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OBJECTIVES Data on the long-term outcomes of endoscopic submucosal dissection (ESD) performed in elderly patients with early colorectal cancer (CRC) are limited. We analyzed the prognosis of elderly CRC patients, not only from the viewpoint of treatment curability but also from the patients' baseline physical condition assessed by several indexes. METHODS A retrospective analysis of 729 patients aged ≥75 years who underwent ESD for Tis/T1 CRC in 16 institutions was conducted. The patients were classified into three groups based on curability: curative ESD (Group A, n = 582), non-curative ESD with additional surgery (Group B, n = 60), and non-curative ESD without additional surgery (Group C, n = 87). Overall survival (OS) was compared among the groups, and factors associated with reduced OS were investigated. RESULTS The median follow-up periods in Groups A, B, and C were 41, 49, and 46 months, respectively (P = 0.62), during which 92 patients died. Two patients (0.3%) in Group A, none (0%) in Group B, and three (3.4%) in Group C died of CRC. Three-year OS rates in Groups A, B, and C were 93.9%, 96.1%, and 90.1%, respectively, without a significant difference (P = 0.07). Multivariate analysis indicated low (

Background The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. Methods This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, β-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. Results A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30–0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. Conclusion Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Background and study aims In patients receiving antithrombotic therapy, the risks of delayed bleeding after endoscopic procedures for gastrointestinal neoplasms become a major problem. Few reports have shown the effects of delayed bleeding in patients taking anticoagulants after colorectal endoscopic submucosal dissection (ESD). This study aimed to evaluate the delayed bleeding events after colorectal ESD in patients receiving anticoagulant therapy. Patients and methods We retrospectively analyzed 87 patients taking anticoagulants who underwent colorectal ESD from April 2012 to December 2017 at 13 Japanese institutions participating in the Osaka Gut Forum. Among these patients, warfarin users were managed with heparin bridge therapy (HBT), continued use of warfarin, a temporary switch to direct oral anticoagulation (DOAC), or withdrawal of warfarin, and DOAC users were managed with DOAC discontinuation with or without HBT. We investigated the occurrence rate of delayed bleeding and compared the rates between warfarin and DOAC users. Results The delayed bleeding rate was 17.2 % among all patients. The delayed bleeding rate was higher in DOAC users than in warfarin users (23.3 % vs. 11.4 %, P = 0.14), although no statistically significant difference was observed. In DOAC users, the delayed bleeding rates for dabigatran, rivaroxaban, apixaban, and edoxaban users appeared similar (30 %, 18.2 %, 22.2 %, and 25 %, respectively). The onset of delayed bleeding in both warfarin and DOAC users was late, averaging 6.9 and 9.4 days, respectively. Conclusions Among patients taking anticoagulants, the risk of delayed bleeding after colorectal ESD was relatively high and the onset of delayed bleeding was late.

Objectives Differentiation between gastric adenocarcinoma and low-grade adenoma/dysplasia (LGA) on endoscopic forceps biopsy is difficult. We aimed to clarify the incidence of carcinoma in specimens—obtained via endoscopic resection (ER)—from cases that had been diagnosed as LGA (Vienna category 3) on endoscopic biopsy. Methods In this multi-center, prospective, observational study, patients with gastric adenoma (Vienna category 3 or 4.1) diagnosed on endoscopic forceps biopsy were enrolled. All the specimens were subjected to histopathological central review. Primary endpoint was the incidence of carcinoma (Vienna category 4.2 or over) among the biopsy-proven gastric LGA. Secondary endpoints were the histological findings of resected specimens, clinicopathological features of carcinoma, and short-term outcomes of all ER cases. Results Ninety-five patients with 104 lesions diagnosed as gastric adenoma were enrolled. After central review of the biopsy specimens, 47 lesions were diagnosed as LGA and 7 lesions (15%) as adenocarcinoma (95% confidence interval, 7.6–28%). Carcinoma was detected in lesions that had a minimum size of 6 mm; the incidence of carcinoma was higher in the larger lesions. There was a histological discrepancy between biopsy and ER material in more than 60% of the cases. Conclusions A substantial proportion of biopsy-proven gastric LGA specimens were diagnosed as adenocarcinoma after ER. This indicated the histological discrepancy between biopsy-proven gastric LGA and histology of the resected material. This article is protected by copyright. All rights reserved.

Environmental factors are suggested to affect the pathogenesis of several diseases, including inflammatory bowel disease (IBD). The seasonality of disease onset and exacerbation in IBD, however, are not well established. We herein aimed to clarify the disease seasonality and to investigate the underlying characteristics in IBD patients exhibiting seasonality of the disease course. This was a multicenter observational study comprising 20 institutions (Osaka Gut Forum) in Japan. Data were collected from November 2013 to August 2014 using survey forms for physicians and questionnaires for patients. Multivariate analysis was performed to clarify the independent factors affecting disease seasonality. A total of 1055 patients, including 298 patients with Crohn’s disease (CD) and 757 patients with ulcerative colitis (UC), were enrolled. The proportion of CD patients with disease onset in the summer was significantly larger than that in the other seasons, while UC patients exhibited no seasonality of disease onset. More than half of the IBD patients (51.1%) experienced seasonal exacerbation of IBD, and winter was the most common season for disease exacerbation in both CD and UC patients. Seasonality of disease onset and exacerbation was observed in young-onset patients (≤40 years old), but not in elderly-onset patients. Age at onset was independently associated with the seasonality of both disease onset and exacerbation. Seasonality of disease onset and exacerbation was observed especially in young-onset IBD patients. Underlying pathophysiologic triggers for disease initiation and exacerbation may be influenced by age at disease onset.

Background and aims Psychologic stress can affect the pathogenesis of inflammatory bowel disease (IBD), but the precise contribution of psychologic stress to IBD remains unclear. We investigated the association of psychologic stress with disease activity in patients with IBD, especially in terms of mental state and sleep condition. Methods This was a multi-center observational study comprising 20 institutions. Data were collected using survey forms for doctors and questionnaires for patients, and the association of psychologic stress with clinical parameters was investigated. Mental state was evaluated using the Center for Epidemiologic Studies Depression (CES-D) scale, and sleep condition was evaluated by querying patients about the severity of insomnia symptoms. Results A total of 1078 IBD patients were enrolled, including 303 patients with Crohn’s disease and 775 patients with ulcerative colitis. Seventy-five percent of IBD patients believed that psychologic stress triggered an exacerbation of their disease (PSTE group) and 25% did not (non-PSTE group). The CES-D scores were significantly higher for patients with clinically active disease than for those in remission in the PSTE group (median (interquartile range) = 7 (4–9.5) vs. 5 (3–7), p < .0001), but not in the non-PSTE group (5 (2–8) vs. 4 (3–7), p = 0.78). Female sex and disease exacerbation by factors other than psychologic stress were independent factors of psychologic stress-triggered disease exacerbation. Also, patients with insomnia had higher disease activity than those without insomnia, especially in the PSTE group. Conclusions A worsened mental state correlates with disease activity in IBD patients, especially those who believe that their disease is exacerbated by psychologic stress.

Gastric cancer and liver cirrhosis (LC) are often comorbid. However, little is known about the clinical outcomes of gastric endoscopic submucosal dissection (ESD) in patients with comorbid LC. This case–control study used a multicentre retrospective cohort. We identified 69 LC patients from the cohort of patients with early gastric cancer, who underwent gastric ESD at 12 hospitals from March 2003 to November 2010. Using the propensity score matching method, 69 patients without LC were used to compare the short- and long-term outcomes of ESD. Among the 69 LC patients, 53 (77 %) were Child-Pugh grade A (CP-A) and 16 (28 %) had past or present histories of hepatocellular carcinoma (HCC). Short-term outcomes did not differ between the LC patients and controls or between the CP-A and CP-B/C patients. Although the LC patients had significantly worse long-term outcomes than the controls (the 5-year overall survival rates were 60 vs. 91 %, respectively), patients with CP-A liver function without HCC histories had an overall survival almost equivalent to that of patients without LC (controls). LC patients appear to be good candidates for ESD if they have CP-A liver function and no history of HCC. Although their short-term outcomes were not inferior, the patients with Child-Pugh grades B/C or with histories of HCC benefited less from ESD.

After endoscopic submucosal dissection (ESD) of early gastric cancer (EGC), patients are at high risk for synchronous or metachronous multiple gastric cancers.To elucidate the time at which multiple cancers develop and to determine whether scheduled endoscopic surveillance might control their development.A multicentre retrospective cohort study from 12 hospitals was conducted. Patients with EGC who underwent ESD with en bloc margin-negative curative resection were included. Synchronous cancer was classified as concomitant cancer or missed cancer. The cumulative incidence of metachronous cancers and overall survival rate were calculated using the Kaplan-Meier method.From April 1999 to December 2010, 1258 patients met the inclusion criteria. Synchronous or metachronous multiple cancers were detected in 175 patients (13.9%) during a mean of 26.8 months. Among the 110 synchronous cancers, 21 were missed at the time of the initial ESD. Many of the missed lesions existed in the upper third of the stomach and the miss rate was associated with the endoscopist's inexperience (500 oesophagogastroduodenoscopy cases). The cumulative incidence of metachronous cancers increased linearly and the mean annual incidence rate was 3.5%. The incidence rate did not differ between patients with or without Helicobacter pylori eradication. Four lesions (0.32%) were detected as massively invading cancers during the follow-up.Nineteen per cent of synchronous cancers were not detected until the initial ESD. The incidence rate of metachronous cancer after ESD was constant. Scheduled endoscopic surveillance showed that almost all recurrent lesions were treatable by endoscopic resection.

Background: Endoscopic submucosal dissection (ESD) was developed for en bloc removal of large and flat gastrointestinal tract neoplasms.In Japan,ESD is performed under conscious sedation.The risks for sedation-related complications of ESD, such as postoperative pneumonia, have not been evaluated. The aim of this study was to evaluate the incidence of postoperative pneumonia after ESD in a multicenter survey. Patients and Methods: A total of 1188 patients with upper gastric neoplasms treated with ESD in nine hospitals were enrolled from May 2003 to September 2008. The en bloc resection rates and complications (bleeding, perforation, and postoperative pneumonia) were assessed. The correlations between the clinical variables and complications were investigated using logistic regression models. Results: The en bloc resection rate was 95.3%.Bleeding,perforation,and pneumonia occurred in 37 (3.1%),49 (4.1%),and 19 (1.6%) patients, respectively. Univariate analysis indicated that procedure time, but not specimen size, or patient age, or sex,was significantly related to bleeding and perforation.The incidence of pneumonia was higher in patients with ulceration, older patients (75 years), and those with a long procedure duration (5 h). Conclusion: The incidence of pneumonia,but not perforation and bleeding,after ESD,is high in older patients (75 years). Special care should be taken with older patients undergoing ESD to minimize the risk of postoperative pneumonia.

Treatment with endoscopic submucosal dissection (ESD) for gastric noninvasive neoplasia (NIN) diagnosed by endoscopic forceps biopsy specimen, whether as a follow-up or "total incisional biopsy", is controversial. To validate the use of ESD for total incisional biopsy in NIN, we examined the underdiagnosis rate of NIN and the rates of complication associated with ESD.This is a cross-sectional multicenter retrospective study from 10 hospitals. Subjects diagnosed with NIN (equivalent to category 3 or 4.1 of the Vienna classification) by endoscopic forceps biopsy and treated with ESD were included. From March 2003 to December 2009, a total of 468 subjects were included and analyzed. The underdiagnosis rate was defined as the proportion of lesions diagnosed with adenocarcinoma after ESD. We assessed the complete en-bloc resection rate and the complication rate of ESD.Among the 468 subjects with NIN, 205 were diagnosed with adenocarcinoma after ESD, with an underdiagnosis rate of 44% (95% confidence interval: 39-49%). Two submucosal cancer lesions had invaded beyond 500 μm and one had lymphatic involvement. The complete en-bloc resection rate was 97%. The incidences of post-ESD bleeding, perforation, and serious complications were 5.5, 4.7, and 0.43%, respectively. There were no procedure-related deaths.In this large-scale, multicenter cross-sectional study, over 40% of the noninvasive gastric neoplasia specimens were determined to have adenocarcinoma, and the ESD-related complication rate was relatively low. Therefore, ESD was useful and may be a therapeutic option for gastric NIN.

Double-balloon endoscopy (DBE) examinations are not yet widely accepted as routine procedures for examining the small bowel of patients with Crohn's disease (CD).To evaluate the feasibility and usefulness of DBE for CD in tertiary-care hospitals.Between July 2004 and September 2008, 1444 DBE procedures were performed for 704 patients in 6 tertiary-care hospitals. Patient profile, indication, diagnosis and treatment of DBE were evaluated using a multicenter database.DBE examinations were most frequently performed in 75 patients with CD, corresponding to 10.5% of all the patients examined by DBE. Fifty patients were diagnosed with CD before DBE, while DBE was performed for the diagnosis of 25 new CD patients. Small bowel lesions were often detected even when the terminal ileum was not involved. In the 75 patients, 21 patients were asymptomatic at the time of DBE examinations. Active inflammatory lesions were detected in 51.2% of the CD patients, and were even detected in 33.3% of the asymptomatic CD patients. The treatment was altered in 53.3% of the CD patients after the DBE evaluation. No severe complications were experienced.DBE procedures can be safely performed in patients with CD and should be considered for the precise evaluation of and to determine the treatment strategy for CD.

The safety and efficacy of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms (SENs) have not been evaluated in a multicenter survey. The aim of this study was to investigate the clinical outcomes in a multicenter study that included municipal hospitals.Of 312 consecutive patients with 373 esophageal lesions treated by ESD at 11 hospitals from May 2005 to December 2012, a total of 368 SENs in 307 patients were retrospectively analyzed.The median tumor size was 18 mm (range 2 - 85 mm). The median procedure time was 90 minutes (range 12 - 450 minutes). The en bloc resection and complete resection rates were 96.7 % (95 % confidence interval [CI] 94.4 % - 98.1 %) and 84.5 % (95 %CI 80.5 % - 87.8 %), respectively. Perforation (including mediastinal emphysema), postoperative pneumonia, bleeding, and esophageal stricture, occurred in 5.2 % (95 %CI 3.3 % - 7.9 %), 1.6 % (95 %CI 0.7 % - 3.5 %), 0 %, and 7.1 % (95 %CI 4.9 % - 10.2 %) of patients, respectively. All of these complications were cured conservatively. No procedure-related mortality occurred. Early treatment periods (odds ratio [OR] = 4.04; P 0.01) and low volume institutions (OR = 3.03; P = 0.045) were significantly independent risk factors for perforation. The circumference of the lesion was significantly associated with postoperative stricture (OR = 32.3; P 0.01). The procedure times significantly decreased in the later period of the study (P 0.01). Follow-up data (median 35 months; range 4 - 98 months) showed significant differences in overall survival (P = 0.03) and recurrence-free survival (P 0.01) rates between patients with curative and noncurative resections.Esophageal ESD has become feasible with acceptable complication risks and favorable long term outcomes.

Bone marrow contains hematopoietic stem cells, nonhematopoietic mesenchymal stem cells, and several precursor cells for osteoblasts, chondrocytes, adipocytes, myocytes, hepatocytes, and even neural cells. Research findings indicate that multipotent stem cells in the adult body may be used to recover the lost functions of damaged tissues. This study examined the involvement of bone marrow-derived cells in the regeneration of the stomach after experimental gastric ulcers were produced in rats. We transplanted the bone marrow of transgenic rats that expressed green fluorescence protein (GFP) throughout the body. Twenty-one days after the bone marrow transplantation (BMT), gastric ulceration was induced, using absolute ethanol. Control animals received saline. After various observation periods, rats harboring GFP-positive bone marrow-derived cells were killed, and the tissues were removed and processed to prepare paraffin-embedded sections. Cells expressing GFP were identified by conventional immunohistochemistry, using anti-GFP antibody. To identify whether cells expressing GFP were epithelial cells or interstitial cells such as fibroblasts, serial sections were examined with anti-cytokeratin antibody or anti-vimentin antibody, respectively. Furthermore, to confirm that cells expressing GFP were epithelial cells or interstitial cells, we used double-staining analysis with anti-GFP antibody or anti-cytokeratin antibody, respectively. GFP-positive, bone marrow-derived cells were found in the cytokeratin-positive gastrointestinal epithelium, as well as among vimentin-positive interstitial cells. Interestingly, the proportions of GFP-positive, cytokeratin-positive epithelial cells and vimentin-positive interstitial cells were significantly greater in the ethanol-treated damaged stomachs than in the saline-treated controls. The present study clearly demonstrates that bone marrow-derived cells are involved in the regeneration of the stomach after ethanol-induced ulcers in rats.

Bone marrow is reported to contain hematopoietic stem cells and other adult somatic stem cells that have phenotypes of cells composing tissues other than bone marrow. To explore the implication of bone marrow-derived cells in the treatment of inflammatory bowel diseases, experimental colitis was induced in wild-type rats after transplantation of bone marrow from transgenic rats expressing green fluorescence protein (GFP). Chronic colitis was induced 21 days later using 30 mg 2,4,6-trinitrobenzenesulfonic acid (TNBS). Control rats received saline. At 28, 56, and 224 days after TNBS administration, rats were euthanized, and tissues were removed and processed for paraffin-embedded sections. Cells derived from bone marrow were identified by immunohistochemistry using anti-GFP antibody. To identify the phenotypes of the cells expressing GFP, we conducted serial-section analysis and double-staining analysis using antibodies against cytokeratin (epithelial cells) or vimentin (interstitial cells). In the present study, GFP-positive, bone marrow-derived cells occupied 37.6% and 4.25% of the colonic epithelium at 28 days and 56 days after the induction of TNBS-colitis, respectively. Also, significant amounts of mucosal and submucosal interstitial cells were derived from the bone marrow. These findings showed that a large amount of bone marrow-derived cells were involved in regeneration of the colon after experimental colitis in rats.

It is necessary to elucidate the noise generating mechanism for reducing engine noise. In a running engine, various impacts in the engine cause excitation sources for structural vibrations and engine noises. Engine noises are classified into the combustion noise, the combustion induced mechanical noise, and the mechanical noise depending on their excitation source. However, it is difficult to measure such noises separately because some impacts generate closely together in time and space. In order to separate the combustion noise from the total engine noise, a transient noise generation model that considers the vibration transmission and the damping effect of the engine structure was proposed. The newly proposed model was verified by conducting the single explosion excitation experiment of a stationary engine. In addition, it was clarified that the time histories of the combustion noise of both gasoline and diesel engines could be estimated at firing condition.

Gastrin, PGs, and growth factors have important roles in maintaining gastrointestinal mucosal integrity. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in PG synthesis. This study aimed to clarify the mechanisms of gastric mucosal protection by gastrin. Fasted rats were administered subcutaneous gastrin 17 with or without gastrin receptor antagonist YM022 pretreatment. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and COX-2 expression were examined using Western blot analysis. Another series of experiments investigated 1) PGE2 levels in gastric mucosa, 2) the protective action of gastrin against gastric damage by acidified ethanol, 3) the effects of a specific HB-EGF-neutralizing antibody on gastrin-induced COX-2 expression, and 4) the effects of a specific COX-2 inhibitor NS-398 on PGE2 synthesis and the mucosal protection afforded by gastrin. Gastrin dose-dependently increased HB-EGF, COX-2 expression, and PGE2 levels and reduced gastric damage. However, pretreatment with YM022 dose-dependently abolished such effects of gastrin. A specific HB-EGF- neutralizing antibody and an EGF receptor inhibitor decreased gastrin-induced COX-2 expression. NS-398 blocked gastrin-induced PGE2 synthesis and mucosal protection. In conclusion, this study demonstrates that gastrin enhances gastric mucosal integrity through COX-2, which is partially mediated by HB-EGF, and PGE2 upregulation in rats.

Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis–related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src – or v-H-ras –expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates. GASTROENTEROLOGY 2002;122:331-339

Background and study aims: The number of patients with chronic kidney disease (CKD) is increasing worldwide and gastric cancer sometimes occurs with CKD. However, the safety and feasibility of endoscopic submucosal dissection (ESD) for patients with CKD are not clear. The aim of this study is to clarify the feasibility and safety of gastric ESD for patients with CKD. Patients and methods: This was a multicenter retrospective cohort study. In total, 144 patients with CKD who underwent gastric ESD between May 2003 and October 2012 were enrolled. The patients were divided into three groups: stage 3 (estimated glomerular filtration rate [eGFR]: 30 – 59 mL/min), stage 4 (eGFR: 15 – 29 mL/min), and stage 5 (eGFR

The therapeutic strategy for biliary obstruction in patients with unresectable pancreatic cancer is controversial. We compared complications and prognosis between 2 groups: the B group, 8 patients who were diagnosed as having inoperable pancreatic cancer at laparotomy and underwent bypass surgery, and the S group, 7 patients who underwent endoscopic stent placement for biliary obstruction due to clinically unresectable pancreatic cancer. Although 1 patient developed cholangitis and surgical site infection in the B group, there was no difference in the duration of hospital stay between the 2 groups. In terms of long-term complications, re-drainage was performed in 1 patient because of stent deviation and gastrointestinal bypass surgery was performed in 2 patients because of duodenum stenosis in the S group. There was no difference in postoperative survival between the 2 groups. Stent placement is less invasive and is recommended for the treatment of biliary obstruction in patients with clinically unresectable pancreatic cancer. However, bypass surgery is acceptable for the treatment of patients diagnosed as having inoperable pancreatic cancer at laparotomy.

Approximately half of all patients with chronic hepatitis C show an initial biochemical response to interferon, but only 15% to 20% of patients achieve a sustained response. We studied the efficacy of retreatment with interferon for patients with chronic hepatitis C who showed transient biochemical responses to initial treatment. Thirty patients who relapsed were retreated 1 to 52 months (median 14) after the end of initial treatment, according to the previously used regimens. The responses were correlated with the pre-retreatment patient data. The liver histologic grades, compared with those found before the initial treatment, were better in eight (27%) patients but worse in six (20%), whereas the fibrosis stage was improved in five (17%) but worsened in eight (27%). All patients displayed end-of-retreatment biochemical responses. Of the 30 patients, 10 (33%) achieved sustained aminotransferase normalization and serum hepatitis C virus (HCV) RNA clearance, but the remaining 20 patients showed relapse within 1 year after cessation of retreatment. Univariate analysis associated the sustained response with low pre-retreatment viral loads (0.8 +/- 0.7 MEq/mL vs. 9.1 +/- 6.5 MEq/mL; p = 0.006), short treatment intervals (13 +/- 13 months vs. 22 +/- 14 months; p = 0.031), and low histologic grades (1.3 +/- 0.7 vs. 1.9 +/- 0.7; p = 0.039). However, multivariate analysis indicated that only the pre-retreatment viral load was predictive of the sustained response (p = 0.049). These findings suggest that transient responders to interferon are likely to respond to retreatment but the achievement of a sustained response depends on the HCV viral load before retreatment.

Background: Gastric antral vascular ectasia (GAVE), as a cause of upper gastrointestinal bleeding, has been treated surgically, endoscopically and pharmacologically for the past 20 years. Methods: We analyzed the clinical effect of endoscopic treatment for 12 cases of GAVE diagnosed at Osaka National Hospital between January 1993 and October 1998. Results: Eight of the 12 cases were treated endoscopically due to marked anemia and histories of gastrointestinal bleeding. All had chronic liver disease (CLD). Mean age was 69 years on diagnosis. Male to female ratio was 1 : 1. Gastric antral vascular ectasia was a cause of 3.9% of bleeding associated with CLD. The modes of endoscopic treatment of the eight cases were laser photocoagulation (1), electrocautery (3), and heater probe thermocoagulation (4). The initial treatment required an average of 5.1 sessions over a period of 43 days. Initial hemostasis was successful in all cases. Treatments for recurrent bleeding were necessary in six cases within 9.2 months, and endoscopic coagulation was again effective in two cases. Corticosteroids were effective in two of three cases resistant to endoscopic therapy. Mean follow-up period after initial treatment was 2.8 years. The mean total number of therapeutic endoscopy sessions was 9.6. Conclusion: Endoscopic treatments and/or corticosteroids have yielded sufficient results in the hemorrhage of GAVE. Factors affecting the recurrence of GAVE need to be analyzed in CLD patients.

Objectives. Heparin replacement (HR) is often performed in patients with a high risk of thrombosis undergoing endoscopic procedures. However, information about the influence of HR is scarce. The aim of this study is to assess the clinical impact of HR for gastric endoscopic submucosal dissection (ESD).Methods. This is a retrospective study comprising approximately 1310 consecutive gastric neoplasms in 1250 patients, who underwent ESD in 5 institutes. We assessed the clinical findings and outcomes of ESD under HR, compared to ESD without HR as control.Results. A total of 24 EGC lesions in 24 patients were treated by ESD under HR. In the HR group, the complete en-bloc resection rate was 100%. The delayed bleeding rate was, however, higher in the HR group than in the controls (38% versus 4.6%). The timing of bleeding in the HR group was significantly later than in controls. In the control group, 209 patients discontinued antithrombotic therapy during perioperative period, and their delayed bleeding rate was not different from those without antithrombotic therapy (5.7% versus. 4.4%). A thromboembolic event was encountered in 1 patient under HR after delayed bleeding.Conclusion. ESD under HR is technically feasible but has a high risk of delayed bleeding.

Poly(α-methylstyrene) (PMS) with a variety of chain lengths was investigated by both fluorescence measurements and 13 C nuclear magnetic relaxation measurements. The molecular weight dependence of excimer formation efficiency agress well with that of the spin-lattice relaxation time, indicating that it is due to the molecular weight dependence of local motion.

Endoscopic submucosal dissection (ESD) was developed for en bloc removal of large and flat gastrointestinal tract neoplasms. In Japan, ESD is performed under conscious sedation. The risks for sedation-related complications of ESD, such as postoperative pneumonia, have not been evaluated. The aim of this study was to evaluate the incidence of postoperative pneumonia after ESD in a multicenter survey.A total of 1188 patients with upper gastric neoplasms treated with ESD in nine hospitals were enrolled from May 2003 to September 2008. The en bloc resection rates and complications (bleeding, perforation, and postoperative pneumonia) were assessed. The correlations between the clinical variables and complications were investigated using logistic regression models.The en bloc resection rate was 95.3%. Bleeding, perforation, and pneumonia occurred in 37 (3.1%), 49 (4.1%), and 19 (1.6%) patients, respectively. Univariate analysis indicated that procedure time, but not specimen size, or patient age, or sex, was significantly related to bleeding and perforation. The incidence of pneumonia was higher in patients with ulceration, older patients (≥75years), and those with a long procedure duration (≥5h).The incidence of pneumonia, but not perforation and bleeding, after ESD, is high in older patients (≥75years). Special care should be taken with older patients undergoing ESD to minimize the risk of postoperative pneumonia.

A63-year-old man was referred to our Gastroenterology Department for insertion of a gastrostomy catheter, owing to repeated aspiration pneumonia after chemoradiation therapy for hypopharyngeal cancer 3 months earlier. His nutritional status was normal. He had been taking prednisolone for interstitial pneumonia beginning 10 days before and also after gastrostomy placement. The course of the pneumoniawas stable. Before performing the gastrostomy, we confirmed the safety of placement by computed tomography and esophagogastroduodenoscopy. A percutaneous endoscopic gastrostomy (PEG) was placed at the anterior wall of the middle body of the stomach without complications using an endoscopyassisted method. We administered ampicillin-sulbactam (3 g/d) for 2 days to avoid bacterial infection. The day after PEG placement, we began to infuse a liquid food formula through the PEG. At first, the infusion proceeded without any problems. A few days later, however, infusion became more difficult, and 7 days later even clear liquids could not be infused. The patient had no abdominal pain or fever. We found no causal abnormalities through computed tomography and radiographic examination. On day 14, we performed an esophagogastroduodenoscopy that showed a hard yellowish mass with a red granular surface inside the bottom part of the gastrostomy tube (Figure A). We completely removed it with a grasp forceps (Figure B). After removal, infusion through the PEG proceeded normally. Pathologic findings included only packed Candida spores and hyphae with no other entities, suggesting that the entire mass was a fungus ball (Figure C). After removing the ball, there was no recurrence of complications. Infection around the gastrostomy and PEG clogging are known complications after gastrostomy placement. Infection occurs in 18% of patients without preprocedural antibiotics. An appropriate antibiotic regimen can prevent this complication. In our case, there were no clinical findings of bacterial infection. Clogging of the tube occurs in 45% of patients owing to thick enteral feedings and medications without water flush. We did not infuse these agents and found no reports showing clogging of the tube in such a short time as in this case. Based on the clinical and pathologic findings, we considered that the PEG tube was clogged by the fungus ball alone, without preceding clogging by food or agents. Gottlieb et al reported that oral Candida could colonize in gastrostomy tubes. They also reported that colonization of fungi in a gastrostomy tube could occur in as little as 1 week after placement. Fungus balls are reported to form a solid mass in vivo. The mechanism of the present case is uncertain, but it is conceivable that the immunosuppressive state promoted the fungus colonization and the growth, and resulted in complete PEG clogging.

The patient, a 79-year-old woman, underwent distal gastrectomy for gastric cancer in November 2002. The lesion was judged to be T1 N0H0POM0 and fStage IA. A hepatohilar tumor was found 1 year after gastrectomy by CT scan. Radiological examinations revealed a presence of right portal vein stenosis and left portal vein obstruction due to hepatohilar bile duct cancer. Surgical treatment was considered to be difficult because of the consequence of the tumor involved in the right hepatic artery. We performed hepatic arterial infusion chemotherapy of 5-fluorouracil 1000 mg/body/week for 8 courses through the reservoir catheter. Radiation therapy was delivered concurrently with hepatic arterial infusion. The condition of the patient was good after receiving 40 Gy, Three months after the additional 20 Gy radiation, the tumor was markedly reduced in size, and was not detected 7 months thereafter. MRI showed no recurrence for three and a half years since chemo-radiation.

The cost of operation and management are growing rapidly in proportion to the increase of the number of network terminals connected to the network. We hope to improve the quality of network service, but it is difficult because of reasons such as manpower and budget limitations. The number of staff members in our information processing center decreased when the organization was restructured in October 2003. To address this situation, we implemented a new network terminal registration system with a web interface. On our campus, users have to register the MAC address to get the DHCP IP address for their personal computers. Prior to the new terminal registration system, it took several days to register them. However, the network terminal registration procedure is now fully automated for DHCP where users can connect their personal computers to the network in a few minutes. The network terminal registration for a fixed IP address is almost automated and reduced in the operation time. As a result, we decreased the staff member's workload and improved the throughput time to register a new network terminal. The system also contains detailed information including the update status of anti-virus software of each computer in a network terminal database. This approach improves the security of our network system. In this paper, we describe the system structure, facility, user interface, and some experience with the system.

Bone marrow is reported to contain hematopoietic stem cells and other adult somatic stem cells that have phenotypes of cells composing tissues other than bone marrow. To explore the implication of bone marrow-derived cells in the treatment of inflammatory bowel diseases, experimental colitis was induced in wild-type rats after transplantation of bone marrow from transgenic rats expressing green fluorescence protein (GFP). Chronic colitis was induced 21 days later using 30 mg 2,4,6-trinitrobenzenesulfonic acid (TNBS). Control rats received saline. At 28, 56, and 224 days after TNBS administration, rats were euthanized, and tissues were removed and processed for paraffin-embedded sections. Cells derived from bone marrow were identified by immunohistochemistry using anti-GFP antibody. To identify the phenotypes of the cells expressing GFP, we conducted serial-section analysis and double-staining analysis using antibodies against cytokeratin (epithelial cells) or vimentin (interstitial cells). In the present study, GFP-positive, bone marrow-derived cells occupied 37.6% and 4.25% of the colonic epithelium at 28 days and 56 days after the induction of TNBS-colitis, respectively. Also, significant amounts of mucosal and submucosal interstitial cells were derived from the bone marrow. These findings showed that a large amount of bone marrow-derived cells were involved in regeneration of the colon after experimental colitis in rats.

Prostaglandin (PG) E(2), a cyclooxygenase (COX) product, and angiotensin II are endogenous and have physiological roles in the body. On the other hand, an inducible isoform of COX (COX-2), insulin-like growth factor (IGF) II, and IGF-I receptor (IGF-IR) are up-regulated in colon carcinoma and might have crucial roles in tumor growth and invasion. The aim of the present study was to investigate the effects of COX-2 inhibitor and drugs blocking the biological activities of angiotensin II [angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)] on IGF-IR expression and tumor growth in vivo. We also investigated the effects of PGE(2), a major COX-2 product, in cancer cells and the effects of angiotensin II on IGF-IR expression and the underlying mechanism of action. In in vivo studies, tumor growth and IGF-IR expression were investigated in Colon 26 cells inoculated into BALB/c mice. In in vitro studies, the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on IGF-IR expression were analyzed in three colon cancer cell lines (Colon 26, HCA-7, and LS174T). IGF-II-induced cell growth and invasion were analyzed in Colon 26 cells in the presence and absence of NSAIDs (indomethacin and celecoxib) and angiotensin II. Celecoxib at the lowest effective dose for suppression of PG production (3 mg/kg) or an ACE inhibitor/ARB alone did not have a significant effect as compared with controls, although a high dose of celecoxib (20 mg/kg) suppressed tumor growth. On the other hand, combination therapy with these two categories of drugs significantly reduced tumor growth in vivo. Treatment with both celecoxib and an ACE inhibitor/ARB decreased IGF-IR expression levels in inoculated tumor cells. In in vitro studies, NSAIDs reduced IGF-IR expression in a dose-dependent manner in all three cell lines. NSAIDs also inhibited IGF-II-stimulated growth and invasion in a dose-dependent manner. PGE(2) or angiotensin II treatment reversed the NSAID-induced down-regulation of IGF-IR expression, growth, and invasion. PGE(2) and angiotensin II induced Akt phosphorylation, and LY294002 or wortmannin inhibited PGE(2)- or angiotensin II-induced IGF-IR expression, indicating that PGE(2) and angiotensin II both regulate IGF-IR expression by the same Akt/phosphatidylinositol-3 pathway. Thus, combination therapy with NSAIDs and ACE inhibitors targeting IGF-IR might be a novel and potentially promising strategy for the chemoprevention of colon cancer.

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

Cyclooxygenase-2 (COX-2) was recently reported (M. Tsujii and R. N. DuBois, Cell, 83: 493-501, 1995) to affect the metastatic potential of cells. Previous studies (M. Fukuda, Cancer Res., 56: 2237-2244, 1996) indicated that sialyl Lewis antigen expression is correlated with hematogenous metastasis of colon cancer. In the present study, we investigated the interaction between COX-2 activity, expression of sialyl Lewis antigens, in vitro cancer cell adhesion to endothelial cells, and in vivo metastatic potential. Effects of COX-2 activity and prostaglandin E(2) on cell adhesion, expression of sialyl Lewis antigens, and glycosyltransferase genes were determined in Caco-2-m (COX-2 low level), Caco-2-COX-2 (programmed to overexpress COX-2), and HT-29 (COX-2 high level) cells. Metastatic spread of these cells to the liver was also investigated. Caco-2-COX-2 cells had increased SPan-1 levels and increased adherence to endothelial cells via SPan-1 compared with Caco-2-m cells. HT-29 cells expressed sialyl Lewis a and adhered to endothelial cells via sialyl Lewis a. Treatment with a COX-2 inhibitor, celecoxib, decreased SPan-1 and sialyl Lewis a expression and adherence to endothelial cells. beta 3Gal-T5 and ST3Gal III and IV expression was inhibited by celecoxib and was enhanced by prostaglandin E(2) treatment. Caco-2-COX-2 and HT-29 cells metastasized to the liver, whereas Caco-2-m cells did not. Pretreatment with celecoxib reduced the metastatic potential as well as anti-sialyl Lewis antibodies. Our results indicate a direct link between COX-2 and enhanced adhesion of carcinoma cells to endothelial cells, and enhanced liver metastatic potential via accelerated production of sialyl Lewis antigens. COX-2 inhibitors may suppress metastasis.