Screening for Barrett's Esophagus Progressors with Multimodality Tethered Capsule Image-Guided Biopsy

食管腺癌是一种致命的癌症，在此之前会发生称为Barrett's的化生性改变 食管（BE）。长期以来，人们一直认为内镜筛查BE后进行内镜监测 能显著降低EAC的死亡率。不幸的是，这并没有证明成本和 清醒镇静的不方便性禁止内窥镜检查用作基于人群的筛选工具。 由于创新的可吞咽系留胶囊，BE筛查在未来可能成为可能 内窥镜或细胞采样装置，可以检测BE而不需要镇静。然而，即使这些 胶囊用于识别美国大量BE患者（约1500万），内镜监测 会非常昂贵如果我们能用组织生物标记物来识别5%的 如果在他们的一生中将发展EAC，那么内窥镜干预可以给予那些真正需要的人， 低风险BE患者不需要进一步随访。 认识到这一需求促使该领域鉴定源自食管癌的BE进展生物标志物。 通过自体荧光/反射靶向内窥镜检查获得的组织样本。这项研究发现， 生物标志物如非整倍体和异常p53/细胞周期蛋白A表达作为BE进展的强预测因子。 不幸的是，目前唯一的靶向和获取这些组织的方法是通过镇静内镜检查。与 这里提出的修改，一种新的BE筛选技术，我们已经开发出所谓的光学相干 断层扫描（OCT）栓系胶囊显微内镜（TCE）可以在没有镇静的情况下实现靶向活检。 OCT-TCE可获得未镇静受试者整个食管的3D显微图像， BE，并已成功地用于护士和技术人员在初级保健设置。在此，我们建议 通过增加自体荧光和反射光谱成像技术改进用于靶向活检的OCT-TCE 这可以帮助识别富含与BE进展风险相关的分子改变的组织。新 胶囊还将具有用于在真实的时间图像下获取目标组织样本的低温活检机构 指导在本提案的目标1中，我们将开发这种多模态TCE活检（MM-TCEB）器械， 在20名BE患者的研究中显示，它的效果与预期相同。然后，我们将在100个 未使用镇静剂的BE患者，以证明MM-TCEB收集组织并鉴定BE进展生物标志物 以及镇静的内窥镜检查在目标3中，我们将开发图像分析和深度学习算法来挖掘 Aim 2数据，揭示了OCT，自发荧光和反射光谱之间的新关系 和组织来源的BE进展生物标志物。通过使用可吞咽的栓系式活检针获得靶向活检， 在未使用镇静剂的受试者中，MM-TCEB可以成为获得食管组织的强大技术 用于BE进展生物标志物发现、验证和最终基于人群的筛查的样本。

Esophageal adenocarcinoma (EAC) is a deadly cancer that is preceded by a metaplastic change called Barrett's esophagus (BE). It has long been thought that endoscopic screening for BE followed by endoscopic surveillance can significantly decrease the mortality of EAC. This unfortunately has not borne out as the cost and inconvenience of conscious sedation prohibits endoscopy from being used as a population-based screening tool. BE screening may become possible in the future, owing to innovative swallowable tethered capsule endomicroscopes or cell sampling devices that can detect BE without requiring sedation. Yet, even if these capsules were to identify the large number of people in the US who have BE (~15M), endoscopic surveillance of this group would be prohibitively expensive. If we could use tissue biomarkers to identify the 5% of those with BE who will develop EAC in their lifetimes, then endoscopic intervention could be given to those who really need it, and those with low-risk BE would not require further follow up. Recognition of this need has motivated the field to identify BE progression biomarkers derived from esophageal tissue samples obtained by autofluorescence/reflectance-targeted endoscopy. This research has identified biomarkers such as aneuploidy and aberrant p53/cyclin A expression as strong predictors of BE progression. Unfortunately, the only way to target and obtain these tissues today is through sedated endoscopy. With the modifications proposed here, a new BE screening technology that we have developed called optical coherence tomography (OCT) tethered capsule endomicroscopy (TCE), could enable targeted biopsy without sedation. OCT-TCE obtains 3D microscopic images of the entire esophagus in unsedated subjects, accurately identifies BE, and has been successfully used by nurses and technicians in primary care settings. Here, we propose to advance OCT-TCE for targeted biopsy by adding autofluorescence and reflectance spectral imaging technology that can help identify tissue enriched in molecular alterations associated with BE progression risk. The new capsule will also have a cryobiopsy mechanism for acquiring targeted tissue samples under real time image guidance. In Aim 1 of this proposal, we will develop this multimodality TCE with biopsy (MM-TCEB) device and show that it works as intended in a study of 20 BE patients. Then, we will conduct a clinical study in 100 unsedated BE patients to demonstrate that MM-TCEB collects tissue and identifies BE progression biomarkers as well as sedated endoscopy. In Aim 3, we will develop image analysis and deep learning algorithms to mine the Aim 2 data, uncovering new relationships between OCT, autofluorescence, and reflectance spectroscopy and tissue-derived BE progression biomarkers. By acquiring targeted biopsies using a swallowable tethered capsule in unsedated subjects, MM-TCEB can become a powerful technique for obtaining esophageal tissue samples for BE progression biomarker discovery, validation, and ultimately population-based screening.