For biomarker discovery, the latter was chosen as a control group because the risk of postprocedural pancreatitis or cholangitis ethically bans ERC from application in healthy subjects. However, as the control group consists of patients with choledocholithiasis, proteomic analysis may reflect the difference between a relatively normal GSK-3 assay biliary tree and liver, and an inflamed, cholestatic liver, which can be expected in patients with PSC and patients with a dominant stenosis due to CC. The PSC/CC model was able to distinguish CC and PSC from nonmalignant lesions with an AUC of 0.93 (P = 0.0001), a sensitivity of 93%, and a specificity of

86% as validated in an independent cohort. These findings are of clinical significance,

as in patients with suspected CC or PSC endoscopic procedures will be performed and thus bile becomes accessible. Furthermore, even in the presence of large masses suspicious of CC, a definite diagnosis often cannot be made. The surveillance of patients with PSC is of crucial importance, as those patients have an increased risk to develop CC and curative treatment such as liver transplantation or radical resection can be performed only at an early stage. Therefore, our aim was to distinguish PSC from CC in a second model. This model was established using a training Metformin molecular weight set consisting of 18 patients with PSC and 16 with CC. Applied to an independent validation set (18 PSC, 25 CC) it showed an AUC of 0.87, a specificity Amylase of 78%, and a high sensitivity of 84%. Our findings indicate a possible role of proteomic analysis for surveillance in patients with PSC. Nevertheless, PSC-associated CC may be of different origin than sporadic cholangiocarcinoma. Ten patients within the CC group developed CC in addition to PSC. Eight of those patients were identified positive for CC by proteomic analysis. This proteomic model

reaches a high sensitivity compared to single biochemical markers. Direct comparison with the widely used CA 19-9 tumor marker is impossible, because previous studies used different cutoff values in various study populations, leading to enormous range of sensitivity (53%-92%) and specificity (50%-98%).44 Our proposed model may be of clinical relevance in diagnosing CC in patients with PSC especially if supplementary to other diagnostic methods, as a higher accuracy can be reached by a combination of different diagnostic tools.45 All in all, proteomic analysis of bile as a diagnostic tool for surveillance of patients with PSC alone or in combination with other methods may provide an early and reliable diagnosis of CC. In summary, our data indicate a possible role of proteomic analysis of bile to differentiate CC from PSC and benign lesions.