Partial-wave spectroscopic microscopy for the diagnosis of cholangiocarcinoma

描述（由申请人提供）：本R21申请的主要目的是证明使用新兴生物光子学技术-部分波光谱显微镜（PWS）诊断和监测胆管癌（CCA）的可行性。CCA是胆管上皮的原发性恶性肿瘤。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，平均存活时间只有几个月。然而，当癌症在早期局部阶段被诊断出来时，生存率有可能显著提高。目前的成像技术要么灵敏度低，要么有时会导致严重的并发症，如胰腺炎和胆管炎。组织病理学确认是出了名的困难，即使采用先进的分子技术（如荧光原位杂交（FISH）），其灵敏度也在9%到67%之间。如此低的检出率在很大程度上是由于在炎症背景下用传统的显微镜技术识别恶性细胞的挑战，并强调了通过检测细胞内细微变化来诊断恶性肿瘤的新型生物光子方法的潜在作用。PWS代表了一种新的分子分析方法，可以在单细胞水平上对细胞内固体（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进行分析，而传统显微镜技术无法揭示这种变化。我们已经完成了成功的人体试验，以证明PWS在提高胰腺癌诊断准确性和分层风险方面的可行性。本研究将以三个具体目标为指导：目的1将评估PWS在使用档案细胞学标本的回顾性研究中通过识别疑似胆道狭窄患者的CCA来提高细胞学诊断准确性的能力。目标2将在一组独立的人类受试者的前瞻性人类研究中验证目标1中确定的PWS的光学特征。Aim 3将展示PWS通过识别CCA的“场效应”（即通过评估胆管附近的十二指肠上皮细胞来检测远离病变的肿瘤改变）来诊断CCA并对CCA风险进行分层的潜力。我们认为，所提出的项目的合理结果是证明我们的光学技术在十二指肠中识别CCA存在的可能性，并提高CCA的细胞学诊断。长期目标是开发一种微创监测策略，以识别高风险个体，在可治愈的治疗阶段，需要使用更具侵入性的程序进行强化检查，以发现CCA，而无需直接检查胆管。

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.