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.

项目摘要 这笔赠款的目的是优化肝疗法，以在任何 位置在大型动物，人尺度模型中。肝癌是死亡的主要原因， 在某些患者中消融有限的治疗选择之一。不幸的是，目前可用 消融程序的局部故障率为约10-40％。此外，肿瘤位于附近 关键结构（例如胆管和肠道）通常不会接受治疗治疗 消融与增加伤害风险有关。组织疗法是第一个非侵入性的，非侵入性的 使用聚焦超声能量创造空化的热和非电离烧蚀方式， 导致机械组织破坏。在初步研究中，组织疗法表现出能力 引起组织中断，以延长了具有胶原式结构的某些结构，包括 胆管和肠道，并在处理和正常之间创建薄薄的裂纹区 组织。催化组织疗法的临床翻译，并可能增加 有资格治疗治疗的患者人数需要回答一个关键问题： 我们可以在保持疗效的同时利用组织疗法的潜在安全优势 这样更多的肿瘤将有资格治疗吗？首先，减轻 通过高频喷气通风减少肝运动或使用，呼吸运动的影响 在AIM 1中，将对肝运动和修改处方进行建模的套管锥束CT。 目的2我们将确定剂量阈值以处理切除的HCC，同时将关键结构放到 确定任何位置肿瘤的安全有效治疗剂量，然后验证该剂量 生存，体内猪肝模型。最后，在AIM 3中，我们将推动类似SCID的HCC猪 肝肿瘤模型，这将使​​我们能够将这些策略应用于特定的肿瘤 肝脏的高风险位置以确认安全性和功效，最终证明了我们的假设 这种组织疗法可以安全地治疗任何肝脏的肿瘤。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 提高组织疗法消融的精度和安全性。目标2：确定剂量阈值 肝癌和关键结构在体内，允许对安全有效的治疗参数进行试验 在关键位置进行体内治疗。 AIM 3：推进高度相关的大型动物肝HCC 医疗设备的模型，并在此大型动物模型中确认安全性和功效。这个项目 将产生关键的临床前数据，在广泛采用之前必要 组织疗法以治疗非手术肝细胞癌患者。