Seok Ryeol Choi

Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma

AIM To investigate the role and clinicopathological significance of aberrant expression of Notch receptors and Delta-like ligand-4 (DLL4) in extrahepatic cholangiocarcinoma and gallbladder carcinoma. METHODS One hundred and ten patients had surgically resected extrahepatic cholangiocarcinoma (CC) and gallbladder carcinoma specimens examined by immunohistochemistry of available paraffin blocks. Immunohistochemistry was performed using anti-Notch receptors 1-4 and anti-DLL4 antibodies. We scored the immunopositivity of Notch receptors and DLL4 expression by percentage of positive tumor cells with cytoplasmic expression and intensity of immunostaining. Coexistent nuclear localization was evaluated. Clinicopathological parameters and survival data were compared with the expression of Notch receptors 1-4 and DLL4. RESULTS Notch receptor proteins showed in the cytoplasm with or without nuclear expression in cancer cells, as well as showing weak cytoplasmic expression in non-neoplastic cells. By semiquantitative evaluation, positive immunostaining of Notch receptor 1 was detected in 96 cases (87.3%), Notch receptor 2 in 97 (88.2%), Notch receptor 3 in 97 (88.2%), Notch receptor 4 in 103 (93.6), and DLL4 in 84 (76.4%). In addition, coexistent nuclear localization was noted [Notch receptor 1; 18 cases (18.8%), Notch receptor 2; 40 (41.2%), Notch receptor 3; 32 (33.0%), Notch receptor 4; 99 (96.1%), DLL4; 48 (57.1%)]. Notch receptor 1 expression was correlated with advanced tumor, node, metastasis (TNM) stage (P = 0.043), Notch receptor 3 with advanced T stage (P = 0.017), tendency to express in cases with nodal metastasis (P = 0.065) and advanced TNM stage (P = 0.052). DLL4 expression tended to be related to less histological differentiation (P = 0.095). Coexistent nuclear localization of Notch receptor 3 was related to no nodal metastasis (P = 0.027) and Notch receptor 4 with less histological differentiation (P = 0.036), while DLL4 tended to be related inversely with T stage (P = 0.053). Coexistent nuclear localization of DLL4 was related to poor survival (P = 0.002). CONCLUSION Aberrant expression of Notch receptors 1 and 3 play a role during cancer progression, and cytoplasmic nuclear coexistence of DLL4 expression correlates with poor survival in extrahepatic CC and gallbladder carcinoma.

A comparison of the BISAP score and serum procalcitonin for predicting the severity of acute pancreatitis

Background/Aims The bedside index of severity in acute pancreatitis (BISAP) is a new, convenient, prognostic multifactorial scoring system. As more data are needed before clinical application, we compared BISAP, the serum procalcitonin (PCT), and other multifactorial scoring systems simultaneously. Methods Fifty consecutive acute pancreatitis patients were enrolled prospectively. Blood samples were obtained at admission and after 48 hours and imaging studies were performed within 48 hours of admission. The BISAP score was compared with the serum PCT, Ransons score, and the acute physiology and chronic health examination (APACHE)-II, Glasgow, and Balthazar computed tomography severity index (BCTSI) scores. Acute pancreatitis was graded using the Atlanta criteria. The predictive accuracy of the scoring systems was measured using the area under the receiver-operating curve (AUC). Results The accuracy of BISAP (≥ 2) at predicting severe acute pancreatitis was 84% and was superior to the serum PCT (≥ 3.29 ng/mL, 76%) which was similar to the APACHE-II score. The best cutoff value of BISAP was 2 (AUC, 0.873; 95% confidence interval, 0.770 to 0.976; p < 0.001). In logistic regression analysis, BISAP had greater statistical significance than serum PCT. Conclusions BISAP is more accurate for predicting the severity of acute pancreatitis than the serum PCT, APACHE-II, Glasgow, and BCTSI scores.

Abstract 5709: Prevention of colitis-induced carcinogenesis with TNF-α antibody, infliximab; top-down strategy for colitic cancer prevention

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Prevention of colitis-induced carcinogenesis with TNF-α antibody, infliximab; top-down strategy for colitic cancer prevention Since colitis-associated cancers arise in the setting of chronic inflammation, during which “inflammation-dysplasia-carcinoma” sequence prevails, we investigated whether infliximab can prevent the development of inflammation-associated colon cancer in rat models, for which 6 week old C57BL/6J mice were exposed to 15 cycles of dextran sulfate sodium (DSS) with each cycle consisting of 0.7% DSS for 1 week followed by distilled water for 10days. Infliximab, 4mg/kg, was given intravenously on 1st, 3rd, and 7th week or 25th, 27th, and 31th week after commencement of repeated bouts of colitis to compare cancer preventing effect of “step-up” versus “top-down” strategy. Additionally, molecular changes regarding inflammation and carcinogenesis were compared between colitis cancer group and colitis cancer group treated with infliximab in addition to in vitro documentation of molecular changes in cells. Multiple colorectal tumors developed in 75-80% of control mice, whereas only 16.7% of mice treated with infliximab at 1st, 3rd, and 7th weeks developed colon tumors. This significant reduction in tumor development with earlier administration of infliximab was correlated with significant decreases in serum NO levels, serum and tissue levels of TNF-α, iNOS, and COX-2. The expressions and activities of matrix metalloprotease (MMP)-3, MMP-9, and MMP-11 were significantly decreased in mice treated with infliximab in accordance with attenuated expression of β-catenin accumulated crypts in infliximab treated mice group. However, in repeated set of colitis-induced carcinogenesis experiment, where infliximab was administered at later stage of 25th, 27th, and 31th weeks, no reduction in colon tumor was noted compared to control group. In conclusion, potent anti-inflammatory treatment in the early stage of inflammation could reduce colitis-associated cancer, stratifying the rationale that earlier and intensive therapy with infliximab should be considered for either ameliorating clinical course or preventing colitic cancer in high risk patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5709.