Cytoskeleton-associated protein 2 is a potential predictive marker for risk of early and extensive recurrence of hepatocellular carcinoma after operative resection.

BACKGROUND: De principe transplantation is an attractive strategy for the treatment of patients with hepatocellular carcinoma (HCC). The most important issue for this strategy is how to predict the risk of early and extensive recurrence. The present study aimed to identify a molecule associated with early and extensive recurrence of HCC after resection. METHODS: Differentially expressed genes were screened by DNA microarray analysis with the use of 12 HCC samples from patients who had different clinical courses based on the timing and extent of recurrence after operative resection. Furthermore, the obtained results were validated in 60 independent samples by quantitative real-time reverse transcription-polymerase chain reaction. Immunohistochemistry was performed to assess gene expression at the protein level. RESULTS: Microarray analysis and quantitative reverse transcription-polymerase chain reaction revealed cytoskeleton-associated protein 2 (CKAP2) as a candidate gene associated with early and extensive recurrence of HCC after resection. This observation was confirmed through examination of independent set samples, in which patients with greater-level CKAP2 mRNA expression exhibited shorter recurrence-free survival. Immunohistochemistry showed CKAP2 protein expression was associated with early (≤3 years) and extensive recurrence (beyond Milan criteria) after operative resection. CONCLUSION: Immunohistochemical CKAP2 expression might be a potential biologic marker for identifying HCC patients at risk of early and extensive recurrence after operative resection.

Surgical resection after downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer: a retrospective single-center study.

BACKGROUND: Surgical resection is the only method for curative treatment of biliary tract cancer (BTC). Recently, an improved efficacy has been revealed in patients with initially unresectable locally advanced BTC to improve the prognosis by the advent of useful cancer chemotherapy. The aim of this study was to evaluate the effect of downsizing chemotherapy in patients with initially unresectable locally advanced BTC. METHODS: Initially unresectable locally advanced cases were defined as those in which therapeutic resection could not be achieved even by proactive surgical resection. Gemcitabine was administered intravenously once a week for 3 weeks followed by 1 week's respite. Patients whose disease responded to chemotherapy were reevaluated to determine whether their tumor was resectable. RESULTS: Chemotherapy with gemcitabine was provided to 22 patients with initially unresectable locally advanced BTC. Tumor was significantly downsized in nine patients, and surgical resection was performed in 8 (36.4%) of 22 patients. Surgical resection resulted in R0 resection in four patients and R1 resection in four patients. Patients who underwent surgical resection had a significantly longer survival compared with those unable to undergo surgery. CONCLUSIONS: Preoperative chemotherapy enables the downsizing of initially unresectable locally advanced BTC, with radical resection made possible in a certain proportion of patients. Downsizing chemotherapy should be proactively carried out as a multidisciplinary treatment strategy for patients with initially unresectable locally advanced BTC with the aim of expanding the surgical indication.

Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells.

BACKGROUND: Although gemcitabine has been widely used as a first-line chemo reagent for patients with pancreatic cancer, the response rate remains low. We previously identified Annexin II as a factor involved in gemcitabine resistance against pancreatic cancer. The aims of this study were to elucidate the signaling mechanism by which Annexin II induces gemcitabine resistance and to develop a new therapy that overcomes the resistance against gemcitabine. METHODS: We compared the specific profiles of 12 targeted phosphorylated (p-) signaling proteins in gemcitabine-resistant (GEM-) and its wild-type pancreatic cancer cell lines (MIA PaCa-2) using the Bio-Plex assay system. We also evaluated the expression levels of Annexin II and two phosphoproteins, which showed different expressions in these two cell lines, by immunohistochemistry. RESULTS: Annexin II overexpression was significantly associated with rapid recurrence after gemcitabine-adjuvant chemotherapy in patients with resected pancreatic cancer (P < 0.05). Bio-Plex analysis showed up-regulation of p-Akt in GEM-MIA PaCa-2 cells in which Annexin II is highly expressed. The expression level of p-Akt was significantly correlated with that of the downstream protein, p-mTOR, in pancreatic cancer tissues. Inhibition of mTOR phosphorylation canceled gemcitabine resistance in GEM-MIA PaCa-2 cells. CONCLUSIONS: The Akt/mTOR pathway is involved in mechanisms of gemcitabine resistance induced by Annexin II in pancreatic cancer cells. This indicates that combination therapy with the mTOR inhibitor may overcome gemcitabine resistance. Annexin II as an indicator for selection of gemcitabine resistance could thus be applied to the development of novel tailor-made approaches for pancreatic cancer treatment.

Intrahepatic cholangiojejunostomy (Longmire procedure) for recurrent bilioenteric anastomotic stricture with hepatolithiasis.

Interventional procedure via percutaneous transhepatic route is often performed, as an initial treatment, in patients with benign bilioenteric anastomotic stricture. However, surgical management is required in most cases in which radiological intervention is unsuccessful. In this report, we describe a case of a 67-year-old woman with recurrent bilioenteric anastomotic stricture, accompanying bilateral hepatolitiasis after several times of transhepatic interventions. The patient underwent intrahepatic cholangiojejunostomy (Longmire procedure) and cholangioscopic lithotomy after resection of an atrophic left lateral segment resulting from hepatolithiasis. Although the damaged hilar bile duct had to be isolated and divided from the corresponding vasculature for re-anastomosis, it was quite impossible due to severe inflammatory change at the hepatic hilus. We, therefore, anastomosed the intact biliary stump on the cut surface of the left lateral segment to the jejunal loop with a stent tube. The patient's postoperative course was uneventful and she exhibited no evidence of cholangitis during follow-up period of 1 year after surgery. At present, the indications for intrahepatic cholangiojejunostomy for biliary obstruction, are quite limited, but biliary surgeons should keep this procedure in mind at the time of biliary reconstruction for benign proximal bile duct stricture, particularly in cases of multiply operated hilum.

Hepatic S4a + S5 and bile duct resection for gallbladder carcinoma.

In the surgical treatment of gallbladder cancer, segment 4a + 5 hepatic resection and bile duct resection is usually recommended for T2 and/or T3 gallbladder cancer involving hepatic parenchyma without hepatic biliary confluence. This procedure does not affect liver function excessively, provided there is correct identification of hepatic S4a and S5, the most important aspect of this procedure. In this paper, the technique of hepatic S4a + 5 and bile duct resection is described in detail. This surgical procedure could be a useful option for the surgical treatment of the hepatobiliary pancreatic malignancies. Surgeons should therefore master the surgical techniques for this procedure.

Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.

BACKGROUND: Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC. METHODS: We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of FGF19 and FGFR4 to regulate their concentrations. RESULTS: We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29). CONCLUSIONS: FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.

The alterations in hepatic microcirculation and Kupffer cell activity after biliary drainage in jaundiced mice.

BACKGROUND/PURPOSE: The aim of this study is to examine the effects of biliary drainage on hepatic microcirculation and Kupffer cell activity in the liver with obstructive jaundice. METHODS: Common bile duct ligation and division was performed on C57BL/6 mice to induce obstructive jaundice. Seven or 14 days after surgery, some mice underwent biliary drainage. Three days after biliary drainage, sinusoidal perfusion, leukocyte rolling and sticking in the postsinusoidal venules, and the diameters of sinusoids containing blood flow were evaluated using intravital microscopy. Kupffer cell phagocytic activity was estimated as the ratio of Kupffer cells that phagocytosed fluorescent-labeled particles to sinusoids containing blood flow. RESULTS: Sinusoidal perfusion after biliary drainage was significantly increased compared with that in livers with obstructive jaundice, but remained decreased compared with controls. Although the number of rolling leukocytes and sticking leukocytes was significantly decreased, the diameters of sinusoids remained reduced, associated with an increase in Kupffer cell phagocytic activity compared with controls even after biliary drainage. CONCLUSIONS: Leukocyte-endothelial cell interaction is ameliorated but sinusoids remain narrowed due to swelling of activated Kupffer cells; this might cause deterioration of hepatic microcirculation during the early phase of biliary drainage.

CXCR4/CXCL12 expression profile is associated with tumor microenvironment and clinical outcome of liver metastases of colorectal cancer.

Interaction between CXCR4 and CXCL12 plays a role in tumor progression. The present study examined CXCR4, CXCL12 and CD133 expression in liver metastases of colorectal cancer (CLM) and determined whether the expression profiles affect the tumor microenvironment and thus progression, and whether they could serve as a prognostic marker for survival. Liver metastases of colorectal cancer collected from 92 patients were evaluated by CXCR4, CXCL12 and CD133 immunohistochemistry and clinicopathological data were analyzed. The expression profile of CXCR4 was determined in the colorectal cancer cell line, SW48. The expression of cytoplasmic CXCR4 was higher in 36 (39%) patients than that indicated by CXCR4 staining intensity of hepatocytes. High levels of nuclear CXCR4 expression in 23 (25%) patients significantly correlated with CXCL12 expression in hepatocytes. Nuclear CXCR4 expression was increased in the cancer cells after exposure to CXCL12. Univariate and multivariate analyses demonstrated that the high levels of nuclear CXCR4 and CXCL12 expression in hepatocytes were significantly better prognostic factors for overall and hepatic disease-free survival in patients with CLM. The expression of CXCR4 and CXCL12 in CLM may have an interactive effect that could alter the tumor microenvironment. CXCR4 expression in metastatic liver tumors together with the upregulation of CXCL12 in hepatocytes may help to predict the clinical outcomes of patients with CLM after hepatectomy.

[A successful treatment of conversion chemotherapy by mFOLFOX6 plus cetuximab for initially unresectable synchronous colorectal liver metastases].

A 63-year-old woman with a synchronous huge colorectal liver metastasis was referred to our institution.The lesion was technically diagnosed unresectable because the estimated future remnant liver volume was insufficient due to the invasion of the three hepatic veins and hepatic hilum.She underwent 7 courses of mFOLFOX6 and 14 administrations of cetuximab as conversion chemotherapy.Periodic abdominal CT scans revealed the tumor becoming PR, and she was free of cancer invasion to the left hepatic vein.After the remainder of chemotherapy lasting 4 weeks, right trisectionectomy and combined partial resection of the inferior vena cava and primary closure was performed.The postoperative course was uneventful and the patient was discharged at 20 days after the operation.She underwent chemotherapy postoperatively, and then underwent laparoscopic sigmoidectomy.A conversion chemotherapy using cetuximab may contribute to ward rapidly reducing tumor size and improving the resectability of initially unresectable huge colorectal liver metastases, thus leading to prolonged survival.

Treatment strategy for hepatocellular carcinoma with major portal vein or inferior vena cava invasion: a single institution experience.

BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) invading the main trunk of the portal vein and the inferior vena cava is dismal. The best strategy for treatment is not well known. STUDY DESIGN: We retrospectively reviewed the medical records of 641 patients treated for HCC between 1990 and June 2009. Eighty-four (13%) of these patients had HCC, with a tumor thrombus invading the main trunk or the first-order branch of the portal vein, or the inferior vena cava. Thirty-four patients underwent hepatectomy and 50 patients underwent transcatheter arterial chemoembolization (TACE). We specifically focused on these 34 patients to describe our results of surgical treatment for advanced HCC. RESULTS: Among the 34 patients who underwent hepatectomy, preoperative TACE was performed in 15 patients. Six patients were identified as having a tumor size reduction or necrosis of 50% or higher (TE3) by TACE. The median operative duration was 355 minutes. Postoperative morbidity and mortality rates were 44% and 2.9%, respectively. The 5-year survival rate after hepatectomy was 20%, which was better than that of patients after TACE alone. The response after preoperative TACE (hazard ratio 4.65; 95% CI, 1.39 to 15.5) and tumor diameter (hazard ratio 2.78; 95% CI, 1.16 to 6.64) were identified as significant favorable preoperative prognostic factors for survival using the multivariable Cox model. Patients with tumors smaller than 10 cm and TE3 effect had a more favorable survival than patients with tumors 10 cm or larger and who did not have a good TACE outcome. CONCLUSIONS: A combination of aggressive surgical treatment and effective preoperative TACE treatment for HCC with major vascular invasion may be beneficial for selected patients.

Similarities and differences between intraductal papillary tumors of the bile duct with and without macroscopically visible mucin secretion.

Intraductal papillary neoplasms of the bile duct (IPNB) have been recently proposed as the biliary counterpart of intraductal papillary mucinous neoplasms of the pancreas (IPMN-P). However, in contrast to IPMN-P, IPNB include a considerable number of the tumors without macroscopically visible mucin secretion. Here we report the similarities and differences between IPNB with and without macroscopically visible mucin secretion (IPNB-M and IPNB-NM). Surgically resected 27 consecutive cases with IPNB were divided into IPNB-M (n=10) and IPNB-NM (n=17), and their clinicopathologic features were examined. Clinically, both tumors were similar. Pathologically, the most frequent histopathologic types were pancreatobiliary in IPNB-NM and intestinal in IPNB-M. Various degrees of cytoarchitectural atypia within the same tumor were exhibited in 8 IPNB-M, but only 3 in IPNB-NM. Although the tumor size was similar, 9 IPNB-NM were invasive carcinoma, whereas all but 1 IPNB-M with carcinoma were in situ or minimally invasive. Immunohistochemically, positive MUC2 expression was significantly more frequent in IPNB-M than in IPNB-NM, whereas MUC1 tended to be more frequently expressed in IPNB-NM compared with IPNB-M. Among IPNB-NM with positive MUC1 expression, 3 had negative MUC2 and MUC5AC expressions. These tumors showed a tubulopapillary growth with uniform degree of cytoarchitectural atypia. All IPNB-M were negative for p53, and the frequency of positive p53 protein in IPNB-NM was at the middle level of that in IPNB-M and nonpapillary cholangiocarcinoma. In conclusion, IPNB-M showed striking similarities to IPMN-P, but IPNB-NM contained heterogeneous disease groups.

Hepatocyte apoptosis is enhanced after ischemia/reperfusion in the steatotic liver.

Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury. The aim of the current study was to determine the precise mechanism leading to hepatocyte apoptosis after steatotic liver ischemia/reperfusion. Using a murine model of partial hepatic ischemia for 90 min, we examined the levels and pathway of apoptosis, and the peroxynitrite expression, serum alanine aminotransferase levels, and liver histology 1 and 4 h after reperfusion. In the steatotic liver, the peroxynitrite expression increased after ischemia/reperfusion. Significant hepatocyte apoptosis in the steatotic liver was seen after reperfusion, caused by upregulation of cleaved caspases 9 and 3, but not caspase 8. Serum alanine aminotransferase levels were elevated and histological examination revealed severe liver injury in the steatotic liver 4 h after reperfusion. In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline. Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine. Our data suggested that the steatotic liver is vulnerable to hepatic ischemia/reperfusion, leading to significant hepatocyte apoptosis by the mitochondrial permeability transition, and thereby resulting in organ dysfunction.

Usefulness of preoperative partial splenic embolization in hepatocellular carcinoma and hypersplenic thrombocytopenia.

BACKGROUND/AIMS: Patients with both hepatocellular carcinoma and hypersplenic thrombocytopenia are occasionally seen and this condition can severely complicate liver resection. This study evaluated the usefulness of preoperative partial splenic embolization (PSE) as an alternative to splenectomy (SP). METHODOLOGY: Twenty-eight patients with hypersplenic thrombocytopenia underwent hepatectomy for hepatocellular carcinoma. Five patients underwent preoperative PSE and 23 patients underwent concomitant splenectomy. The blood cell counts, laboratory chemistry data, and operative morbidity, prognosis were all examined. RESULTS: There were no severe PSE-related complications such as splenic abscess seen after PSE. The platelet counts in the PSE group significantly increased in comparison to those in the SP group before the operation. The frequency of blood transfusion and postoperative complications in the PSE group was significantly less than that in the SP group. The duration of surgery, blood loss, and performance of PSE were significant factors to predict postoperative complications. The overall survival after liver resection was not significantly different between patients in the PSE and SP group. CONCLUSIONS: Preoperative PSE could be safely performed without severe adverse effects prior to liver resection and it was thus considered to be useful for increasing the number of platelets and reducing postoperative complications.

Immunosuppression following surgical and traumatic injury.

Severe sepsis and organ failure are still the major causes of postoperative morbidity and mortality after major hepatobiliary pancreatic surgery. Despite recent progress in understanding the immune conditions of abdominal sepsis, the postoperative incidence of septic complications after major visceral surgery remains high. This review focuses on the clinical and immunological parameters that determine the risk of the development and lethal outcome of postoperative septic complication following major surgery and trauma. A review of the literature indicates that surgical and traumatic injury profoundly affects the innate and adaptive immune responses, and that a marked suppression in cell-mediated immunity following an excessive inflammatory response appears to be responsible for the increased susceptibility to subsequent sepsis. The innate and adaptive immune responses are initiated and modulated by pathogen-associated molecular-pattern molecules and by damage-associated molecular-pattern molecules through the pattern-recognition receptors. Suppression of cell-mediated immunity may be caused by multifaceted cytokine/inhibitor profiles in the circulation and other compartments of the host, excessive activation and dysregulated recruitment of polymorphonuclear neutrophils, induction of alternatively activated or regulatory macrophages that have anti-inflammatory properties, a shift in the T-helper (Th)1/Th2 balance toward Th2, appearance of regulatory T cells, which are potent suppressors of the innate and adaptive immune system, and lymphocyte apoptosis in patients with sepsis. Recent basic and clinical studies have elucidated the functional effects of surgical and traumatic injury on the immune system. The research studies of interest may in future aid in the selection of appropriate therapeutic protocols.

Endothelin-1 aggravates hepatic ischemia/reperfusion injury during obstructive cholestasis in bile duct ligated mice.

BACKGROUND: Cholestasis of the liver is known to be an important risk factor for surgical morbidity and mortality after major hepatectomy. However, the mechanism of liver injury in cholestatic liver is not fully understood. The goal of this study was to investigate the process of liver injury due to hepatic ischemia/reperfusion in obstructive cholestasis. MATERIALS AND METHODS: Male C57BL/6 mice underwent common bile duct ligation and subsequently developed obstructive cholestasis. The mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion. RESULTS: The survival rate of the mice with cholestatic livers after hepatic ischemia/reperfusion was lower than that of the mice with normal livers. Biochemical and histological analyses showed that the cholestatic mice had a much higher degree of hepatocellular injury after reperfusion than the normal mice. Neutrophil accumulation after reperfusion was significantly decreased in the cholestatic livers; however, considerable microcirculatory disturbances were observed in cholestatic livers after reperfusion. Hepatic stellate cell activation and hepatic expression of endothelin-1 were evaluated by immunohistochemical staining in cholestatic livers after reperfusion. These observations were also associated with increased serum levels of endothelin-1. CONCLUSIONS: Hepatic stellate cell activation and increased endothelin-1 production play a crucial role in hepatic ischemia/reperfusion injury in cholestatic liver.

Effects of partial hepatic venous congestion on hepatic hemodynamics and histology.

BACKGROUND/AIMS: Extensive liver resection potentially causes hepatic venous congestion resulting in critical liver damage. The effects of partial hepatic venous congestion on hepatic hemodynamics and histology were studied. METHODOLOGY: Male Wistar rats underwent hepatic vein ligation of left lateral lobe (35%) or left lateral and median lobes (70%). Systemic and hepatic hemodynamics was measured following hepatic vein ligation of 35% lobe. RESULTS: Rats with 35% hepatic venous congestion survived while rats with 70% hepatic venous congestion died within 2 days after surgery. Blood pressure of carotid artery and central vein, and blood flow of hepatic artery and portal vein transiently decreased after surgery (p < 0.05), while portal venous pressure increased significantly after surgery (p < 0.05). Partial hepatic venous congestion blocked portal flow to the congested lobe, and blood flow of the congested lobe was maintained only by hepatic arterial flow. Partial hepatic venous congestion caused massive necrosis of hepatocytes in the central vein lobules and intermediate area, while hepatocytes in the periportal area were being preserved. CONCLUSIONS: These results suggest that in patients undergoing extensive liver resection or LDLT, preservation of hepatic arterial flow or hepatic vein reconstruction of the congested area should be recommended depending on congested liver volume.

Effects of perioperative immunonutrition on cell-mediated immunity, T helper type 1 (Th1)/Th2 differentiation, and Th17 response after pancreaticoduodenectomy.

BACKGROUND: The mechanisms of immunonutrition on reducing infectious complications are still poorly understood. This prospective randomized study was designed to determine whether immunonutrition influences the following factors: cell-mediated immunity, differentiation of T helper type 1 (Th1) and Th2 cells, interleukin (IL)-17-producing CD4(+) helper T (Th17) cell response, and infectious complication rate after pancreaticoduodenectomy. METHODS: Thirty patients who underwent pancreaticoduodenectomy were divided into 3 groups. Ten patients in the perioperative group received immune-enhancing diets enriched with arginine, omega-3 fatty acids, and RNA for 5 days before operative resection, which was prolonged after operative resection by enteral infusion. Ten patients in the postoperative group received early postoperative enteral infusion of the same enriched formula with no artificial nutrition before operative resection. Ten patients in the control group received total parenteral nutrition postoperatively. The primary endpoint was immune responses; the secondary endpoint was the rate of infectious complications. RESULTS: Concanavalin A (Con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation and natural killer cell activity were significantly higher in the perioperative group than in the other groups. Messenger RNA (mRNA) expression levels of T-bet, interferon-gamma (IFN-gamma), related orphan receptor gammat (RORgammat), and interleukin-17F (IL-17F) were significantly higher in the perioperative group than in the other groups. In the perioperative group, the rate of infectious complications was significantly reduced compared with that in the other groups. CONCLUSION: Perioperative immunonutrition reduced stress-induced immunosuppression after a major stressful operative resection. The modulation of Th1/Th2 differentiation and Th17 response may play important roles in this immunologic effect.

Hepatocyte nuclear factor-kappa beta (NF-kappaB) activation is protective but is decreased in the cholestatic liver with endotoxemia.

BACKGROUND: Obstructive jaundice (OJ) is an important clinical consideration associated with a high risk of bacteremia. Hepatocyte nuclear factor-kappa B (NF-kappaB) activation confers an antiapoptotic function. Although the occurrence of hepatocyte apoptosis has been shown in OJ, the activation and role of NF-kappaB over the time course of OJ in conjunction with endotoxemia have not yet been well defined. We hypothesized that NF-kappaB activation may be decreased over the time course of OJ and endotoxemia, which leads to severe liver injury. The aim of the current study was to examine whether NF-kappaB activation can decrease hepatocyte apoptosis and liver injury over the time course of OJ in response to lipopolysaccharide (LPS) administration. METHODS: Male C57BL/6 mice were subjected to bile duct ligation and were administered LPS intravenously at 3 days (OJ3) or 14 days (OJ14) after bile duct ligation. NF-kappaB activation; protein expressions of NF-kappaB p65, IkappaB-alpha, Ikappabeta-b, and Pin1; immunohistochemistry of poly adenosine diphosphate (ADP)-ribose polymerase p85 fragment (PARP); and serum alanine transaminase (ALT) levels were examined. RESULTS: Hepatocyte NF-kappaB activation was observed during OJ. After LPS administration, the hepatic NF-kappaB activation defined by electrophoretic mobility shift assay was decreased in the OJ14 group compared with the OJ3 group, which is consistent with a decrease in NF-kappaB p65 protein expression. Changes in phosphorylated Ikappa-B-beta but not phosphorylated IkappaB-alpha mirrored these results. Significant hepatocyte apoptosis defined by PARP immunohistochemistry was observed in the LPS-treated OJ14 relative to the LPS-treated OJ3. Hepatic expressions of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the LPS OJ14 mice were upregulated relative to those in the LPS OJ3. Serum ALT levels increased significantly in the LPS OJ14 relative to other mice. The survival rate was significantly less in the LPS OJ14 relative to other mice. CONCLUSION: After prolonged OJ, exposure to endotoxemia was associated with a decrease in hepatocyte NF-kappaB activation and an increase in hepatocyte apoptosis and secondary necrosis, thus resulting in liver dysfunction.

Aggressive surgical resection for hilar cholangiocarcinoma of the left-side predominance: radicality and safety of left-sided hepatectomy.

OBJECTIVES: To evaluate the clinicopathologic outcomes in patients with hilar cholangiocarcinoma (HC) after left-sided hepatectomy (L-H). SUMMARY BACKGROUND DATA: L-H is indicated as radical surgery for HC, predominantly involving left hepatic duct. However, several reports have demonstrated that L-H often results in tumor-positive margin and unfavorable prognosis compared with right-sided hepatectomy (R-H). METHODS: A total of 224 patients with HC underwent surgical resection with curative intent at our institution: L-H for Bismuth-Corlette (B-C) type IIIb tumors in 88 patients (39.3%) including 75 left hemihepatectomies and 13 left trisectionectomies, and R-H mainly for B-C type IIIa and IV tumors in 84 patients (37.5%). In this study, clinicopathologic outcomes and perioperative morbidity and mortality rates after L-H were investigated and compared with those after R-H. RESULTS: Histologically negative margin (R0) resection was achieved in 56 cases (63.6%) with L-H, similar to the results for R-H (58/84, 69.1%). However, the R0 resection rate in L-H cases with portal vein (PV) resection was lower (11/25, 44.0%), and various types of PV reconstruction were required. Proximal ductal stumps and excisional surface at periductal structures were the most common sites of positive margins. However, when curative resection was achieved, 5-year survival was comparable to that in R-H cases. Furthermore, lower mortality was noted in L-H cases, even with left trisectionectomy. Multivariate analysis indicated curability and hepatic artery resection as independent prognostic factors. CONCLUSIONS: Since L-H is a safe procedure and represents the only curative resectional option for type IIIb tumor, aggressive surgical resection should be performed even in cases with PV involvement, if R0 resection is possible.

[A resected case of non-invasive type of intraductal papillary mucinous carcinoma penetrating to the duodenum].

A 74-year-old man was admitted to a nearby clinic complaining of high fever. Abdominal CT showed a 10 mm diameter cystic mass in the head of pancreas and dilation of the pancreatic duct. Endoscopy revealed a fistula filled with mucin in the posterior wall of the duodenum. The patient was referred to our institution for a surgical resection. Endoscopic ultrasonography revealed dilation of the pancreatic duct and also mural nodules in the pancreatic duct, ERP demonstrated a fistula from the pancreatic duct to the duodenum. Biopsied specimen from the papillary nodule in the pancreatic duct showed adenoma. We performed pancreaticoduodenectomy for main-duct IPMN penetrating to the duodenum. Pathological findings showed a non-invasive type of IPMC. Furthermore, a cancer invasion to the duodenum was not detected. These findings suggest that the increased pressure within the pancreatic duct caused a fistula to the duodenum.