Partial-wave spectroscopic microscopy for the diagnosis of cholangiocarcinoma

描述(申请人提供)：本R21申请的主要目的是证明使用一种新兴的生物光子学技术--部分波光谱显微镜(PWS)诊断和监测胆管细胞癌(CCA)的可行性。CCA是胆管上皮细胞的主要恶性肿瘤。虽然这是一种罕见的癌症，但这种癌症的全球发病率正在上升。这是一种致命的疾病，中位生存期为几个月。然而，当癌症在早期局部阶段被诊断出来时，存活率可能会有显著的提高。目前的成像技术要么灵敏度低，有时会导致严重的并发症，如胰腺炎和胆管炎。组织病理学的确认是出了名的困难，即使应用先进的分子技术(如荧光原位杂交)，其敏感性也不太理想，只有9%到67%。这些低发生率在很大程度上是由于在炎症背景下使用传统显微镜技术识别恶性细胞的挑战，并突显了一种新的生物光子学方法通过检测细胞内的细微变化来诊断恶性肿瘤的潜在作用。PWS是对细胞内固体(DNA、RNA和蛋白质等)浓度变化引起的细胞纳米结构折射率波动的一种新的分子分析。在单个细胞水平上，这超出了传统显微镜所揭示的。我们已经完成了成功的初步人体研究，以证明PWS在提高胰腺癌诊断准确性和风险分层方面的可行性。这项研究将以三个具体目标为指导：目标1将通过使用档案细胞学标本的回顾性研究，评估PWS通过在可疑胆管狭窄患者中识别CCA来提高细胞学诊断准确性的能力。AIM 2将在一组独立的人类受试者中进行预期的人体研究，验证AIM 1中确定的PWS的光学签名。目的3通过评估胆管附近的十二指肠上皮细胞，识别CCA的“场效应”，即发现远离病变的肿瘤性改变，从而证明PWS在诊断和分层CCA风险方面的潜力。我们认为，拟议项目的合理结果是证明了我们的光学技术识别十二指肠CCA存在的可能性，并提高了CCA的细胞学诊断。长期目标是开发一种微创监测策略，以识别高危个体，在可以治愈的治疗阶段，有理由使用更具侵入性的程序进行密集检查，以检测CCA，而不需要直接询问胆管。

DESCRIPTION (provided by applicant): The major objective of this R21 application is to demonstrate the feasibility of using an emerging biophotonics technology - partial-wave spectroscopic microscopy (PWS) for the diagnosis and surveillance of cholangiocarcinoma (CCA). CCA is a primary malignancy in bile duct epithelium. Although it is a rare cancer, the global incidence of this cancer is on the rise. It is a deadly disease with a median survival of months. However, significant improvements in survival rates are possible when the cancer is diagnosed at an early localized stage. Current imaging techniques suffer from either low sensitivity and sometimes lead to significant complications such as pancreatitis and cholangitis. The histopathological confirmation is notoriously difficult, with a suboptimal sensitivity of 9% up to 67% even when the advanced molecular techniques (e.g., fluorescence in situ hybridization (FISH)) were applied. These low rates are in large part due to the challenges of identifying malignant cells with conventional microscopic techniques in the setting of inflammation, and highlight a potential role for a novel biophotonic approach to diagnose malignancy by detecting subtle changes within a cell. PWS represents a novel molecular analysis of cell nano-architectural refractive index fluctuation arising from the changes in the concentration of intracellular solids (DNA, RNA and proteins, etc.) at a single cell level beyond what conventional microscopy reveals. We have completed successful pilot human studies to demonstrate the feasibility of PWS to improve the diagnostic accuracy and stratify risk for pancreatic cancer. This study will be guided by three specific aims: Aim 1 will assess the ability of PWS to improve the diagnostic accuracy of cytology by identifying CCA in patients with suspected biliary strictures in a retrospective study using archival cytologic specimens. Aim 2 will validate the optical signatures from PWS identified in Aim 1 in a prospective human study in an independent set of human subjects. Aim 3 will demonstrate the potential of PWS to diagnose as well as stratify risk for CCA through the identification of the "field-effect" of CCA, a concept of detecting a neoplastic alteration far away from the lesion, through the assessment of the duodenal epithelial cells in the vicinity of the bile duct. We believe that reasonable outcomes of the proposed project are to demonstrate the possibility of our optical technique to identify the presence of CCA in the duodenum and to improve the cytologic diagnosis of CCA. The long term goal is to develop a minimally invasive surveillance strategy to identify high risk individuals in whom intensive examination using more invasive procedures is warranted to detect a CCA at a stage when curable treatment is available, without the need for direct interrogation of the bile duct.