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

抽象的。肝脏肿瘤是世界上与癌症相关的死亡的第三大原因。外科手术(切除或 移植)形成了治疗肝肿瘤意图治愈的历史基础。然而，晚期疾病 诊断时的分期(包括肝内和肝外转移疾病)，可移植器官的缺乏，潜在的 肝脏病理、肝内肿瘤的位置和广泛的血管受累常常限制手术的进行。 将干预作为可行的选择。热消融已成为手术切除的替代方案。虽然有可能治愈，但肿瘤 血管形成和定位(与重要结构相关)常常使热消融仅限于部分肝病患者。 肿瘤。因此，在所有被诊断为肝肿瘤的患者中，只有不到25%的人可以接受现有的治疗方法 治疗意向和五年存活率(15%-25%)在过去30年基本保持不变。 需要创新的方法来为那些被诊断为肝脏肿瘤的人开发新的治疗选择。不可逆转 电穿孔(IRE)是热消融的一种替代方法，利用这种方法，在电极之间传输快速电脉冲 放置在肿瘤内或肿瘤周围。在IRE传输过程中产生的电场导致永久电池的形成 膜缺陷使细胞不能调节正常的动态平衡，并导致细胞死亡。因为愤怒引发了 最小程度的热坏死或组织失活，IRE的优点是保留了 潜在的组织架构。然而，与现有IRE相关的临床和技术复杂性意味着它已经 临床应用缓慢。 我们开发了一种新的高频IRE(HFIRE)系统，它克服了许多技术挑战 通过发射超短、双极电脉冲与IRE相关联。然而，HFIRE系统并不能克服 临床挑战需要在具有挑战性的解剖环境中放置多个电极或无法 准确实时监测消融进度。这让我们假设，创造一个单针-双电极 HFIRE(SN-HFIRE)输送平台将直接推动这项技术的发展，以选择性地治疗肝脏肿瘤 不适合切除或热消融。为了验证这一假设，我们提出了三个目标。《目标1》将采用一部小说 体外机器灌流肝脏模型，以测试现有SN-HFIRE设备的功能，并开发和评估 新型SN-HFIRE装置，结合了用于HFIRE输送的降温材料。这些研究将被执行 结合组织消融特性的实时测量；AIM 2将定义SN的临床潜力- 在复杂的活体环境中使用急性和慢性大型动物(猪)肝脏模型进行HFIRE；目标3将建立 SN-HFIRE通过治疗和切除方案治疗犬肝癌患者的临床可行性。建议数 方法将建立在聚集的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、 转化性方法治疗和管理那些被诊断为不能治疗的肝肿瘤，同时， 创造了一种新的消融技术，很容易适应于治疗其他无法手术的实体肿瘤。

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.