Circulating levels of soluble urokinase plasminogen activator receptor predict outcome after resection of biliary tract cancer.

Surgical resection is the only potentially curative therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has been associated with distinct types of cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing BTC resection. Tumor expression of uPAR was analyzed by immunohistochemistry in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 patients with BTC and 76 healthy controls. High tumoral uPAR expression was associated with an adverse outcome after BTC resection. Accordingly, circulating levels of suPAR were significantly elevated in patients with BTC compared to healthy controls, as well as in patients with primary sclerosing cholangitis. Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72 ng/ml for patients with BTC. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including various clinicopathological parameters such as tumor stage, markers of inflammation and organ dysfunction, as well as tumor markers, revealed circulating suPAR levels as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative of acute kidney injury after tumor resection. Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might help to preoperatively identify the ideal candidates for liver surgery. Surgical resection represents the only curative treatment option for patients with biliary tract cancer, but not all patients benefit to the same extent in terms of overall survival. Here, we provide evidence that serum levels of an inflammatory mediator (suPAR) are indicative of a patient's postoperative outcome and might thus help to identify the ideal surgical candidates.

Loosen SH ，Breuer A ，Tacke F ，Kather JN ，Gorgulho J ，Alizai PH ，Bednarsch J ，Roeth AA ，Lurje G ，Schmitz SM ，Brozat JF ，Paffenholz P ，Vucur M ，Ritz T ，Koch A ，Trautwein C ，Ulmer TF ，Roderburg C ，Longerich T ，Neumann UP ，Luedde T ... -  《-》

Serum levels of soluble urokinase plasminogen activator receptor (suPAR) predict outcome after resection of colorectal liver metastases.

Loosen SH ，Tacke F ，Binnebosel M ，Leyh C ，Vucur M ，Heitkamp F ，Schoening W ，Ulmer TF ，Alizai PH ，Trautwein C ，Koch A ，Longerich T ，Roderburg C ，Neumann UP ，Luedde T ... -  《Oncotarget》

High baseline soluble urokinase plasminogen activator receptor (suPAR) serum levels indicate adverse outcome after resection of pancreatic adenocarcinoma.

Surgical resection represents the only potentially curative therapy for patients with pancreatic adenocarcinoma (PDAC), an aggressive malignancy with a very limited 5-year survival rate. However, even after complete tumor resection, many patients are still facing an unfavorable prognosis underlining the need for better preoperative stratification algorithms. Here, we explored the role of the secreted glycoprotein soluble urokinase plasminogen activator receptor (suPAR) as a novel circulating biomarker for patients undergoing resection of PDAC. Serum levels of suPAR were measured by enzyme-linked immunosorbent assay (ELISA) in an exploratory as well as a validation cohort comprising a total of 127 PDAC patients and 75 healthy controls. Correlating with a cytoplasmic immunohistochemical expression of uPAR in PDAC tumor cells, serum levels of suPAR were significantly elevated in PDAC patients compared to healthy controls and patient with PDAC precursor lesions. Importantly, patients with high preoperative suPAR levels above a calculated cutoff value of 5.956 ng/ml showed a significantly reduced overall survival after tumor resection. The prognostic role of suPAR was further corroborated by uni- and multivariate Cox-regression analyses including parameters of systemic inflammation, liver and kidney function as well as clinico-pathological patients' characteristics. Moreover, high baseline suPAR levels identified those patients particularly susceptible to acute kidney injury and surgical complications after surgery. In conclusion, our data suggest that circulating suPAR represents a novel prognostic marker in PDAC patients undergoing tumor resection that might be a useful addition to existing preoperative stratification algorithms for identifying patients that particularly benefit from extended tumor resection.

Loosen SH ，Tacke F ，Püthe N ，Binneboesel M ，Wiltberger G ，Alizai PH ，Kather JN ，Paffenholz P ，Ritz T ，Koch A ，Bergmann F ，Trautwein C ，Longerich T ，Roderburg C ，Neumann UP ，Luedde T ... -  《-》

Elevated Serum Levels of CCL23 Are Associated with Poor Outcome after Resection of Biliary Tract Cancer.

Surgical tumor resection is the only potentially curative treatment option for patients with biliary tract cancer (BTC). However, 5-year survival rates are still below 50% mainly due to tumor recurrence. The preoperative identification of ideal surgical candidates has remained a major challenge and easily accessible algorithms including parameters of the individual tumor biology are missing. Chemokine (C-C motif) ligand 23 (CCl23) has been associated with tumor progression in hepatocellular carcinoma (HCC), but its role in the context of BTC is largely unknown. Here, we evaluated circulating levels of CCL23 as potential diagnostic and prognostic biomarker in patients with resectable BTC. CCl23 serum levels were analyzed by multiplex immunoassay in a cohort of 119 BTC patients receiving surgical tumor resection as well as 50 healthy control samples and 11 patients with primary sclerosing cholangitis (PSC). Baseline serum CCL23 levels were significantly elevated in BTC patients compared to PSC patients as well as healthy controls. CCL23 increased the diagnostic sensitivity and specificity of established tumor markers including CA19-9 and correlated with patients' age and makers of systemic inflammation. Elevated preoperative CCL23 levels were associated with a significantly impaired postoperative outcome. BTC patients with a preoperative CCL23 level above the optimal prognostic cut-off value of 702.4 pg/ml showed a median OS of only 110 days compared to 501 days for patients with low initial CCL23 levels. The prognostic value of circulating CCL23 was confirmed in Cox-regression analysis. Serum levels of CCL23 are elevated in patients with BTC, and high preoperative CCL23 levels were associated with an impaired postoperative survival. CCL23 serum levels could help to identify the ideal surgical candidates for BTC resection in the future.

Roderburg C ，Labuhn S ，Bednarsch J ，Lang SA ，Schneider AT ，Hammerich L ，Vucur M ，Ulmer TF ，Neumann UP ，Luedde T ，Loosen SH ... -  《-》

Golgi Protein 73 (GP73) Serum Levels Predict Outcome after Resection of Biliary Tract Cancer.

Loosen SH ，Halpaap J ，Labuhn S ，Bednarsch J ，Alizai PH ，Roeth AA ，Lang SA ，Vucur M ，Kather JN ，Knoefel WT ，Ulmer TF ，Neumann UP ，Roderburg C ，Luedde T ... -  《Cancers》