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.

Splenic infarction associated with sorafenib use in a hepatocellular carcinoma patient.

Sorafenib, a multitargeted tyrosine kinase inhibitor, has been shown to improve survival in patients with advanced hepatocellular carcinoma (HCC). As the clinical use of sorafenib increases, many adverse effects have been reported, such as hand-foot skin reaction, diarrhea, anorexia, asthenia, alopecia, weight loss, hypertension and arterial thromboembolism. However, there are no prior reports of splenic infarction as an adverse effect of sorafenib. Here, a case of splenic infarction in a patient with HCC who was treated with sorafenib is reported. The patient had no other predisposing factors to explain the splenic infarction except for the administration of sorafenib. The splenic infarction improved after sorafenib was discontinued; however, the HCC progressed.

A phase II study of irinotecan with biweekly, low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFIRI) as first line therapy for patients with recurrent or metastatic gastric cancer.

BACKGROUND: To determine the activity and toxicities of a low-dose leucovorin plus 5-fluorouracil (5-FU) regimen, combined with irinotecan and administered every 2 weeks (modified FOLFIRI), as a first-line therapy for patients with advanced gastric cancer. METHOD: Patients were treated with cycles of 150 mg/m irinotecan on day 1 plus 50 mg of LV, followed by a 400 mg/m 5-FU bolus and a 22-hour continuous infusion of 600 mg/m 5-FU on days 1 and 2. RESULTS: The median patient age was 55 years (range, 29-75 years), and 77% (34/44) of the patients had a performance status (Eastern Cooperative Oncology Group) of 0 or 1. Of the 44 patients evaluated for their tumor response, 3 patients (6.8%) and 14 patients (31.8%) achieved a complete and partial response, respectively, with an overall response rate of 38.6% (95% confidence interval, 23.7%-53.6%). 13 patients (29.6%) evidenced a stable disease, and 14 patients (31.8%) progressed during the course of the treatment. The median time to progression and overall survival time were 4.9 months (range, 0.9-22.8 months) and 10.3 months (range, 1.2-29.0 months) from the start of the chemotherapy, respectively. A total of 293 cycles were assessed for toxicity. The major hematologic toxicities included grade 1 to 2 anemia (27.6%), neutropenia (48.8%), and grade 3 to 4 neutropenia (12.6%). There were 7 cycles of neutropenic fever. Nonhematological toxicities were observed grade 3 vomiting (6.8%), grade 3 diarrhea (4.5%), and grade 3 mucositis (2.3%). We noted no treatment-related deaths. CONCLUSIONS: The modified FOLFIRI regimen-lowering of irinotecan and LV doses-is a safe and feasible regimen as a first-line therapy for patients with recurrent or metastatic gastric cancer.

Clinical significances of preoperative serum interleukin-6 and C-reactive protein level in operable gastric cancer.

BACKGROUND: The interleukin-6 (IL-6) pathway is one of the mechanisms that link inflammation and angiogenesis to malignancy. Because the C-reactive protein (CRP) is a representative marker for inflammation, CRP has recently been associated with the progression of disease in many cancer types. The principal objective of this study was to determine the preoperative serum levels of IL-6 and CRP in gastric carcinoma, and to correlate them with disease status and prognosis. METHODS: A total of 115 patients who underwent gastrectomy were enrolled in this study. Serum levels of IL-6 were assessed via Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured via immunoturbidimetry. Histological findings included tumor size, depth of tumor invasion, lymph node (LN) metastasis, and TNM stage (6th AJCC Stage Groupings: The staging systems; Primary tumor, regional LN, metastasis). RESULTS: Increases in cancer invasion and staging are generally associated with increases in preoperative serum IL-6 levels. IL-6 and CRP levels were correlated with invasion depth (P < 0.001, P = 0.001), LN metastasis (P < 0.001, P = 0.024) and TNM stage (P < 0.001, P < 0.001). The presence of peritoneal seeding metastasis is associated with IL-6 levels (P = 0.012). When we established the cutoff value for IL-6 level (6.77 pg/dL) by ROC curve, we noted significant differences in time to progression (TTP; P < 0.001) and overall survival (OS; P = 0.010). However, CRP evidenced no significance with regard to patients' TTP and OS levels. Serum IL-6 levels were correlated positively with CRP levels (r2 = 0.049, P = 0.018). CONCLUSION: Preoperative serum IL-6 and CRP levels might be markers of tumor invasion, LN metastasis, and TNM stage. Preoperative high IL-6 levels were proposed as a poor prognostic factor for disease recurrence and overall survival in patients with gastric cancers.

Second-line treatment with a combination of continuous 5-fluorouracil, doxorubicin, and mitomycin-C (conti-FAM) in gemcitabine-pretreated pancreatic and biliary tract cancer.

BACKGROUND: Gemcitabine-based chemotherapy is a commonly used first-line treatment for patients with pancreatic and biliary tract cancer. However, a standard second-line chemotherapy regimen has yet to be developed after gemcitabine treatment. We attempted to evaluate the efficacy and safety of a combination of continuous 5-fluorouracil, doxorubicin, and mitomycin-C (conti-FAM) as a second-line treatment in pancreatic and biliary tract cancer. METHODS: Patients with advanced pancreatic or biliary tract cancer who were previously treated with gemcitabine-based chemotherapy were enrolled in the study. Chemotherapy was administered as follows: 5-fluorouracil, 800 mg/m2 on days 1 to 5 over 10 hours; mitomycin-C, 8 mg/m2 on day 1; and doxorubicin, 30 mg/m2 on day 1 every 4 weeks. RESULTS: A total of 31 patients received 95 cycles of chemotherapy. Fifteen of the patients had pancreatic cancer. Eleven of the patients had cholangiocarcinoma. Gallbladder cancer was observed in 5 patients. Four (12.9%) patients evidenced partial responses. Eight patients (25.8%) had stable disease. The median time to progression and overall survival time were 2.3 (95% CI: 1.0-3.6) months and 6.7 (95% CI: 4.4-9.0) months, respectively. Major hematologic toxicities included grade 1 to 2 anemia (64.2%), neutropenia (32.6%), thrombocytopenia (20%), and grade 3 to 4 neutropenia (10.5%). The most frequently detected nonhematological toxicities were grade 2 and 3 nausea/vomiting (35.5%). One patient was diagnosed with hemolytic uremic syndrome after 8 cycles of treatment. CONCLUSION: The conti-FAM regimen seems to constitute a safe and feasible salvage therapy in patients with advanced bilio-pancreatic cancer who had been treated previously via gemcitabine-based chemotherapy.