Development and application of non-thermal high frequency IRE to treat hepatic tumors

非热高频IRE治疗肝脏肿瘤的开发及应用

基本信息

批准号：
10375472
负责人：
Rafael Vidal Davalos
金额：
$ 49.67万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375472
关键词：
Ablation Acute Address Adjuvant Chemotherapy Adopted Adoption Affect Age Algorithms Anatomy Animal Model Animals Architecture Biliary Biological Models Blood Vessels Breast cancer metastasis Cancer Etiology Canis familiaris Cardiac Cardiac Output Cell Death Cell Death Induction Cell membrane Cells Charge Cholangiocarcinoma Chronic Cirrhosis Clinical Clinical Data Colorectal Complex Custom Data Data Collection Defect Desiccation Development Devices Diagnosis Disease Electrodes Electroporation Environment Etiology Evaluation Evolution Excision Family suidae Frequencies Hemangiosarcoma Hepatic Hepatic Mass Homeostasis Human Image-Guided Surgery In Situ Length Link Liver Liver diseases Liver neoplasms Location Malignant Neoplasms Measurement Medical Metastatic Neoplasm to the Lung Modality Modeling Monitor Morbidity - disease rate Necrosis Needles Operative Surgical Procedures Organ Transplantation Outcome Palliative Care Paralysed Pathologic Pathology Patient Selection Patients Performance Physiologic pulse Primary carcinoma of the liver cells Procedures Property Protocols documentation Radiofrequency Interstitial Ablation Recurrence Reporting Reproducibility Research Residual state Risk Risk Factors Safety Solid Neoplasm Staging Structure Survival Rate System Technical Expertise Technology Testing Thermal Ablation Therapy Time Tissues Translating Translations Transplantation Vascularization Veterinary Schools advanced disease base cancer cell cell killing design electric field experience in silico in vivo in vivo Model innovation interest intrahepatic cancer invention liver function microsensor microwave ablation mortality nanopore necrotic tissue next generation novel patient population patient subsets porcine model pre-clinical prototype response technology development temporal measurement translational approach tumor

项目摘要

ABSTRACT. Liver tumors represent the third leading cause of cancer-related mortality in the world. Surgery (resection or transplant) have formed the historical basis for treating hepatic tumors with intent to cure. However, advanced disease staging at diagnosis (including intra- and extra-hepatic metastatic disease), a paucity of transplantable organs, underlying hepatic pathology, intrahepatic tumor location, and extensive vascular involvement often contrive to limit surgical intervention as viable options. Thermal ablation has emerged as an alternative to resection. While potentially curative, tumor vascularization and location (relative to vital structures) often restricts thermal ablation to a subset of patients with liver tumors. As a result, less than 25% of all patients diagnosed with hepatic tumors are amenable to existing treatment with intent to cure, and five-year survival rates (15-25%) have remained largely unchanged over the last three decades. Innovative approaches are required to develop new treatment options for those diagnosed with liver tumors. Irreversible electroporation (IRE) is an alternative to thermal ablation, whereby rapid electrical pulses are delivered between electrodes placed in or around the tumor. The electric field generated during IRE delivery leads to formation of permanent cell membrane defects that render cells incapable of regulating normal homeostasis and induces cell death. Because IRE induces minimal thermal necrosis or tissue devitalization, IRE offers the advantage of sparing the structural integrity of the underlying tissue architecture. However, clinical and technical complexities associated with existing IRE means it has been slow to be adopted clinically. We have developed a novel high-frequency IRE (HFIRE) system that overcomes many of the technical challenges associated with IRE by delivering ultrashort, bipolar electrical pulses. However, the HFIRE system does not overcome the clinical challenge of requiring multiple electrodes to be placed in a challenging anatomic environment or the inability to accurately monitor ablation progress in real-time. This led us to hypothesize that creating a single needle-dual electrode HFIRE (SN-HFIRE) delivery platform will directly enable development of this technology to selectively treat hepatic tumors not amenable to resection or thermal ablation. To test this hypothesis three Aims are proposed. Aim 1 Will employ a novel ex vivo machine perfused liver model to test the functionality of existing SN-HFIRE devices, and to develop and evaluate novel SN-HFIRE devices incorporating thermally-mitigating materials for HFIRE delivery. These studies will be performed in conjunction with real-time measurement of tissue-ablation properties; Aim 2 Will define the clinical potential of SN- HFIRE in the complex in vivo environment using acute and chronic large animal (swine) liver models; Aim 3 will establish the clinical viability of SN-HFIRE by treating canine HCC patients using a treat-and-resect protocol. The proposed approaches will build on the technical and clinical expertise of the research groups assembled to develop an innovative, translational approach to treating and managing those diagnosed with untreatable hepatic tumors, while simultaneously creating a novel ablation technology that is readily adaptable for treating other, inoperable solid tumors.

抽象的。肝脏肿瘤是世界上癌症相关死亡的第三大原因。手术（切除或移植）已经形成了以治愈为目的治疗肝肿瘤的历史基础。然而，疾病晚期诊断时的分期（包括肝内和肝外转移性疾病）、缺乏可移植器官、潜在的肝脏病理学、肝内肿瘤位置和广泛的血管受累往往会限制手术干预作为可行的选择。热消融已成为切除术的替代方案。虽然肿瘤有潜在的治愈作用血管化和位置（相对于重要结构）通常将热消融限制在肝病患者的子集上肿瘤。因此，在所有诊断为肝肿瘤的患者中，只有不到 25% 适合接受现有的治疗过去三十年里，治愈意愿和五年生存率（15-25%）基本保持不变。需要创新方法来为诊断患有肝肿瘤的患者开发新的治疗方案。不可逆电穿孔 (IRE) 是热消融的替代方法，可在电极之间传递快速电脉冲放置在肿瘤内或周围。 IRE 传递过程中产生的电场导致永久细胞的形成膜缺陷使细胞无法调节正常的体内平衡并诱导细胞死亡。因为 IRE 会诱发 IRE 具有最小化热坏死或组织失活的优点，可以保护组织的结构完整性底层组织结构。然而，与现有 IRE 相关的临床和技术复杂性意味着它已经临床应用较慢。我们开发了一种新颖的高频 IRE (HFIRE) 系统，克服了许多技术挑战通过提供超短双极电脉冲与 IRE 相关。然而，HFIRE系统并没有克服需要将多个电极放置在具有挑战性的解剖环境中或无法实时准确监控消融进度。这使我们假设创建一个单针双电极 HFIRE（SN-HFIRE）输送平台将直接促进该技术的开发，以选择性地治疗肝脏肿瘤不适合切除或热消融。为了检验这一假设，提出了三个目标。目标 1 将采用一本小说离体机器灌注肝脏模型，用于测试现有 SN-HFIRE 设备的功能，并开发和评估新颖的 SN-HFIRE 设备采用了用于 HFIRE 传输的散热材料。这些研究将进行结合组织消融特性的实时测量；目标 2 将定义 SN- 的临床潜力使用急性和慢性大型动物（猪）肝脏模型在复杂的体内环境中进行 HFIRE；目标 3 将建立通过使用治疗和切除方案治疗犬 HCC 患者来评估 SN-HFIRE 的临床可行性。拟议的方法将建立在研究小组的技术和临床专业知识的基础上，以开发创新的、治疗和管理那些诊断为无法治疗的肝肿瘤的转化方法，同时创造了一种新颖的消融技术，该技术很容易适用于治疗其他无法手术的实体瘤。