The Effectiveness of Hepatic Arterial Infusion Chemotherapy with 5-Fluorouracil/Cisplatin and Systemic Chemotherapy with Ramucirumab in Alpha-Fetoprotein-Producing Gastric Cancer with Multiple Liver Metastases.

Alpha-fetoprotein- (AFP-) producing gastric cancer (AFPGC) is characterized by a high incidence of liver and lymph node metastases and poor prognosis. Although several case reports have described successful multidisciplinary treatment, there are currently no standard therapies for AFPGC. A 57-year-old man presented with upper abdominal pain. His serum AFP level was extremely high (588.9 ng/mL). Computed tomography (CT) revealed multiple liver metastases with several lesions at an imminent risk of rupture. Five days after admission to our hospital, one lesion ruptured. Transarterial chemoembolization (TACE) of the ruptured tumor was performed, and hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU)/cisplatin (CDDP) to the other liver metastases was administered. The patient's AFP levels decreased to 297.1 ng/mL. Gastrointestinal endoscopy revealed Borrmann type 2 lesion in the pyloric portion. Pathological examination indicated hepatoid adenocarcinoma of the stomach and metastatic liver. The final diagnosis was AFPGC and multiple liver metastases. The patient underwent systemic chemotherapy with capecitabine/CDDP (cape/CDDP) for three months. His AFP level increased extremely, and CT revealed progression of the liver metastases. TACE was performed, and HAIC (5FU/CDDP) was administered to the progressive lesion of the liver. Originating from the gastric lesion, a distal gastrectomy and D2 + α lymph node resection were performed. One month after the operation, the patient underwent systemic chemotherapy with paclitaxel/ramucirumab (PTX/RAM). After eight cycles of chemotherapy, his AFP level had declined, and CT showed a complete response. After three months of drug withdrawal, the patient has undergone maintenance treatment with RAM. It has been two years since the recurrence. Our experience suggests that HAIC with 5-FU/CDDP and systemic chemotherapy with a regimen including RAM may be an effective treatment for AFPGC.

Usefulness of Endoscopic Managements in Patients with Ceftriaxone-Induced Pseudolithiasis Causing Biliary Obstruction.

Ceftriaxone (CTRX) is known to cause reversible biliary stones/sludge, which is called biliary pseudolithiasis. We report two rare cases of biliary obstruction by pseudolithiasis shortly after completing CTRX treatment. Stones and sludge, which had not been detected before CTRX administration, appeared in the gallbladder and common bile duct and led to biliary obstruction and acute cholangitis. The obstructions were successfully treated with endoscopic retrograde biliary drainage and endoscopic sphincterotomy. CTRX-induced biliary pseudolithiasis has been reported mainly in children and adolescents but is also seen in adults with similar incidence rate. Although CTRX-induced biliary pseudolithiasis is usually asymptomatic and disappears spontaneously after discontinuing the drug, some patients develop biliary obstruction. Endoscopic managements should be considered in such cases.

mPGES-1 expression in non-cancerous liver tissue impacts on postoperative recurrence of HCC.

AIM: To investigate whether microsomal prostaglandin E synthase-1 (mPGES-1) expression in hepatocellular carcinoma (HCC) and in non-cancerous liver affects HCC prognosis after hepatectomy. METHODS: The relationship between patient clinical profiles, tumor factors, surgical determinants, and mPGES-1 expression and the recurrence-free survival rate were examined in 64 patients who underwent curative hepatectomy between March 2003 and December 2006. RESULTS: The scores for mPGES-1 expression were higher in well differentiated and moderately differentiated HCC tissues than in poorly differentiated HCC tissues (well differentiated, 5.1 ± 2.7; moderately differentiated, 5.1 ± 1.7; poorly differentiated, 3.0 ± 1.8). In non-cancerous liver tissues, the mPGES-1 levels were higher in injured liver tissues than in normal tissues. Cirrhotic livers had higher mPGES-1 levels than livers with chronic hepatitis (normal livers, 3.3 ± 0.7; chronic hepatitic livers, 5.4 ± 1.9; cirrhotic livers, 6.4 ± 1.6). A univariate analysis revealed that the recurrence-free survival rate was significantly lower in patients with vascular invasion, a higher mPGES-1 level in non-cancerous liver tissue, a larger tumor diameter (≥ 5 cm), and a lower serum albumin level (≤ 3.7 g/dL). The mPGES-1 expression in HCC tissues did not correlate well with postoperative recurrence. A multivariate analysis demonstrated that the presence of vascular invasion and higher mPGES-1 levels were statistically significant independent predictors for early postoperative recurrence of HCC. CONCLUSION: Increased mPGES-1 expression in non-cancerous liver tissues is closely associated with the early recurrence of HCC after curative resection.

Oxaliplatin-induced allergic reaction in patients with colorectal cancer in Japan.

BACKGROUND: Oxaliplatin is a platinum compound that is clinically effective for colorectal cancer (CRC), in combination with 5-fluorouracil (5-FU) and leucovorin (LV), and it is widely used for metastatic disease and for the adjuvant treatment of stage III CRC. With the increasing use of oxaliplatin in Japan, serious adverse events have been experienced other than hematologic and neurologic toxicities. METHODS: In order to clarify the clinical features of allergic reactions to oxaliplatin, we retrospectively investigated CRC patients who had received oxaliplatin-based chemotherapies. RESULTS: One hundred and twenty-five CRC patients who had been treated with FOLFOX regimens (containing oxaliplatin, 5-FU, and LV) were examined, and 21 patients (17%) were found to have developed allergic reactions. Sixteen patients (13%) had grade 1/2 adverse events, classified according to the common terminology criteria for adverse events (CTC-AE) version 3.0 and 5 (4%) had grade 3/4 adverse events. The allergic reaction appeared after a median number of nine cycles (range, 2-15 cycles). Previous chemotherapy included 5-FU/LV, CPT-11, and S-1. All of the patients with allergic reactions recovered completely when treated with antiallergy drugs. Oxaliplatin was reintroduced in 11 patients, with the use of prophylactic agents; allergic reaction to the reintroduction was not observed in 8 patients and grade 1/2 allergic reactions developed in 3 patients. No correlation was identified between allergic reaction and patients' background characteristics such as sex, history of allergy, and profile of other adverse events. CONCLUSION: Allergic reactions to oxaliplatin remain an important issue for patients being able to safely continue effective chemotherapies; further analysis will be needed to establish methods for the prediction and prophylaxis of such reactions.

Increased expression of Toll-like receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers.

Background Toll-like receptors (TLRs) may play active roles in both innate and adaptive immune responses in human intrahepatic biliary epithelial cells (HIBECs). The role of TLR3 expressed by HIBECs, however, remains unclear. Methods We determined the in vivo expression of TLRs in biopsy specimens derived from diseased livers immunohistochemically using a panel of monoclonal antibodies against human TLRs. We then examined the response of cultured HIBECs to a TLR3 ligand, polyinosinic-polycytidylic acid (polyI:C). Using siRNAs specific for Toll-IL-1R homology domain-containing adaptor molecule 1 (TICAM-1) and mitochondrial antiviral signaling protein (MAVS), we studied signaling pathways inducing IFN-beta expression. Results The expression of TLR3 was markedly increased in biliary epithelial cells at sites of ductular reaction in diseased livers, including primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and chronic viral hepatitis (CH) as compared to nondiseased livers. Although cultured HIBECs constitutively expressed TLR3 at both the protein and mRNA levels in vitro, the addition of polyI:C to culture media induced only minimal increases in IFN-beta mRNA. In contrast, transfection of HIBECs with polyI:C induced a marked increase in mRNAs encoding a variety of chemokines/cytokines, including IFN-beta, IL-6, and TNF-alpha. The induction of IFN-beta mRNA was efficiently inhibited by an siRNA against MAVS but not against TICAM-1, indicating that the main signaling pathway for IFN-beta induction following polyI:C transfection is via retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) in HIBECs. Conclusions TLR3 expression by biliary epithelial cells increased at sites of ductular reaction in diseased livers; further study will be necessary to characterize it's in vivo physiological role.

Expression of microsomal prostaglandin E synthase-1 in human hepatocelluar carcinoma.

BACKGROUND/AIMS: The objective of this study was to evaluate the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in hepatocellular carcinoma (HCC) tissues. METHODS: Forty surgically resected HCC tissues with adjacent non-tumorous liver tissues and 14 surgically resected, histologically normal liver tissues were used. The immunohistochemical expressions of the mPGES-1 protein in these HCC tissues and normal control livers were analysed. mPGES-1 mRNA expression was also analysed by the real-time polymerase chain reaction method using the same tissues. RESULTS: Microsomal prostaglandin E synthase-1 was not expressed in hepatocytes but instead in vascular endothelial cells and bile duct epithelial cells in normal liver tissues. The mPGES-1 expression in HCC tissues was significantly greater than its expression in the non-tumorous tissues. All types of HCC expressed more mPGES-1 than normal or hepatitis livers, and the levels of mPGES-1 expression in poorly differentiated HCC were similar to the levels in well-differentiated HCC. The mPGES-1 mRNA expression paralleled its protein expression in these tumorous and non-tumorous tissues. CONCLUSIONS: The present study is the first to demonstrate a high expression of mPGES-1 in well-differentiated HCC as well as in poorly differentiated HCC. These findings suggest that mPGES-1 may play a role in the advanced as well as early stage of hepatocarcinogenesis.

Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis.

UNLABELLED: The predictive role of antinuclear antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end-point, positive anti-gp210 antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuer's stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive anti-centromere antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti-gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere antibodies was most significantly associated with more severe ductular reaction. CONCLUSION: These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive-anti-gp210 and positive-anticentromere antibodies, respectively.

Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-kappaB and -MAPK signaling pathways.

BACKGROUND: Human intrahepatic biliary epithelial cells (HIBECs) may play active roles in both the innate and adaptive immune responses. Little is known, however, about the role of toll-like receptors (TLRs) on HIBECs in inflammatory cholangiopathies. METHODS: The expression of TLR1-9 and the biological responses to their ligands, lipopolysaccharide (LPS) or lipoteichoic acid (LTA), were studied in cultured HIBECs by reverse transcription-polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay. RESULTS: HIBECs constitutively expressed transcripts encoding TLR1-6 and 9, as well as myeloid differentiation factor 88 (MyD88), MD2, and CD14. Stimulation of HIBECs with LPS resulted in translocation of NF-kappaB subunits from the cytoplasmic to the nuclear fraction, followed by increased secretion of a variety of chemokines/cytokines, including interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and IL-6. Treatment with BAY11-7082 efficiently inhibited the LPS-induced transcription and secretion of these chemokines/cytokines. In HIBECs, the mitogen-activated protein kinases (MAPKs) were also activated by LPS stimulation. These results indicated that LPS activates HIBECs via a TLR4-MyD88-dependent pathway. Stimulation of HIBECs with LTA induced the secretion of a similar profile of cytokines/chemokines via a TLR2-MyD88-dependent pathway. CONCLUSIONS: In HIBECs, at least TLR2 and 4 are capable of mediating innate immune system function in vitro. This result, in conjunction with our recent finding that TLR4 expression is increased in biliary epithelial cells in primary biliary cirrhosis, suggests the involvement of TLRs in the development of chronic inflammatory cholangiopathies.

Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis.

BACKGROUND: Although the pathogenesis of non-alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients. METHODS: Serum cytokines and soluble cytokine receptors levels were determined using an enzyme-linked immunosorbent assay kit in 23 patients with NASH, 21 patients with simple steatosis, and 18 healthy volunteers. RESULTS: Patients with NASH had significantly higher serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels than did the simple steatosis patients. Similarly, when compared with simple steatosis, NASH was associated with higher soluble TNF receptor 1 (sTNFR1) and soluble IL-6 receptor (sIL-6R) levels, and a significant positive correlation was seen between the levels of sTNFR1 and aminotranferases in NASH patients. CONCLUSIONS: This study shows that circulating TNF-alpha/sTNFR1 and IL-6/sIL-6R levels are significantly increased in NASH patients as compared with simple steatosis patients and healthy volunteers, and that these increased levels may be implicated in the pathogenesis of NASH.

Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis.

The sustained antibody response to nuclear envelope gp210 antigen indicates a group of primary biliary cirrhosis (PBC) patients at high risk for the progression to end-stage hepatic failure. To address this issue, we immunohistochemically studied the expression of gp210 antigen in needle liver biopsy specimens from PBC patients using a monoclonal antibody specific for gp210 antigen. The specimens from autoimmune hepatitis (AIH), chronic viral hepatitis B (CHB) and C (CHC) patients served as disease controls. The expression of gp210 antigen was apparently increased on the nuclear envelope of biliary epithelial cells (BECs) of small bile ducts in almost all specimens from PBC. In contrast, the expression of gp210 antigen was negative in BECs of small bile ducts in normal liver, while relatively weak anti-gp210 immunostaining was observed in AIH, CHC and CHB. In addition, the degree of gp210 expression in BECs of small bile ducts was positively correlated to that of portal inflammation, interface hepatitis and lobular inflammation in PBC. These results indicate that the increased expression of gp210 in small bile ducts, which is probably associated with damage to BECs by inflammation, is possibly involved in autoimmune response to gp210 leading to the progression to end-stage hepatic failure in PBC.

Immunosuppressant FK506 inhibits matrix metalloproteinase-9 induction in TNF-alpha-stimulated human hepatic stellate cells.

Activated hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic inflammation and fibrosis through the production of matrix metalloproteinases (MMPs). Cytokines and growth factors are thought to activate HSCs. TNF-alpha has pleiotropic functions in hepatitis, but its role in liver fibrosis remains elusive. In this study we investigated the regulation of tumor necrosis factor-alpha (TNF-alpha) in the expression of MMPs by HSCs. We also examined whether the immunosuppressant FK506 influences the MMPs expression in human HSCs. Human HSCs, LI90, were treated with TNF-alpha in the presence of FK506. Release of MMPs into culture media, levels of MMP-9 mRNA and activation of NF-kappaB were compared between the cells cultured with or without FK506. Stimulation of human HSCs, LI90 cells, with TNF-alpha caused the induction of pro-MMP-9. Further, TNF-alpha stimulation induced the degradation of IkappaB-alpha and resulted in the transcriptional activation of NF-kappaB. FK506 suppressed this TNF-alpha-induced NK-kappaB activation, alone with pro-MMP-9 mRNA and protein induction, in HSC. TNF-alpha contributes to the perpetuation of liver fibrosis through MMP-9 production from HSCs and that FK506 inhibits the induction of MMP-9 through NF-kappaB pathway suggesting the anti-inflammatory properties of FK506.

Synergistic interaction between oxaliplatin and SN-38 in human gastric cancer cell lines in vitro.

The interaction between CPT-11 and oxaliplatin, a new platinum derivative that has a great antitumor activity against colon cancer, has not been determined in gastric cancer cells. In this study, we investigated in vitro cytotoxic activity of oxaliplatin alone or in combination with SN-38, an active metabolite of CPT-11, using different exposure schedules in three human gastric cancer cell lines (AZ-521, MKN-45, and NUGC-4). Cytotoxicity was determined by WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation was evaluated by flow cytometry. In 24-h exposure, simultaneous administration of oxaliplatin and SN-38 showed a synergistic effect in AZ-521 and NUGC-4 cells, and an additive effect in MKN-45 cells. Greater than additive effects were observed in all of the cell lines when cells were treated with oxaliplatin followed by SN-38, whereas such effects were observed only in NUGC-4 cells in the reverse sequence. Flow cytometric analyses at IC(50) indicated that apoptosis was most prominent in simultaneous exposures with accumulation of cells in both G(0)/G(1) and S phases. These results suggest that SN-38 may kill the cells recovering from the G(1) block produced by oxaliplatin as they progress into the S phase. Simultaneous administration appears most active in gastric cancer cell lines. These results may provide important information for a clinical trial of oxaliplatin and CPT-11 combination for patients with gastric cancer.

Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis.

Toll-like receptor 4 (TLR4) is a receptor for bacterial lipopolysaccharide, which is suggested to be involved in the pathogenesis of disease of hepatobiliary tracts. To explore a possible role for this receptor in primary biliary cirrhosis (PBC), we investigated the expression of TLR4 in liver tissues from PBC patients. We studied liver biopsy sections from 62 PBC patients and 41 patients with chronic hepatitis C (CHC). Expression of TLR4 in paraffin-embedded sections was analyzed by immunohistochemistry. The bile duct epithelial cells (BECs) of PBC liver tissues markedly expressed TLR4, whereas BECs of CHC liver tissues barely expressed TLR4. The TLR4 expression was also observed in periportal hepatocytes of PBC liver tissues and its expression was extended to interlobular hepatocytes in advanced stage PBC. Although periportal hepatocytes of CHC liver tissues expressed TLR4, its expression levels were not correlated with the fibrosis stage. Our data demonstrated that TLR4 was expressed in BECs and periportal hepatocytes in PBC livers, suggesting the possible involvement of bacterial pathogens and TLR4 in the inflammatory processes of PBC.

Idiopathic portal hypertension associated with systemic sclerosis and Sjögren's syndrome.

We report a patient with idiopathic portal hypertension (IPH) associated with systemic sclerosis (SSc) and Sjögren's syndrome. A 72-year-old Japanese woman was admitted to our hospital because of Raynaud's phenomenon, sclerodactyly, and dyspnea. The patient had splenomegaly, esophageal varices in the absence of extrahepatic portal obstruction, and cirrhosis of the liver. Immunological studies revealed positive anti-nuclear antibodies and high titers of anti-Scl-70, anti-SS-A, anti-centromere, and anti-mitochondrial M2 antibodies. Histological examinations of the liver biopsy specimen revealed stenosis and loss of small portal veins without findings of primary biliary cirrhosis. The patient was diagnosed as having IPH associated with SSc and Sjögren's syndrome. These observations suggest an immunological role in the pathogenesis of IPH.

Peroxynitrite-mediated matrix metalloproteinase-2 activation in human hepatic stellate cells.

To investigate whether hepatic stellate cells (HSCs) alter their expression of MMPs after exposure to nitrogen oxide intermediate (NOI), a human hepatic stellate cell line, LI90 cells, was stimulated with an NO donor, SNAP, or a peroxynitrite donor, SIN-1, and the culture supernatants were analyzed by gelatin zymography or anti-MMPs immunoblot. Although SIN-1 did not enhance the secretions of MMP-1 and 13, SIN-1 induced the NF-kappaB activation, MT1-MMP expression and the secretion of activated MMP-2 in LI90 cells. These results suggest that peroxynitrite may contribute to the remodeling of the extracellular matrix in liver by activating pro-MMP-2.

In vitro sequence-dependent interaction between nedaplatin and paclitaxel in human cancer cell lines.

PURPOSE: To define the most effective combination schedule of paclitaxel and nedaplatin, a new platinum derivative, we investigated the in vitro interaction between these drugs in AZ-521 and NUGC-4 gastric adenocarcinoma and KSE-1 esophageal squamous carcinoma cell lines. MATERIALS AND METHODS: Cytotoxic activity was determined by the WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism using a quantitative method based on the median-effect principle of Chou and Talalay. Cell-cycle perturbation and apoptosis were evaluated by means of flow cytometry. RESULTS: Upon 24-h sequential exposure, the sequence paclitaxel followed by nedaplatin induced greater than additive effects in all of the cell lines, with synergistic interactions in NUGC-4 and KSE-1 cells. By contrast, antagonistic effects were observed with the reverse sequence. Simultaneous treatment resulted in either a synergistic or antagonistic effect, depending on the cell line. Therefore, the sequence paclitaxel followed by nedaplatin appears most active, at least in these three cell lines. Flow cytometric analyses at IC50 indicated that paclitaxel induced G2/M arrest with subsequent induction of apoptosis (56%) in the sub-G1 phase. When paclitaxel preceded nedaplatin, apoptosis was most prominent (70%) with pronounced G2/M arrest. By contrast, the reverse sequence yielded only 28% induction of apoptotic cells, with almost identical cell-cycle distribution patterns to those observed with nedaplatin alone, indicating that the activity of paclitaxel is abolished by pretreatment with nedaplatin. CONCLUSIONS: Our findings suggest that the interaction of nedaplatin and paclitaxel is highly schedule dependent and that the sequential administration of paclitaxel followed by nedaplatin should be thus incorporated into the design of a clinical trial.

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis.

The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-alpha, -beta, -gamma, interleukin (IL)-1beta, -4, -6, -10, -12p40, -18, tumor necrosis factor-alpha) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-alpha, -beta and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-alpha, -beta) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-alpha is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-beta and TLR-3. Furthermore, the level of IFN-alpha mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC.

Acute hepatitis E of a man who consumed wild boar meat prior to the onset of illness in Nagasaki, Japan.

Zoonotic infection of hepatitis E virus (HEV) has been suggested. To date, pigs, deer, and wild boar have been implicated as reservoirs of HEV in Japan. However, it is not known to what extent zoonotic transmission of HEV play roles of causing HEV transmission. In the present report, we describe a case of acute hepatitis E in which a transmission of HEV by a zoonotic transmission is strongly suggested. The patient had eaten grilled wild boar meat 59 days prior to onset of acute hepatitis. Although the meat was not stored, one of the two people who ate boar meat with the patient at the same time showed high levels of HEV-IgM and -IgG and normal levels of liver enzymes, suggesting a subclinical infection of HEV. Accumulating evidence suggests that eating wild boars is associated with a high risk of acquiring hepatitis E infection.

Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis.

BACKGROUND/AIMS: The presence of antibodies to the 210-kDa glycoprotein of the nuclear pore complex (gp210) is highly indicative of primary biliary cirrhosis (PBC). However, the significance of anti-gp210 antibody titers for monitoring PBC remains unresolved. METHODS: We used an ELISA with a gp210 C-terminal peptide as an antigen to assess serum antibody titers in 71 patients with PBC. RESULTS: Patients were classified into three groups: Group A in whom anti-gp210 titers were sustained at a high level, Group B in whom anti-gp210 status changed from positive to negative under ursodeoxycholic acid (UDCA) therapy, Group C in whom anti-gp210 antibodies were negative at the time of diagnosis. The rate of progression to end-stage hepatic failure was significantly higher in group A (60%) as compared to groups B (0%) and C (4.2%). The sustained antibody response to gp210 was closely associated with the severity of interface hepatitis. The significance of anti-gp210 antibody was confirmed by National Hospital Organization Study Group for Liver Disease in Japan. CONCLUSIONS: The serial quantitation of serum anti-gp210-C-terminal peptide antibodies is useful for monitoring the effect of UDCA and for the early identification of patients at high risk for end-stage hepatic failure.

In vitro schedule-dependent interaction between paclitaxel and oxaliplatin in human cancer cell lines.

PURPOSE: In order to define the most effective administration schedule of the combination of paclitaxel and oxaliplatin, we investigated the in vitro interaction between these drugs in a panel of three human cancer cell lines (AZ-521 gastric adenocarcinoma cell line, HST-1 tongue squamous carcinoma cell line, and KSE-1 esophageal squamous carcinoma cell line). MATERIALS AND METHODS: Cytotoxic activity was determined by the WST-1 assay. Different administration schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. RESULTS: Simultaneous treatment of cells with paclitaxel and oxaliplatin showed greater than additive effects. Upon 24-h sequential exposure, the sequence of paclitaxel followed by oxaliplatin showed synergistic effects in AZ-521 and HST-1 cells, and greater than additive effects in KSE-1 cells, while the opposite sequence yielded marked antagonistic effects in all three cell lines. Flow cytometric analysis indicated that paclitaxel induced G(2)/M arrest with subsequent induction of apoptosis in the sub-G(1) phase. Apoptosis was most prominent when paclitaxel preceded oxaliplatin, which produced apoptosis in the majority of treated cells (75%). By contrast, the reverse sequence yielded only 39% induction of apoptotic cells, the rate being not different from those induced by each drug singly. CONCLUSIONS: Our findings suggest that the interaction of paclitaxel and oxaliplatin is highly schedule-dependent and that the sequential administration of paclitaxel followed by oxaliplatin should thus be incorporated into the design of a clinical trial.