Firpo Matthew A, Gay David Z, Granger Steven R, Scaife Courtney L, DiSario James A, Boucher Kenneth M, Mulvihill Sean J
Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
World J Surg. 2009 Apr;33(4):716-22. doi: 10.1007/s00268-008-9853-9.
Timely, accurate diagnosis of pancreatic adenocarcinoma (PA) is hampered by the lack of effective circulating biomarkers. No single test has emerged that improves upon the commonly used biomarker cancer antigen 19-9 (CA 19-9) to discriminate PA from benign conditions effectively. The goals of this study were to validate two acute-phase proteins, haptoglobin and serum amyloid A (SAA), as biomarkers for PA and determine if the combination of haptoglobin, SAA, and CA 19-9 would improve PA diagnosis over CA 19-9 alone.
Levels of haptoglobin, SAA, and CA 19-9 were measured in pretreatment sera from 75 PA patients, 32 patients with chronic pancreatitis, 42 patients with other benign pancreatic disease or biliary stricture, and 150 healthy control subjects by enzyme-linked immunosorbent assay or colorimetric binding assay. Relative levels of haptoglobin or SAA were compared between groups using analysis of variance. The diagnostic accuracy of serum haptoglobin and SAA levels were investigated using receiver operating characteristics (ROC) analysis. Using classification tree analysis, an algorithm was developed that used haptoglobin, SAA, and CA 19-9 in a diagnostic screening panel.
Both haptoglobin and SAA were significantly elevated in sera from PA patients compared to healthy control subjects (p<0.0001) and patients with chronic pancreatitis (p=0.01). Haptoglobin was significantly elevated in sera from PA patients relative to patients with other benign diseases (p=0.0015), whereas SAA fell short of significance in the same comparison (p=0.0508). ROC analysis indicated that haptoglobin [area under the curve (AUC)=0.792] was a better diagnostic marker than SAA (AUC=0.691) over multiple threshold cutoffs. Using specific cutoffs that minimized overall misclassification, haptoglobin yielded a sensitivity of 82.7% and a specificity of 71.1%, and SAA yielded a sensitivity of 34.7% and a specificity of 90.2% when discriminating PA cases from all non-PA controls. In the same sample set, CA 19-9 yielded a sensitivity of 77.3% and a specificity of 91.1%. Combining data from haptoglobin, SAA, and CA 19-9 in a diagnostic screening panel improved the overall accuracy when compared to CA 19-9 alone, yielding a sensitivity of 81.3% and a specificity of 95.5%.
These data demonstrate that haptoglobin and SAA are useful for discriminating PA from benign conditions as well as healthy controls when used in a diagnostic screening panel. This study supports the use of combined biomarkers for improved accuracy in the diagnosis of PA.
有效的循环生物标志物的缺乏阻碍了胰腺腺癌（PA）的及时、准确诊断。目前尚未出现能优于常用生物标志物癌抗原19-9（CA 19-9）来有效区分PA与良性疾病的单一检测方法。本研究的目的是验证两种急性期蛋白，即触珠蛋白和血清淀粉样蛋白A（SAA）作为PA的生物标志物，并确定触珠蛋白、SAA和CA 19-9的组合是否比单独使用CA 19-9能改善PA的诊断。
通过酶联免疫吸附测定法或比色结合测定法，测量了75例PA患者、32例慢性胰腺炎患者、42例其他良性胰腺疾病或胆管狭窄患者以及150名健康对照者的治疗前血清中触珠蛋白、SAA和CA 19-9的水平。使用方差分析比较各组之间触珠蛋白或SAA的相对水平。使用受试者工作特征（ROC）分析研究血清触珠蛋白和SAA水平的诊断准确性。通过分类树分析，开发了一种在诊断筛查面板中使用触珠蛋白、SAA和CA 19-9的算法。
与健康对照者（p<0.0001）和慢性胰腺炎患者（p=0.01）相比，PA患者血清中的触珠蛋白和SAA均显著升高。与其他良性疾病患者相比，PA患者血清中的触珠蛋白显著升高（p=0.0015），而在相同比较中SAA未达到显著水平（p=0.0508）。ROC分析表明，在多个阈值临界值下，触珠蛋白[曲线下面积（AUC）=0.792]比SAA（AUC=0.691）是更好的诊断标志物。使用使总体错误分类最小化的特定临界值，在区分PA病例与所有非PA对照时，触珠蛋白的敏感性为82.7%，特异性为71.1%，SAA的敏感性为34.7%，特异性为90.2%。在同一样本集中，CA 19-9的敏感性为77.3%，特异性为91.1%。与单独使用CA 19-9相比，在诊断筛查面板中结合触珠蛋白、SAA和CA 19-9的数据可提高总体准确性，敏感性为81.3%，特异性为95.5%。
这些数据表明，当用于诊断筛查面板时，触珠蛋白和SAA可用于区分PA与良性疾病以及健康对照。本研究支持使用联合生物标志物提高PA诊断的准确性。
