Junichiro Furui

Role of Carcinoembryonic Antigen in the Progression of Colon Cancer Cells That Express Carbohydrate Antigen

Carcinoembryonic antigen (CEA) has been reported to promote the metastatic potential in some experimental tumors. Adhesion molecules are known to play an important role in the process of metastasis. Cytokines, including interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), which are produced by Kupffer cells, induce endothelial cells to express adhesion molecules. As a result, the present study was designed to investigate whether the interaction between CEA and Kupffer cells accelerated the metastatic potential of tumors in the liver. Kupffer cells isolated from the liver of male BALB/c mice were cultured with CEA, either with or without the addition of a cytokine inhibitor. The levels of IL-1beta and TNF-alpha were examined in a culture medium. An adhesion assay of colon cancer cell lines to human umbilical vein endothelial cells was also performed. When CEA was added to the Kupffer cell culture medium, cytokines were produced. Elevated levels of cytokines appeared to lead to increased rates of adhesion of cancer cells to endothelial cells. However, these phenomena were blocked by the addition of cytokine inhibitors. CEA stimulated Kupffer cells to produce cytokines. An elevated number of cytokines have been proven to promote the expression of adhesion molecules in endothelial cells. These processes are therefore considered to contribute to the metastasis of malignant cells to the liver. These results suggest that cytokine inhibitors may therefore play an important role in the inhibition of hepatic metastasis.

Use of the time–signal intensity curve from dynamic magnetic resonance imaging to evaluate remnant pancreatic fibrosis after pancreaticojejunostomy in patients undergoing pancreaticoduodenectomy†

This study assessed the value of the time–signal intensity curve (TIC) obtained from dynamic magnetic resonance imaging (MRI) in the evaluation of remnant pancreatic fibrosis after pancreaticojejunostomy in patients undergoing pancreaticoduodenectomy.

Identification of extracapsular invasion of the metastatic lymph nodes as a useful prognostic sign in patients with resectable colorectal cancer.

PURPOSE: The present study was undertaken to evaluate whether the microscopic patterns of distribution and extracapsular invasion of cancer cells in the regional lymph nodes were linked to the survival rates for patients with advanced colorectal cancer who undergo a curative surgical resection. METHODS: Two hundred ninety-six surgically resected metastatic lymph nodes from 84 patients with node-positive colorectal cancer were microscopically examined. The distribution of cancer cells in the lymph nodes were grouped into two types: type A (≥50 percent cancer) and type B (<50 percent cancer). The extracapsular invasion of cancer cells in the nodes were divided into three subgroups: pattern X (no evidence of cancer cell invasion into the adjacent tissue); pattern Y (less than five cancer cells were seen in the adjacent tissue); and pattern Z (more than five cancer cells invaded the adjacent tissue). The patients, based on these microscopic manifestations of metastatic patterns in the nodes, were divided into three groups: Group 1, patients with pattern X nodal metastases only; Group 2, patients with pattern Y and pattern (X + Y) nodal metastases; and Group 3, patients with pattern Z, pattern (X + Z), pattern (Y + Z), and pattern (X + Y + Z) nodal metastases. RESULTS: The survival rates and disease-free survival rates for patients with metastatic lymph nodes showing an extracapsular invasion pattern (Groups 2 and 3) were significantly worse than those for patients with metastatic nodes showing no extracapsular invasion pattern only (Group 1;P<0.01). There was no significant difference for the above-cited survival rates among the groups classified according to the Dukes and TNM systems. CONCLUSIONS: It is the thesis of this article that the identification of extracapsular invasion of the metastatic lymph nodes can be taken as a useful prognostic sign in patients with resectable colorectal cancer.

Utility of technetium-99m-labeled-galactosyl human serum albumin scintigraphy for estimating the hepatic functional reserve.

Technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (Tc-GSA) is a receptor binding agent, specific for asialoglycoprotein receptor, that resides exclusively on the plasma membrane of mammalian hepatocytes. The usefulness of Tc-GSA for estimating the hepatic functional reserve was retrospectively evaluated in patients undergoing a hepatic resection. Tc-GSA scintigraphy was performed in 35 patients before hepatectomy, and the hepatic uptake ratio (LHL15) was calculated. The LHL15 was then compared with the findings of conventional liver function tests, the indocyanine green retention rate in 15 minutes (ICG R15), and histologic activity index (HAI) score. Significant correlations were observed between the LHL15 and values of ICG R15, prothrombin time activity, serum levels of total bilirubin, hyaluronic acid, and values of HAI score. Ratios of LHL15 to preoperative liver volume (LHL-V) correlated well with the regenerative rates of the residual liver after major hepatectomy. In addition, patients with more than 0.76 of LHL-V value had no complications in postoperative course, whereas those with less than 0.73 had several complications due to hepatic dysfunction. Tc-GSA scintigraphy thus appears to be a useful diagnostic tool for evaluating functioning mass of the liver and the values of LHL-V seems to be able to demonstrate regenerative activity in the residual liver after hepatectomy.

Herniation of the Small Bowel through the Port Site following Removal of Drains during Laparoscopic Surgery

Background/Aims: Generally, the port site is used as the delivery route for drainage after laparoscopic abdominal surgery. We report this case because of the rarity of the complication related to laparoscopic procedures. Methods: A 75-year-old woman underwent a laparoscopic-assisted sigmoid colectomy for early stage cancer. Results: After the operation, her postoperative course was uneventful. However, just after removing the drains, the small bowel was found to have herniated through the port site used as the insertion route for the drains. An emergency relaparotomy was done and a segment of the necrotic small bowel had to be resected. Conclusion: To prevent this complication, we suggest that, first of all, in elderly and thin patients smaller trocar insertion sites (<10 mm) should be utilized as insertion routes for the drains and, secondly, the fascial defect should be closed just after removing the drains whenever the defect measures 10 mm or more in size.

[d-Ala2, d-Leu5] enkephalin (DADLE) protects liver against ischemia-reperfusion injury in the rat

BACKGROUND [D-Ala(2), D-Leu(5)] enkephalin (DADLE) is a synthetic delta class of opioid and is reported to induce hibernation as well as hibernation induction trigger (HIT) in the serum of hibernating mammals. DADLE and HIT have been demonstrated to protect the heart, lung, and jejunum against ischemia-reperfusion (I-R) injury. In the present study, we examined the effect of DADLE on I-R injury of the liver in rats. METHODS After administration of DADLE (DADLE group) or normal saline as a vehicle (Control group), partial hepatic ischemia was induced by occluding the vessels supplying 92% of the liver for 45 min, followed by declamping the vessels and resection of the non-ischemic lobe. After 120 min of reperfusion, serum glutamic-pyruvic transaminase (GPT), hyaluronic acid (HA) levels, and concentrations of malondialdehyde (MDA) of the liver tissue were measured. Additionally, bile output from the ischemic lobes was measured after reperfusion. RESULTS GPT levels were significantly lower in the DADLE group as compared to those of the Control group (P < 0.05), but the serum levels of HA were not different between the two groups. The concentrations of MDA of the liver tissue were significantly lower in the DADLE group than in the Control group (P < 0.01). The bile output after reperfusion was not significantly different between the two groups. CONCLUSIONS DADLE protects against I-R injury in hepatocytes, but not in the sinusoidal endothelial cells of the liver in rats. An anti-oxidative effect is suggested to be responsible for this effect.

Detection of carcinoembryonic antigen mRNA in the mesenteric vein of patients with resectable colorectal cancer

The detection of tumor cells in the drainage venous blood of patients with colorectal cancer was made feasible by demonstrating carcinoembryonic antigen (CEA) mRNA in the mononuclear cell component of the blood, using a nested reverse transcription-polymerase chain reaction. CEA mRNA was detected in the drainage venous blood from 11 (42%) of 26 patients, and the rate of detection increased according to the grade of vessel invasion. CEA mRNA was detected in all patients with synchronous liver metastases, even though there was no significant correlation between the presence of CEA mRNA in the drainage venous blood and the clinicopathological findings. As the presence of CEA mRNA in the drainage venous blood is an indicator of the spread of tumor cells in patients with colorectal cancer, this assay can be used to assess the possible outcome of patients with colorectal cancer, providing one more tool for the physician-oncologist to use in designing appropriate treatments.

Inactivation of porcine endogenous retrovirus by human serum as a function of complement activated through the classical pathway

BACKGROUND: The clinical use of organs and cells of pig donors as a source of tissue for xenotransplantation and extracorporeal therapies has been problematic due to the risk for zoonotic infection of porcine endogenous retroviruses (PERV). METHODS: The effect of human serum on PERV was evaluated using an infectivity assay and virolysis assay. Cell-free PERV infection to human 293 cells was determined by the presence of proviruses 5 days post-infection by a highly sensitive nested PCR, and the lysis of PERV virions was determined by the reverse transcriptase activities released into the supernatant. RESULTS: Treatment of PERV-PK, the culture supernatant of a pig kidney cell line containing the virus titer of 10(2.8) TCID(50) units/ml, with a quarter volume of human serum completely inactivated the infectivity. This activity was heat-labile and sensitive to an anti-complement agent, nafamostat mesilate, and a Ca(2+)-chelator, EGTA, indicating the crucial involvement of complement activated through the classical pathway. Since a synthetic galactosyl alpha1-3 galalactose (Galalpha1-3Gal) largely absorbed the activity from the serum, natural antibodies to the Galalpha1-3Gal epitopes are likely to trigger the complement activation. CONCLUSION: Cell-free PERV seems no longer be infectious in human serum. This greatly encourages the clinical application of pig tissues in particular for extracorporeal therapies such as a bioartificial liver, in which pig cells do not come in direct contact with a recipient.

Role of intrasplenic hepatocyte transplantation in improving survival and liver regeneration after hepatic resection in cirrhotic rats.

We studied the effect of preoperative hepatocyte transplantation on the prevention of liver failure in cirrhotic rats after hepatic resection. Two groups of Lewis rats were rendered cirrhotic by IP injection of 1% dimethylnitrosamine and were subjected to 33% hepatectomy. Two days before the resection, 36 rats in group I received intrasplenic hepatocyte transplantation, and 25 rats in group II were given intrasplenic injection of normal saline as a control. By the end of the third postoperative day, the rats in group I had better survival and a better biochemical profile than those in group II. The liver growth rate and the labeling index of proliferating cell nuclear antigen (PCNA-LI) showed a steady rise in group I. Compared with group II, group I had a significantly lower transforming growth factor (TGF-β1) level (p < 0.05). We conclude that preoperative intrasplenic hepatocyte transplantation improves survival and facilitates regeneration in cirrhotic rats after hepatic resection.

Changes in liver regenerative factors in a case of living-related liver transplantation

Liver regeneration in a patient with fulminant hepatic failure (FHF) who underwent living‐related partial liver transplantation (LRLT) was investigated regarding hepatic growth factors. The patient was a 16‐yr‐old Japanese male who developed severe subacute FHF. LRLT was performed using an extended left lobe of the ABO matched patients mother. In the recipient, the pre‐transplant levels of both plasma hepatocyte growth factor (HGF) and transforming growth factor (TGF)‐β were extremely high and rapidly decreased following the liver replacement. The liver volume evaluated using a CAT scan increased 195% after 2 wk in graft liver and 110% after 2 wk in the hepatectomized donor. The explanted liver (FHF liver), the liver from donor (normal liver), and the graft liver [the 3rd post‐transplant day (POD 3)] were all investigated immunohistochemically. FHF liver: No liver regeneration was observed [proliferative cell nuclear antigen (PCNA) labeling index (L.I.): 0%]. In the liver, both HGF in the hepatocytes and c‐met on the membrane of the hepatocytes were positive. TGF‐β was positive in the hepatocytes and no apoptosis was detected by the TUNEL method. Donor liver (POD 0): Few PCNA stained hepatocytes were detected. No HGF was detected but c‐met was clearly detected on the cell membrane of the hepatocytes. Neither TGF‐β nor apoptosis was detected. Graft liver (POD 3): The PCNA L.I. was conspicuous at 40%. HGF was positive in non‐parenchymal cells and c‐met was positive in the cytoplasm of the hepatocytes. TGF‐β was negative while apoptosis was positive in the zone 3 hepatocytes. In conclusion, these findings suggested that the liver of the patient with FHF did not respond to liver regenerative stimulus, in part, through involvement of inhibitor TGF‐β. On POD 3, the transplanted graft was in a vigorous regenerative status in comparison to that in the hepatectomized donor. The HGF/c‐met system is thought to be involved in the mechanism of regeneration. Intrahepatic apoptosis was detected in the graft on the 3rd post‐transplant day probably due to transient ischemia in the liver, which was not related to the Fas/Fas‐ligand system.