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

项目总结 临床影像技术的进步提高了胰腺囊性病变的偶然发现率 损伤。然而，患者仍然处于危险之中，因为缺乏准确评估是否 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 由于囊性病变快速和侵袭性进展为严重的胰腺恶性肿瘤所致的安全性 与手术干预相关的经济和身体发病率和死亡率。回溯性研究有 研究发现，近四分之一的外科手术治疗胰腺囊肿是不必要的。令人困惑的是 这种回溯性研究还表明，当临床医生使用观望方法时，高达四分之一 的患者接受手术切除的时间太晚。这一进程的双刃性突出表明有必要 更好的早期诊断工具。对诊断信息的临床需求仍然没有得到满足，这些信息可以 准确地分层与癌前病变、充满液体的胰腺病变相关的风险，这些病变通常是 担忧的第一个迹象。 目前，临床医生可以从偶然发现的胰腺囊肿中获取液体，用于疾病的化学分析- 相关的分子标记。胰腺囊肿液样本通常是高粘性的，这使得很难 等分，根据囊腔大小的不同，其体积可能非常有限。此外，现有的生物标志物分析 灵敏度低，周转时间长，需要高样本量。这些特点限制了数量 以及来自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 在适当的分析之间进行选择时的经验，这进一步混淆了标准化的尝试 临床护理的基础上。Amplated Sciences开发了一个强大的分析平台，可以分析低容量(低至1微米L) 临床胰腺囊肿液中蛋白酶活性检测对非粘液性和粘液性胰腺的鉴别 包囊种群。在这份提案中，Amplated Sciences正在扩展平台，以提供更高的内容 粘液性胰腺囊肿组恶性潜能的诊断信息。 放大科学分析和检测平台可适应新的生物标志物靶标。这项提议旨在 要创建一个多维分析小组，准确地确定胰腺囊肿进展到 癌症。三(3)个标记的组合正在由Aunus Biosciences的合作者和 加州大学旧金山分校有望在有限数量的临床粘液性胰腺囊肿中对不典型增生进行分级 样本。这项建议将1)验证这些标记物区分低级别和高级别异型增生的能力 在回溯性粘液临床样本中，2)将这些标记物的低容量分析转化为CLIA就绪 允许对单个样品进行堆叠分析的协议。完成后，一个新的化验小组将被 可使用最小囊液体积来量化经过验证的生物标记物，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，并迅速周转。

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.