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

开发精确、安全、靶向定位的肝脏肿瘤特异性组织切片方法

• 批准号: 10276750
• 负责人: Timothy J Ziemlewicz
• 金额: $ 55.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276750
• 关键词: Ablation; Acoustics; Address; Adoption; Animal Model; Animals; Architecture; Area; Bile fluid; Breast; Breathing; Caliber; Cancer Patient; Cause of Death; Cessation of life; Cirrhosis; Clinical; Clinical Data; Clinical Treatment; Collagen; Data; Dependence; Development; Disease; Dose; Failure; Family suidae; Financial compensation; Focused Ultrasound; Frequencies; Goals; Grant; Hepatic; Human; Injury; Intestines; Kidney; Knowledge; Liver; Liver neoplasms; Location; Malignant neoplasm of liver; Mechanics; Medical Device; Methods; Modality; Modeling; Motion; Normal tissue morphology; Operative Surgical Procedures; Organ; Pancreas; Patients; Phase I Clinical Trials; Physiologic pulse; Primary carcinoma of the liver cells; Procedures; Recovery; Recurrence; Resistance; Risk; Safety; Shapes; Spain; Structure; System; Techniques; Testing; Thermal Ablation Therapy; Thinness; Thyroid Gland; Time; Tissues; Translations; Ultrasonic Therapy; Work; base; bile duct; clinical translation; cone-beam computed tomography; curative treatments; effective therapy; high risk; improved; in vivo; porcine model; pre-clinical; preclinical evaluation; prototype; respiratory; side effect; tumor; ventilation

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.

项目概要 这笔赠款的目标是优化肝组织解剖学，以在任何情况下创建安全有效的消融术 大型动物、人体模型中的位置。肝癌是导致死亡的主要原因 消融是特定患者的有限治疗选择之一。不幸的是，目前可用 消融手术的局部失败率约为 10-40%。另外，肿瘤位于附近 关键结构，例如胆管和肠，通常不会因为热而接受治疗 消融与受伤风险增加相关。组织解剖学是第一个非侵入性、非 热和非电离消融方式，使用聚焦超声能量产生空化， 导致机械组织破坏。在初步研究中，组织解剖学显示出一种能力 造成组织破坏，从而保留某些具有胶原结构的结构，包括 胆管和肠道，并在治疗区域和正常区域之间创建边缘较薄的消融区域 组织。促进组织解剖学的临床转化并可能增加 考虑到有多少患者符合治愈性治疗的条件，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解剖学的潜在安全优势 这样更多的肿瘤将有资格获得治愈性治疗？首先，缓解策略 通过高频喷射通气减少肝脏运动或使用 目标 1 将试验用于模拟肝脏运动和修改处方的套房内锥形束 CT。 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 确定针对任何部位肿瘤的安全、有效的治疗剂量，然后在以下方面验证该剂量 存活的体内猪肝脏模型。最后，在目标 3 中，我们将推进类似 SCID 的 HCC 猪 肝肿瘤模型，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 组织解剖学可以安全地治疗肝脏任何位置的肿瘤。这三个具体目标是 下列的。目标 1：确定减轻呼吸运动影响的最佳策略 提高组织解剖消融的精确度和安全性。目标 2：确定剂量阈值 肝癌和离体关键结构，允许试验安全、有效的治疗参数 用于关键部位的体内治疗。目标 3：推进高度相关的大型动物肝脏 HCC 医疗设备模型并确认该大型动物模型的安全性和有效性。这个项目 将产生关键的临床前数据，这些数据在广泛采用之前是必要的 组织解剖学用于治疗非手术肝细胞癌患者。