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

基本信息

项目摘要

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.
项目总结 胰腺囊性病变(PCL)为早期发现胰腺癌提供了机会。 高度不典型增生或浸润性腺癌囊性病变的准确识别 作为“晚期新生血管病”(AN),需要手术治疗代表着严重的未满足的需求 多氯联苯的管理。大多数有可能发展为AN的胰腺囊肿是粘液性的;相比之下,非粘液性的 粘液性PCL的恶性潜能很小或没有。抽吸囊肿的生化和细胞学分析 体液是PCLS诊断和风险分层的重要工具。然而,临床上唯一的敏感性 粘液囊肿的生物标志物,癌胚抗原(CEA),不足以让临床医生有信心地 将病人从外科手术考虑中剔除。此外,最常见的CEA检测需要 500L的液体,这往往是无法获得的。对于50%以上接受侵袭性经胃囊肿治疗的患者 液体抽吸时,获得的生物检验液不足以进行标准的护理生化检测。在一次努力中 为了提高囊液分析的灵敏度和适用性,我们使用了我们的新型复合肿块 用光谱分析技术鉴定能准确识别粘液囊肿的胃蛋白酶 AUC0.98,只需要5的L液。尽管临床医生依赖这些分析来指导临床 决策方面,很少有人致力于优化胰腺的生物素制剂 囊液。没有处理囊液的标准化途径,而且不像其他生物旋毛虫那样 作为血清,胰腺囊液具有可变的粘度以及与血液和蛋白质类物质的污染。 这可能会干扰检测的重复性。目前尚不清楚我们在囊液中临床观察到的可变性 CEA和细胞学反映了真正的生物学差异或不一致的分析前生物标本处理。这个 本提案的总体目标是提高数据的完整性、重复性和准确性 胰腺囊液诊断评价提高胰腺癌早期诊断率 同时避免过度诊断和过度治疗的负担。为了实现我们的目标,我们将 系统评价分析前变量对囊液生化和细胞学分析的影响 (目标1)并确定缓解可用囊液数量较少的战略(目标2),以便发展 一种简化的、可重复的方案(AIM 3),可提高胰腺癌的可靠早期检测。 然后,我们将使用预期收集的临床数据来验证我们简化方案的性能 我们将通过在两个独立的地点实施这些协议来评估检测间的可变性。 通过提高我们分析的可靠性,临床医生将能够适当地指导手术干预 早期胰腺癌患者在避免其他人不必要的死亡风险的同时, 发病率和医疗保健费用。

项目成果

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Kimberly Saunders Kirkwood其他文献

Neoadjuvant Therapy Decreases Postoperative Pancreatic Fistula, Delayed Gastric Emptying, and Systemic Morbidity in Patients Undergoing Pancreaticoduodenectomy: An American College of Surgeons NSQIP Analysis
  • DOI:
    10.1016/j.jamcollsurg.2020.07.529
  • 发表时间:
    2020-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alexa Glencer;Jeremy Sharib;Paige Bracci;Tyler J. York;Sophia Hernandez;Kimberly Saunders Kirkwood;Carlos Uriel Corvera
  • 通讯作者:
    Carlos Uriel Corvera
Minimally Invasive Splenectomy Is Associated with Decreased Serious Complications: A 2008-2018 NSQIP Analysis
  • DOI:
    10.1016/j.jamcollsurg.2020.07.195
  • 发表时间:
    2020-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Sophia Hernandez;Tyler J. York;Alexa Glencer;Jeremy Sharib;James Ross;Alexander Sehyun Kim;Paige Bracci;Kimberly Saunders Kirkwood
  • 通讯作者:
    Kimberly Saunders Kirkwood

Kimberly Saunders Kirkwood的其他文献

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{{ truncateString('Kimberly Saunders Kirkwood', 18)}}的其他基金

Neural Regulation of Pancreatic Function
胰腺功能的神经调节
  • 批准号:
    8277330
  • 财政年份:
    1995
  • 资助金额:
    $ 35.93万
  • 项目类别:
NEURAL REGULATION OF PANCREATIC FUNCTION
胰腺功能的神经调节
  • 批准号:
    6380780
  • 财政年份:
    1994
  • 资助金额:
    $ 35.93万
  • 项目类别:
NEURAL REGULATION OF PANCREATIC FUNCTION
胰腺功能的神经调节
  • 批准号:
    6176209
  • 财政年份:
    1994
  • 资助金额:
    $ 35.93万
  • 项目类别:
NEURAL REGULATION OF PANCREATIC FUNCTION
胰腺功能的神经调节
  • 批准号:
    2905536
  • 财政年份:
    1994
  • 资助金额:
    $ 35.93万
  • 项目类别:
NEURAL REGULATION OF PANCREATIC FUNCTION
胰腺功能的神经调节
  • 批准号:
    6524108
  • 财政年份:
    1994
  • 资助金额:
    $ 35.93万
  • 项目类别:
NEURAL REGULATION OF PANCREATIC FUNCTION
胰腺功能的神经调节
  • 批准号:
    2706261
  • 财政年份:
    1994
  • 资助金额:
    $ 35.93万
  • 项目类别:

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