Outpatient Screening for Early-Stage High-Grade Serous Ovarian Cancer in Higher Risk Women

项目摘要 今年，美国将有超过22，000名女性被诊断患有卵巢癌（OvCa），约14，000人将死亡 从这种疾病。其中约9，000例死于高级别浆液性上皮癌（HGSC） 主要是因为我们无法在疾病的早期阶段发现它。OvCa占所有女性的2.5% 癌症病例，但5%的死亡，由于HGSC存活率低，因为大多数妇女 被诊断为对化疗产生抗药性的晚期疾病。众所周知，及时发现 早期疾病的治疗可以将5年生存率提高到> 90%， 发病率和死亡率。不幸的是，该疾病的生物学、遗传学和生活史已被证明是 在开发广泛可用的、准确的和具有成本效益的筛选测试方面尤其令人沮丧。 我们针对这一未满足的临床需求的创新方法利用了大多数患者的显著观察结果， HGSC并非起源于卵巢，而是起源于输卵管（FT），随后迁移至输卵管。 卵巢我们已经开发出一种具有高分辨率功能和结构的显微内窥镜（输卵管镜） 在0.5-mm至5-mm病变尺寸下识别早期HGSC所需的成像能力， 对死亡率的影响是深远的 在本提案中，我们将开发所需的临床特征：（a）允许快速使用输卵管镜， 在门诊环境中安全和有效，以及（B）允许在 类似于结肠镜检查或阴道镜检查的方式。为了实现我们的目标，我们建议建立一个机制， 与输卵管口对接并进入输卵管口（具体目标1），以便执行该手术 并且改善了该装置广泛临床应用的主要障碍之一。 在特定目标2中，我们将开发一种将内窥镜输送到远端FT的机制。这将包括一个 自动输送系统，具有压力敏感反馈，以确保安全输送和回收 设备，以及验证筛选试验所需的可再现成像条件。第三，具体目标 3将建立90%的特异性门诊为基础的筛选。我们将对手术后丢弃的组织进行成像， 使用来自约100名患者的样品，离体，但在其他临床代表性程序中， 既有良性疾病又有降低风险手术的个体。成像结果将与 金标准病理学继续建立高阴性所需的严格的统计基础， 筛选测试的预测值。在第一阶段申请结束时，我们将能够 在临床环境中测试我们的成像设备，作为第二阶段提案的一部分。

Project Summary This year, over 22,000 women in the U.S. will be diagnosed with ovarian cancer (OvCa), and ~14,000 will die from this disease. Approximately 9,000 of these deaths occur from high-grade serous epithelial cancer (HGSC) primarily because of our inability to detect the disease in its early stages. OvCa accounts for 2.5% of all female cancer cases but 5% of deaths, resulting from the low HGSC survival rate as the majority of women are diagnosed with advanced disease that becomes resistant to chemotherapy. It is well known that timely detection of early-stage disease could improve 5-year survival rates to >90%, with a significant associated reduction in morbidity and mortality. Unfortunately, the biology, genetics, and life history of the disease have proven to be particularly frustrating in terms of development of a widely available, accurate, and cost-effective screening test. Our innovative approach to this unmet clinical need exploits the remarkable observation that the majority of HGSC does not originate in the ovary but rather in the fallopian tube (FT), with subsequent migration to the ovary. We have developed a micro-endoscope (falloposcope) with the high-resolution functional and structural imaging capabilities needed to identify early-stage HGSC at the 0.5-mm to 5-mm lesion size, when the impact on mortality could be profound. In this proposal, we will develop the clinical features needed (a) to allow the falloposcope to be used quickly, safely and effectively in an outpatient setting, and (b) to allow immediate clinical feedback to the patient in a manner analogous to colonoscopy or colposcopy. To achieve our goals, we propose to develop a mechanism to dock with and enter the ostia of the fallopian tubes (Specific Aim 1), such that this procedure can be performed by a single operator and ameliorate one of the primary obstacles to widespread clinical adoption of the device. In Specific Aim 2, we will develop a mechanism to deliver the endoscope to the distal FT. This will consist of an automated delivery system with pressure-sensitive feedback to ensure the safe delivery and recovery of the device, and the reproducible imaging conditions needed for validation of the screening test. Lastly, Specific Aim 3 will establish 90% specificity for outpatient-based screening. We will image surgical discard tissue from approximately 100 patients ex vivo, but in an otherwise clinically representative procedure, using samples from individuals with both benign conditions and risk-reducing surgeries. The imaging results will be correlated to gold-standard pathology to continue building the rigorous statistical foundation needed for a high negative predictive value on which to base the screening test. At the end of this Phase I application, we will be in a position to test our imaging device in a clinical setting as part of a Phase II proposal.