Development of EndoScreen Chip, a Microfluidic Pre-Endoscopy Triage Test for Esophageal Adenocarcinoma.
Development of EndoScreen Chip, a Microfluidic Pre-Endoscopy Triage Test for Esophageal Adenocarcinoma.
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DOI：
10.3390/cancers13122865
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发表时间：
2021-06-08
期刊：
影响因子：
5.2
通讯作者：
Hill MM
中科院分区：
文献类型：
--
作者：
Webster JA;Wuethrich A;Shanmugasundaram KB;Richards RS;Zelek WM;Shah AK;Gordon LG;Kendall BJ;Hartel G;Morgan BP;Trau M;Hill MM
食管腺癌（EAC）通常发现较晚，生存率低。目前，根据临床风险因素（如Barrett食管的前驱疾病、胃灼热/反流病史、年龄和高体重指数）选择患者进行内镜活检诊断。为了实现基于血液的筛查，我们先前发现并验证了用于早期EAC的新型血液生物标志物。为了支持临床应用，在这里，我们报告了微流控EndoScreen芯片的技术开发，并在46个样本的测试队列中使用生物标志物JAC-C9（Jacalin-lectin结合补体成分C9）进行验证。与单独的临床风险因素相比，我们发现除了临床风险因素外，使用血液生物标志物JAC-C9和总C9改善了该队列中的EAC预测，这表明简单的血液检查可以帮助医生优先考虑患者进行内镜评估。未来的工作将在EndoScreen芯片的护理点版本上部署一组标记物，以实现EAC的人群筛查和早期诊断，从而降低这种癌症的死亡率。目前内镜和活检诊断食管腺癌（EAC）及其癌前病变巴雷特食管（BE）是不符合成本效益。为了实现EAC筛查和患者内窥镜分诊，我们开发了一种微流体凝集素免疫测定，EndoScreen芯片，它允许灵敏的多重血清生物标志物测量。在这里，我们报告了EAC生物标志物Jacalin凝集素结合补体C9（JAC-C9）的概念验证部署，我们以前发现并通过质谱法验证了该概念。产生单克隆C9抗体（m26 3C 9）并在微孔板ELISA中验证，然后在EndoScreen芯片上部署用于JAC-C9测量。队列评价（n = 46）证实了EAC中血清JAC-C9的预期升高，沿着总血清C9水平升高。接下来，我们询问当与患者风险因素（年龄，体重指数和胃灼热史）结合使用时，血清生物标志物的小组是否改善了该队列中EAC的检测。使用逻辑回归建模，我们发现血清C9和JAC-C9显著改善了EAC预测，从AUROC 0.838至0.931，其中JAC-C9对EAC具有强预测性（vs. BE OR = 4.6，95%CI：1.6-15.6，p = 0.014; vs.健康OR = 4.1，95%CI：1.2-13.7，p = 0.024）。这项概念验证研究证实了微流控EndoScreen芯片技术，并支持血液生物标志物在改善诊断性内窥镜检查分诊方面的潜在效用。未来的工作将从我们的经验证的EAC生物标志物列表中扩展EndoScreen芯片上的标志物数量。
Esophageal adenocarcinoma (EAC) is often detected late and has a poor survival rate. Currently, patients are selected for endoscopy-biopsy diagnosis based on clinical risk factors such as the precursor condition Barrett’s esophagus, history heartburn/reflux, age and high body mass index. To enable blood-based screening, we previously discovered and validated novel blood biomarkers for early stage EAC. To support clinical application, here, we report the technology development of the microfluidic EndoScreen chip and validation using the biomarker JAC-C9 (Jacalin-lectin binding complement component C9) in a test cohort of 46 samples. Compared to clinical risk factors alone, we found that use of blood biomarkers JAC-C9 and total C9 in addition to clinical risk factors improved EAC prediction in this cohort, suggesting that a simple blood test can help the physician prioritize patients for endoscopic evaluation. Future work will deploy a panel of markers on a point-of-care version of EndoScreen chip, to enable population screening and early diagnosis of EAC and thereby reduce mortality from this cancer. The current endoscopy and biopsy diagnosis of esophageal adenocarcinoma (EAC) and its premalignant condition Barrett’s esophagus (BE) is not cost-effective. To enable EAC screening and patient triaging for endoscopy, we developed a microfluidic lectin immunoassay, the EndoScreen Chip, which allows sensitive multiplex serum biomarker measurements. Here, we report the proof-of-concept deployment for the EAC biomarker Jacalin lectin binding complement C9 (JAC-C9), which we previously discovered and validated by mass spectrometry. A monoclonal C9 antibody (m26 3C9) was generated and validated in microplate ELISA, and then deployed for JAC-C9 measurement on EndoScreen Chip. Cohort evaluation (n = 46) confirmed the expected elevation of serum JAC-C9 in EAC, along with elevated total serum C9 level. Next, we asked if the small panel of serum biomarkers improves detection of EAC in this cohort when used in conjunction with patient risk factors (age, body mass index and heartburn history). Using logistic regression modeling, we found that serum C9 and JAC-C9 significantly improved EAC prediction from AUROC of 0.838 to 0.931, with JAC-C9 strongly predictive of EAC (vs. BE OR = 4.6, 95% CI: 1.6–15.6, p = 0.014; vs. Healthy OR = 4.1, 95% CI: 1.2–13.7, p = 0.024). This proof-of-concept study confirms the microfluidic EndoScreen Chip technology and supports the potential utility of blood biomarkers in improving triaging for diagnostic endoscopy. Future work will expand the number of markers on EndoScreen Chip from our list of validated EAC biomarkers.
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