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We evaluated the efficacy and safety of radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) in presumably high-risk locations. Between February 1999 and December 2001, we performed RF ablation on 1419 nodules in 636 consecutive HCC patients, of which 231 nodules in 207 patients were in high-risk locations, defined as less than 5 mm from a large vessel or an extrahepatic organ. Eighty-one patients had a nodule adjacent to a large vessel, 145 patients had a nodule adjacent to an extrahepatic organ, of whom 19 also had one adjacent to a large vessel. Early complications and local tumor progression were analyzed with regard to the location of each nodule. The mean nodule diameter and average number per patient were 27 mm and 2.3, respectively. Early complications, within 30 days after ablation, occurred in 12 of 207 patients (5.8%) with a nodule in a high-risk location and in 15 of 429 patients (3.5%) without (P = .1776). There was no significant difference in local tumor progression rate between nodules in high-risk locations (1 year: 2.1%, 2 years: 3.1%, 3 years: 3.1%) and those elsewhere (1 year: 0.6%, 2 years: 1.7%, 3 years: 2.5%) (P = .2745). In conclusion, HCC nodules adjacent to a large vessel or extrahepatic organ were treated with RF ablation without compromising the efficacy of the procedure. However, even though without significant difference, some complications occurred at risky locations and need to be carefully considered.

The activation of Hedgehog (Hh) signaling has been implicated in the growth of various tumor types, including gastric carcinoma. However, the precise mechanisms of Hh activation and suppression of tumor growth by the blockade of Hh signaling in gastric carcinoma cells remain unknown. The aim of this study was to elucidate the mechanism of abnormal Hh signaling and the key molecules contributing to dysregulated growth of gastric carcinoma. The Sonic hedgehog (Shh) ligand and its receptor Patched were expressed in all five gastric carcinoma cell lines examined (MKN1, MKN7, MKN45, MKN74, and AGS cells). The blockade of Hh signaling with anti-Shh antibody inhibited the growth of all five gastric carcinoma cell lines. Shh was overexpressed (mean, 12.8-fold) in 8 of 14 (57.0%) cancerous tissue samples from patients with gastric carcinoma as compared with expression in the surrounding noncancerous tissues. The disruption of glioma-associated oncogene 1 (Gli1) by small interfering RNA induced an increase in p21/cyclin-dependent kinase–interacting protein 1 (CIP1), interfered with the G1-S transition, and suppressed cell proliferation. The stimulation or inhibition of Hh signaling did not affect p53 activity and the induction of p21/CIP1 expression and the G1 arrest by inhibition of Hh signaling were not affected by the p53 status. These findings suggest that the overexpression of Shh contributes to constitutive Hh activation and that this signaling pathway negatively regulates p21/CIP1 through a Gli1-dependent and p53-independent mechanism in gastric carcinoma cells.

Background: The pediatric colonoscope is superior to the standard colonoscope in some patients with a fixed, angulated colon. A colonoscope thinner than the pediatric one is thought to outperform even the pediatric colonoscope in such cases. This study was conducted to assess the efficacy of an ultrathin colonoscope, 9.8 mm in diameter, comparing it with pediatric and standard colonoscopes. Methods: Three types of colonoscopes were used: ultrathin, pediatric, and standard. A total of 287 consecutive patients were assigned to three groups: ultrathin (n = 94), pediatric (n = 98), and standard (n = 95). First assessment was the ratio of cecal intubation and the reasons for unsuccessful colonoscopy. The second was the time to cecal intubation. Results: Cecal intubation rates were not different among three groups (96% in each). The main reasons for failed colonoscopy were looping in the ultrathin group, and angulation or stricture in the pediatric and standard groups. Mean time to the cecum was slightly longer in the ultrathin group (6.5 minutes) than the pediatric group (5.6 minutes) and standard group (6.1 minutes), but there were no significant differences among three groups. Conclusion: Colonoscopy with the ultrathin colonoscope was as successful as with the pediatric and standard colonoscopes. The advantage of the ultrathin colonoscope might be notable in cases with stricture or severe angulation.

BACKGROUND We evaluated the association between variations in hepatitis C virus (HCV) core protein and hepatitis severity in patients with chronic HCV infection who achieved remission without viral eradication and had a biochemical response to interferon (IFN) therapy, to evaluate the effect of HCV core sequence in the absence of the influence of host factors. METHODS. Using serum from 10 patients with a biochemical response and 10 patients with no response, we measured serum levels of interleukin (IL)-1 beta , IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFN- gamma , and tumor necrosis factor- alpha before and after IFN therapy. Expression vectors with the core region were transfected into Huh7 cells, and cytokine induction was evaluated by reporter assay. RESULTS In biochemical responders, only IL-8 levels decreased after IFN therapy (P=.04). Changes in the C-terminal hydrophobic region were observed more frequently in biochemical responders. Activation of the IL-8 promoter by HCV core protein was significantly decreased in biochemical responders after IFN therapy (P=.04). When 69 C-terminal amino acids from before IFN therapy were replaced with those from after IFN therapy in 3 biochemical responders, their ability to transactivate IL-8 decreased. CONCLUSIONS Differences in amino acids in the HCV core protein correlates with hepatitis activity through the modulation of IL-8 induction in HCV-infected patients.

Percutaneous radiofrequency ablation is a recently introduced treatment for hepatocellular carcinoma, whereas ethanol injection is now a standard therapy. We compared their long-term outcomes.Two hundred thirty-two patients with hepatocellular carcinoma who had 3 or fewer lesions, each 3 cm or less in diameter, and liver function of Child-Pugh class A or B were entered onto a randomized controlled trial. The primary end point was survival, and the secondary end points were overall recurrence and local tumor progression.One hundred eighteen patients were assigned to radiofrequency ablation and 114 to ethanol injection. The number of treatment sessions was smaller (2.1 times vs 6.4 times, respectively, P.0001) and the length of hospitalization was shorter (10.8 days vs 26.1 days, respectively, P.0001) in radiofrequency ablation than in ethanol injection. Four-year survival rate was 74% (95% CI: 65%-84%) in radiofrequency ablation and 57% (95% CI: 45%-71%) in ethanol injection. Radiofrequency ablation had a 46% smaller risk of death (adjusted relative risk, 0.54 [95% CI: 0.33-0.89], P = .02), a 43% smaller risk of overall recurrence (adjusted relative risk 0.57 [95% CI: 0.41-0.80], P = .0009), and an 88% smaller risk of local tumor progression (relative risk, 0.12 [95% CI: 0.03-0.55], P = .006) than ethanol injection. The incidence of adverse events was not different between the 2 therapies.Judging from higher survival but similar adverse events, radiofrequency ablation is superior to ethanol injection for small hepatocellular carcinoma.

The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK (p38) has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38alpha(+/-) donor graft induced more acute GVHD-related mortality and more severe gut injury. The survival of p38alpha(+/-) donor-derived intestinal intraepithelial lymphocytes (IEL) was prolonged in vitro and in vivo, and TNF-alpha expression in the p38alpha(+/-) donor-derived IEL was also increased compared with wild-type cells. In contrast, the p38alpha(+/-) grafted mice resulted in decreased expansion of donor lymphocytes in mesenteric lymph nodes, and the up-regulation of IL-12p40 and IL-18 was diminished. These findings suggest that p38 has dichotomous effects for inflammatory response in vivo; not only regulates inflammatory cytokine expression and lymphocyte expansion, but also has distinct regulatory functions for IEL in intestinal GVHD. In conclusion, the inhibition of p38 may not be a suitable anti-inflammatory strategy for GVHD due to the associated intestinal injury.

Background and aim: Helicobacter pylori infection and gastric atrophy are both risk factors for gastric cancer. We aimed to elucidate the natural history of gastric cancer development according to H pylori infection and gastric atrophy status. Subjects and methods: A total of 9293 participants in a mass health appraisal programme were candidates for inclusion in the present prospective cohort study: 6983 subjects revisited the follow up programme. Subjects were classified into four groups according to serological status at initial endoscopy. Group A (n = 3324) had “normal” pepsinogen and were negative for H pylori antibody; group B (n = 2134) had “normal” pepsinogen and were positive for H pylori antibody; group C (n = 1082) had “atrophic” pepsinogen and were positive for H pylori antibody; and group D (n = 443) had “atrophic” pepsinogen and were negative for H pylori antibody. Incidence of gastric cancer was determined by annual endoscopic examination. Results: Mean duration of follow up was 4.7 years and the average number of endoscopic examinations was 5.1. The annual incidence of gastric cancer was 0.04% (95% confidence interval (CI) 0.02–0.09), 0.06% (0.03–0.13), 0.35% (0.23–0.57), and 0.60% (0.34–1.05) in groups A, B, C, and D, respectively. Hazard ratios compared with group A were 1.1 (95% CI 0.4–3.4), 6.0 (2.4–14.5), and 8.2 (3.2–21.5) in groups B, C, and D, respectively. Age, sex, and “group” significantly served as independent valuables by multivariate analysis. Conclusions: The combination of serum pepsinogen and anti- H pylori antibody provides a good predictive marker for the development of gastric cancer.

Objectives: New modalities, namely, endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and helical computed-tomographic cholangiography (HCT-C), have been introduced recently for the detection of common bile duct (CBD) stones and shown improved detectability compared to conventional ultrasound or computed tomography. We conducted this study to compare the diagnostic ability of EUS, MRCP, and HCT-C in patients with suspected choledocholithiasis. Methods: Twenty-eight patients clinically suspected of having CBD stones were enrolled, excluding those with cholangitis or a definite history of choledocholithiasis. Each patient underwent EUS, MRCP, and HCT-C prior to endoscopic retrograde cholangio-pancreatography (ERCP), the result of which served as the diagnostic gold standard. Results: CBD stones were detected in 24 (86%) of 28 patients by ERCP/IDUS. The sensitivity of EUS, MRCP, and HCT-C was 100%, 88%, and 88%, respectively. False negative cases for MRCP and HCT-C had a CBD stone smaller than 5 mm in diameter. No serious complications occurred while one patient complained of itching in the eyelids after the infusion of contrast agent on HCT-C. Conclusions: When examination can be scheduled, MRCP or HCT-C will be the first choice because they were less invasive than EUS. MRCP and HCT-C had similar detectability but the former may be preferable considering the possibility of allergic reaction in the latter. When MRCP is negative, EUS is recommended to check for small CBD stones.

Vitamin K is a cofactor for gamma-glutamyl carboxylase, an enzyme that is important for blood coagulation. Recent studies have shown that vitamin K has other roles, in addition to post-transcriptional modification, such as bone metabolism and antitumoral actions; these findings have indicated that there might be unknown intracellular binding proteins that are specific for vitamin K. In this study, vitamin K-binding proteins were characterized by pull-down experiment using a chemically synthesized biotynylated vitamin K followed by mass spectrometric identification of the pull-downed components. The results indicated that 17beta hydroxy steroid dehydrogenase 4, apolipoportein E, and 40S ribosomal proteins S7 and S13 might be the candidates of the vitamin K-binding proteins. Subsequent experiments showed that vitamin K2 binds 17beta hydroxysteroid dehydrogenase 4 and decreases the intracellular estradiol:estrone ratio, which resulted in the inhibition of the amount of estrogen receptor alpha-binding to its target DNA. These results suggest a possible novel role for vitamin K in modulating estrogen function.

Background & Aims: Pancreatitis remains the major complication of endoscopic retrograde cholangiopancreatography (ERCP), and hyperenzymemia after ERCP is common. Because ulinastatin, a protease inhibitor, has proved effective in the treatment of acute pancreatitis, the aim of this study was to assess the efficacy of ulinastatin for the prevention of post-ERCP pancreatitis and hyperenzymemia. Methods: In a multicenter, randomized, double-blind, placebo-controlled trial, patients undergoing a first ERCP were randomized to receive ulinastatin (150,000 U) or placebo by intravenous infusion for 10 minutes starting immediately before ERCP. All patients were hospitalized at least 24 hours after ERCP for evaluation of clinical symptoms. Serum pancreatic enzyme levels were measured before and at 4 and 18 hours after ERCP. The primary end point was the incidence of post-ERCP pancreatitis and the secondary objective was the occurrence of hyperenzymemia. Results: A total of 406 patients were enrolled (204 in the ulinastatin group and 202 in the placebo group). There were no differences between the 2 groups regarding baseline characteristics, details of fluoroscopic findings, or endoscopic procedure. The incidence of hyperenzymemia was significantly lower in the ulinastatin group than in the placebo group (amylase, P = .011; lipase, P = .008). Six patients in the ulinastatin group and 15 patients in the placebo group developed pancreatitis (2.9% vs. 7.4%, P = .041). There was no case of severe pancreatitis in either group. Patients who received ulinastatin did not present any side effects related to the medication. Conclusions: Prophylactic short-term administration of ulinastatin decreases the incidence of pancreatitis and hyperenzymemia after ERCP.

Flat-type colorectal cancer is frequently reported in Japan and Europe, but its clinical features remain obscure. Thus, we investigated the clinical features of flat-type early colorectal cancer with respect to tumor location and patient age and compared them with those of polypoid-type early and advanced cancer. Between January 1999 and June 2001, total colonoscopy was performed in 6,178 patients (mean age, 61 years; 4,290 males and 1,888 females). Of these patients, 402 patients with 429 colorectal cancers were found: 202 at advanced stage (invading beyond muscularis propria) and 227 at early stage (carcinoma in situ or invading within submucosa). Early-stage cancer was classified into two macroscopic subgroups: flat-type and polypoid-type. Out of 227 early cancers, 44 were flat type and 183 were polypoid. Flat-type early cancer was more frequently located in the right colon (57 percent, 25/44) than polypoid-type cancer (19 percent, 35/183; P < 0.001). Adenomatous component in flat-type early cancer was less frequent than in polypoid-type cancer (23 percent vs. 92 percent, P < 0.001). The proportion of right-sided colon in flat-type early cancer increased with age (33 percent in patients ≤59 years, 50 percent in patients between 60 and 69 years, and 72 percent in patients ≥70 years), whereas polypoid-type early cancer showed minimal change (16 percent, 18 percent, and 25 percent, respectively). An increase in the proportion of right-sided colon with age was also found in advanced cancer (20 percent, 38 percent, and 52 percent, respectively). The incidence of flat-type early cancer in right-sided colon increased with age, similar to the pattern of advanced cancer. This suggests that flat-type early cancer may be a precursor of advanced cancer in the right colon, especially in older people.

Endoscopic papillary balloon dilation has been accepted as a possible alternative to endoscopic sphincterotomy, especially in patients with impaired hemostasis. However, pancreatitis associated with endoscopic papillary balloon dilation has remained a controversial, serious issue. The aim of the study was to investigate the risk factors for postendoscopic papillary balloon dilation pancreatitis in a single-center study.A total of 304 patients who underwent endoscopic papillary balloon dilation for the management of common bile duct stones were enrolled. The risk of postendoscopic papillary balloon dilation pancreatitis was evaluated and the risk factors were analyzed by univariate and multivariate analysis. Definition and grade of the severity of postendoscopic papillary balloon dilation pancreatitis were based on the 1991 consensus guidelines.Common bile duct was cleared in 292 of 304 patients (96%). Procedure-related pancreatitis occurred in 15 patients (5.0%). The grade was mild in 8 and moderate in 7. Two risk factors, stone diameter and contrast medium injection to the pancreas, were identified by univariate analysis. Finally, only the contrast medium injection to the pancreas was statistically significant by multivariate analysis. Prior history of pancreatitis was identified as a risk factor for postendoscopic papillary balloon dilation pancreatitis in previous studies, but this factor was not identified as a risk factor in our series.Although the pathogenesis of pancreatitis after endoscopic papillary balloon dilation remains unresolved, the unnecessary injection of contrast medium to the pancreas can certainly be considered to be associated with the increased risk of pancreatitis.

Background & Aims: Hepatocellular carcinoma (HCC) is one of the most common human malignancies. Its high mortality rate is mainly a result of high intrahepatic recurrence. The novel synthetic retinoid acyclic retinoid (ACR) has been reported to prevent the recurrence of human HCC after surgical resection of primary tumors, but the molecular mechanisms underlying its effects remain to be elucidated. In this study, we clarified the molecular targets of ACR. Methods: The inhibitory effects by ACR on growth were examined. Intracellular signaling induced by ACR was comprehensively studied by a reporter assay. Gene expression changes by ACR were examined using a microarray. From these results, a candidate signaling pathway modulated by ACR was determined and whether antagonizing this pathway reverses the effect was examined. Results: We show that ACR inhibits the growth of HCC cells through the down-regulation of fibroblast growth factor (FGF) receptor 3 expression and FGF-mediated signaling, which in turn suppresses the activity of Rho and serum response factor-mediated transcription. Conversely, overexpression of the active form of FGF receptor 3 or the addition of FGF reverses the ACR-mediated inhibition of growth. In addition, silencing the FGF receptor 3 gene by RNA interference inhibits cell growth. Conclusions: These studies show that ACR is a potent inhibitor of FGF signaling and that selective blocking of the FGFmediated pathway could be a promising therapeutic approach for the management of patients with HCC.

Mutations in the B-raf gene have been reported in a number of human cancers, including melanoma and lung cancer. More than 80% of the reported B-raf mutations were V599E; however, non-V599E mutations have been frequently found in non-small cell lung cancers as compared with melanoma. Some non-V599E mutations have been found surrounding Thr439, which is thought likely to be one of the three Akt phosphorylation sites in the B-raf protein. However, as a previous report indicated that Thr439 was not phosphorylated by Akt, the functional consequences of these mutations have been unclear. Here, we examined the effects of cancer-related B-raf mutations surrounding Thr439 on the activation of the mitogen-activated protein/ extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (Erk) pathway and the transformation of NIH 3T3 fibroblasts. Among the three reported mutations (K438Q, K438T, and T439P) found in non-small cell lung carcinoma and melanoma, none elevated the activity of the MEK/Erk cascade as determined by in vitro kinase assays, immunoblots using antibody specific for phosphorylated Erk, or Elk1-dependent reporter assays. The inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling by LY294002 increased the Erk activation induced by the mutant B-raf proteins, as well as by wild-type B-raf. Furthermore, the B-raf mutants did not have increased NIH 3T3-transforming activities, as determined by colony-formation assays. These results suggest that the B-raf mutations surrounding Thr439 found in human cancers are unlikely to contribute to increased oncogenic properties of B-raf.

The dropout from the waiting list for liver transplantation among patients with hepatocellular carcinoma (HCC) is reportedly as high as 12% to 40% per year, mostly due to tumor progression. Considering the scarcity of donor organs, it would be beneficial if we could retain them within the Milan criteria with a bridging therapy. We retrospectively analyzed the prognosis of 288 HCC patients with relatively preserved liver function we treated with ablation therapy between 1997 and 2001, concentrating on whether they subsequently remained in the criteria, and analyzed the risk factors of dropout with Cox proportional hazards model. During a median follow-up period of 39 months (range, 1–86 months), 33 (11%) died without tumor progression, while 85 (30%) dropped out due to tumor progression. The overall dropout rate was 9.0% and 32.8% at 1 and 3 years, respectively, and that due to tumor progression was 6.2% and 23.0%. Cox regression analysis indicated that a high serum level of alpha-fetoprotein or des-γ-carboxy prothrombin, and a tumor size exceeding 3 cm in diameter affected the dropout due to tumor progression, while low albumin concentration was a risk factor of death independently of tumor progression. In conclusion, local ablation therapy for HCC was effective in containing the tumor progression within the Milan criteria in selected patients. (Liver Transpl 2005;11:508–514.)

CagA protein of Helicobacter pylori is injected into the epithelium, where CagA undergoes tyrosine phosphorylation and activates proliferation signals. However, the importance of these CagA activities for pathogenesis has yet to be resolved. The aim of this study is to analyze the genetic and functional variability of cagA gene of clinical strains in relation to gastric diseases. Thirty-six H. pylori strains were isolated from Japanese patients with various gastric diseases and examined. All 36 strains were found to contain cagA and cagE gene and to induce CagA phosphorylation upon infection. The intensity of CagA phosphorylation expressed in HeLa cells by transfection was highly correlated to the number of R1 region. The phosphorylation intensity was slightly higher in strains from chronic atrophic gastritis (CG); however, the differences were not statistically significant. These CagA proteins also activated the serum response element (SRE) reporter by 5- to 14-fold, above the level of the control. CagA proteins which lack R2 or R3 region exhibited smaller ability for SRE activation. The average of SRE activation was slightly higher in strains from cases of gastric cancer (GC; 11.4+/-1.6), MALT lymphoma (ML; 10.7+/-1.0), and chronic atrophic gastritis (CG; 11.2+/-1.6) than in those of duodenal ulcer (DU; 8.3+/-1.9) or gastric ulcer (GU; 9.0+/-1.1). In summary, most Japanese H. pylori strains contained CagA transport system and induced CagA phosphorylation, and the levels of the intensity of phosphorylation and the ability to induce SRE varied among strains. Although the association between CagA activities and disease outcome shown in this study is not very strong, variety of CagA structure, which induces variable activities, may be one of the reasons why H. pylori induces distinct diseases on host.

Recently, mutations in the B-Raf gene have been identified in a variety of human cancers, such as melanoma and colorectal carcinoma, and more than 80% of the B-Raf mutations have been V599E. Although other mutations have been reported, their functional consequences are poorly understood. In our earlier study, we demonstrated that colon tumor-associated B-Raf mutations within the kinase activation segment are not necessarily associated with an increase in mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/Erk) or nuclear factor κB (NFκB) signaling activity or in NIH3T3-transforming ability [T. Ikenoue et al., Cancer Res., 63: 8132–8137, 2003]. In this study, we examined the effect of colon tumor-associated mutations within the B-Raf glycine-rich loop (G loop) on MEK/Erk and NFκB signaling and on the transformation of NIH3T3 fibroblasts or IEC-6 intestinal epithelial cells. Of the six G loop mutations examined, only the B-Raf G468A significantly increased MEK/Erk and NFκB signaling and NIH3T3 transformation. Only this mutation induced transformed phenotypes of IEC-6 cells. In contrast, the B-Raf G468E mutation significantly decreased MEK/Erk signaling and NIH3T3 transformation and had no effect on NFκB signaling. The B-Raf F467C mutation moderately elevated MEK/Erk signaling and NIH3T3 transformation. The other three B-Raf mutations, R461I, I462S, and G463E, did not increase MEK/Erk or NFκB signaling or NIH3T3 transformation. Except for F467C, none of the tumors with B-Raf mutations examined in this study had K-Ras mutations. These results suggest that some of the B-Raf G loop mutations reported in colorectal tumors do not increase kinase or transforming activities but might contribute to carcinogenesis via other mechanisms or be irrelevant to carcinogenesis.

Understanding the function of the hepatitis B virus X protein (HBx) is fundamental to elucidating the underlying mechanisms of hepatitis and hepatocarcinogenesis caused by hepatitis B virus (HBV) infection. We identified heat shock protein 60 (Hsp60) as a novel cellular target of HBx by the combination of affinity purification and mass spectrometry. Physical interaction between HBx and Hsp60 was confirmed by standard immunoprecipitation and immunoblot methods. Analysis of HBx deletion constructs showed that amino acids 88–117 of HBx were responsible for the binding to Hsp60. Confocal laser microscopy demonstrated that HBx and Hsp60 colocalized in mitochondria. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP end labeling (TUNEL) revealed that the introduction of Hsp60 into cells facilitated HBx-induced apoptosis. These findings suggest the importance of the molecular chaperon protein Hsp60 to the function of HBV viral proteins.

The BRAF gene is mutated in 66% of melanomas and less frequently in various human cancers. More than 80% of these mutations are T to A transversions at nucleotide 1796 (T1796A), leading to a substitution of glutamic acid for valine at amino acid 599 (V599E). We established a new method for rapidly detecting V599E mutations using real-time polymerase chain reaction and melting curve analysis. Furthermore, we examined mutations in gastrointestinal cancer cell lines using this method. We found a mutation in 1 of 12 (8%) colorectal cancer cell lines, but no mutation was detected in 9 gastric cancer cell lines. These results suggest that the BRAF mutation is unlikely to be involved in gastric carcinogenesis.

Although Helicobacter pylori is classified as a definite carcinogen, the mechanism underlying gastric carcinogenesis is not yet clear. We previously have shown that H. pylori activates an antiapoptotic gene, the cellular inhibitor of apoptosis protein 2 (c-IAP2), the underlying mechanism of which was investigated in the present study. cDNA array and real-time PCR analyses indicated that H. pylori showed a stimulatory effect on the expression of c-IAP2. Isogenic mutant strains with impaired cag pathogenicity island (cagPAI) expression showed weaker induction. Analyses that used the in situ terminal deoxynucleotide transferase-mediated dUTP nick end-labeling method indicated suppression of antiapoptosis by the antisense c-IAP2 oligonucleotide. Reporter assays with deletion and mutation constructs for the c-IAP2 promoter showed that nuclear factor-kappaB (NF-kappaB) binding sites are indispensable for transactivation. Super-repressor IkappaBalpha or NF-kappaB inhibitor reduced c-IAP2 transactivation by H. pylori, and exogenous expression of c-IAP2 inhibited apoptosis seen with H. pylori. In conclusion, H. pylori induces antiapoptosis through c-IAP2 transactivation following cagPAI-dependent NF-kappaB activation. The interaction of these stimuli may play a role in gastric carcinogenesis.

Background & Aims: The aim of this study was to define the bile duct changes associated with autoimmune pancreatitis. Methods: Eight patients with autoimmune pancreatitis were followed for a mean of 4 years. The clinical features of these patients, including extrapancreatic bile duct changes, were examined by using biochemical parameters and several imaging modalities. Pathologic features of the pancreas and liver were examined by using the biopsy specimens of 7 patients. Results: Diffuse or focal narrowing of the main pancreatic duct was observed in all patients. Histologic examination of the pancreas showed lymphoplasmacyte infiltration with severe fibrosis and acinar cell depletion. In 6 patients extrapancreatic bile duct changes such as stricture of the bile duct at hilus or intrahepatic area were observed. In 2 patients abnormalities in the bile duct and pancreas were detected simultaneously at diagnosis, and changes in the bile duct were observed later in 4 patients. Lymphoplasmacyte infiltration and fibrosis were observed in the portal area of all 7 liver biopsy samples. Five of the patients with bile duct changes received steroid therapy, and the pathological changes improved. Conclusions: Extrapancreatic bile duct changes are frequently associated with autoimmune pancreatitis. Similar pathogenic mechanism might produce the biliary tract and pancreatic abnormalities in autoimmune pancreatitis resulting in a similar histopathology in the liver and pancreas and response to steroid therapy.

Background: Two types of quantitative assay kits for K-ras mutations, PCR–preferential homoduplex formation assay (PHFA) and enriched PCR and enzyme-linked mini-sequence assay (ELMA), were recently developed. The K-ras mutations were analyzed using these assays. Materials and methods: DNA was extracted from the pancreatic juice which was obtained by endoscopy from 38 patients with pancreatic neoplasms (23 adenocarcinomas and 15 intraductal papillary neoplasms) and from 62 without it. Results: The results of the two methods were mutually correlative. K-ras mutation was detected at high levels (mutant ras genes occupied >2% of all K-ras genes) in 25 of the 38 cases (66%) with pancreatic neoplasm. It was also detected at high levels in 9 of the 14 cases (64%) with pancreatic cyst. In contrast, the mutant gene was detected at a lower level (

Background: One of the most important endoscopic findings for the diagnosis of chronic gastritis is erythema. Erythema is classified into two groups: spotted or scattered erythema and linear erythema. We feel that red streaking has a tendency to be found on the apparently normal gastric mucosa without inflammation. Methods: To evaluate this association prospectively, we conducted the present study in 1513 consecutive patients undergoing endoscopy. Helicobacter pylori infection was assessed by rapid urease test, culture, pathological test, serological test and urea breath test using 13C. Results: Of these patients, red streaking was recognized in 94 patients (6.2%). All of the tests showed very low prevalence (0–3.5%) of H. pylori infection in patients with red streaking whereas positive results were obtained recognized in 42–49% of 94 age-sex-matched patients without red streaking. Additionally, no peptic-ulcer diseases, such as gastric ulcer/ulcer scar and duodenal ulcer/ulcer scar, were found in the patients with red streaks. In conclusion, red streaking is a negative sign for H. pylori infection and peptic-ulcer diseases. Conclusions: The understanding of these results might also improve the effort and cost-effectiveness of endoscopic examinations by avoiding unnecessary further testing.

Aims: Endoscopic variceal ligation (EVL) is a recently developed alternative to endoscopic injection sclerotherapy (EIS) for the treatment of oesophageal varices. Endoscopic variceal ligation and EIS were compared in an attempt to clarify the efficacy and safety of EVL for patients with cirrhosis due to hepatitis C. Methods: Endoscopic variceal ligation was performed in 60 patients and EIS in 30. Varices were eradicated in all patients by EVL and 87% (26 out of 30) by EIS. Results: There was no significant difference between EVL and EIS in relation to the incidence of bleeding and the 5 year survival rate after treatment. There were no severe complications except mild substernal pain after EVL, while pulmonary embolism occurred in one patient receiving EIS. Conclusions: Endoscopic variceal ligation is a safe and effective technique for eradicating oesophageal varices in patients with hepatitis C cirrhosis.

Few virulence determinants of Helicobacter pylori have been tested in vivo. We conducted this study to establish an animal model for their screening. Six-week-old male Mongolian gerbils were inoculated with wild-type H. pylori (TN2) or its isogenic mutant with deletion of cagE (TN2DeltacagE), total cag pathogenicity island (TN2DeltacagPAI), HP0499 (TN2DeltaHP499), or HP0638 (TN2DeltaHP638) (n=5 each). The animals were killed 3 weeks later, and the density of bacteria and the degree of inflammation in the stomach were compared. Infection was established in all animals except those inoculated with TN2DeltaHP638. TN2 and TN2DeltaHP499, but not TN2DeltacagE and TN2Deltacag PAI, induced intense inflammation, although the densities of bacteria were similar. The Mongolian gerbil model was useful for the screening of virulence determinants in vivo, which confirmed the importance of cag PAI while questioning that of HP0499.

We investigated the frequency and mechanism of beta-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the beta-catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or beta-catenin, and Tcf-4 was highly expressed in these cell lines with upregulated signaling. Nuclear beta-catenin was observed not only in the signaling-activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling-upregulated gastric cancer cell lines with intact APC and beta-catenin suggests the involvement of other mechanisms than mutations of APC or beta-catenin.

BACKGROUND—The relationship between Helicobacter pylori and reflux oesophagitis remains controversial. AIMS—To evaluate the relationship between H pylori and reflux oesophagitis in a large number of Japanese subjects. SUBJECTS—A total of 5732 consecutive Japanese subjects during a health screening were enrolled. METHODS—Gastrointestinal endoscopy was performed on all subjects. We simultaneously measured serum anti-H pylori antibody and pepsinogen as markers of H pylori infection together with gastric atrophy. The risk of reflux oesophagitis was evaluated in relation to these markers, and the results were compared with those of gastric cancer. RESULTS—Reflux oesophagitis was found in 108 subjects. Both positivity for H pylori antibody (adjusted odds ratio (OR) 0.67 (95% confidence interval 0.45-1.0)) and "low" pepsinogen indicating gastric atrophy (OR 0.35 (0.18-0.68)) were negatively associated with reflux oesophagitis. After subjects were classified into four groups based on positivity or negativity for H pylori antibody and "low" pepsinogen, the prevalence of reflux oesophagitis showed a decreasing trend as H pylori induced gastric atrophy became more severe. The risk of gastric cancer showed an increasing trend, exactly the opposite to that of reflux oesophagitis. CONCLUSIONS—Analysis of a large series of Japanese subjects revealed a decreasing prevalence of reflux oesophagitis in conjunction with progress of gastric atrophy induced by H pylori infection. This pattern was completely opposite to that of gastric cancer cases. A protective role of H pylori for reflux oesophagitis through the development of gastric atrophy has been suggested. Keywords: Helicobacter pylori; oesophagitis; gastro-oesophageal reflux disease; atrophic gastritis; gastric cancer

To identify additional genes targeted for microsatellite instability (MSI), we search for human genes which contain mononucleotide repeats in their coding region, selected 7 genes (RAD50, DNA‐PKcs, FLASH, Apaf‐1, XPG, CtIP, and MLSN1), and analyzed frameshift mutations in them. Here we report that 60% (3 out of 5) of human colorectal cancer cell lines exhibiting a high frequency of MSI (MSI‐H) and 46% (6 out of 13) of MSI‐H primary colorectal tumors had mutations in the (A)9 repeat of RAD50 recombinational repair gene. In contrast, no frameshift mutations were found in any of the 5 MSI‐negative colorectal cancer cell lines, 8 colorectal tumors exhibiting a low frequency of MSI (MSI‐L), or 28 MSI‐negative colorectal tumors. No mutations were found in the mononucleotide repeats of 6 other genes, even in MSI‐H cancers. These results suggest that RAD50 frameshift mutations may play a role in the tumorigenesis of MSI‐H colorectal cancers.

We have previously reported mixed infection with wild-type (sensitive) and mutant (resistant) Helicobacter pylori strains using a PCR-based preferential homo-duplex formation assay (PCR-PHFA) to detect gene mutations associated with clarithromycin resistance. Half of the cases with mixed infection were determined as sensitive by conventional MIC assessment and yet failed to respond to clarithromycin-based therapy. The aim of this study is to assess the efficacy of clarithromycin-based triple therapy in patients infected exclusively with wild-type strains as determined by PCR-PHFA.Ninety patients who had pure wild-type H. pylori infection were randomly assigned to receive clarithromycin (200 mg b.i.d.), amoxicillin (500 mg q.i.d.) and lansoprazole (30 mg b.i.d.) for either 5 days or 7 days (n = 48 and n = 42, respectively). The outcome of eradication was assessed by [13C] urea breath test.Eradication was achieved in 36/48 (75%) versus 39/42 (93%) by intention-to-treat analysis (P = 0.02), and in 36/45 (80%) versus 39/40 (98%) by per protocol analysis (P = 0.01), for the 5-day and 7-day protocols, respectively. Compliance and the incidence of untoward effects were similar in both groups.Seven-day administration is necessary and sufficient for the triple therapy with clarithromycin, amoxicillin and lansoprazole in patients with pure wild-type H. pylori infection.

Our patient was a 70-year-old man with hepatocellular carcinoma (HCC) and liver cirrhosis (Child-Pugh B). He had a history of distal gastrectomy with Billroth II reconstruction for duodenal ulcer and hepatectomy for HCC. One month after percutaneous radiofrequency ablation (RFA) for recurrent HCC, biliocutaneous fistula was observed. The cholangiogram demonstrated leakage of contrast material from an intrahepatic duct into the fistula, and a nasobiliary catheter was placed. Subsequently, the discharge of bile steadily decreased and stopped. Follow-up cholangiogram revealed no evidence of bile leakage. Biliocutaneous fistula is an extremely rare complication after percutaneous RFA, and the present case report suggests that endoscopic drainage is the first-line therapy for bile leaks after RFA.

BACKGROUND Previous epidemiologic studies produced inconsistent results when examining the relation between Helicobacter pylori infection and the risk of gastric carcinoma by measuring various anti–H. pylori antibodies. This study investigated the increased risk of cancer by examining different antibodies, including the specific anti-CagA antibody and antibodies from two commercially available kits. METHODS An ELISA for the detection of serum anti-CagA was established using a recombinant CagA protein that the authors previously reported. Serum anti-CagA titer was determined for 80 patients with gastric carcinoma and 80 gender- and age-matched controls. Two anti–H. pylori antibodies from the commercially available kits HEL-p (Amrad, Kew Vic, Australia) and HM-CAP (Enteric Product Inc., Westbury, NY) were also evaluated. RESULTS Anti-CagA seropositivity differed significantly between gastric carcinoma patients and controls (92.5% vs. 55.0%; P = 0.0001), showing an odds ratio of 10.4 (95% confidence interval [CI]: 4.23–29.74). The difference was less prominent for the seropositivity of HEL-p (77.5% vs. 58.8%; P = 0.0139; odds ratio: 2.38; 95% CI: 1.20–4.82) and insignificant for that of HM-CAP (65.0% vs. 57.5%; P = 0.4325; odds ratio: 1.30; 95% CI: 0.68–2.49). CONCLUSIONS The current study revealed that the antibody assay system used could be one important factor in the assessment of gastric carcinoma risk for patients with H. pylori. Cancer 2000;88:1530–5. © 2000 American Cancer Society.

BACKGROUND/AIMS—It was recently reported that the quantitative analysis of mutant K-ras gene in pancreatic juice could be useful for the diagnosis of pancreatic cancer. This methodology was applied to patients with pancreatic cystic lesions. METHODS—DNA was extracted from pancreatic juice collected at the time of endoscopy with injection of secretin. The ratio of the K-ras mutant allele to the wild-type allele was measured by two methods to detect and semiquantify mutant K-ras gene: polymerase chain reaction/preferential homoduplex formation assay and enriched polymerase chain reaction/enzyme linked mini-sequence assay. RESULTS—A high frequency of K-ras mutation was detected (more than 2% of all K-ras genes) in six of 14 patients (43%) with pancreatic cysts. This frequency was similar to those detected in patients with pancreatic adenocarcinoma and in intraductal papillary neoplasms of the pancreas. In contrast, the frequency of mutation was low (less than 2%) in patients without either pancreatic cysts or pancreatic neoplasms. CONCLUSIONS—K-ras gene mutation may be derived from duct cells in the pancreas with a high potential for tumorigenesis. Therefore careful follow up of patients with a pancreatic cyst is recommended if they are found to have a high level of the mutant gene in the pancreatic juice. Keywords: pancreas; cyst; K-ras; pancreatic adenocarcinoma; quantitative analysis

Purpose This study was conducted to evaluate the sonographic characteristics of common bile duct (CBD) stones and stone fragments scanned in vitro with a high-frequency (20-MHz) microprobe. Methods We sonographically examined 4 whole CBD stones (1 cholesterol stone with radiant cross section, 1 cholesterol stone with lamellar cross section, 1 black pigment stone, and 1 brown pigment stone), 44 fragments of a cholesterol stone (diameter range, 1.1–3.0 mm; mean diameter, 2.0 mm), and 75 fragments of a black pigment stone (diameter range, 1.1–3.0 mm; mean diameter, 2.0 mm). The chemical composition of all stones was analyzed by infrared absorption spectroscopy. All stones and fragments were placed in a plastic box filled with physiologic saline solution for scanning with a 20-MHz microprobe and a 5-MHz probe. Echogenic foci and acoustic shadows revealed at each frequency were compared. Results At 5 MHz, the 4 CBD stones showed different sonographic characteristics. The cholesterol stone with radiant cross section showed an echogenic focus but no definite acoustic shadow, whereas the cholesterol stone with lamellar cross section showed an echogenic line, several echogenic spots, and a definite acoustic shadow. The black pigment stone showed an echogenic line with a vague acoustic shadow, and the brown pigment stone showed echogenicity of the whole stone and a definite acoustic shadow. At 20 MHz, the 4 stones showed an echogenic line with a definite acoustic shadow. All fragments appeared as echogenic foci at 20 and 5 MHz. Seventy-seven percent (34) and 5% (2) of 44 cholesterol stone fragments cast a definite acoustic shadow at 20 and 5 MHz, respectively. Sixty-nine percent (52) and 15% (11) of 75 black pigment stone fragments cast a definite acoustic shadow at 20 and 5 MHz, respectively. Among fragments 1.5 mm in diameter and smaller, only 45% (5 of 11) from a cholesterol stone and 30% (6 of 20) from a black pigment stone showed a definite acoustic shadow at 20 MHz. Conclusions High-frequency (20-MHz) sonography demonstrates a definite acoustic shadow more frequently among CBD stones and fragments 1.6 mm in diameter or larger than does low-frequency (5-MHz) sonography, but it does not discriminate the chemical composition. © 1999 John Wiley & Sons, Inc. J Clin Ultrasound 27:249–257, 1999.

Background: Complete bile duct clearance of stones should be achieved in patients managed with endoscopic papillary balloon dilation. However, complete retrieval of small stones or tiny fragments sometimes proves difficult using conventional devices. Methods: We attempted the removal of fine stone fragments by saline infusion using a specially designed retrieval balloon catheter with a blind tip and a side hole located proximal to the balloon in 14 patients. Results: Using this technique, bile duct clearance was achieved in a single attempt in 13 of 14 patients; 2 attempts were required in 1 patient. Cholecystitis occurred in 2 patients with gallstones in situ after the procedure. Conclusions: Saline washout using a side-holed retrieval balloon catheter effectively cleans stones and stone fragments from the bile duct in patients treated with endoscopic papillary balloon dilation.

Tyrosine kinases, which are important regulators of intracellular signal-transduction pathways, have mutated forms that are often associated with oncogenesis and are attractive targets for therapeutic intervention. Recently, systematic mutational analyses of tyrosine kinases revealed that a minimum of 30% of colorectal cancer contain at least one mutation in the tyrosine kinases. To further explore these mutations, we examined all reported mutations of NTRK3, FES, KDR, EPHA3, NTRK2, JAK1, PDGFRA, EPHA7, EPHA8, ERBB4, FGFR1, MLK4 and GUCY2F genes in the 24 colorectal cancer cell lines. Unexpectedly, among 24 colorectal cancer cell lines, only two cell lines (LoVo and CaR1) harbored mutation C1408T (R470C) in MLK4 gene. The mutation rate was extremely low compared to that previously reported. Therefore, we analyzed mutations in 46 colorectal cancer samples resected from the same number of Japanese patients. Surprisingly, none of the 46 samples contained any of the mutations reported. Based on our study, we advise that a more comprehensive tyrosine kinase gene mutation assay is necessary in the future.

Angiogenesis plays a pivotal role in gastric ulcer repair. Several growth factors are involved in angiogenesis, and of these, vascular endothelial growth factor (VEGF) has received considerable attention, since it is the only factor that specifically acts on endothelial cells. However, the role of VEGF in gastric ulcer repair is not known. In the present study, we demonstrate the specific expression of VEGF at the gastric ulcer margin, using immunohistochemistry and RT-PCR. The specific receptors of VEGF, flt-1 and KDR were also detected in gastric mucosa. We further demonstrate the expression of VEGF by cultured human gastric fibroblasts which is enhanced by tumor necrosis factor-alpha. These data suggest that VEGF may play a role in angiogenesis in the process of gastric ulcer healing.

CagA-positive H. pylori is reported to be associated with gastroduodenal disease in Western countries. To evaluate the relationship between CagA and disease, cloning of the entire cagA gene (3771 bp), insertion of a partial fragment (1272 bp) into an expression vector, purification of the recombinant protein, production of an antibody against the recombinant CagA protein through rabbits, and use of the recombinant CagA protein as an antigen, detection of the anti-CagA antibody by western blotting were all performed. Sera of 132 H. pylori-infected patients undergoing endoscopy were studied. Anti-CagA antibodies were detected in 90%, 87%, 90%, 94%, and 93% of patients with gastric ulcer (N = 34), duodenal ulcer (N = 27), chronic gastritis (N = 31), gastric cancer (N = 17), and normal mucosa (N = 15), respectively. High seropositivity of anti-CagA antibody even in individuals with normal mucosa indicated that CagA may not be a unique marker for disease by H. pylori infection in Japan.

A recent study revealed that the p110alpha (PIK3CA), catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is somatically mutated in many types of cancer. For example, PIK3CA is mutated in an estimated 35.6% of hepatocellular carcinoma (HCC) cases. To measure the frequency of PIK3CA hotspot mutations in Japanese HCC patients, exons 9 and 20 of the PIK3CA gene were sequenced in 47 clinical HCC samples. Contrary to expectations, no hotspot mutations were found any of the HCC samples. In addition, we found abnormally migrating waves near the end of exon 9 in the PCR chromatograms from 13 of the 47 samples. PCR amplification and subsequent cloning and sequencing revealed that these chromatograms contained two distinct sequences, the wild-type p110alpha sequence and a different sequence found on human chromosome 22q11.2, the Cat Eye Syndrome region, which contains a putative pseudogene of PIK3CA. These abnormally migrating waves were also found in noncancerous liver tissue, indicating that this was not a result of HCC-associated mutations. Therefore, it is likely that the percentage of hotspot mutations in the PIK3CA gene of Japanese HCC patients is lower than was previously reported.

AIM: To compare the utility of single-balloon colonoscopy (SBC) or double-balloon colonoscopy (DBC) for difficult colonoscopies. METHODS: Between August 2008 and June 2010, patients in whom total colonoscopy failed within 30 min of insertion were assigned randomly to undergo either SBC or DBC. No sedatives were used. After the endoscopy, all patients were asked to evaluate pain during the procedure on a 10-point analog scale (1 = no pain; 10 = worst imaginable pain) with a questionnaire. The study outcomes were the cecal intubation rate and time, endoscopic findings, complications, and pain score. RESULTS: The SBC and DBC groups included 11 and 10 patients, respectively. All but one SBC patient achieved total colonoscopy successfully. The cecal intubation times were 18 min (range: 10-85 min) and 12.8 min (range: 9.5-42 min) in the SBC and DBC groups, respectively (P = 0.17). No difference was observed in the prevalence of colon polyps between the SBC and DBC groups (45% vs 30%, P = 0.66). SBC showed advanced colon cancer in the ascending colon, which was inaccessible using conventional colonoscopy. The respective pain scores were 5 (1-10) [median (range)] and 5 (1-6) in the SBC and DBC groups (P = 0.64). No complications were noted in any patient. CONCLUSION: The utility of single- and double-balloon endoscopy for colonoscopy seems comparable in patients with incomplete colonoscopy using a conventional colonoscope.

Background and Study Aims : Endoscopic papillary balloon dilation (EPBD) is a less invasive alternative to endoscopic sphincterotomy (EST). This study reviews a series of cirrhotic patients with bile duct stones who were treated with EPBD. Patients and Methods : EPBD was used to remove common bile duct stones in nine cirrhotic patients (one in Child-Pugh grade A, four in grade B, and four in grade C). After the papilla was dilated with balloon-tipped catheter, the stones were removed with a retrieval basket catheter or a retrieval balloon, or both. Mechanical lithotripsy was required in two patients with stones of more than 1 cm in diameter. Results : Clearance of the common bile duct was achieved in all patients without any serious complications such as hemorrhage or perforation. Conclusions : These results suggest that EPBD is a safe and effective technique for the treatment of common bile duct stones in patients with liver cirrhosis.

In an attempt to predict virological sustained responders among patients with chronic hepatitis C after interferon therapy, HCV-RNA in serum was measured by a one tube RT-PCR assay kit using the RNA corresponding to 5 microL serum (standard assay) or 300 microL serum (enhanced-sensitivity assay). Dilution analysis revealed that sensitivity of the 'enhanced-sensitivity assay' increased by 10-100-fold when compared with a 'standard assay'. Using these assays, prospective study of interferon therapy on 38 HCV-RNA seropositive cases with chronic hepatitis (total amount 702 MU; duration of treatment 5-6 months) was performed. At the end of treatment, six were still positive and 32 became negative by the "standard assay', whereas an additional eight cases became positive (total 14 cases positive; the remaining 24 cases negative) by the 'enhanced-sensitivity assay'. Hepatitis C viral RNA state at the end of treatment remained the same 6 months later in 23 cases (61%) by a 'standard assay' and in 31 (82%) by the 'enhanced-sensitivity assay'. Of importance was that all patients (14 cases) demonstrating HCV-RNA in serum at the end of therapy, even by the "enhanced-sensitivity assay', did not show the disappearance of HCV-RNA in serum despite the long follow up. From these results, in order to improve our treatment efficacy, we should try to modify our treatment protocol to the extent that at least HCV-RNA becomes undetectable. That can be only feasible during treatment by real-time monitoring of HCV-RNA.

Covered metallic stent (covered MS) is useful to improve quality-of-life in patients with unresectable malignant distal biliary obstruction. We have managed 129 patients with three types of covered MS; polyurethane-covered Wallstent (hand-craft), polyurethane-covered Diamond stent (hand-craft), and silicone-covered Wallstent (commercially available). They were compared with 115 cases treated with uncovered metallic stent (uncovered MS). There was no significant difference in survival between the two groups. The cumulative stent patency was significantly higher in the covered MS group than uncovered MS group (P = 0.0027). Stent occlusion occurred in 17 patients (13%) in the covered MS group, and in 48 patients (42%) in the uncovered MS group (P

We examined whether the presence of pancreatic cysts could be a risk for pancreatic cancer by comparing the incidence and characteristics of cysts found by magnetic resonance (MR) imaging in patients with and without pancreatic cancer.Half-Fourier rapid acquisition with relaxation enhancement images and MR cholangiopancreatography were performed in 116 patients with pancreatic cancer (PC group) and 1226 with nonpancreatic disease (NP group). Incidence and characteristics of cysts were analyzed.Pancreatic cysts were detected in 65 patients (56%) of the PC group and in 123 patients (10%) of the NP group. According to the multivariate analysis, cyst presence was a significant risk factor for pancreatic cancer (odds ratio [OR], 10.27; P0.01), especially cysts larger than 10 mm (OR, 4.718; P0.01). When the definition of cyst presence in the PC group was restricted to the 33 cases with cysts considered to have existed before the development of cancer, the incidence was still high (OR, 2.976; P0.01) and size remained significant (OR, 4.428; P0.01).Patients with pancreatic cysts, especially larger than 10 mm, were considered to be at an increased risk of pancreatic cancer over the entire pancreas.

A 63-year old woman who had experienced melena for 2 weeks was admitted to Tokyo University Hospital. Gastric adenocarcinoma was diagnosed endoscopically and histologically, and a total gastrectomy was performed soon thereafter. Pathological examination of the resected stomach revealed choriocarcinoma of the stomach. Although chemotherapy was administered after surgery, she died 3 months after admission. Autopsy confirmed the diagnosis of primary gastric choriocarcinoma, a rare, but highly malignant tumor. It is characteristic; macroscopically it forms a necrotic mass with bleeding, and microscopically it often consists of adenocarcinoma and choriocarcinoma. Since its prognosis is extremely poor, we must take into account the possibility of primary gastric choriocarcinoma when a hemorrhagic gastric tumor with necrosis is found.

We recently developed a primary culture system for gastric epithelial cells from adult rabbits that allows the investigation of growth regulation at the cellular level. In this study, we demonstrated that epidermal growth factor (EGF), insulin, and dibutyryl adenosine 3',5'-cyclic monophosphate (dBcAMP) all stimulated cell proliferation. Insulin and dBcAMP potentiated the stimulation of cell proliferation by EGF, while transforming growth factor-beta 1 (TGF-beta 1) inhibited it. Expression of c-fos and c-myc was induced in response to the stimulation by these growth regulators, but the degree of expression did not necessarily correlate with the effects of these agents on cell proliferation. In conclusion, EGF, insulin, and dBcAMP were positive growth regulators, while TGF-beta 1 was a negative regulator in gastric epithelial cells. These growth modulators may exert their effects by distinct pathways from a standpoint of the expression of c-fos and c-myc.

Background/Aims: Physiological regulation of gastric mucus secretion has not been well studied. The present study investigated the effects of adenosine 5′-triphosphate (ATP), a P 2 purinergic receptor agonist, and its analogues on gastric mucus secretion using gastric mucous cells in a primary culture. Methods: A monolayer culture of gastric mucous cells from adult rabbits were prepared after enzyme digestion. Mucus secretion was estimated from the release of [ 3 H]glucosamine from prelabeled cells. Intracellular calcium concentration ([Ca 2+ ] i ) was monitored by a Ca 2+ -sensitive probe, indo-1. Prostaglandin E 2 (PGE 2 ) in the media was measured by an enzyme-linked immunoassay. Results: ATP significantly stimulated mucus secretion by these cells at nontoxic doses in a dose-dependent fashion. The order of potency of ATP analogues stimulating mucus secretion was αβ-methylene ATP > ATP > 2-methylthio ATP, whereas adenosine, a P 1 purinergic receptor agonist, had no effect. ATP also induced an elevation of [Ca 2+ ] i in a dose-dependent fashion. The efficacy of ATP analogues to increase [Ca 2+ ] i showed a similar potency to their actions on mucus secretion. ATP increased PGE 2 at relatively higher concentrations, whereas indomethacin did not block ATP-induced increase of mucus secretion. Conclusions: These results suggest that ATP stimulates mucus secretion by gastric mucous cells through P 2 purinergic receptors; this appears to be mediated by intracellular calcium not by endogenous PGE 2 .