Transmembrane serine protease 4 expression in the prognosis of radical resection for biliary tract cancer.

Recent advancements in biliary tract cancer (BTC) treatment have expanded beyond surgery to include adjuvant therapy, yet the prognosis remains poor. Identifying prognostic biomarkers could enhance the assessment of patients who have undergone radical resection for BTC. To determine transmembrane serine protease 4 (TMPRSS4) utility as a prognostic biomarker of radical resection for BTC. Medical records of patients who underwent radical resection for BTC, excluding intrahepatic cholangiocarcinoma, were retrospectively reviewed. The associations between TMPRSS4 expression and clinicopathological factors, overall survival, and recurrence-free survival were analyzed. Among the 85 patients undergoing radical resection for BTC, 46 (54%) were TMPRSS4-positive. The TMPRSS4-positive group exhibited significantly higher preoperative carbohydrate antigen 19-9 (CA19-9) values and greater lymphatic invasion than the TMPRSS4-negative group (P = 0.019 and 0.039, respectively). Postoperative overall survival and recurrence-free survival were significantly worse in the TMPRSS4-positive group (median survival time: 25.3 months vs not reached, P < 0.001; median survival time: 28.7 months vs not reached, P = 0.043, respectively). Multivariate overall survival analysis indicated TMPRSS4 positivity, pT3/T4, and resection status R1 were independently associated with poor prognosis (P = 0.032, 0.035 and 0.030, respectively). TMPRSS4 positivity correlated with preoperative CA19-9 values ≥ 37 U/mL and pathological tumor size ≥ 30 mm (P = 0.016 and 0.038, respectively). TMPRSS4 is a potential prognostic biomarker of radical resection for BTC.

Shibata Y ，Sudo T ，Tazuma S ，Tanimine N ，Onoe T ，Shimizu Y ，Yamaguchi A ，Kuraoka K ，Takahashi S ，Tashiro H ... -  《World Journal of Gastrointestinal Surgery》

Prognostic value of carbohydrate antigen 19-9 in patients undergoing resection of biliary tract cancer.

The clinical significance of abnormally high levels of carbohydrate antigen (CA) 19-9 after resection of biliary tract cancer (BTC) is not well established. The aim of this study was to determine the prognostic value of CA19-9 normalization in patients undergoing resection of BTC with curative intent. Patients with BTC undergoing resection with curative intent (1996-2015) were divided into those with normal preoperative CA19-9 level (normal CA19-9 group), those with an abnormally high preoperative CA19-9 level (over 37 units/ml) and normal postoperative CA19-9 level (normalization group), and those with an abnormally high preoperative CA19-9 level and abnormally high postoperative CA19-9 level (non-normalization group). Overall survival (OS) was analysed and predictors of OS were determined. The normal CA19-9 group (180 patients) and normalization group (74) had better OS than the non-normalization group (58) (3-year OS rate 70·4, 73 and 31 per cent respectively; both P < 0·001). The normal CA19-9 and normalization groups had equivalent OS (P = 0·880). On multivariable analysis, factors associated with worse OS were lymph node metastases (hazard ratio (HR) 1·78; P = 0·014) and abnormally high postoperative CA19-9 level (HR 3·16; P < 0·001). In the normalization group, OS did not differ after R0 versus R1 resection (3-year OS rate 69 versus 62 per cent respectively; P = 0·372); in the non-normalization group, patients with R1 resection had worse OS (3-year OS rate 36 and 20 per cent for R0 and R1 respectively; P = 0·032). Non-normalization of CA19-9 level after resection of BTC with curative intent was associated with worse OS. R1 resection was associated with a particularly poor prognosis when CA19-9 levels did not normalize.

Yamashita S ，Passot G ，Aloia TA ，Chun YS ，Javle M ，Lee JE ，Vauthey JN ，Conrad C ... -  《-》

Utility of TMPRSS4 as a Prognostic Biomarker and Potential Therapeutic Target in Patients with Gastric Cancer.

Transmembrane serine protease 4 (TMPRSS4) belongs to the family of type II transmembrane serine proteases that are known to be upregulated in many malignant tumors. However, there is a paucity of studies documenting the clinical impact and biological effects of TMPRSS4 on gastric cancer (GC) patients who underwent surgery. Tissues samples were obtained from 105 patients with GC who underwent gastrectomy followed by adjuvant chemotherapy, excluding those at stage I. The expression of TMPRSS4 was examined through immunohistochemical analysis. The association between TMPRSS4 expression and clinico-pathological features as well as prognosis was assessed. Moreover, the effects of TMPRSS4 expression on cell migration and sensitivity to 5-FU were investigated. The expression rate of TMPRSS4 was 56.3% (59/105) in GC cases. The expression of TMPRSS4 was positively correlated with the depth of tumor (T) and venous (V) invasion. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of the TMPRSS4-positive group was significantly lower than that of the TMPRSS4-negative group (p=0.0001 and p=0.005, respectively). Especially, there was significant differences in OS and RFS of patients with stage III cancer between the two groups (p=0.0064 and 0.012, respectively). Multivariate analysis demonstrated that TMPRSS4 expression and the stage of cancer were crucial prognostic factors for RFS. TMPRSS4-silenced GC cells exhibited increased sensitivity to 5-FU when compared with the non-specific control siRNA-transfected cells. TMPRSS4 can be considered as a potential prognostic biomarker, especially for stage III, and a promising therapeutic target for GC.

Tazawa H ，Suzuki T ，Saito A ，Ishikawa A ，Komo T ，Sada H ，Shimada N ，Hadano N ，Onoe T ，Sudo T ，Shimizu Y ，Kuraoka K ，Tashiro H ... -  《-》

Prognostic significance of TMPRSS4 in gastric cancer.

Sheng H ，Shen W ，Zeng J ，Xi L ，Deng L ... -  《NEOPLASMA》

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 ... -  《-》