Natural History of Barrett's Esophagus Using Capsule Endomicroscopy

描述（由申请人提供）：巴雷特食管（BE）是一种正常食管鳞状黏膜因慢性胃酸反流而转变为化生柱状黏膜的疾病。BE可发展为食管癌（EAC），这是一种常见的（每年约12,000例）和致命的癌症（5年死亡率约15%）。目前的BE管理策略包括抗反流治疗、内镜筛查、定期内镜活检监测和消融治疗，对降低EAC的死亡率在很大程度上无效。治疗标准失败的一个重要原因是我们缺乏对BE的微观自然历史/演变的理解，这导致了对其定义的争议，对其进展和临床意义的不确定性，以及无法评估药物和消融治疗的有效性。出现这些问题的部分原因是用于研究BE的唯一方法是内窥镜活检，这是侵入性的，昂贵的，并且存在严重的活检采样限制。我们的实验室开发了一种新的成像概念，称为系栓胶囊内窥镜（TCE），克服了内窥镜活检的这些局限性。TCE包括吞咽一个系绳胶囊，当它通过蠕动穿过管腔器官或通过系绳向上拉向口腔时，获得整个食管壁的三维显微图像。与内窥镜检查相反，TCE通过评估整个食管的显微结构来减轻抽样误差。TCE手术可以在未使用镇静剂的患者中进行，比内窥镜检查更简单、更快、耐受性更好、更便宜。我们展示的第一个TCE原型使用光学相干断层扫描（OCT）以10微米的分辨率获得食道微观结构的横截面图像。在本提案中，我们将通过将OCT与称为光谱编码共聚焦显微镜（SECM）的高速反射共聚焦显微镜技术相结合，进一步推进TCE技术，以便从同一设备获得建筑和细胞形态学信息。我们还将加入一个位置传感器，这将允许在不同时间点从同一患者获得的微观数据集相互注册。一旦该装置被开发出来，我们将在一个多中心（5个地点）的临床试验中使用TCE来研究500名患者的BE自然病史。每年对所有患者进行影像学检查，为期3年（1500患者-年），并对TCE图像进行评估，以确定be如何随时间变化。本研究的结果将显著有助于BE的认识，使我们能够回答长期存在的关于其显微定义，其进展和临床意义，以及消融BE治疗的有效性的问题。从本研究中获得的知识将用于改进基于有关该疾病自然史的强有力科学证据的be管理策略。

DESCRIPTION (provided by applicant): Barrett's esophagus (BE) is a condition where normal esophageal squamous mucosa changes to metaplastic columnar mucosa in response to chronic acid reflux. BE can progress to esophageal adenocarcinoma (EAC), a prevalent (~12,000 cases per year) and deadly cancer (~15% 5-year mortality rate). Current BE management strategies of anti-reflux therapy, endoscopic screening, and regular endoscopic biopsy surveillance and ablation therapy, has been largely ineffective for decreasing the mortality of EAC. One important reason for the failure of the standard of care is our lack of understanding of the microscopic natural history/evolution of BE which has led to controversies about its definition, uncertainty regarding its progression and clinical significance, and an inability to evaluate the effectiveness of pharmacologic and ablative therapies. These questions have arisen in part because the only method used to study BE is endoscopic biopsy, which is invasive, costly, and suffers from severe biopsy sampling limitations. Our laboratory has developed a new imaging concept termed tethered capsule endomicroscopy (TCE) that overcomes these limitations of endoscopic biopsy. TCE involves swallowing a tethered capsule that acquires three-dimensional microscopic images of the entire esophageal wall as it traverses the luminal organ via peristalsis or is pulled up towards the mouth using the tether. As opposed to endoscopy, TCE mitigates sampling error by evaluating the microscopic structure of the entire esophagus. The TCE procedure can be conducted in unsedated patients, making it simpler, faster, better tolerated, and less expensive than endoscopy. The first TCE prototype that we have demonstrated uses optical coherence tomography (OCT) to obtain cross-sectional images of the microscopic architecture of the esophagus at a resolution of 10 �m. In this proposal, we will advance TCE technology further by combining OCT with a high-speed reflectance confocal microscopy technique called spectrally encoded confocal microscopy (SECM) so that obtain both architectural and cellular morphologic information can be obtained from the same device. We will additionally incorporate a position sensor that will allow microscopic datasets acquired from the same patients at different time points to be registered to one another. Once this device is developed, we will utilize TCE in a multicenter (5-site) clinical trial to study the natural history of BE in 500 patients. Imaging will be conducted on a yearly basis in all patients for a duration of 3 years (1500 patient-years) and the TCE images will be evaluated to determine how BE changes over time. The results of this study will significantly contribute to the knowledge of BE, allowing us to answer longstanding questions about its microscopic definition, its progression and clinical significance, and the effectiveness of ablativ BE therapies. The knowledge gained from this study will be used to improve BE management strategies based on strong scientific evidence about the natural history of this disease.