Translational Assays for Inflammatory Biomarkers for the Risk Stratification of Pancreatic Cystic Lesions

项目摘要 临床影像学技术的进步提高了胰腺囊性病变的偶然检出率， 病变然而，由于缺乏明确的诊断，患者仍然处于危险之中， 这些囊肿是癌前病变在缺乏强有力的诊断指标的情况下，临床医生必须平衡患者 安全性，因为囊性病变的快速和积极的进展，恶性胰腺肿瘤的严重 与手术干预相关的经济和身体发病率和死亡率。回顾性研究 发现几乎四分之一的外科手术治疗胰腺囊肿是不必要的。混淆因素是 回顾性研究还表明，当临床医生采用观望的方法时， 的患者接受手术切除太晚。这一进程的两面性突出表明， 更好的早期诊断工具仍然存在对诊断信息的未满足的临床需求， 准确地对与癌前病变、充满液体的胰腺病变相关的风险进行分层， 第一个关心的迹象。 目前，临床医生可以从偶然发现的胰腺囊肿中获得液体，用于疾病的化学分析- 相关分子标记。胰腺囊肿液样本通常是高粘度的，使得难以 囊肿的大小决定了它的体积是非常有限的。此外，可用的生物标志物测定法 缺乏灵敏度，可能具有长的周转时间，并且需要高的样品体积。这些特征限制了 和单个胰腺囊肿液样本的信息质量。临床医生必须依靠他们独特的 当在适当的分析之间进行选择时，这进一步混淆了标准化的尝试 临床护理。Amplified Sciences开发了一个强大的分析平台，用于分析低容量（低至1微升） 用于区分非粘液性胰腺与粘液性胰腺的蛋白酶活性的临床胰腺囊肿液样品 包囊种群在这项提案中，Amplified Sciences正在扩大平台，以提供更高的内容 胰腺粘液囊肿的恶性潜能的诊断信息。 Amplified Sciences分析和检测平台可适应新的生物标志物靶标。这项建议旨在 建立一个多维的分析面板，准确地确定胰腺囊肿进展的风险， 癌Allaunus Biosciences的合作者正在研究的三（3）种标记物的组合， UCSF有望对少数临床粘液性胰腺囊肿的异型增生进行分级 样品该提案将1）验证这些标记物区分低度和高度异型增生的能力 在回顾性粘液性临床样品中，和2）将这些标志物低容量测定转化为CLIA就绪 协议，以实现对单个样品的测定的堆叠。完成后，一个新的检测面板将 使用最小囊液体积来定量经验证的生物标志物，包括一种新方法 为临床医生提供最大限度地从宝贵的临床样本中获得准确的诊断信息，并快速周转。

PROJECT SUMMARY Advances in clinical imaging technologies have increased the incidental detection rate of cystic pancreatic lesions. However, patients remain at risk due to the lack of a definitive diagnosis that accurately assesses if these cysts are pre-malignant. In the absence of robust diagnostic indicators, clinicians must balance patient safety due to a cystic lesion's rapid and aggressive progression to a malignant pancreatic tumor with the severe financial and physical morbidity and mortality associated with surgical interventions. Retrospective studies have found almost a quarter of surgical interventions to address a pancreatic cyst are unwarranted. A confounder is that retrospective studies have also revealed that when clinicians use a wait-and-see approach, up to a quarter of patients receive surgical resection too late. The dual-edged nature of this process highlights the need for better early-stage diagnostic tools. There remains an unmet clinical need for diagnostic information that can accurately stratify the risk associated with pre-cancerous, fluid-filled pancreatic lesions that are commonly the first sign of concern. Currently, clinicians can obtain fluid from incidentally detected pancreatic cysts for chemical analysis of disease- associated molecular markers. Pancreatic cyst fluid samples are most often highly viscous, making it difficult to aliquot, and can be very limited in volume depending on the size of cyst. Furthermore, available biomarker assays lack sensitivity, can have long turnaround times, and require high sample volumes. These traits limit the amount and quality of information from single pancreatic cyst fluid samples. Clinicians must rely on their unique experiences when choosing between appropriate analyses, which further confuses attempts at standardization of clinical care. Amplified Sciences has developed a robust assay platform to analyze low-volume (down to 1 µL) clinical pancreatic cyst fluid samples for protease activity to distinguish non-mucinous from mucinous pancreatic cyst populations. In this proposal, Amplified Sciences is expanding the platform to provide higher content diagnostic information about the malignant potential of the mucinous pancreatic cyst population. Amplified Sciences assay and detection platforms are adaptable to new biomarker targets. This proposal aims to create a multidimensional assay panel that accurately determines the risk of pancreatic cysts progression to cancer. A combination of three (3) markers under investigation by collaborators at Alaunus Biosciences and UCSF show promise to stratify the grade of dysplasia in a limited number of clinical mucinous pancreatic cyst samples. This proposal will 1) validate the capacity of these markers to distinguish low- from high-grade dysplasia in retrospective mucinous clinical samples and 2) translate low-volume assays for these markers into CLIA-ready protocols to enable stacking of assays on individual samples. Upon completion, a novel assay panel will be available that uses minimal cyst fluid volumes to quantitate the validated biomarkers, comprising a new method for clinicians to maximize accurate diagnostic information from precious clinical samples with rapid turnaround.