Developing Methods for Precise, Safe and Target-location Specific Histotripsy of Liver Tumors

项目摘要 该基金的目标是优化肝组织切除术，以在任何 在一个大型动物模型中的位置，人类规模的模型。肝癌是导致死亡的主要原因， 消融术是选择患者的有限治疗选择之一。不幸的是，目前 消融手术具有约10 - 40%的可变局部失败率。此外，肿瘤位于 关键的结构，如胆管和肠，通常不接受治疗性治疗， 消融术与增加的损伤风险有关。组织解剖是第一个非侵入性，非- 热和非电离消融模式，使用聚焦超声能量来产生空化， 导致机械性组织破裂。在初步研究中，组织破坏术显示出 造成组织破坏，使某些结构与胶原结构无关，包括 胆管和肠道，并在治疗和正常之间创建薄边缘的消融区 组织中促进组织摧毁术的临床转化，并可能增加 有资格接受治愈性治疗的患者人数，需要回答一个关键问题： 我们能否在保持疗效的同时利用组织破坏术潜在的安全优势 这样更多的肿瘤就有资格接受治愈性治疗？第一，减轻 通过高频喷射通气减少肝脏运动或使用 将在目标1中试验室内锥形束CT，以模拟肝脏运动并修改处方。在 目标2：我们将确定治疗切除的HCC的剂量阈值，同时保留关键结构， 为任何部位的肿瘤确定安全、有效的治疗剂量，然后在 存活的体内猪肝模型。最后，在目标3中，我们将提出一个类似SCID的HCC猪 肝脏肿瘤模型，这将使我们能够将这些策略应用于位于特定区域内的肿瘤， 肝脏的高风险部位，以确认安全性和有效性，最终证明我们的假设 组织摧毁术可以安全地治疗任何肝脏部位的肿瘤。三个具体目标是： 以下.目的1：确定减轻呼吸运动影响的最佳策略 提高组织破坏消融的精确性和安全性。目的2：确定以下剂量阈值： 肝癌和关键结构离体，允许安全，有效的治疗参数试验 用于关键部位的体内治疗。目的3：建立一个高度相关的大型动物肝细胞癌模型 并在该大型动物模型中确认安全性和有效性。这个项目 将产生关键的临床前数据，这在广泛采用 组织破坏术治疗非手术肝细胞癌患者。

PROJECT SUMMARY The goal of this grant is to optimize hepatic histotripsy to create safe and effective ablation in any location in a large animal, human-scale model. Liver cancer is a leading cause of death with ablation one of the limited curative options in select patients. Unfortunately, currently available ablation procedures have a variable local failure rate of ~10-40%. Also, tumors located near critical structures, such as bile ducts and bowel, often do not receive curative treatment as thermal ablation is associated with increased risk of injury. Histotripsy is the first non-invasive, non- thermal, and non-ionizing ablation modality, using focused ultrasound energy to create cavitation, resulting in mechanical tissue disruption. In preliminary studies, histotripsy has shown an ability to cause tissue disruption that spares certain structures with collagenous architecture, including bile ducts and bowel, and to create ablation zones with a thin margin between treated and normal tissues. To catalyze the clinical translation of histotripsy and potentially increase the number of patients eligible for curative treatment, a key question needs to be answered: Can we leverage the potential safety advantages of histotripsy while maintaining efficacy such that more tumors will be eligible for curative treatment? First, strategies to mitigate the effects of respiratory motion by decreasing liver motion with high-frequency jet ventilation or using in-suite cone-beam CT to model liver motion and modify prescriptions will be trialed in Aim 1. In Aim 2 we will determine dose thresholds to treat excised HCC while sparing critical structures to identify a safe, effective treatment dose for tumors of any location and then validate this dose in a survival, in vivo swine liver model. Finally, in Aim 3 we will advance a SCID-like HCC porcine liver tumor model, which will allow us to apply these strategies to tumors located within specific high-risk locations of the liver to confirm safety and efficacy, ultimately, proving our hypothesis that histotripsy can treat tumors in any liver location safely. The three Specific Aims are the following. Aim 1: Determine the best strategy to mitigate the effects of respiratory motion to increase the precision and safety of histotripsy ablation. Aim 2: To determine dose thresholds for liver cancer and critical structures ex vivo, allowing a trial of safe, effective treatment parameters for in vivo treatment in critical locations. Aim 3: Advance a highly relevant large animal liver HCC model for medical devices and confirm safety and efficacy in this large animal model. This project will yield critical preclinical data which will be necessary before the widespread adoption of histotripsy to treat patients with non-surgical hepatocellular carcinoma.