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

食管腺癌(EAC)是一种致命的癌症，在此之前有一种称为Barrett‘s的化生变 食道(BE)。长期以来，人们一直认为内窥镜筛查之后是内窥镜监视 能显著降低EAC的死亡率。不幸的是，这并没有证明成本和 意识镇静的不便阻碍了内窥镜检查作为一种基于人群的筛查工具。 由于创新的可吞咽系绳胶囊，BE筛查在未来可能成为可能 无需镇静即可检测BE的内窥镜或细胞采样设备。然而，即使这些 胶囊是为了识别在美国进行(~1500万)内窥镜监测的大量人 这一群体的成本将高得令人望而却步。如果我们可以使用组织生物标记物来识别5%的 是谁会在他们的一生中发展为EAC，那么就可以对那些真正需要的人进行内窥镜干预 它和那些低风险的BE将不需要进一步的跟进。 对这一需求的认识促使该领域识别源自食道的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。这项研究确定了 生物标记物，如非整倍体和异常的P53/Cyclin A表达是BE进展的强烈预测因素。 不幸的是，今天靶向和获得这些组织的唯一方法是通过镇静的内窥镜检查。与 这里提出的修改是我们开发的一种新的BE筛选技术，称为光学相干 断层扫描(OCT)栓系胶囊内窥镜(TCE)，可以在没有镇静的情况下进行靶向活检。 OCT-TCE获得了未服用镇静剂的受试者整个食道的3D显微图像，准确地识别 BE，并已被护士和技术人员成功地用于初级保健环境。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OCT-TCE靶向活检技术 这有助于识别与BE进展风险相关的分子变化丰富的组织。新的 太空舱还将具有低温生物机制，以在实时图像下获取目标组织样本 指导。在本提案的目标1中，我们将开发这种带活组织检查的多模式TCE(MM-TCEB)设备，并 在一项对20名BE患者的研究中显示出它的预期效果。然后，我们将在100年内进行临床研究 未服用镇静剂的BE患者证明MM-TCEB收集组织并识别BE进展生物标记物 以及镇静剂内窥镜检查。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OCT、自体荧光和反射光谱之间的新关系 和组织衍生的BE进展生物标记物。通过使用可吞咽的绳索获取靶向活检 胶囊在未服用镇静剂的受试者中，MM-TCEB可成为获取食道组织的有力技术 用于BE进展生物标记物发现、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.