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

• 批准号: 10577902
• 负责人: Rafael Vidal Davalos
• 金额: $ 44.47万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577902
• 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 Induction; Cell membrane; Cells; Charge; Cholangiocarcinoma; Chronic; Cirrhosis; Clinical; Colorectal; Complex; Custom; Data; Data Collection; Defect; Desiccation; Development; Devices; Diagnosis; Disease; Electrodes; Electroporation; Environment; Etiology; Evaluation; Evolution; Excision; Extrahepatic; 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; Perfusion; Phase; Physiologic pulse; Primary carcinoma of the liver cells; Procedures; Property; Protocols documentation; Radiofrequency Interstitial Ablation; Recurrence; Reporting; Reproducibility; Research; Resected; 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; cancer cell; cell killing; design; electric field; experience; in silico; in vivo; in vivo Model; innovation; interest; intrahepatic cancer; invention; liver function; manufacture; microsensor; microwave ablation; mortality; nano; nanopore; necrotic tissue; next generation; novel; patient population; patient subsets; pre-clinical; prototype; response; technology development; temporal measurement; translational approach; tumor

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.

摘要。肝肿瘤是世界上第三大癌症相关死亡原因。手术（切除或 移植）已经形成了治疗肝肿瘤的历史基础。然而，晚期疾病 诊断时分期（包括肝内和肝外转移性疾病），可移植器官缺乏，基础 肝脏病理、肝内肿瘤位置和广泛血管受累常常限制了外科手术 干预是可行的选择。热消融已成为切除术的替代方案。虽然有治愈的潜力， 血管化和位置（相对于重要结构）通常将热消融限制于具有肝损伤的患者的子集。 肿瘤的因此，在所有诊断为肝肿瘤的患者中，只有不到25%的患者能够接受现有的治疗， 在过去的三十年里，治愈意图和五年生存率（15-25%）基本保持不变。 需要创新的方法来为那些被诊断患有肝脏肿瘤的人开发新的治疗选择。不可逆 电穿孔（IRE）是热消融的替代方案，由此在电极之间递送快速电脉冲 位于肿瘤内部或周围。IRE输送过程中产生的电场导致永久细胞的形成 膜缺陷使细胞不能调节正常的稳态并诱导细胞死亡。因为IRE诱导 最小的热坏死或组织失活，IRE提供了保留结构完整性的优点， 潜在的组织结构。然而，与现有的IRE相关的临床和技术复杂性意味着它已经被 临床上采用缓慢。 我们开发了一种新型的高频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 实时准确监测消融过程。这使我们假设，创建单针双电极 HFIRE（SN-HFIRE）输送平台将直接推动该技术的发展，以选择性治疗肝肿瘤 不适合切除或热消融。为了验证这一假设，提出了三个目标。目标1将使用小说 离体机器灌注肝脏模型，以测试现有SN-HFIRE设备的功能，并开发和评估 新型SN-HFIRE器件，其结合了用于HFIRE输送的热缓解材料。这些研究将在 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- HFIRE在复杂的体内环境中使用急性和慢性大动物（猪）肝脏模型;目的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 方法将建立在研究小组的技术和临床专业知识的基础上，以开发一种创新的， 转化的方法来治疗和管理那些被诊断患有不可治疗的肝脏肿瘤，同时 创造了一种新的消融技术，该技术易于适用于治疗其他不可手术的实体瘤。