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

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

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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。肝肿瘤是世界上与癌症相关死亡率的第三大主要原因。手术（切除或移植）已经形成了以治疗肝肿瘤治疗的历史基础。但是，晚期疾病诊断时分期（包括肝内转移性疾病），可移植器官的匮乏肝病病理学，肝内肿瘤位置和广泛的血管受累通常会限制手术干预作为可行的选择。热消融已成为切除的替代方法。虽然可能治愈，但肿瘤血管形成和位置（相对于重要结构）通常将热消融限制为肝脏患者的一部分肿瘤。结果，只有不到25％的所有被诊断为肝肿瘤的患者可以接受现有治疗在过去的三十年中，治愈的意图和五年生存率（15-25％）在很大程度上保持不变。需要创新的方法来为被诊断为肝肿瘤的人开发新的治疗选择。不可逆转电穿孔（IRE）是热消融的替代品，从而在电极之间传递快速的电脉冲放置在肿瘤中或周围。发射期间产生的电场导致形成永久电池膜缺陷使细胞无法调节正常的稳态并诱导细胞死亡。因为愤怒会引起最小的热坏死或组织失业，IRE提供了保留结构完整性的优势基础组织结构。但是，与现有IRE相关的临床和技术复杂性意味着它已经缓慢地在临床上采用。我们已经开发了一种新颖的高频IRE（HFIRE）系统，该系统克服了许多技术挑战通过传递超短型双极电脉冲与IRE相关。但是，HFIRE系统没有克服要求将多个电极放置在具有挑战性的解剖环境或无法的临床挑战中准确监视实时的消融进度。这导致我们假设创建一个单针偶电极 HFIRE（SN-HFIRE）交付平台将直接使该技术的开发能够选择性治疗肝肿瘤不适合切除或热消融。为了检验该假设，提出了三个目标。 AIM 1将采用小说离体机灌注肝模型，以测试现有SN-HFIRE设备的功能，并开发和评估新型的SN-HFIRE设备融合了用于HFIRE传递的热限制材料。这些研究将进行结合实时测量组织燃烧特性； AIM 2将定义SN-的临床潜力使用急性和慢性大动物（猪）肝模型在复杂的体内环境中的HFIRE； AIM 3将建立通过使用治疗方案治疗犬HCC患者，SN-HFIRE的临床生存能力。提议方法将基于研究小组的技术和临床专业知识，这些研究小组组装了创新，转化方法治疗和管理那些诊断患有不可治疗肝肿瘤的人，同时又创建一种新颖的消融技术，很容易适应其他无法处理的实体瘤。