Advancing the Clinical Translation of Cyst Fluid Assays for Early Detection of Pancreatic Cancer

推进囊肿液检测的临床转化以早期检测胰腺癌

• 批准号: 10639705
• 负责人: Kimberly Saunders Kirkwood
• 金额: $ 35.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639705
• 关键词: Adenocarcinoma; Amylases; Aspartic Endopeptidases; Attention; Biochemical; Biological; Biological Assay; Blood; Carcinoembryonic Antigen; Cells; Cellularity; Clinical; Collaborations; Collection; Cyst; Cyst Fluid; Cytology; Data; Diagnosis; Diagnostic; Diagnostic tests; Dysplasia; Early Diagnosis; Epithelial Cells; Evaluation; Excision; Fluorescence; Freezing; Gastroenterology; Glucose; Health Care Costs; High grade dysplasia; Industry; Intervention; Liquid substance; Malignant - descriptor; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Morbidity - disease rate; Mucinous; Mucins; Mucous body substance; Needles; Neoplasms; Operative Surgical Procedures; Pancreatic Adenocarcinoma; Pancreatic Cyst; Pancreatic cystic neoplasia; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Performance; Pharmaceutical Chemistry; Procedures; Protocols documentation; Publishing; Reader; Reproducibility; Running; Sampling; Serine Protease; Serum; Site; Standardization; Stomach; Technology; Temperature; Testing; United States; Viscosity; Warm Ischemia; aspirate; clinical biomarkers; clinical decision-making; clinical practice; clinical translation; detection assay; detection limit; diagnostic accuracy; gastricsin; improved; mortality risk; neoplastic; novel; overtreatment; prospective; radiological imaging; risk stratification; sample collection; standard of care; tool; tripeptidyl aminopeptidase; Adenocarcinoma; Amylases; Aspartic Endopeptidases; Attention; Biochemical; Biological; Biological Assay; Blood; Carcinoembryonic Antigen; Cells; Cellularity; Clinical; Collaborations; Collection; Cyst; Cyst Fluid; Cytology; Data; Diagnosis; Diagnostic; Diagnostic tests; Dysplasia; Early Diagnosis; Epithelial Cells; Evaluation; Excision; Fluorescence; Freezing; Gastroenterology; Glucose; Health Care Costs; High grade dysplasia; Industry; Intervention; Liquid substance; Malignant - descriptor; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Morbidity - disease rate; Mucinous; Mucins; Mucous body substance; Needles; Neoplasms; Operative Surgical Procedures; Pancreatic Adenocarcinoma; Pancreatic Cyst; Pancreatic cystic neoplasia; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Performance; Pharmaceutical Chemistry; Procedures; Protocols documentation; Publishing; Reader; Reproducibility; Running; Sampling; Serine Protease; Serum; Site; Standardization; Stomach; Technology; Temperature; Testing; United States; Viscosity; Warm Ischemia; aspirate; clinical biomarkers; clinical decision-making; clinical practice; clinical translation; detection assay; detection limit; diagnostic accuracy; gastricsin; improved; mortality risk; neoplastic; novel; overtreatment; prospective; radiological imaging; risk stratification; sample collection; standard of care; tool; tripeptidyl aminopeptidase

PROJECT SUMMARY Pancreatic cystic lesions (PCLs) represent an opportunity for early detection of pancreatic adenocarcinoma. The accurate identification of cysts with high grade dysplasia or invasive adenocarcinoma, together referred to as “Advanced Neoplasia” (AN), that warrant surgical intervention represents a critical unmet need in the management of PCLs. Most pancreatic cysts with the potential to develop AN are mucinous; in contrast, non- mucinous PCLs have little or no malignant potential. Biochemical and cytological analysis of aspirated cyst fluid are important tools in the diagnosis and risk stratification of PCLs. However, sensitivity of the only clinical biomarker for mucinous cysts, carcinoembryonic antigen (CEA), is insufficient to allow clinicians to confidently remove patients from surgical consideration. Moreover, the most commonly performed CEA assay requires 500 L of fluid, which is often unavailable. For over 50% of patients that undergo invasive trans-gastric cyst fluid aspiration, inadequate biospecimen is obtained to run the standard of care biochemical tests. In an effort to improve the sensitivity and applicability of cyst fluid analysis, we used our novel multiplex mass spectrometry technology to identify the protease gastricsin which accurately identifies mucinous cysts with an AUC of 0.98 and requires only 5 L fluid. Despite reliance by clinicians on these analyses to guide clinical decision-making, little effort has been directed toward optimization of biospecimen processing for pancreatic cyst fluid. There are no standardized pathways for cyst fluid processing and, unlike other biospecimens such as serum, pancreatic cyst fluid has variable viscosity and contamination with blood and proteinaceous material that could interfere with assay reproducibility. It is unknown if the variability we observe clinically in cyst fluid CEA and cytology reflects true biological differences or inconsistent preanalytical biospecimen processing. The overall objective of this proposal is to improve completeness, reproducibility, and accuracy in pancreatic cyst fluid diagnostic evaluation in order to improve the early diagnosis of pancreatic cancer while avoiding the burdens of overdiagnosis and overtreatment. To achieve our objective, we will systematically evaluate the impact of preanalytical variables on cyst fluid biochemical and cytological analysis (Aim 1) and identify strategies to mitigate the small volumes of available cyst fluid (Aim 2) in order to develop a streamlined, reproducible protocol (Aim 3) that improves the reliable early detection of pancreatic cancer. We will then validate the performance of our streamlined protocol using prospectively - collected clinical samples, and we will evaluate inter-assay variability by implementing the protocols at two independent sites. By improving the reliability of our assays, clinicians will be able to direct surgical intervention appropriately to patients with incipient pancreatic cancer while sparing others unnecessary risks of mortality, substantial morbidity, and health care costs.

项目摘要 胰腺囊性病变（PCLS）代表了早期检测胰腺腺癌的机会。 精确鉴定具有高级发育异常或侵入性腺癌的囊肿，共同鉴定 作为“先进的肿瘤”（AN），保证手术干预代表了关键的未满足需求 PCL的管理。大多数具有开发A的潜力的胰腺囊肿都是粘液性的。相反，非 - 粘液PCL几乎没有或没有恶性潜力。抽吸囊肿的生化和细胞学分析 流体是PCL诊断和风险分层的重要工具。但是，唯一的临床灵敏度 用于粘液囊肿的生物标志物，癌肠抗原（CEA）不足以使临床医生自信地允许临床医生 从手术考虑中删除患者。而且，最常见的CEA测定要求 500 l的流体，通常不可用。超过50％的患者患有侵入性的转冬胃囊肿 流体抽吸，生物仿生不足以运行护理生化测试的标准。努力 为了提高囊肿流体分析的灵敏度和适用性，我们使用了新型的多重质量 光谱技术识别蛋白质胃蛋白，该蛋白质胃胃融合准确地识别了用 AUC为0.98，仅需要5 ly液。尽管临床医生依靠这些分析来指导临床 决策，几乎没有努力用于优化胰腺的生物测量加工 囊肿流体。没有用于囊肿流体加工的标准化途径，与其他生物测量不同 作为血清，胰腺囊肿液具有可变的粘度和血液和蛋白质材料的污染 这可能会干扰测定可重复性。我们在囊肿液中临床观察到的变异性是否尚不清楚 CEA和细胞学反映了真正的生物学差异或不一致的精髓生物测定处理。这 该建议的总体目的是提高完整性，可重复性和准确性 胰腺囊肿液体诊断评估，以改善胰腺癌的早期诊断 同时避免过度诊断和过度治疗的伯恩斯。为了实现我们的目标，我们将 系统地评估放分析变量对囊肿液生化和细胞学分析的影响 （目标1）并确定减轻少量可用囊肿液（AIM 2）的策略以开发 一种简化的可再现方案（AIM 3），可改善胰腺癌的可靠发现。 然后，我们将使用前瞻性收集的临床来验证流线型协议的性能 样本，我们将通过在两个独立站点上实施协议来评估测定间的可变性。 通过提高评估的可靠性，临床医生将能够适当地指导外科手术干预 初期胰腺癌的患者在避开其他不必要的死亡风险时，大量 发病率和医疗保健费用。