Imaging and Molecular Correlates of Progression in Cystic Neoplasms of the Pancreas

 描述(由申请人提供)：超过2%的美国普通人群患有无症状的胰腺囊肿，由于越来越多地使用腹部成像，发病率正在上升。胰腺囊性病变包括分泌粘液的囊性病变，特别是导管内乳头状粘液性肿瘤(IPMN)和粘液性囊性肿瘤(MCNs)，它们是胰腺癌的真正前驱病变，以及其他一些肿瘤，如浆液性囊腺瘤(SCA)，其恶性程度很低。即使在IPMN和MCNs的微观世界中，大多数囊肿都是惰性的，目前公认的治疗分层指南在许多情况下导致过度治疗。尽管如此，一旦发生侵袭，非侵袭性粘液囊肿患者的长期存活率从90%-100%下降到近一半，这突显了筛查囊肿群的持续重要性。区分最有可能进展为恶性的胰腺囊肿和明确无痛的胰腺囊肿，将有助于对这种迅速流行的疾病进行合理的筛选和管理。我们假设胰腺囊肿形成的遗传驱动因素与物理微环境相互作用以促进恶性进展，后者反映在可测量的成像特征和体液免疫反应中。为了解决这一假设，我们将在MD Anderson创建一个“成像和分子表征实验室”(IMCL)，并与四个高容量胰腺中心(加州大学旧金山分校、加州大学圣地亚哥分校、印第安纳大学和犹他大学)合作，以获取&GT；1000个手术切除的回顾囊肿样本，并在本提案期间预期获得约1,300名预期的囊肿患者。在目标1中，我们将把胰腺囊肿物理微环境的定量测量(从标准护理诊断CT扫描获得)与潜在的组织病理学和基因组图谱相关联。在目标2中，我们将通过使用人类多肽阵列(Roche-NimbleGen)检测血清中针对300多万个全基因组表位的自身抗体反应来识别胰腺囊肿恶性进展的宿主免疫反应。在这两个目标中，我们将使用现有的诊断成像和来自手术切除并经组织病理学验证的胰腺囊肿患者的血清样本作为训练集，然后从预期累积的样本中应用于测试集中。最后，在目标3中，我们将合并之前两个目标的数据，以开发一个预测胰腺囊肿肿瘤进展的综合算法。多中心协调回顾和未来的生物检疫收集以及数据管理的所有方面，将由统计和中央数据管理中心内的一个数据管理核心提供支助。通过将宿主免疫反应的幅度和靶点与使用标准护理诊断成像研究获得的定量物理特征相结合，我们希望开发出可靠的算法，使用相对非侵入性和便携的方法来预测胰腺囊肿的进展风险，从而解决对公共卫生具有最高意义的未得到满足的需求。

 DESCRIPTION (provided by applicant): More than 2% of the US general population harbors an asymptomatic pancreatic cyst, and the incidence is rising due to increasing use of abdominal imaging. Pancreatic cystic lesions include mucin-secreting cysts - specifically, Intraductal Papillary Mucinous Neoplasms (IPMNs) and Mucinous Cystic Neoplasms (MCNs), which are bona fide precursor lesions of pancreatic adenocarcinoma, and others, such as serous cystadenomas (SCAs) that have minimal potential for malignancy. Even within the microcosm of IPMNs and MCNs, the majority of cysts are indolent, and current consensus guidelines for therapeutic stratification lead to over-treatment in many cases. Nonetheless, the long-term survival of patients with non-invasive mucinous cysts drops from 90-100% to nearly half once invasion occurs, underscoring the continuing importance of screening cyst populations. Distinguishing pancreatic cysts that harbor greatest potential for progression to malignancy from those that are unequivocally indolent will allow rational screening and management of this burgeoning epidemic. We hypothesize that genetic drivers of pancreatic cyst formation interact with the physical microenvironment to fuel malignant progression, and the latter is reflected in measureable imaging features and humoral immune responses. To address this hypothesis, we will create an "Imaging and Molecular Characterization Laboratory" (IMCL) at MD Anderson, and partner with four high volume pancreatic centers (UCSF, UCSD, Indiana University and University of Utah), for access to >1,000 surgically resected retrospective cyst samples, and an expected accrual of ~1,300 prospective cyst patients over the period of this proposal. In Aim 1, we will correlate quantitative measurements of the physical microenvironment of pancreatic cysts (obtained from standard-of-care diagnostic CT scans) with underlying histopathology and genomic profiles. In Aim 2, we will identify the host immune response to malignant progression in pancreatic cysts by measuring autoantibody responses in the serum to over three million genome-wide epitopes using a Human Peptide Array (Roche-NimbleGen). In both aims, we will use existing diagnostic imaging and banked serum samples from patients with surgically resected and histopathology validated pancreatic cysts as a training set, followed by application in a test set from prospectively accrued samples. Finally, in Aim 3, we will merge the data from both prior aims to develop an integrated algorithm for predicting neoplastic progression in pancreatic cysts. Multi-center coordination of retrospective and prospective biospecimen collection and all aspects of data management will be supported by a Statistical and Centralized Data Management Core (SCDMC) within the IMCL. By integrating the amplitude and targets of the host immune response with quantitative physical features obtained using standard-of-care diagnostic imaging studies, we hope to develop reliable algorithms that can predict the risk of progression in pancreatic cysts using relatively non-invasive and portable approaches, and thereby address an unmet need of highest significance to public health.