术结合电聚焦转向完全分离~32 mL（~ 4 cm直径） 离体牛肝在10分钟内，超过两倍的速度比任何目前的非手术干预方法。 这些结果表明，组织摧毁术有可能显着改善现有的肿瘤干预 方法.对于该提案，具体目标集中在技术进步，以允许组织破坏术克服 目前以肝癌为第一靶点的肿瘤介入治疗方法的局限性。的 四个目标是：1）开发电子聚焦转向策略和参数以实现快速（> 5 mL/min）， 通过覆盖组织安全地进行大体积（>3cm）和多体积（>3）的均匀消融; 2）开发 运动跟踪方法，实现在存在呼吸运动的情况下快速准确的治疗; 3）设计 构建一体化的超声图像引导下肝癌组织摧毁消融系统 患者;以及4）测试目标1-3中的技术和器械的体内安全性和有效性， 在大型动物（猪）肝模型和土拨鼠肝肿瘤模型中的肝肿瘤消融。拟议 技术改进和集成的肝脏消融系统，都在体内验证，将是必不可少的， 推进组织摧毁术向未来临床转化以治疗肝脏肿瘤，并可扩展到许多其他领域。 肿瘤类型，包括肾脏、前列腺、胰腺和子宫肿瘤。

Title: Novel, Noninvasive, Rapid Tumor Ablation Technology using Histotripsy Abstract Our goal is to develop a noninvasive ablation technique that can achieve rapid, homogeneous tumor ablation with the ability to overcome the limitations of current tumor interventions. Many cancer patients are not eligible for surgery. Existing minimally invasive and non-invasive tumor interventions have significant limitations that prevent them from being effective at treating tumors near major vessels, large tumors (>3 cm diameter), or tumors with multiple (>3) nodules. Histotripsy is a non-invasive ultrasound ablation technique that produces cavitation to disrupt the target tissue with millimeter precision. Our previous in vivo studies in normal tissues and tumor models have shown 1) homogenous, complete cellular disruption in targeted areas without damaging the overlying tissue, 2) ability to treat tissue adjacent to large vessels, 3) ability to treat ~5 cm diameter tumors within one hour, 4) real-time treatment monitoring with ultrasound imaging, and 5) potential of complete tumor ablation without residual tumor, recurrence, or new metastasis. Further, our recent results show that histotripsy combined with electrical focal steering completely fractionated ~32 mL (~4cm diameter) ex vivo bovine liver within 10 min, more than twice the rate than any current non-surgical intervention method. These results suggest that histotripsy has the potential to significantly improve upon existing tumor intervention methods. For this proposal, the specific aims focus on technical advancements to allow histotripsy to overcome the limitations of current tumor intervention methods with liver cancer as the first target clinical application. The four aims are: 1) develop an electronic focal steering strategy and parameters to achieve rapid (>5mL/min), homogenous ablation of large (>3cm) and multiple (>3) volumes safely through overlying tissue; 2) develop a motion tracking method to achieve rapid and accurate treatment in the presence of breathing motion; 3) design and construct an integrated ultrasound image-guided histotripsy ablation system for human liver cancer patients; and 4) test the in vivo safety and efficacy of the techniques and device from Aims 1-3 for complete liver tumor ablation in a large animal (porcine) liver model and a woodchuck liver tumor model. The proposed technical improvements and the integrated liver ablation system, all validated in vivo, will be essential to advance histotripsy towards future clinical translation to treat liver tumors and could be extended to many other tumor types, including tumors in the kidney, prostate, pancreas, and uterus.