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The technique of endoscopic submucosal dissection (ESD) was introduced to obtain en bloc specimens of large early gastrointestinal neoplasms. The drawback of ESD is its technical difficulty and, consequently, its higher rate of complication. In this multicenter study, we investigated the therapeutic outcomes of ESD in consecutive patients.From January 2002 to December 2008, 485 early gastric neoplasms in 418 patients were consecutively treated by using ESD procedure performed by 6 endoscopists in 4 institutions in Tokyo. Demorgraphics, tumor location, therapeutic outcomes, and complication rates were analyzed.The rates of en bloc resection, complete en bloc resection, submucosal invasion, and piecemeal resection were 93.6%, 85.4%, 10.9%, and 5.4%, respectively. In multivariate analysis, the en bloc resection rate was independently lower in lesions in upper portion than in lower portion (P0.01), lower in larger lesions (30 mm, P0.05; 20 to 30 mm, P0.05), and lower in lesions with a scar (P0.01). Delayed bleeding occurrence was independently high in larger lesions (30 mm, P0.01; 20 to 29 mm, P0.01) than in small lesions (20 mm). Institution and endoscopists were not risk factors of en bloc resection and complicationsESD is an effective and safe therapy in the management of early gastric neoplasms when performed by well-trained endoscopists. Endoscopists should recognize the difficulty to perform ESD for en bloc resection of upper lesion, and the risk of delayed bleeding in cases of lesions2 cm in size.

Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P = 0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. Conclusion: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study. (HEPATOLOGY 2011;)

The results of a phase III, placebo-controlled study demonstrated that endoscopic direct spraying of L: -menthol onto the gastric mucosa effectively suppressed gastric peristalsis in the study patients. The aim of the study reported here was to determine whether the anti-peristaltic effect of an L: -menthol preparation facilitates endoscopic examinations in a clinical setting.This was a multicenter, open-label, single-arm trial in which the study cohort comprised patients in whom L: -menthol was likely to be used to facilitate endoscopic examination in clinical settings. The primary outcome was the proportion of subjects with no peristalsis (Grade 1) after treatment and at the end of endoscopy (defined as the complete suppression of gastric peristalsis). This variable was assessed according to the level of anti-Helicobacter pylori immunoglobulin G (IgG) antibody, pepsinogen test results, whether sedation was performed, and whether subjects were considered unsuitable for the use of conventional antispasmodics.Of the 119 enrolled subjects, data from 112 were included in the primary efficacy analysis. Gastric peristalsis was completely suppressed in 37.5% of the patients [42/112 patients; 95% confidence interval (CI) 28.5-47.1]. Subgroup analyses revealed that the rate of peristalsis suppression was significantly higher in patients with elevated levels of anti-H. pylori IgG antibody (26/44, 59.1%; 95% CI 43.2-73.7); P 0.001] and positive pepsinogen test results (21/35, 65.6%; 95% CI 46.8-81.4; P 0.001]. There was no significant difference according to sedation (17/52, 32.7%; 95% CI 20.3-47.1; P = 0.434) or whether subjects were considered unsuitable for use of conventional antispasmodic agents (14/28, 50.0%; 95% CI 30.6-69.4; P = 0.12].These findings are comparable to those of the phase III placebo-controlled study and provide further evidence that endoscopic direct spraying of L: -menthol effectively suppresses gastric peristalsis during upper gastrointestinal endoscopy.

Background Balloon endoscopy has been accepted as an effective tool for examining the small intestine. Two types of balloon endoscopy, single and double, are commercially available. The difference in performance between these 2 types of balloon endoscopy has not yet been elucidated. Objective To compare the yield of single-balloon endoscopy (SBE) and double-balloon endoscopy (DBE). Design Single-center, randomized, controlled trial. Setting University hospital in Tokyo, Japan. Patients Patients with suspected small-bowel disease. Interventions SBE and DBE. Main Outcome Measurements Outcomes were the total enteroscopy rate, diagnostic yield, complication rate, and clinical outcomes. Analysis was done by intent to treat. Results The study started in April 2008 and was terminated in April 2010 because of an obvious disadvantage for the SBE group. Thirty-eight patients were enrolled in the study; 18 patients were assigned to the SBE group and 20 to the DBE group. The total enteroscopy rate was 0% in the SBE group and 57.1% in the DBE group ( P = .002). In terms of complications, the DBE group had 1 patient with Mallory-Weiss syndrome, and the SBE group had 1 patient with hyperamylasemia. There was no difference in the overall diagnosis rate between the SBE and DBE groups (61.1% vs 50.0%, P = .49). There was no difference in therapeutic outcome between the SBE and DBE groups (27.8% vs 35.0%, P = .63). Limitations Relatively small number of study patients. Conclusions Total enteroscopy is more easily performed with DBE than with SBE.

Background: Patients with hepatocellular carcinoma (HCC) sometimes suffer from obscure gastrointestinal bleeding. Portal hypertension (PH), common in cirrhosis, induces esophagogastric varices. Because of the location, PH also may influence mucosal abnormalities in the small intestine. The objective of this study is to estimate the prevalence of small intestinal mucosal abnormalities in HCC patients using capsule endoscopy (CE). Patients and Methods: We prospectively conducted CE in HCC patients, and analyzed the findings in relation to hepatic function, the number and size of HCC tumor and findings obtained by conventional endoscopy. Results: Thirty-six patients (aged 66.7 ± 7.5 years, 29 men) underwent CE. Abnormal findings in the small bowel were found in 16 patients (44%), angioectasias in eight patients (22%), erosions in five (14%), varices in four (11%), polyps in four (11%), and submucosal tumor in one (3%). The patients with angioectasia had a larger spleen index than the no abnormal lesions group (85.4 ± 15.8 vs 59.0 ± 24.4, P = 0.02). The former group had been more frequently treated for esophageal varices endoscopically (62% vs 15%, P = 0.02). Large HCC nodules seemed more common in the patients with angioectasia than subjects without abnormal lesions (38% vs 5%, P = 0.06). Small intestinal varices also seemed to have a positive association with large HCC. During the follow up after CE, one patient with small intestinal polyps suffered from obscure gastrointestinal bleeding. Conclusions: CE revealed that HCC patients frequently have small intestinal mucosal lesions. In particular, small intestinal angioectasia, which may cause obscure gastrointestinal bleeding, seems to be associated with portal hypertension.

Transient elastography (with the FibroScan® apparatus) is a recently developed method for evaluating the severity of liver fibrosis by measuring liver elasticity. Liver elasticity may differ from the normal level in patients with obstructive jaundice because the retained bile may expand the liver. Because little is known about liver elasticity in patients with obstructive jaundice, we evaluated this feature in these patients. Between April 2007 and April 2008, 178 patients with biliary or pancreatic disease underwent transient elastography at the University of Tokyo Hospital. We excluded 77 patients because of concomitant cirrhotic liver disease, liver tumors, or a history of abdominal surgery. The remaining 101 patients were included in the study and were divided into obstructive jaundice (OJ; n = 43) and nonobstructive jaundice (NJ; n = 58) groups. The basic patient characteristics did not differ significantly between the two groups, except for the causative diseases. The mean liver elasticity was significantly higher in the OJ group than in the NJ group (12.0 vs. 6.2 kPa, p

Background: The efficacy of double-balloon enteroscopy (DBE) for biliary interventions has been shown in patients with surgical anatomy. However, the use of available endoscopic retrograde cholangiography accessories during this procedure is limited because of the length of the conventional instrument (200 cm). The aim of this study was to evaluate the feasibility of short DBE for managing biliary disorders in patients with a Roux-en-Y gastrectomy or hepaticojejunostomy (HJ). Patients and Methods: Using a short enteroscope (152 cm) and commercially available endoscopic retrograde cholangiography accessories, biliary interventions were performed in six patients with Roux-en-Y reconstruction or HJ anastomosis. Results: A total of 12 biliary interventions were performed; balloon dilations of the HJ anastomosis or intrahepatic ducts (four patients), nasobiliary drainages (three patients), bile duct stone removal after endoscopic papillary large balloon dilation with or without small sphincterotomy (two patients), and a biliary stent placement (one patient). One patient showed retroperitoneal air following endoscopic papillary large balloon dilation, but recovered conservatively. Conclusions: Biliary interventions via DBE using a short enteroscope are feasible in patients with surgical anatomy.

Cytochrome P450 2C19 (CYP2C19) is clinically important for the metabolism of many therapeutic drugs. CYP2C19 has two main point mutation sites leading to low metabolic capacity. Several CYP enzymes are also important for the metabolism of chemical carcinogens, and several studies have reported associations between CYP polymorphism and cancer susceptibility. Speculating on a potential association between CYP2C19 polymorphism and cancer susceptibility, we conducted this study in two phases. Cell lines of various gastroenterological cancers were screened in the first phase. A clinical investigation was then conducted to confirm the association with the candidate cancer in the second phase. Genetic polymorphism of CYP2C19 was investigated in a total of 114 cell lines of five gastroenterological cancers. Based on this screening investigation suggesting an association with biliary tract cancer, we conducted a related study by recruiting 65 patients with biliary tract cancer and 566 patients with benign diseases as controls. Among the 114 cell lines investigated, biliary tract cancer was suggested to be most strongly associated with poor metabolizers of CYP2C19. Among 65 patients with biliary tract cancer, 18 (28%) were poor metabolizers of CYP2C19, whereas 87 (15%) of 566 control patients were poor metabolizers. The age- and gender-adjusted odds ratios for intermediate and poor metabolizers regarding the risk of biliary tract cancer were 1.5 (95% CI: 0.8–3.0, P = 0.17) and 2.7 (1.3–5.9, P = 0.006) compared to extensive metabolizers. A genetic polymorphism of CYP2C19 is associated with susceptibility to biliary tract cancer.

The aim of this study was to evaluate short- and long-term outcomes in relatively young patients (≤ 60 years old) who underwent endoscopic papillary balloon dilation (EPBD) for bile duct stone removal.Immediate and long-term outcomes were evaluated in 311 patients who were 60 years old or younger at the time of EPBD. The stone recurrence rate was compared among four groups stratified according to gallbladder (GB) status before and after EPBD (cholecystectomy after EPBD, GB left in situ with stones, GB left in situ without stones, and cholecystectomy before EPBD).Bile duct stones were completely removed via EPBD alone in 304 patients (97.7%). Post-EPBD pancreatitis occurred in 24 patients (7.7%), and was mild in 18 patients, moderate in 5 patients, and severe in 1 patient. The rate of pancreatitis was significantly higher in these patients than in patients aged more than 60 years who underwent EPBD during the same study period (4.7%). Long-term outcomes were evaluated in 217 patients who were followed for at least 1 year after complete stone removal via EPBD. During a mean follow-up period of 5.6 years (range, 1.0-13.4 years), stone recurrence was observed in 13 patients (6.0%). The cumulative stone recurrence rates at 5 and 10 years after EPBD were 5.9 and 7.1%, respectively. Patients in the cholecystectomy after EPBD group had the lowest risk of stone recurrence among the four groups (2.0%).EPBD removes bile duct stones in the majority of younger patients without increasing the risk of severe pancreatitis. Post-EPBD pancreatitis is more likely to occur in younger patients as compared to older patients. The long-term outcomes of EPBD appear favorable, especially in patients who have undergone cholecystectomy after EPBD.

We studied the safety and effectiveness of TSU-68, an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor and fibroblast growth factor receptor, in patients with advanced hepatocellular carcinoma (HCC).Patients with unresectable or metastatic HCC were eligible for enrollment. In phase I, the safety, tolerability and pharmacokinetics were assessed in patients stratified based on liver function, from no cirrhosis to Child-Pugh class B. The safety and effectiveness were assessed in phase II at the dose determined in phase I.Twelve patients were enrolled in phase I. Dose-limiting toxicities were found with TSU-68 at the dose of 400 mg bid in Child-Pugh B patients, and 200 mg bid was established as the phase II dose. Phase II included 23 additional patients, and the safety and efficacy were evaluated in a total of 35 patients. One patient (2.9%) had a complete response. Two patients (5.7%) had a partial response, and 15 patients (42.8%) showed a stable disease. The median time to progression was 2.1 months, and the median overall survival was 13.1 months. Common adverse events were hypoalbuminemia, diarrhea, anorexia, abdominal pain, malaise, edema and AST/ALT elevation. The analysis of angiogenesis-related parameters suggests that serum-soluble vascular cell adhesion molecule-1 is a possible marker to show the response.TSU-68 at a dose of 200 mg bid determined by stratification into liver function, showed promising preliminary efficacy with a high safety profile in patients with HCC who had been heavily pre-treated.

Recent advances in colonoscopic techniques have resulted in more frequent detection of superficial-type colorectal tumors, that is, laterally spreading tumors (LSTs), although little is known about the characteristic clinical features and genetic alterations of LSTs. To elucidate the molecular characteristics of LSTs, genetic alterations in the KRAS, BRAF and PIK3CA genes and abnormal expression of the p53, beta-catenin and MYC proteins were analyzed using direct DNA sequencing and immunohistochemistry for 50 protruded-type tumors (Protruded), 35 granular-type LSTs (LST-G) and 19 nongranular-type LSTs (LST-NG). In addition, loss of heterozygosity (LOH) close to the adenomatous polyposis coli (APC) gene (5q21) was examined in these tumors. In univariate analyses, significant differences were noted in the percentages with KRAS mutations (Protruded, LST-G, LST-NG = 30.0%, 54.3%, 21.1%, respectively, p = 0.0156), nuclear accumulation of beta-catenin (Protruded, LST-G, LST-NG = 50.0%, 37.1%, 68.4%, respectively, p = 0.0267), expression of MYC (Protruded, LST-G, LST-NG = 26.0%, 17.1%, 42.1%, respectively, p = 0.0456) and LOH at the APC gene locus (Protruded, LST-G, LST-NG = 22.0%, 20.0%, 47.4%, respectively, p = 0.0302). Multivariate analysis demonstrated that the macroscopic subtype of LST was significantly associated with KRAS mutation (for LST-NG: odds ratio [OR] 0.23, 95% CI 0.06-0.90) and nuclear accumulation of beta-catenin (for LST-NG: OR 4.05, 95% CI 1.11-14.8). Our data revealed that the 2 subtypes of LST have different molecular characteristics, suggesting that 2 or more different molecular mechanisms result in colorectal tumors with a similar growth pattern.

Intrapancreatic bile duct stricture in autoimmune pancreatitis (AIP) is usually diagnosed as sclerosing cholangitis even if the stricture is limited to the intrapancreatic area. However, it is not known whether compression caused by pancreatic edema or biliary wall thickening causes such a biliary stricture.Our purpose was to clarify the factor that contributes to intrapancreatic biliary stricture in AIP: pancreatic head lesion or biliary wall thickening.Single-center retrospective study.This study was performed in a tertiary care academic medical center.Fifty-six patients with AIP were included.The relationship between the presence of a pancreatic head lesion and intrapancreatic biliary stricture was examined. In addition, the relationship between the extent of the intrapancreatic biliary stricture and the wall thickening was evaluated.Among 44 patients with a pancreatic head lesion, 41 (93%) had intrapancreatic bile duct stricture. Among 12 patients without a pancreatic head lesion, only 2 had such a stricture (P.0001). Intraductal US showed average intrapancreatic biliary wall thickening with severe stricture of 2.7 +/- 1.0 mm, significantly thicker than that with mild stricture (1.9 +/- 0.35 mm; P = .0200).Intraductal US was not performed in all patients.Both pancreatic edema and biliary wall thickening influenced intrapancreatic biliary stricture in AIP. This type of stricture should be differentiated from extrapancreatic biliary stricture that may be caused by biliary wall thickening only.

Ecodesign plays one of the most important roles in manufacturing sectors towards a sustainable society. As a practical tool of ecodesign, manufactures often use checklists to support product design as well as to obtain eco-label certification. However, current checklists are insufficient due to undetermined effects of individual requirements in the checklists on environmental impact. This paper proposes a method for supporting ecodesign assessment by developing a weighted checklist, where potential environmental improvements in each requirement are derived based on the life cycle simulation. In the case study involving a digital duplicator, the proposed method successfully identified requirements that needed to be improved. When suggested improvements were applied, 8% of total CO2 emissions were estimated to be reduced.

The hedgehog and mitogen-activated protein kinase (MAPK) signaling pathways regulate growth in many tumors, suggesting cooperation between these two pathways in the regulation of cell proliferation. However, interactions between these pathways have not been extensively studied. We assessed cross-talk between hedgehog and MAPK signaling in the regulation of cell proliferation in gastric cancer. We showed that PTCH expression was significantly correlated with extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (P = 0.016) as well as SHH expression (P = 0.034) in the 35 gastric cancers assessed by immunohistochemistry. Indeed, MAPK signaling increased the GLI transcriptional activity and induced the expression of hedgehog target genes in gastric cancer cells. The inductive effect of activated KRAS and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1 was blocked by the suppressor of fused (SUFU), indicating that MAPK signaling regulates GLI activity via a SUFU-independent process. Moreover, the deletion of the NH2-terminal domain of GLI1 gene resulted in reduced response to MEK1 stimulation. Our results suggest that the KRAS-MEK-ERK cascade has a positive regulatory role in GLI transcriptional activity in gastric cancer.

Background: Progression of disease after hepatitis C virus (HCV) infection differs among individuals, indicating a possibility of participation of host genetic factors. 2′-5′-oligoadenylate synthetase 1 (OAS-1), an important component of the innate immune system, has an antiviral function, and may therefore have a certain relationship with progression of disease. Aim: To evaluate single nucleotide polymorphisms (SNPs) of OAS-1 and its relationship with the disease status of HCV infection. Methods: Six SNPs of OAS-1 were selected and examined in 409 Japanese patients with chronic HCV infection using the TaqMan PCR genotyping method. The relationship of SNP genotypes and clinical manifestations of patients was analysed. Then, a pair of OAS-1-expression plasmids mimicking the clinical-related SNPs were created and transfected into liver cells carrying the HCV subgenomic replicon or the full-length genome, JFH1, and HCV replication after transfection was compared. Results: Patients with genotypes A/A, A/G and G/G of an SNP of OAS-1 at the exon 3 of its coding sequence were at gradient increased risks of suffering from higher serum alanine aminotransferase (P

Infiltration of IgG4-positive plasma cells in the pancreas and other organs is characteristic of autoimmune pancreatitis (AIP). However, it is undetermined whether needle or forceps biopsy of pancreas or other organs is indeed useful for the diagnosis of AIP. We aimed to clarify this point. Among 39 AIP patients, tissue sampling without laparotomy was performed in 27. Biopsy of pancreas, gastric mucosa, liver, bile duct, and duodenal papilla was performed in 15, 17, 11, 5 and 7, respectively. The obtained specimens were examined for IgG4-positive plasma cells. We also examined gastric mucosa of 18 patients with pancreatic cancer as controls. When the number of IgG4-positive plasma cells was more than 10 per high-power field, we regarded it as diagnostic. Diagnostic sensitivity in pancreas, gastric mucosa, liver, bile duct, and duodenal papilla was 47% (7/15), 47% (8/17), 36% (4/11), 0% (0/5), and 57% (4/7), respectively. Sensitivity of IgG4 immunostaining was unsatisfactory when tissue sampling was performed by needle or forceps biopsy. Biopsy of gastric mucosa might be a good subsidiary diagnostic tool.

Endoscopists seek to conduct more aggressive surgical procedures that surpass the limitations of existing endoscopic procedures. Endoscopic pancreatic necrosectomy and natural orifice transluminal endoscopic surgery (NOTES) are typical examples of this new trend; both are performed through the gastrointestinal wall without a skin incision. Endoscopic necrosectomy is effective for managing organized pancreatic necrosis and abscesses. The necrotic tissues are removed endoscopically by directly entering the cavity of the organized pancreatic necrosis. NOTES is a possible advance over surgical intervention, as it is a less invasive, more cosmetic, and effective procedure. There are various approaches, including the esophagus, stomach, colon, and vagina; Various procedures are possible using NOTES, such as cholecystectomy, appendectomy, full-thickness stomach resection, splenectomy, gastrointestinal (GI) anastomosis, and peritoneoscopy. The requirements for NOTES include high proficiency in endoscopic techniques, including knowledge of various devices, anatomy, and surgical procedures. Since most GI endoscopists have no surgical background, to increase the usage of NOTES, GI endoscopists should form and lead teams that include various specialists. We believe that endoscopic necrosectomy and NOTES represent a major shift in the treatment paradigm because physicians can treat beyond the gastrointestinal wall and endoscopic procedures will replace surgical treatment.

Background & Aims Although colorectal cancer (CRC) progression has been associated with alterations in KRAS and RAS signaling, not all CRC cells have KRAS gene mutations. RAS activity is modulated by RAS-GTPase-activating proteins (RASGAPs), so we investigated the role of RASGAPs in CRC progression. Methods The level of RASGAP expression in CRC cells was analyzed using quantitative real-time polymerase chain reaction. The expression of the RAS protein activator like-1 (RASAL1) was examined in clinical colorectal neoplasms using immunohistochemistry. The clinicopathologic (age, sex, and tumor site and grade) and molecular ( KRAS gene mutation, as well as CTNNB1 and TP53 expression patterns) factors that could affect RASAL1 expression were examined. Results Of 12 RASGAPs examined, expression levels of only RASAL1 decreased in CRC cells; RASAL1 expression decreased in most CRC cells with wild-type KRAS gene but rarely in those with mutant KRAS gene. A transfection assay showed that RASAL1 repressed RAS/mitogen-activated protein kinase signaling in response to growth factor stimulation and reduced proliferation of CRC cells that contained wild-type KRAS gene. RASAL1 expression was detected in 46.9% (30/64) of adenocarcinoma, 17.4% (8/46) of large adenoma, and no (0/42) small adenoma samples. RASAL1 expression levels were correlated with the presence of wild-type KRAS gene in CRC tumor samples ( P = .0010), distal location ( P = .0066), and abnormal expression of TP53 ( P = .0208). Conclusions RASAL1 expression is reduced in CRC cells that contain wild-type KRAS gene. Reductions in RASAL1 expression were detected more frequently in advanced lesions than in small adenomas, suggesting that RASAL1 functions in the progression of benign colonic neoplasms.

Objectives: We performed a pilot study of a modified combination chemotherapy regimen with S-1 plus gemcitabine for patients with advanced pancreatic cancer. Methods: Gemcitabine was administered at a dose of 1,000 mg/m2 in a 30-min intravenous injection on days 1 and 15. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 14 consecutive days followed by a 14-day rest. Each cycle was repeated every 28 days. Results: Sixteen patients were enrolled. No complete response was observed and partial response was observed in 5 patients (31.3%), stable disease in 10 patients (62.5%) and progressive disease in 1 patient (6.3%). The median time to progression was 10.0 months (95% CI 4.4–N.A.) and the median survival time was 20.4 months (95% CI 8.6–24.1 months). The major toxicities were grade 3 neutropenia (25.0%) and grade 3 anemia (6.3%). There were no grade 4 toxicities. Conclusions: Combination therapy with gemcitabine and S-1 using the modified 4-week schedule was well tolerated and efficacious for advanced pancreatic cancer.

Postcholecystectomy patients show moderate risk of colorectal cancer. However, few studies have investigated the relationship between cholelithiasis and colorectal adenoma. We examined this possibility through a combination of colonoscopy and ultrasonography in asymptomatic Japanese.We reviewed a subgroup of subjects drawn from a prospective annual colonoscopy screening survey. Subjects who underwent both ultrasonography and colonoscopy, and completed a questionnaire regarding lifestyle habits were entered. We investigated whether subjects with cholelithiasis or a previous cholecystectomy showed an increased risk of colorectal adenoma, as compared with subjects with normal gallbladders.Data of 4,458 subjects (men 3,053, women 1,405, mean age +/- SD 46.1 +/- 8.62 yr) were analyzed. Cholelithiasis was detected in 206 subjects, 4,189 subjects had normal gallbladders, and 63 subjects had cholecystectomies. The prevalence of colorectal adenoma was 29.6% (61/206) in subjects with cholelithiasis, which was significantly higher when compared with normal subjects, with a prevalence of 17.7% (741/4,189, P0.001). In cholecystectomy patients, only 15.9% (10/63) developed colorectal adenomas, which was not significantly different from the control group. In a multivariate analysis controlling for sex, age, family history of colorectal cancer, alcohol, smoking, and body mass index, cholelithiasis was shown to be an independent risk factor for colorectal adenoma (adjusted OR 1.57, 95% CI 1.14-2.18). Cholelithiasis was strongly associated with multiple (or = 3 lesions, adjusted OR 2.39, 95% CI 1.21-4.72) and left-sided colorectal adenomas (adjusted OR 1.82, 95% CI 1.28-2.59).Cholelithiasis is a risk factor for colorectal adenoma.

Loss of genomic imprinting is an epigenetic alteration of some cancers involving the absence of parental origin-specific expression of imprinted genes. Loss of genomic imprinting of insulin-like growth factor II is often detected in colorectal cancer. However, the genetic alterations accompanied by colorectal cancer with insulin-like growth factor II loss of genomic imprinting have not been fully determined. Genomic DNA samples were collected from 52 colorectal cancer tissues and analyzed. The loss of insulin-like growth factor II genomic imprinting status was determined by assessing the demethylation of the insulin-like growth factor II differentially methylated region using bisulfite sequencing. The molecular signatures were also examined: genetic mutations of KRAS, BRAF, and PIK3CA; the expression of CTNNB1 and TP53; and microsatellite instability status. Several cases of colorectal cancer with normal insulin-like growth factor II imprinting were located in the distal colon; in contrast, colorectal cancer with loss of genomic imprinting tended to be found in the proximal colon (22.7 versus 56.6%). The PIK3CA gene mutation was highly detected in normal imprinting tumors compared to colorectal cancers with insulin-like growth factor II loss of genomic imprinting (27.3% versus 6.7%). In multivariate analysis of these clinicopathologic and molecular factors of tumors, statistically significant relationships were observed among the proximal location of the tumor (odds ratio, 12.9; 95% confidence interval, 1.52-110.13), PIK3CA genetic mutation (odds ratio, 0.082; 95% confidence interval, 0.01-0.73), and insulin-like growth factor II genomic imprinting status. Our findings indicate that colorectal cancers with demethylation of the insulin-like growth factor II gene are distinct from normal imprinting tumors, both in clinical and genetic features.

OBJECTIVES Obesity is thought to be associated with colorectal cancer and adenoma. We aimed to investigate the effect of body weight on the risk of colorectal adenoma both in cross-sectional and longitudinal analyses. METHODS This is a retrospective cohort study in a large-scale health appraisal institution in Japan. A total of 7,963 asymptomatic, average-risk Japanese were enrolled at initial examinations, and 2,568 subjects who underwent a second colonoscopy after 1 yr were investigated. The association with the prevalence of colorectal adenoma was evaluated according to the body mass index (BMI) at the initial examination. The incidence of colorectal adenoma at the second colonoscopy was investigated according to the initial BMI and body weight changes during the year. RESULTS The prevalence of colorectal adenoma increased in relation to increases in the BMI: 15.4%, 20.6%, 22.7%, and 24.2%, respectively, in the first (BMI < 21.350), second (21.350 < or = BMI < 23.199), third (23.199 < or = BMI < 25.156), and fourth (25.156 < or = BMI) quartiles. The adjusted odds ratios in reference to Group Q1 were 1.15 (95% CI 0.97-1.37, P= 0.1) for Group Q2, 1.19 (1.01-1.41, P= 0.04) for Group Q3, and 1.32 (1.12-1.56, P= 0.001) for Group Q4. The incidence rates of colorectal adenoma after 1 yr also increased proportionally according to the initial BMI: Group Q1 (12.9%), Group Q2 (15.7%), Group Q3 (18.3%), and Group Q4 (19.0%). CONCLUSIONS Obesity was associated with the risk for colorectal adenoma, and body weight reduction was suggested to decrease this risk.

Background: Self-expandable metallic stents (EMSs) have been widely used for the palliative treatment of unresectable malignant biliary obstructions, but EMSs are often occluded owing to tumor ingrowth via the wire mesh. Currently, there is no consensus on the management of occluded EMSs. We evaluated the efficacy of a covered EMS as a second endoprosthesis in patients with an occluded EMS. Methods: Forty patients with an occluded uncovered EMS (14 men, 26 women; mean age 72 y, range 41 to 89 y) were studied. The patients suffered from the following: pancreatic cancer in 18, bile duct cancer in 11, gallbladder cancer in 5, lymph node metastasis in 4, and papillary cancer in 2. Of these, 26, 7, and 7 were treated with a covered EMS, an uncovered EMS, and a plastic stent (PS), respectively. The second stent was inserted as a stent-in-stent. Results: The mean patent period for the covered EMS was 220 days, whereas the mean patent periods for the uncovered EMS and plastic stent were 141 and 58 days, respectively. The cumulative patency of the covered EMS group was significantly higher (P = 0.0404) than that of the uncovered EMS group. No significant differences in survival were observed between the covered and uncovered groups. No serious complications occurred. Conclusion: Insertion of a covered EMS is an effective and safe treatment for an occluded uncovered EMS.

Background and aims: Interferon (IFN) regulatory factor 7 (IRF-7) has been shown to play an essential role in the transcriptional activation of virus-inducible cellular genes, especially IFN genes. Polymorphisms of the IRF-7 gene may probably affect both the quality and the quantity of IRF-7. We investigated the role of IRF-7 polymorphisms in Japanese patients with chronic hepatitis C virus (HCV) infection. Methods: We studied a total of nine polymorphisms of the IRF-7 gene including SNP1047A/G (Lys/Glu) and SNP2157A/G (Gln/Arg) using the Taqman allelic discrimination and sequencing techniques in 406 Japanese patients with chronic HCV infection. We further performed functional analysis of SNP1047 and SNP2157 by transcriptional activation of the IFNA promoter. Results: We found that SNP1047AG and SNP2157AG genotypes were in complete linkage disequilibrium and were present in a significantly higher proportion in HCV-infected patients with cirrhosis (5.6%) than in those without cirrhosis (1.7%) (P=0.03). Multivariate analysis also revealed that SNP1047 and SNP2157 were independently associated with cirrhosis at an odds ratio of 2.5. Functional analysis revealed that SNP1047G and SNP2157G alleles increased IFNA expression. Conclusion: SNP1047AG and SNP2157AG genotypes were strongly associated with cirrhosis. SNP1047G and SNP2157G alleles might be used as markers of host factors associated with a higher risk of cirrhosis in Japanese patients with chronic HCV infection.

Background: The efficacy of gemcitabine alone has not been established in comparison with conventional chemoradiotherapy for locally advanced pancreatic cancer. Methods: Of 180 consecutive patients with unresectable advanced pancreatic cancer, 93 were locally advanced. Among these 93 patients, 45 were treated with gemcitabine, 18 with concurrent radiotherapy and 5-fluorouracil-based chemotherapy, and 30 received best supportive care (BSC). In cases of metastatic disease, 42 were treated with gemcitabine and 32 received BSC. Overall survival and adverse events were analyzed retrospectively. Results: Median survival time and 1-year survival rate were 11.6, 9.3, 6.7, 7.8 and 2.4 months and 47, 39, 27, 21 and 7% in the groups of gemcitabine, chemoradiotherapy, BSC of locally advanced cancer, and in those of gemcitabine, BSC of metastatic disease, respectively. Gemcitabine and chemoradiotherapy prolonged overall survival time compared with BSC (p = 0.0071). No significant difference in survival was observed between gemcitabine and chemoradiotherapy for locally advanced cases. Adverse events >grade 3 were observed in 25 of 87 (29%) of gemcitabine-treated and in 3 of 18 (17%) of chemoradiotherapy-treated patients. Conclusion: Gemcitabine monotherapy for locally advanced pancreatic cancer could be as effective as previous chemoradiotherapy.

Although commonly practiced in Japan, the effectiveness of regular screening with upper gastrointestinal (UGI) endoscopy against gastric cancer has not been well evidenced. The aim of the study was to investigate if gastric cancer-related mortality can be reduced by regular endoscopy.The medical records of 833 patients with gastric ulcer (GU) and 2547 without ulcer (NU) were analyzed; these patients received long-term, repeated endoscopic examinations between 1969 and 2004. Gastric cancer incidence, death by gastric cancer, and overall survival were compared with those in a Japanese general population by calculating the standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs).The interval between UGI endoscopic examinations was 1.4 +/- 1.4 years in the GU group and 1.8 +/- 1.5 years in the NU group. During follow-up, 32 patients with GU and 61 in the NU group developed gastric cancer, showing annual incidence rates of 0.40% (95% CI: 0.24-0.56%) and 0.38% (0.28-0.48%), and SIRs of 2.21 (1.44-2.98) and 1.72 (1.29-2.15), respectively. The 5-year survival rate exceeded 80% among patients who developed gastric cancer. SMRs for gastric cancer and overall deaths were 0.50 (0.01-0.99) and 1.05 (0.87-1.23) in GU patients, and 0.45 (0.15-0.74) and 0.78 (0.69-0.88) in NU patients. There were no significant differences between the two groups in gastric cancer incidence, mortality from gastric cancer, and overall survival.Mortality from gastric cancer could be reduced by regular UGI endoscopy in a population with a high incidence of gastric cancer.

Objective: To chart molecular genetic events in pancreatic cancer. Methods: We analyzed genome-wide copy number alterations and loss of heterozygosity (LOH) in 25 established pancreatic cancer cell lines using a high-density single nucleotide polymorphism (SNP) array. We verified the data using genomic PCR and applied them to clinical samples. Results: Twenty-six homozygous deletion regions were detected in at least 1 cell line and LOH was found at 9p, 18q, 17p, 8p, 13q, 6q, 3p, 6p, 22q, 9q and 12q with high frequency (>50%), consistent with a previous study. Moreover, we found 23 amplified regions in at least 2 cell lines, including 8 unreported loci. We then examined representative genes at the 8 amplified loci in matched pairs of pancreatic cancer and normal tissues. The amplification was detected in 1 (7.1%) to 5 (35.7%) of 14 microdissected tissue specimens. Conclusion: Using high-resolution SNP arrays, we studied genome-wide copy number alterations and LOH simultaneously. We identified several novel and minute genomic amplifications, which contained candidate oncogenes in human pancreatic cancers.

BACKGROUND: Liver stiffness measurement (LSM) by transient elastography has recently been validated for the evaluation of liver fibrosis in chronic liver diseases. The present study focused on cases in which liver biopsy and LSM were discordant.METHODS: Three hundred eighty-six patients with chronic hepatitis C who underwent a liver biopsy between December 2004 and April 2007 were studied. First, the optimal cut-off value of LSM was selected for the determination of cirrhosis based on the receiver operating characteristic curve. Then, the cases in which liver histology and evaluation by LSM were discordant were selected. Laboratory test results such as serum total bilirubin concentration, prothrombin activity, albumin concentration, platelet count and the aspartate aminotransferase to platelet ratio index, together with the presence of esophageal varices, were analyzed.RESULTS: The optimal cut-off value was chosen to be 15.9 kPa for cirrhosis (fibrosis stage [F] 4) determination to maximize the sum of sensitivity (78.9%) and specificity (81.0%). There were 78 discordant cases: 51 patients showed an LSM of 15.9 kPa or higher and a fibrosis stage of F1 to F3 (high LSM group), and 27 patients had an LSM lower than 15.9 kPa and a fibrosis stage of F4 (low LSM group). Esophageal varices were seen in 11 patients in the high LSM group (n=51) and in no patients in the low LSM group (n=27) (P=0.0012). The aspartate aminotransferase to platelet ratio index was significantly higher in the high LSM group (1.49 versus 0.89, P=0.019). Other parameters did not differ significantly. However, platelet count, prothrombin activity and albumin concentration tended to be lower in the high LSM group.CONCLUSIONS: Patients with a high LSM need proper attention for cirrhosis, even if liver biopsy does not reveal cirrhosis.

In a DI diesel engine, reducing the compression ratio is effective to reduce smoke emissions without deterioration of NOx and thermal efficiency. However, with lower compression ratios, a low coolant temperature, or during the transient state, THC emissions significantly increase when using ordinary diesel fuel. The THC emissions during increasing loads significantly increased to very high concentrations from just after the start of the load increase until around the 10th cycle, rapidly decreased until the 20th cycle, and then gradually decreased to a steady state value after 1000 cycles. The dominant components present in the THC transient spike were lower hydrocarbons with carbon numbers around or below eight. In particular, ethylene showed a much higher concentration than the other components. In fully-warmed steady state operation with a compression ratio of 16 and diesel fuel, THC is reasonably low, but THC increases with lower coolant temperature or during the transient period just after increasing the load. This problem can be eliminated with a low distillation temperature fuel such as normal heptane. Benzene, butadiene, and other unregulated harmful emissions also increase under the high THC conditions with diesel fuel.

Aims: While triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin is the standard therapy for Helicobacter pylori eradication, it is ineffective against clarithromycin-resistant strains. To seek a better regimen for eradication therapy, we assessed the sensitivity of clinical strains seen in Japan to faropenem and then evaluated the efficacy and safety of eradication therapy containing this antibiotic. Methods: Minimum inhibitory concentrations (MICs) of faropenem were determined in 78 Japanese clinical H. pylori isolates using the agar dilution method. H. pylori-positive patients were consecutively assigned to a 7-day eradication therapy protocol with LAF (lansoprazole 60 mg/day, amoxicillin 2000 mg/day, and faropenem 600 mg/day), and then to a 14-day protocol. The outcomes of the therapies were assessed by 13C-urea breath tests. Results: All 78 strains showed MICs of faropenem that were equal to or less than 0.2 µg/mL. The eradication rates according to intention-to-treat analyses were 46.5% with the 7-day therapy (n = 43) and 62.5% with the 14-day therapy (n = 32). No special measures were required to treat the adverse events observed in approximately one-third of the patients. Conclusions: Faropenem was found to have good antimicrobial action against H. pylori in vitro. The 14-day LAF therapy successfully eradicated H. pylori in about two-thirds of the patients although the incidence of adverse events was high.

Recent studies have suggested that Runt-related transcription factor 3 (Runx3) is associated with genesis and progression of gastric carcinoma. A proteomic approach was used to search for Runx3-interacting proteins to elucidate the molecular mechanisms of gastric carcinogenesis. Runx3 bound with myc and flag tags (MEF tags) is expressed in HEK293T cells, and the protein complex formed with Runx3 was purified and identified by mass spectrometry. Ku70 and Ku80, members of the DNA repair protein complex, were identified as Runx3-interacting proteins. Runx3, Ku70, and Ku80 associate in vivo, and in vitro interaction between Runx3 and Ku70 was confirmed via His-tag pull-down assay. The amino acids 241-322 of Runx3, which correspond to the transcriptional activation domain, and the amino acids 1-116 of Ku70 were necessary for binding with each other, and immunocytochemistry under confocal laser microscopy demonstrated that Runx3 and Ku70 localized throughout the nucleus excluding the nucleoli. Furthermore, Runx3 highly activated the transcription of p21, the target gene of Runx3, in Ku70 knockdown cells. These results suggest a possible link between a tumor suppressor function and DNA repair.

Acute suppurative cholangitis is fatal unless adequate biliary drainage is obtained in a timely manner. The major cause of acute suppurative cholangitis is bile duct stones, but it is not known which patients with bile duct stones are likely to develop acute suppurative cholangitis.Between May 1994 and December 2005, 343 consecutive patients with bile duct stones were referred to our department. Of these, 38 patients presented with acute suppurative cholangitis. A nasobiliary catheter or biliary stent was emergently inserted endoscopically to control acute suppurative cholangitis in those patients. Risk factors for the development of acute suppurative cholangitis in the 343 patients were investigated using univariate and multivariate analyses.A nasobiliary catheter or stent was inserted endoscopically in all 38 patients with acute suppurative cholangitis. Although biliary drainage was considered to be effective in all patients, two patients (5.3%) died of deteriorating comorbid diseases despite subsiding cholangitis. In the univariate analysis, ageor=70 years, neurological disease, and peripapillary diverticulum were identified as risk factors for the development of acute suppurative cholangitis. In the multivariate analysis, these three factors remained significant.Advanced age, comorbid neurological disease, and peripapillary diverticulum were identified as independent risk factors for the development of acute suppurative cholangitis in patients with bile duct stones.

Background & Aims: The clinical outcomes for endoscopic submucosal dissection (ESD), a novel endoluminal surgery for gastrointestinal neoplasm in the colorectum, are reported. Methods: ESD was performed on 186 consecutive patients with 200 colorectal epithelial neoplasms who had preoperative diagnoses of mucosal or slight submucosally invasive neoplasms. In addition, these could be of large size, with submucosal fibrosis, or located on an intestinal fold. The therapeutic efficacy and safety were assessed. Results: The targeted lesions consisted of 102 adenomas, 72 noninvasive carcinomas, and 26 invasive carcinomas. Seven lesions (3.5%) were histologically considered to be at substantial risk for nodal metastasis after ESD. The rate of en bloc resection was 91.5% (183/200), and en bloc resection with tumor-free lateral/basal margins (R0 resection) was 70.5% (141/200). Two lesions (1%) required emergency colonoscopies as a result of hematochezia after ESD. Eleven (5.5%) immediate perforations that occurred during ESD were successfully managed conservatively, but 1 (0.5%) delayed perforation required laparotomy. Two multiple-piece resections of 111 tumors (1.8%), which were successfully followed by colonoscopy (median follow-up, 18 months; range, 12–60 months), were found as locally recurrent tumors 2 and 21 months after ESD. No lymph node or distant metastasis was detected in 77 patients with noninvasive or invasive carcinoma (median follow-up, 24 months; range, 6–74 months). Conclusions: ESD is applicable in the colorectum with promising results. However, when considering the risks and benefits, piecemeal endoscopic resection or colorectal resection might be more appropriate for some subgroups of large flat neoplasms or those with submucosal fibrosis.

Extracorporeal shockwave lithotripsy (ESWL) and endoscopic lithotripsy are useful for the fragmentation and extraction of pancreatic stones. However, pancreatic stones often recur, for which an adequate strategy is needed. Treatment for stricture of the main pancreatic duct (MPD) with a pancreatic stent after clearance of pancreatic stones may reduce the recurrence of pancreatic symptoms and stones.Forty patients with chronic pancreatitis with MPD stones were treated with ESWL in combination with endoscopic stone extraction. After clearance of the stones, a pancreatic stent was inserted when a stricture of MPD was observed on pancreatography. The stent was exchanged every 3 months and removed after a total of 1 year. We examined episodes of recurrent pain and pancreatitis in patients with and without stenting, as well as the MPD diameter, during follow-up.MPD stricture was seen in 27 patients, and a stent was successfully inserted in 24 of them. Pancreatic symptoms recurred in five patients (21%) in the stenting group and in three patients (23%) in the control group during a mean follow-up period of 1.5 and 1.2 years, respectively. The diameter of the MPD, before, just after, and 1 year after treatment, was 7.6, 5.4, and 5.8 mm, respectively. It was significantly decreased after 1 year of follow-up, as well as just after stent removal, compared with before treatment (P0.05).Additional stenting for MPD after extraction of pancreatic stones may reduce the risk of recurrence of pancreatic symptoms.

Purpose: It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues. Experimental Design: Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, β-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions. Results: Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 ± 2.0%; high-grade dysplasia, 82.9 ± 1.6%; cancer, 87.5 ± 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells. Conclusions: Bmi1 overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1 dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.

Background Patients with duodenal ulcer are not at high risk although Helicobacter pylori infection is no doubt associated with gastric cancer development. However, little is known about the risk after long-term follow-up. Aims We investigated the incidence for gastric cancer development in peptic ulcer patients in a long term. Patients and methods Between 1965 and 2004, endoscopic follow-up of more than 1 year was conducted on 1504 peptic ulcer patients in our hospital. They consisted of 978 gastric ulcer patients, 444 duodenal ulcer patients and 82 gastric and duodenal ulcer patients. Gastric and duodenal ulcer patients were excluded from the analysis because of their limited number. Results Gastric cancers developed in 32 (3.3%) of gastric ulcer patients and 3 (0.68%) of duodenal ulcer patients. Kaplan–Meier analysis showed that the incidence of gastric cancer in duodenal ulcer patients was significantly lower than that in gastric ulcer patients (log-rank test, p = 0.0059). Cox's proportional hazard model denoted the relative risk for duodenal ulcer against gastric ulcer adjusted by sex and age as 0.23 (95% CI: 0.072–0.77, p = 0.016). Conclusion The risk for patients with duodenal ulcer to develop gastric cancer over the long term is significantly less than in those with gastric ulcer.

Background and study aims Endoscopic submucosal dissection (ESD) is a novel technique used for the treatment of gastrointestinal neoplasia. One of its major limitations, however, is the complication of perforation. Patients and methods We included in our study all the cases of perforation that occurred during ESD procedures for gastrointestinal epithelial neoplasia between February 2000 and February 2005. Clinical outcomes after perforation were investigated. Results Perforation was experienced at 27 lesions in 27 patients (four in the esophagus, fourteen in the stomach, seven in the colon, and two in the rectum). Fibrosis under the lesions was confirmed histologically in seven patients (26 %). Immediate closure using endoclips was performed in all patients except for three asymptomatic patients in whom a stomach perforation was first noticed when free air was noticed on a radiograph the morning after the ESD procedure. Air accumulation was detected radiographically in 21 patients (78 %). The mean duration of antibiotic treatment was 6.7 days and the patients were fasted for a mean period of 5.3 days. The mean maximum body temperature was 37.3 degrees C, the mean white blood cell count was 9733/mm3, and the mean C-reactive protein level was 5.0 mg/dl. All the patients were discharged well from the ward after a mean time of 12.1 days after ESD, and no recurrence caused by tumor spread from the perforation occurred in any patient after a median follow-up period of 36 months (range 9 - 52 months). Conclusion Successful nonsurgical management after ESD complicated by perforation is a highly feasible option if intensive conservative treatments are used following immediate endoscopic closure of the perforation.

Background & Aims: K-ras mutation is frequently detected in pancreatic juice of patients with pancreatic small cystic lesions, as well as those with pancreatic cancer. Those cystic lesions are often found by chance with modern radiologic imaging modalities. In this study, we prospectively examined the prognosis of patients with pancreatic cystic lesions, focusing on pancreatic cancer development. Methods: A total of 197 patients with pancreatic cystic lesions, 80 with intraductal papillary mucinous neoplasm (IPMN) and 117 with non-IPMN cysts, were followed up for 3.8 years on average. Blood tests and imaging diagnosis were performed twice a year. The observed incidence of pancreatic cancer was compared with the expected incidence calculated on the basis of age- and gender-matched mortality of pancreatic cancer in the general Japanese population. Results: Pancreatic cancer developed in 7 patients during the observation period (0.95% per year), infiltrating ductal carcinoma in 5 and intraductal papillary mucinous carcinoma in 2. Three of the ductal cancer cases had pancreatic non-IPMN cyst as preexisting lesion. At least 2 of the carcinomas arose in regions remote from preexisting lesions. The observed incidence of pancreatic cancer was 22.5 times higher (95% confidence interval, 11.0–45.3) than expected mortality from this cancer among general population. Conclusions: Patients with pancreatic cystic lesions are at a considerably high risk for pancreatic cancer, with a standardized incidence rate of 22.5. Cancer might develop in regions remote from the preexisting cystic lesion, suggesting diffuse pathologic changes predisposing to malignant transformation in the entire pancreas harboring cystic lesions.

Background & Aims: Cholecystitis after metallic stent (MS) placement is an issue requiring attention. From our experience, cholecystitis seemed to occur mainly in patients with tumor involvement to the cystic duct orifice. The aim of the present study was to identify risk factors for cholecystitis in patients treated with covered or uncovered MS. Methods: We analyzed 246 patients who received MS placement (covered MS in 171 and uncovered in 75) between August 1997 and May 2005 for the treatment of unresectable distal malignant biliary obstruction. Causative diseases were as follows: pancreatic cancer in 162, papillary cancer in 10, bile duct cancer in 41, and metastatic nodes in 33 patients. Tumor involvement to orifice of the cystic duct (OCD) was diagnosed based on cholangiography and intraductal ultrasonography. Results: Cholecystitis after MS placement was found in 13 patients (5.3%). There was no significant difference in the incidence of cholecystitis between covered (5.8%) and uncovered (4.0%) MS. By univariate analysis, tumor involvement of the OCD, MS placed above the papilla, and stricture located at midportion were associated significantly with cholecystitis. By multivariate analysis, only tumor involvement of the OCD was a risk factor, with an odds ratio of 47.206 (95% confidence interval, 5.84–381.60). Conclusions: Cholecystitis after MS placement is associated with tumor involvement to the orifice of the cystic duct, regardless of the type of stent.

Hemorrhage is among the most serious complications of colorectal polypectomy and may occur after a longer postprocedure interval.We aimed to elucidate the risk factors for delayed postpolypectomy hemorrhage, including both polyp characteristics and the general condition of the patients.Retrospective cohort study.A total of 6617 cases of colorectal polypectomy was performed in 3138 consecutive patients in Japan.The risk factors for delayed postpolypectomy hemorrhage were assessed among polyp characteristics (form, size, histologic features) and the method of resection by unconditional logistic regression. Patient conditions (smoking, alcohol, hypertension, diabetes mellitus, hyperlipidemia) were compared between case-control pairs matched on polyp-related characteristics by conditional logistic regression.Hemorrhage occurred in 38 lesions (0.57%) of 37 patients (1.2%): 22 required endoscopic hemostasis and 1 required blood transfusion. Although polyp size was associated with the occurrence of delayed hemorrhage (10.0 +/- 6.9 mm in hemorrhage cases vs 5.6 +/- 3.8 mm in others, P.0001), other polyp-related factors were not significant. Hypertension was a complication in 25 of 37 (68%) cases and in 21 of 74 (28%) matched controls, showing an adjusted odds ratio of 5.6 (95% CI 1.8-17.2, P = .001). Other patient characteristics were not significant. The interval between polypectomy and hemorrhage was significantly longer in patients with hypertension (median 6 days, range 2-14 days) than in those without hypertension (2.5 days, 1-9 days; P = .019).This study does not provide information regarding prevention of hemorrhage.Hypertension is a significant risk factor for delayed colorectal postpolypectomy hemorrhage. The interval between polypectomy and hemorrhage can be as long as 14 days in the presence of hypertension.

Background & Aims: Endoscopic submucosal dissection (ESD) has recently been developed for en bloc resection of stomach neoplasms, which results in high tumor eradication rates as well as a modality for the precise histologic assessment of the entire lesion. Application of the technique is desirable for esophageal squamous cell neoplasms (SCNs), but there have been no reports on the use of this procedure in the esophagus. Methods: An ESD with methods similar to those used for resections of early gastric cancer was performed on 58 consecutive esophageal SCNs with preoperative diagnoses of intraepithelial neoplasm or intramucosal invasive carcinoma occurring in 43 enrolled patients. The therapeutic efficacy, complications, and follow-up results were assessed. Results: The rate of en bloc resection was 100% (58/58), and en bloc resection with tumor-free lateral/basal margins (R0 resection) was 78% (45/58). There was no evidence of significant bleeding. Perforation occurred in 4 (6.9%) patients during the ESD, who were managed by conservative medical treatments after endoscopic closure of the perforation. Removal of 9 (16%) lesions resulted in esophageal stricture requiring balloon dilation after ESD. Of 40 lesions occurring in 31 patients fulfilling the criteria of node-negative tumors (mean follow-up, 17 months), 1 lesion resected by en bloc resection with nonevaluable tumor-free lateral margins (Rx [lateral] resection) recurred locally 6 months after ESD, which was treated successfully by a second ESD procedure. Conclusions: The ESD is applicable to the esophagus with promising results, but notification of risk is essential.

Helicobacter pylori induces NF-κB activation, leading to mucosal inflammation via cag pathogenicity island. Although recent studies have implicated several candidate proteins of both H. pylori and host, the molecular mechanism by which H. pylori activates NF-κB remains unclear. The aim of this study was to analyze the mechanism of cag pathogenicity island-mediated NF-κB activation in epithelial cells. The responses of human cell lines and mouse embryonic fibroblasts to infection with wild-type H. pylori or cagE mutant were investigated. The effect of small interfering RNAs (siRNAs) for several NF-κB signaling intermediate molecules was evaluated in H. pylori-induced IκBα phosphorylation and IL-8 production. Protein interactions of exogenously expressed TNFR-associated factor 6 (TRAF6) and MyD88 or receptor-interacting protein 2 and nucleotide-binding oligomerization domain 1 or those of endogenous IκB kinase, TGF-β-activated kinase 1 (TAK1), and TRAF6 were assessed by immunoprecipitation. Cag pathogenicity island-dependent NF-κB activation was observed in human cell lines, but not in mouse fibroblasts. In human epithelial cells, H. pylori-induced IκBα phosphorylation and IL-8 production were severely inhibited by siRNAs directed against TAK1, TRAF6, and MyD88. In contrast, siRNAs for TRAF2, IL-1R-associated kinases 1 and 4, and cell surface receptor proteins did not affect these responses. H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation. H. pylori also induced TAK1 and TRAF6 complexes. These results suggest that the cag pathogenicity island of H. pylori is a cell type-specific NF-κB activator. TAK1, TRAF6, and MyD88 are important signal transducers in H. pylori-infected human epithelial cells.

NF-κB is an important transcriptional factor that is involved in multiple cellular responses, such as inflammation and antiapoptosis. IκB kinase α (IKKα) and IKKβ, which are critical regulators of NF-κB activity, possess various mechanisms for NF-κB activation. This variability in NF-κB signaling may be associated with distinct inflammatory responses in specific cell types. The gastric pathogenHelicobacter pyloriis known to activate NF-κB. However, the role of IKK inH. pyloriinfection remains unclear. In this report, we show thatH. pyloriactivates both IKKα and IKKβ in gastric cancer cells and enhances NF-κB signaling in distinct manners. We found that IKKβ acted as an IκBα kinase duringH. pyloriinfection, whereas IKKα did not.H. pyloriinduced IKKα nuclear translocation in time-, multiplicity of infection-, andcagpathogenicity island-dependent manners. In contrast, p100 processing, which is a known IKKα activity induced by several cytokines, was not induced byH. pylori. Both IKKs were responsible for chemokine secretion by infected cells. However, the antiapoptotic effect ofH. pyloriwas merely transduced by IKKβ. Microarray analysis and real-time PCR indicated that both IKKs were involved in the transcriptional activation of genes associated with inflammation, antiapoptosis, and signal transduction. Our results indicate thatH. pyloriactivates NF-κB via both IKKα and IKKβ using distinct mechanisms. IKKα nuclear translocation induced byH. pyloriis indispensable for appropriate inflammatory responses but not for antiapoptosis, which suggests a critical role for IKKα in gastritis development.

Autoimmune pancreatitis (AIP) has extrapancreatic complications such as Sjögren's syndrome, retroperitoneal fibrosis and sclerosing cholangitis. We studied 30 patients with AIP. Of these, we identified pulmonary involvement in four patients during follow up. Among them, two patients had respiratory failure. They showed good response to steroid therapy, but a higher dose of prednisolone was necessary to maintain remission than that required in biliary involvement. Elevation of immunoglobulin G(4) and Krebs von den Lungen-6 levels were characteristic of pulmonary involvement. They may be useful for early detection of pulmonary complication.