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: 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
• 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

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为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 热坏死或组织失活最小化，IRE 具有不破坏组织结构完整性的优点 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。