Administration of anti-vascular endothelial growth factor antibody following hepatectomy does not inhibit remnant liver regeneration or growth of remnant metastases.

In addition to the use of chemotherapeutic agents for the prevention of multiple liver metastases from colorectal cancer, the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, is often used, and its effectiveness has been established. By contrast, it has been reported that the use of bevacizumab prior to or following surgery delays wound healing or liver regeneration. In this study, we investigated whether the administration of bevacizumab following hepatectomy inhibits remnant liver regeneration or the growth of remnant metastases. Mice were partially hepatectomized (31% of the liver was removed), transplanted with the murine colorectal cancer cell line, CT26, in the remnant lobe, and intraperitoneally injected with bevacizumab (4 mg/kg) for a total of 6 times. Serum VEGF levels were measured on day 1 following surgery, and each lobe of the liver was weighed on day 14. Serum VEGF levels in non-hepatectomized, tumor-bearing mice exceeded those in their non-tumor-bearing counterparts; however, the administration of bevacizumab did not reduce the serum VEGF levels. The volume of the liver lobe of the hepatectomized, CT26-transplanted and non-CT26-transplanted mice was 1,349.6 and 735.5 mg, respectively, indicating rapid growth of the CT26 transplant (p=0.023). The volume of the CT26-transplanted lobe of the bevacizumab-administered mice was 1,379.0 mg, which was not significantly different from that (1,349.6 mg) of the non-bevacizumab-administered mice. The volume of the remnant lobe of the bevacizumab-administered mice was 1,051.0 mg, which did not significantly differ from that (957.3 mg) of the non-bevacizumab-administered mice. The administration of bevacizumab following hepatectomy did not delay remnant liver regeneration, and did not suppress the growth of metastases in the remnant lobes or remnant liver regeneration.

Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma.

We previously reported that the administration of bevacizumab for pancreatic neuroendocrine tumors inhibited angiogenesis in the host, resulting in tumor growth inhibition. In light of these results, we compared the effect of bevacizumab/gemcitabine/S-1 combination therapy vs. bevacizumab monotherapy. The QGP-1 pancreatic neuroendocrine carcinoma cell line and the BxPC-3 ductal cell carcinoma cell line were transplanted into the subcutaneous tissue of mice, and the mice were treated for 3 weeks with bevacizumab [50 mg/kg intraperitoneally (i.p.) twice weekly], gemcitabine (240 mg/kg i.p. once weekly) and S-1 (10 mg/kg orally five times weekly). The antitumor effect and side effects were evaluated by measuring the tumor volume and weight and by changes in body weight, respectively. The tumor volume became smaller (from the maximum volume) in the group treated with bevacizumab, gemcitabine and S-1 (BGS) and the group treated with bevacizumab and gemcitabine (BG). A significant difference was noted in the tumor weight between the BG group and the group treated with bevacizumab alone. A relatively significant decrease in the body weight was observed in the BGS and BG groups. We conclude that gemcitabine is appropriate as a drug used in combination with bevacizumab for pancreatic neuroendocrine tumors.

Computed tomography virtual endoscopy with angiographic imaging for the treatment of type IV-A choledochal cyst.

Type IV-A choledochal cysts (CCs) are a congenital biliary anomaly which involve dilatation of the extrahepatic and intrahepatic bile ducts. We present the case of a 30-year-old woman with type IV-A CC, on whom three-dimensional computed tomography (3D CT) and virtual endoscopy were performed. 3D CT revealed partial dilatation in the posterior branch of the intrahepatic bile duct and a relative stricture between it and the extrahepatic bile duct. Virtual endoscopy showed that this stricture was membrane-like and separated from the surrounding blood vessels. Based on these image findings, complete cyst resection, bile duct plasty for the stricture, and hepaticojejunostomy were safely performed. To the best of our knowledge, there are no reports of imaging by virtual endoscopy of the biliary tract which show the surrounding blood vessels running along the bile duct.

Comparison of preoperative images with gross and histopathological findings of liver slices in patients with liver metastases from colorectal cancer after chemotherapy.

BACKGROUND/AIMS: Since there is a difference in the slice thickness between preoperative images of liver metastases (1-3mm slices) and surgical liver pathology specimens (5mm slices), micrometastases may not be detected in these specimens. In addition, the accuracy of preoperative imaging for the detection of metastases degenerated by chemotherapy is unclear. METHODOLOGY: Five patients with liver metastases from colorectal cancer who had received adjuvant chemotherapy and undergone hepatectomy were included. The whole resected liver was sliced at approximately 1mm intervals and the slices were examined carefully for gross lesions. The preoperative CT and EOB-MRI findings of each lesion were compared with gross and histopathological findings. RESULTS: The accuracy of EOB-MRI was higher than that of CT for the detection of liver metastases. The number of lesions detected on EOB-MRI was in agreement with that of histopathologically proven liver metastases in 4 of the 5 patients. All lesions that were grossly identified but turned out to be non-neoplastic were regenerative nodules associated with drug-induced liver injury or lobular nodules associated with marked fatty change, measuring about 1mm in diameter. CONCLUSIONS: EOB-MRI was the most accurate method for the preoperative detection of liver metastases, enabling the visualization of almost all liver metastases.

Significance of CD44s and CD44v6 expression in pancreaticobiliary maljunction.

BACKGROUND/AIMS: Pancreaticobiliary maljunction (PBM) is a high risk factor in biliary tract cancer. The relation of CD44s and CD44v6 expression in biliary epithelium with PBM and the carcinogenetic process was immunohistochemically examined. METHODOLOGY: One hundred and seven lesions were randomly selected from gallbladders and bile ducts, which were resected from 25 patients with PBM, and immunostaining for CD44s, CD44v6 and MIB-1 was carried out. RESULTS: Among gallbladder lesions, cancerous lesions (dysplasia, cancer) had a higher immunoreactivity with statistical significance for CD44s and CD44v6 compared to non-cancerous lesions (normal, hyperplasia). In bile ducts as well, cancerous lesions had a higher immunoreactivity for CD44s and CD44v6. In both gallbladders and bile ducts, positive cases of CD44s and CD44v6 had a higher statistical significance of Ki-67 labeling index in comparison with negative cases. CONCLUSIONS: In biliary epithelium with PBM, CD44 was indicated to be strongly related to cancer progression via an increase of cellular proliferative potential.

Growth inhibitory effects of vitamin K2 on colon cancer cell lines via different types of cell death including autophagy and apoptosis.

Vitamin K2 (menaquinone-4: MK4) has been reported to inhibit cell growth and induce apoptosis in various tumor cells. We examined the effects of MK4 using three types of colon cancer cell lines: PMCO1, COLO201, and DLD-1. Exposure to MK4 was at concentrations from 5 to 50 microM, growth inhibitory effects were observed dose-dependently in COLO201 and PMCO1, whereas the growth inhibition observed in DLD-1 was minimal. Comparison of COLO201 and PMCO1 cells exhibiting distinct growth inhibitory effects showed that cell death via apoptosis accompanied by activation of caspase-3 was induced in PMCO1, while apoptosis was not induced in COLO201. On the contrary, immunoblot assay using an anti-LC3B antibody showed autophagy induction by addition of MK4 and incubation in all three types of colon cancer cell lines. Addition of 3-methyladenine (3-MA) attenuated the growth inhibitory effect of MK4 in COLO201, whereas no influence of 3-MA was noted in PCMO1. Electron microscopy images of COLO201 showed that addition of MK4 induced an increased number of cytoplasmic autophagosomes and autolysosomes as well as morphological changes including scantiness of cytoplasm accompanied by loss of cell organelles, nuclear shrinkage, and fragmentation of cytoplasmic membrane in some cells, indicating the induction of cell death via autophagy not accompanied by the formation of apoptotic bodies in COLO201 cells. These results suggested that the response to MK4 and the way of induction of cell death vary in different colon cancer cell lines.