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A 70-year-old man was admitted to our hospital for the treatment of a large granular-type laterally spreading tumor in the splenic flexure of the descending colon. The preoperative diagnosis was intramucosal colon carcinoma and endoscopic submucosal dissection was performed. During treatment, a small perforation occurred accidentally. After conservative treatment with endoscopic suturing, the patient was discharged without additional surgery. The pathological diagnosis was an intramucosal carcinoma. One year after treatment, no local recurrence was observed on endoscopy, and abdominal computed tomography showed no obvious metastasis. Two years later, fluorodeoxyglucose-positron emission tomography/computed tomography, laparoscopic findings, and histopathologic findings by experimental excision of omentum revealed several disseminated peritoneal metastases from previously treated colon carcinoma. To the best of our knowledge, this is the first report of peritoneal dissemination after a small perforation during endoscopic submucosal dissection and conservative therapy for early-stage colon carcinoma. This report suggests the possibility of tumor dissemination in patients with small perforations during endoscopic procedures. Endoscopists should be aware of these rare potential risks and perform later surveillance carefully., (© 2024. Japanese Society of Gastroenterology.)

Background: The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents., Methods: This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis., Results: Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140)., Conclusions: SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

An advanced small bowel mucinous adenocarcinoma with Peutz-Jeghers syndrome was resected, and we started capecitabine plus oxaliplatin (CapeOX) as adjuvant therapy. However, local recurrence was noted, and the tumor increased even after CapeOX plus bevacizumab and fluorouracil plus leucovorin plus irinotecan plus panitumumab (FOLFIRI plus panitumumab). Pembrolizumab was administered after confirming high-frequency microsatellite instability, and the tumor shrank markedly and remained shrunk for 20 months.

Background: Vonoprazan (VPZ) has the potential to prevent delayed bleeding and promote ulcer healing after endoscopic submucosal dissection (ESD) similar to proton pump inhibitors (PPIs)., Objective: We aimed to evaluate the outcomes of VPZ-treated patients after ESD and compared the efficacy and feasibility in preventing a delayed bleeding and in healing an artificial ulcer after ESD between the VPZ and PPI therapies., Methods: This was a prospective, observation study in 11 Japanese medical institutions. We enrolled and evaluated 223 patients who underwent gastric ESD followed by VPZ treatment (VPZ group). We selected 385 patients who underwent gastric ESD followed by PPI treatment as historical controls (PPI group) to compare the outcomes between the VPZ and PPI groups using a propensity score matching analysis., Results: Among the 223 patients treated with VPZ, 173 were men and 50 were women with a median age of 72 years and with a median tumor size of 12.0 mm. Rates of en bloc resection and complete resection were 99.1 and 94.2%, respectively. Lymphovascular invasion was found in 6 (6.3%) cases. Intraoperative perforation and delayed bleeding occurred in 3 (1.3%) and 10 patients (4.5%), respectively. Scarring of artificial post-ESD ulcer was found in 153 patients (68.6%) at 6 weeks after ESD. The 205 pairs of propensity score-matched patients were comparable between the VPZ and PPI groups. The rate of delayed bleeding in the VPZ and PPI groups was 3.9 and 4.4%, respectively (difference, 0.5 percentage points; 95% confidence interval, -3.7 to 2.8%; non-inferiority, p = 0.01). Therefore, VPZ therapy demonstrated non-inferiority against PPI therapy in reducing the rate of delayed bleeding. The scar-stage ulcer at 6 weeks in the VPZ group and 8 weeks in the PPI group was 68.3 and 74.6%, respectively (p = 0.19)., Conclusions: VPZ therapy showed an efficacy and feasibility in preventing a delayed bleeding after ESD similar to the PPI therapy. VPZ for 6 weeks and PPI for 8 weeks were similarly effective for an artificial ulcer healing after ESD., (© 2020 S. Karger AG, Basel.)

A 53-year-old man who had been diagnosed with moderate ulcerative colitis and treated with mesalazine and glucocorticoid steroid was admitted due to fever of unknown origin and diarrhea. Intravenous feeding and treatment with cephem antibiotics were started, but the febrile reaction did not improve at all. Physical examination and various tests showed no specific symptoms, including headache or meningeal irritation. However, the blood culture test showed a positive result of Gram-positive bacilli. Thus, a lumbar puncture was performed and the patient was finally diagnosed with Listeria monocytogenes bacteremia and meningitis. Administration of intravenous meropenem and ampicillin led to the improvement of symptoms without any neurological sequelae. In addition, several cases with opportunistic infection of L. monocytogenes have been reported in recent years in cases of inflammatory bowel disease (IBD) during immunosuppressive therapy. Consequently, L. monocytogenes infection should be considered as one of differential diagnosis when patients present with IBD patient and are treated by biological or immunosuppressive agents with a fever of unknown origin.

A 59-year-old man was treated for early gastric cancer with endoscopic submucosal dissection (ESD) 10 years prior to the study. Two months after the first ESD, he was diagnosed with recurrence on the ESD scar and treated via ESD again. The horizontal margin could not be evaluated because of cauterization, and the patient was carefully observed. He was admitted to our hospital complaining of low backache and diagnosed with disseminated carcinomatosis of the bone marrow associated with gastric cancer after examination. Although he started chemotherapy, he died after 6 months. In this study, we report a rare case of disseminated carcinomatosis of the bone marrow associated with gastric cancer, which developed 10 years after ESD.

We report a case of idiopathic hypereosinophilic syndrome (IHES) characterized by multiple liver mass lesions in an 82-year-old man. Numerous hypoechoic lesions were observed on ultrasonography and were mainly distributed in the S4, S6, and S7 segments. Plain computed tomography (CT) scans revealed low-density lesions. Dynamic CT images revealed arterial and portal vein branches passing through these lesions, with marginal areas enhanced during the arterial phase. The enhanced areas were extended during the portal venous phase. Contrast-enhanced ultrasonography (CEUS) images revealed enhanced vasculature in the early vascular phase. CEUS images obtained in the late vascular phase revealed enhanced areas containing microbubbles extended into the parenchyma; a prolonged enhancement pattern was observed. Kupffer-phase images revealed large portions of the lesion filled with microbubbles and a star-like defect at the center of the nodule. F18-2-fluoro-2-deoxyglucose (FDG) positron emission tomography/CT scans revealed intense FDG uptake by these lesions, which was similar to that by the segments S4, S6, and S7. Liver biopsy revealed diffused eosinophils infiltrated. The patient was closely followed up and was completely cured 11 weeks later without any treatment. This is a rare case of IHES with multiple liver mass lesions, which was well researched using multi-imaging equipment and cured without any treatment.

Background: Nonalcoholic fatty liver disease is characterized by excessive hepatic fat accumulation. Some individuals frequently present elevated gamma-glutamyl transferase (GGT) levels without fatty liver ultrasound images and other abnormal liver enzymes levels. However, whether these individuals are at an elevated risk for developing fatty liver is unclear. We compared fatty liver change rates and risk factors between individuals with frequently elevated GGT levels and those with normal levels., Methods: We designed a retrospective cohort study on the basis of complete medical checkup records. One group of individuals had presented normal serum GGT levels during the observation period (Normal-GGT group, n = 2713). Another group had had abnormal elevated serum GGT levels frequently (Abnormal-GGT group, n = 264). We determined the fatty liver change incident rates before and after propensity score matching. We explored confounding factors affecting fatty changes in each group using univariate and multivariate Cox models., Results: The change incidence rates were 5.80/1000 and 10.02/1000 person-years in the Normal-GGT and Abnormal-GGT groups, respectively. After propensity score matching, the incidence rates were 3.08/1000 and 10.18/1000 person-years in the Normal-GGT and Abnormal-GGT groups, respectively (p = 0.026). The factors associated with fatty liver changes in the Normal-GGT group included body mass index (BMI), hemoglobin, alanine aminotransferase (ALT), albumin, triglyceride (TG), fasting blood sugar, and high-density lipoprotein levels. Those in the Abnormal-GGT group were platelet counts and TG. In our multivariable analysis, BMI, ALT, albumin, and TG levels were independent predictors of fatty changes in the Normal-GGT group, and high TG level was the only independent predictor in the Abnormal-GGT group., Conclusions: The incidence rate of fatty liver change in the Abnormal-GGT group was higher than that in the Normal-GGT group. Consecutive elevated GGT levels increase the risk for fatty liver, and high TG levels in those individuals further independently increase the risk.

Background: Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1(PD-1), was approved for use in the treatment of patients with advanced gastric or gastroesophageal junction cancer who had been previously treated with B2 chemotherapy regimens in Japan., Methods: We investigated the efficacy of nivolumab therapy in 15 consecutive patients with advanced gastric cancer between October 2017 and December 2018 in our facility., Results: In our study, the 6-month overall survival rate was 67.7%, and the median survival time(MST)was 6.3 months. Immune-related adverse events(irAEs)occurred in the following patients: 2 patients, interstitial pneumonia(13%); 1 patient, myocarditis (6.7%); 1 patient, hypothyroidism(6.7%); and 1 patient, liver dysfunction(6.7%). Of the patients with an absolute lym- phocyte count(ALC)of C2,000/mL at baseline, 33%(4/12)experienced irAEs, while of those with an ALC of >2,000/mL, 67% had irAEs. The 6-month overall survival rate was better in patients with an ALC >1,600/mL(100%, 4/4)than in those with an ALC of C1,600/mL(35%, 4/11). The 6-month overall survival rate of the patients with a neutrophil-to-lymphocyte ratio(NLR)of <4 was 63%, which was better than the 33% rate in those with an NLR of B4., Conclusions: Nivolumab therapy was a safe and feasible treatment option. The cutoff values of ALC of 2,000/mL for irAEs and of ALC of 1,600/mL and NLR of 4 for prognosis might be effective surrogate markers in nivolumab treatment.

Laparoscopy and endoscopy cooperative surgery(LECS)is an excellent surgical procedure that prevents excessive resection of the gastrointestinal wall and maintains gastrointestinal functions. However, LECS is not recommended for large gastrointestinal stromal tumor(GIST)sized more than 5 cm and/or ulcerative GIST because of the oncological risk of peritoneal dissemination. Here, we report the case of an elderly patient who was successfully treated with LECS-assisted open partial gastrectomy for an ulcerative GIST near the esophagogastric junction.

Background and Aims: In the treatment of patients after endoscopic submucosal dissection (ESD), there is no consensus on the optimum time to start Helicobacter pylori eradication therapy or on whether eradication therapy improves ulcer healing rate after ESD. The aim of this study was to examine the effect of immediate eradication of H. pylori on ulcer healing after ESD in patients with early gastric neoplasms., Methods: A total of 330 patients who underwent ESD for early gastric neoplasms were enrolled. Patients were assigned to either H. pylori eradication group (Group A: H. pylori eradication + proton pump inhibitor 7 weeks) or non-eradication group (Group B: proton pump inhibitor 8 weeks). The primary end point was gastric ulcer healing rate (Group A vs Group B) determined on week 8 after ESD., Results: Patients in Group A failed to meet non-inferiority criteria for ulcer scarring rate after ESD compared with that in Group B (83.0% vs 86.5%, P for non-inferiority = 0.0599, 95% confidence interval: -11.7% to 4.7%). There were, however, neither large differences between the two groups in the ulcer scarring rate nor the safety profile., Conclusions: This study failed to demonstrate the non-inferiority of immediate H. pylori eradication therapy after ESD to the non-eradication therapy in the healing rate of ESD-caused ulcers. However, because the failure is likely to attribute to small number of patients enrolled, immediate eradication therapy may be a treatment option for patients after ESD without adverse effects on eradication therapy in comparison with the standard therapy., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background/aims: This study investigated the effect of Helicobacter pylori eradication therapy on latent digestive symptoms in chronic atrophic gastritis., Methods: We enrolled 650 health checkup patients who underwent eradication therapy for chronic gastritis and completed a self-report questionnaire before and after the treatment between January 2014 and December 2016 at the Japanese Red Cross Society Kyoto Daiichi Hospital., Results: H. pylori eradication therapy for chronic atrophic gastritis improved latent digestive symptoms, including both the acid reflux and dyspepsia components in the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) scores. The effect was sustained until 1 year after the treatment. Higher FSSG scores (≥8 points) before H. pylori eradication therapy and age <70 years were significantly associated with the improvement of digestive symptoms after H. pylori eradication therapy., Conclusion: H. pylori eradication therapy may improve patients' quality of life through the resolution of latent abdominal symptoms., (© 2018 S. Karger AG, Basel.)

Here, we report our experience with a case of severe biliary bleeding due to a hepatic arterial pseudoaneurysm that had developed 1 year after endoscopic biliary plastic stent insertion. The patient, a 78-year-old woman, presented with hematemesis and obstructive jaundice. Ruptured hepatic arterial pseudoaneurysm was diagnosed, which was suspected to have been caused by long-term placement of an endoscopic retrograde biliary drainage (ERBD) stent. This episode of biliary bleeding was successfully treated by transarterial embolization (TAE). Pseudoaneurysm leading to hemobilia is a rare but potentially fatal complication in patients with long-term placement of ERBD. TAE is a minimally invasive procedure that offers effective treatment for biliary bleeding., Competing Interests: Conflict-of-interest statement: All of the authors state that they have no conflicts of interests related to this article.

Aim: To investigate usefulness of triple therapy with vonoprazan, a potassium ion-competitive acid blocker and antibiotics, for Helicobacter pylori ( H. pylori ) eradication., Methods: The H. pylori eradication rate was examined in 2507 patients (2055 undergoing primary eradication and 452 undergoing secondary eradication, excluding patients with subtotal gastrectomy) at the Japanese Red Cross Kyoto Daiichi Hospital from March 2013 to September 2015. For patients treated from March 2013 to February 2015, a proton pump inhibitor (PPI) was used to reduce acid secretion, while vonoprazan was used after March 2015. The success rates of the 2 regimens (PPI + amoxicillin + clarithromycin/metronidazole, or vonoprazan + amoxicillin + clarithromycin/metronidazole) were compared., Results: The success rate of primary H. pylori eradication was significantly higher in the vonoprazan group. When stratified by the underlying disease, a significant increase of the H. pylori eradication rate was observed in patients with chronic gastritis. A significantly lower H. pylori eradication rate was observed in younger patients compared to older patients in the PPI group, but there was no difference according to age in the vonoprazan group. On the other hand, the success rate of secondary eradication was similar at approximately 90% in both groups., Conclusion: Vonoprazan is very useful for primary eradication of H. pylori , and may become a first-line acid secretion inhibitor instead of PPIs., Competing Interests: Conflict-of-interest statement: There is no conflict of interest.

A 66-year-old man was admitted to our hospital with high fever. We diagnosed a gas-containing liver abscess and performed percutaneous abscess drainage. However, 15 hours after admission, he developed massive intravascular hemolysis and acidosis. Sepsis due to Clostridium perfringens was suspected and we treated the patient intensively with multidisciplinary approaches, including antibiotics, mechanical ventilation, and renal replacement therapy. Furthermore, we administered freeze-dried gas gangrene antitoxin. Despite intensive care, the patient died 43 hours after admission.

Background: Endoscopic submucosal dissection (ESD) has become the standard endoscopic treatment for early gastric cancer without lymph node metastasis. At present, undifferentiated type intramucosal cancers without ulcer findings <20 mm in size are often chosen as endoscopic treatment lesions for expanded indication. The purpose of this study was to examine the outcome of ESD treatment in undifferentiated carcinomas., Method: Forty-six patients who had undergone ESD from July 2002 until July 2010, where the final pathological diagnosis was undifferentiated carcinoma, were assessed for the en-bloc resection ratio, the accuracy rate of depth or extent of diagnosis and survival., Results: In endoscopic ultrasonography studies, the accuracy rate of mucosal lesions was 86%. The rate of en-bloc resection was 91% (42/46) and 5 cases had a positive margin. Four cases had a positive margin in cases of piecemeal resection. Five cases underwent additional surgery, and residual cancer was found in 1 case. There were 2 cases of perforation, 2 of delayed hemorrhage, and no cases of delayed perforation. One case died of multiple liver metastases and 1 died of hepatocellular carcinoma. After a maximum of 8 years, an average of 3.8 years of observation, including 7 cases who had undergone additional surgery, recurrence occurred in only 1 case of liver metastasis., Conclusion: In this study the lesions of undifferentiated adenocarcinoma, which were limited to the mucosa, <20 mm in diameter and had been completely resected, showed no recurrence and were indicated for endoscopic treatment., (Copyright © 2012 S. Karger AG, Basel.)

The beneficial effects by peroxisome proliferator-activated receptor-γ (PPAR-γ) on gastric injury induced by ischemia-reperfusion have been confirmed, however, the precise mechanism of its cytoprotection is not elucidated thoroughly. The aim of the present study was to determine the gastric localization of PPAR-γ expression in the rat gastric mucosa, and to clarify the mechanism of its cytoprotective properties. The gastric expression of PPAR-γ was confirmed by RT-PCR and western blot, and localized on gastric epithelial cells. The protective effect of PPAR-γ ligands, pioglitazone or 15-deoxy-Δ(12,14)-prostaglandin J(2), on gastric ischemia-reperfusion injury was reversed by the co-administration with PPAR-γ antagonist. The gastric expression of tumor necrosis factor-α and cytokine-induced neutrophil chemoattractant-1 increased significantly in rats treated ischemia-reperfusion, and these increases were significantly inhibited by treatment with pioglitazone. Among the 1,032 probes, 18 probes were up-regulated at least 1.5-fold, 17 were down-regulated at least 1.5-fold by pioglitazone. The network including calnexin, endoplasmic reticulum stress protein, heat shock proteins, and proteasome genes was induced by pioglitazone treatment. In conclusion, activation of gastric epithelial PPAR-γ receptor by its ligands may represent a novel therapeutic approach for gastric inflammation via up-regulation of heat shock proteins and endoplasmic reticulum-related proteins.

Background: Proton pump inhibitors (PPIs) are effective in healing reflux esophagitis and relieving the symptoms of gastroesophageal reflux disease (GERD). Prevention of recurrence of symptoms has become a therapeutic aim in patients with these conditions., Aims: We investigated the effects of rebamipide, a mucosal protective anti-ulcer agent, on recurrence of reflux symptoms during PPI maintenance therapy., Methods: Patients with esophagitis of Los Angeles classification A or B were treated with PPIs for 8 weeks. Patients with relief of symptoms were enrolled for further study. Forty-one patients were randomized to maintenance therapy with 15 mg of lansoprazole daily or 15 mg of lansoprazole and 300 mg rebamipide daily, and recurrence of symptoms was monitored over 12 months. In some patients, concentration of rebamipide and interleukin(IL)-8 expression in the esophageal mucosa were estimated., Results: During the 12-month period, 11/20 patients (52.4%) taking lansoprazole 15 mg daily suffered recurrence of symptoms, compared to 4/20 patients (20%) treated with lansoprazole 15 mg and rebamipide 300 mg daily (P < 0.05). Rebamipide was detected in the esophageal mucosa 90-180 min after oral administration. IL-8 mRNA expression in the esophageal mucosa of patients with rebamipide was significantly decreased compared with that of patients without rebamipide., Conclusions: Combination therapy with rebamipide and lansoprazole appears to be highly effective in preventing recurrence of symptoms during long-term maintenance treatment for GERD.

Background and Aims: MicroRNA (miRNA) are endogenous, approximately 22-nucleotide non-coding RNA that suppress gene expression at post-transcriptional levels by binding to the 3'-untranslated region of specific mRNA targets through base-pairing. It has been recently reported that miRNA have critical functions in key biological processes such as cell proliferation and cell death in various cancer cells. However, the relationship between intestinal inflammation and miRNA expression remains unclear. In the present study, we used microarray technology to identify miRNA induced in the colonic mucosa of patients with active ulcerative colitis (UC)., Methods: Two colonic biopsy specimens from patients with active stage (>Matts grade 2) of UC under colonoscopy and two colonic biopsy specimens from healthy volunteers were obtained for gene expression profiles. Total RNA was extracted, and miRNA expression profiles were investigated using miRNA Microarray. Subsequently, to confirm the result of the Microarray investigation, we checked the expression of several selected miRNA using real-time polymerase chain reaction (PCR) in 12 colonic biopsy specimens from patients with active UC under colonoscopy and 12 specimens from the healthy volunteers., Results: In the microarray study, the expression of several miRNA was upregulated in the colonic mucosa of patients with active UC. Furthermore, two miRNA (miR-21, miR-155) were selected in the study using real-time PCR., Conclusion: Upregulated miRNA may be responsible for the development of intestinal inflammation in UC.

A 64-year-old man was admitted to our hospital with anal pain on evacuation. MRI revealed a large rectal submucosal tumor, more than 6 cm in diameter. Fine needle histological diagnosis indicated GIST with moderate risk. The patient was treated with imatinib mesylate in order to preserve the anus. The anal pain and tumor size decreased. Trans-anal local excision was performed. This case suggests that imatinib mesylate can make it possible to treat large rectal GIST cases by preserving anus, if neoadjuvant chemotherapy can be effective.

Proinflammatory factors, including neutrophil-derived oxygen free radicals and inflammatory cytokines, have recently been implicated in the pathogenesis of reflux esophagitis. Rebamipide has been widely used as an anti-ulcer agent. The aim of the present study was to assess the protective effect of rebamipide against acute reflux esophagitis in rats. Esophagitis was induced in rats by ligation at the limiting ridge and the lower portion of the duodenum. Vehicle or rebamipide were given as a single dose intraduodenally. Lesion index (LI), thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, mRNA and protein of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC)-1 in the esophageal mucosa were markedly increased; pretreatment with rebamipide, however, significantly reduced both macroscopic and microscopic injuries and increases in inflammatory mediators. The results of this study indicate that rebamipide protects against the occurrence of esophagitis and has highly promising potential as a new therapeutic agent for reflux esophagitis.

Although recent reports indicate an increasing incidence of patients with reflux esophagitis, its pathomechanism remains unclear. Cytokines and neutrophils, the latter of which produce reactive oxygen species (ROS), have been implicated in the formation of gastrointestinal diseases. This study investigated the roles of neutrophils, ROS, and cytokines in the pathogenesis of experimental reflux esophagitis. Esophagitis was induced in male Wistar rats by ligation at both the limiting ridge of the stomach and lower portion of the duodenum. The esophagus was then removed, and the lesion index, wet weight, thiobarbituric acid-reactive substances (an index of lipid peroxidation), myeloperoxidase activity (an index of neutrophil accumulation), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant (CINC)-1 in the esophageal mucosa were estimated, and a histological study (hematoxylin-and-eosin staining) was performed. The mRNA expression of TNF-alpha and CINC-1 was analyzed. Anti-neutrophil serum (ANS) was injected intraperitoneally prior to the induction of esophagitis, and inflammatory markers were estimated as described above. The values of all markers increased, and the histological study revealed neutrophil infiltration and edema in mucosa and submucosa at both 12 and 18 h after induction. However, the mRNA expression of both cytokines was observed earlier at 3 and 6 h after induction. ANS inhibited the increases in all inflammatory markers. These results indicate that ROS and lipid peroxidation mainly derived from neutrophils, which are stimulated and mobilized by TNF-alpha and CINC-1, are implicated in the pathogenesis of esophageal inflammation induced by the reflux of gastroduodenal contents.

Aim: To investigate the protective effect of lansoprazole on ischemia and reperfusion (I/R)-induced rat intestinal mucosal injury in vivo., Methods: Intestinal damage was induced by clamping both the superior mesenteric artery and the celiac trunk for 30 min followed by reperfusion in male Sprague-Dawley rats. Lansoprazole was given to rats intraperitoneally 1 h before vascular clamping., Results: Both the intraluminal hemoglobin and protein levels, as indices of mucosal damage, significantly increased in I/R-groups comparison with those of sham-operation groups. These increases in intraluminal hemoglobin and protein levels were significantly inhibited by the treatment with lansoprazole at a dose of 1 mg/kg. Small intestine exposed to I/R resulted in mucosal inflammation that was characterized by significant increases in thiobarbituric acid-reactive substances (TBARS), tissue-associated myeloperoxidase activity (MPO), and mucosal content of rat cytokine-induced neutrophil chemoattractant-1 (CINC-1). These increases in TBARS, MPO activities and CINC-1 content in the intestinal mucosa after I/R were all inhibited by pretreatment with lansoprazole at a dose of 1 mg/kg. Furthermore, the CINC-1 mRNA expression was increased during intestinal I/R, and this increase in mRNA expression was inhibited by treatment with lansoprazole., Conclusion: Lansoprazole inhibits lipid peroxidation and reduces development of intestinal mucosal inflammation induced by I/R in rats, suggesting that lansoprazole may have a therapeutic potential for I/R injury.

The overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may contribute to the pathophysiology of intestinal injury induced by ischemia-reperfusion. The aim of the present study was to examine the effect of selective iNOS inhibition by a cyclic amidine analogue, ONO-1714, on reperfusion-induced small intestinal injury and inflammation in rats. Intestinal damage was induced in male Sprague-Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion. The luminal nitrite concentration in the small intestine was measured by Griess reaction and the iNOS mRNA expression by RT-PCR. The severity of the intestinal mucosal injury and inflammation were evaluated by several biochemical markers and by the histological findings. The rats which were killed after ischemia-reperfusion had increased luminal concentrations of nitrite and iNOS mRNA expression, in addition to severe intestinal inflammation characterized by significant increases in myeloperoxidase activity, a marker of neutrophil infiltration, and by the mucosal content of CINC-1 cytokine, a neutrophil chemotactic cytokine. Administration with ONO-1714 significantly inhibited the luminal NO production. Reperfusion after 30-min ischemia resulted in an increase in luminal protein and hemoglobin concentrations, with levels reaching a maximum after 60 min of reperfusion. In contrast, pre-treatment with ONO-1714 2h before the ischemia inhibited the increases in luminal protein and hemoglobin concentration in a dose-dependent manner (0.001-0.1mg/kg). The contents of the thiobarbituric acid-reactive substances (a marker of oxidative lipid peroxidation) were significantly increased by ischemia-reperfusion, and this increase was reduced by ONO-1714. After reperfusion, the increase in tissue-associated myeloperoxidase activity, an index of neutrophil infiltration, was significantly inhibited by pre-treatment with ONO-1714. ONO-1714 also inhibited increases in intestinal CINC-1 protein and mRNA expression, as determined by ELISA and RT-PCR, respectively. In conclusion, the improvement of reperfusion-induced intestinal injury by ONO-1714 suggested that an excess of NO, produced by iNOS, may have contributed to the initiation/amplification of intestinal inflammatory injury by various mechanisms, including nitrosative and oxidative damage as well as the enhancement of inflammatory cytokine release.

Red wine polyphenolic compounds have been demonstrated to possess antioxidant properties, and several studies have suggested that they might constitute a relevant dietary factor in the protection from coronary heart disease. The aim of the present study is to examine whether red wine extracts (RWE) can ameliorate oxysterol-induced endothelial response, and whether inhibition of adhesion molecule expression is involved in monocyte adhesion to endothelial cells. Surface expression and mRNA levels of adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) were determined by ELISA and RT-PCR performed on human aortic endothelial cells (HAEC) monolayers stimulated with 7beta-hydroxycholesterol or 25-hydroxycholesterol. Incubation of HAEC with oxysterols (10 microM) increased expression of adhesion molecules in a time-dependent manner. Pretreatment of HAEC with RWE at final concentrations of 1, 10, and 100 ng/ml significantly inhibited the increase of surface protein expression and mRNA levels. Adherence of monocytes to oxysterol-stimulated HAEC was increased compared to that of unstimulated cells. Treatment of HAEC with RWE significantly inhibited adherence of monocytes. These results suggest that RWE works as an anti-atherogenic agent through the inhibition of endothelial-dependent adhesive interactions with monocytes induced by oxysterols.

Introduction: Recent studies have demonstrated the anti-inflammatory action of 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)), a derivative of the PGD(2) metabolic pathway. Acute inflammation, including neutrophil activation, plays a critical role in the pathogenesis of ischemia-reperfusion (I/R). The aim of the present study was to determine the effect of 15d-PGJ(2) on I/R-induced gastric mucosal injury in rats., Methods: Gastric mucosal damage was induced in male Wistar rats by clamping the celiac artery for 30 min followed by reperfusion. 15d-PGJ(2) (0.01-1.0 mg/kg) was given to the rats intraperitoneally 1 h before the vascular clamping. The area of gastric mucosal erosions (erosion index) was measured. Thiobarbituric acid reactive substances (TBARS) and tissue-associated myeloperoxidase (MPO) activity were measured in the gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The expression of tumor necrosis factor-alpha (TNF-alpha) in gastric mucosa was measured by ELISA. In addition, to elucidate whether the protective effects of 15d-PGJ(2) are related to the activation of the PPAR-gamma receptor, we also investigated the effects of a PPAR-gamma antagonist, GW9662., Results: After 60 min of reperfusion, the area of gastric erosion index had significantly increased from the mean basal levels. The increase in the erosion index was significantly inhibited by pretreatment with 15d-PGJ(2) in a dose-dependent manner. On the other hand, GW9662 reversed the protective effect of 15d-PGJ(2). The concentration of TBARS and MPO activity in the gastric mucosa were both significantly increased after I/R, and pretreatment with 15d-PGJ(2) significantly reduced these increases. The TNF-alpha content was significantly higher in the I/R group than in the sham-operated group. However, the increase in TNF-alpha was significantly inhibited by pretreatment with 15d-PGJ(2)., Conclusions: 15d-PGJ(2) significantly inhibited the severity of acute gastric mucosal injury induced by I/R in rats through PPAR-gamma-dependent mechanisms. This effect may be due, in part, to a reduction in the infiltration of neutrophils into the gastric mucosa, possibly via the inhibition of inflammatory cytokine.

Although edaravone (3-methyl-1-phenyl-pyrazolin-5-one), a newly developed radical scavenging agent, has been widely used for protection against ischemia-reperfusion (I-R) injury in patients with cerebral infarction, its effects on gastrointestinal I-R injury have not been evaluated. In the present study, we examined the effects of edaravone on experimental intestinal I-R damage in rats. In male Wistar rats with and without edaravone treatment, intestinal damage was induced by clamping the superior mesenteric artery for 30 min, followed by reperfusion. Edaravone was administered via intravenous infusion at 5 min before reperfusion was achieved by removal of the clamp. The rats were sacrificed after 60 min of reperfusion. Luminal protein and hemoglobin concentrations were measured as an index of mucosal injury and histological examination of hematoxylin and eosin-stained sections was performed. Thiobarbituric acid (TBA)-reactive substances and tissue-associated myeloperoxidase (MPO) activity were measured in the mucosa as indicators of lipid peroxidation and neutrophil infiltration, respectively. The mucosal concentration of cytokine-induced neutrophil chemoattractant (CINC)-1 (a member of the IL-8 family) was determined by enzyme-linked immunosorbent assay (ELISA). Additionally, CINC-1 messenger RNA (mRNA) was measured by the reverse-transcription polymerase chain reaction (RT-PCR). As a result, the levels of luminal protein and hemoglobin, TBA-reactive substances, and MPO activity were all increased significantly by I-R injury, and these increases were significantly inhibited by treatment with edaravone. Multiple erosions and bleeding were observed macroscopically after the small intestine was exposed to I-R injury, and these changes were inhibited by administration of edaravone. Microscopic I-R damage was also reduced by treatment with edaravone. CINC-1 protein and CINC-1 mRNA were both increased by I-R injury, while edaravone markedly reduced the levels of both protein and mRNA. In summary, these results suggest that edaravone can protect the small intestine against I-R injury by scavenging oxygen-derived free radicals.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. The aim of the present study was to investigate the effects of pioglitazone on ischemia-reperfusion (I/R)-induced gastric mucosal injury in rats. Gastric ischemia was induced for 30 min by applying a small vascular clamp to the celiac artery and reperfusion was produced by removal of the clamp in male Sprague-Dawley rats treated with and without pioglitazone. Pioglitazone was given to the rats intraperitoneally 2 h before the vascular clamping. The area of gastric mucosal erosion (erosion index) significantly increased from mean basal levels after 60 min of reperfusion. This erosion index was significantly inhibited by pretreatment with pioglitazone in a dose-dependent manner. The concentration of thiobarbituric acid reactive substances (TBARS) and myeloperoxidase (MPO) activity in the gastric mucosa were both significantly increased after I/R, and pretreatment with pioglitazone significantly reduced these increases. The contents of both mucosal TNF-alpha and CINC-2beta in the I/R group were significantly increased compared with the levels in the sham-operated group. These increases in TNF-alpha and CINC-2beta were significantly inhibited by pretreatment with pioglitazone at a dose of 10 mg/kg. The results of the present study indicate that pioglitazone inhibited lipid peroxidation and reduced development of the gastric mucosal inflammation induced by I/R in rats. This investigation suggests that pioglitazone has potential as a new therapeutic agent for reperfusion injury.

Nuclear factor-kappaB-dependent up-regulation of inflammatory cytokines occurs in inflammatory bowel disease. We investigated the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma ligand, on dextran sulfate sodium-induced colonic mucosal injury and inflammation in mice. Acute colitis was induced in female mice receiving 0, 1, 3, and 10 mg/kg i.p. of pioglitazone daily. Colonic mucosal inflammation was evaluated chemically and histologically. Thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity were measured in intestinal mucosa as indices of lipid peroxidation and neutrophil infiltration, respectively. Colonic mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase was measured by reverse transcription-PCR and nuclear factor-kappaB activation was evaluated by electrophoretic mobility shift assay. Dextran sulfate sodium administration resulted in decreases in body weight and colon length and increases in lipid peroxide and neutrophil accumulation of the intestine. In contrast, co-administration with pioglitazone prevented these changes. Transcripts coding for pro-inflammatory cytokines and inducible nitric oxide were expressed in high levels after the development of colitis, and pioglitazone markedly reduced mRNA expression of these genes. DNA binding activity of nuclear factor-kappaB was markedly increased, whereas in pioglitazone co-treated intestines the effect was significantly reduced. These data suggest that peroxisome proliferator-activated receptor-gamma may be a novel therapeutic target for the therapy of inflammatory bowel disease.

Neutrophil activation and tumor necrosis factor-alpha (TNF-alpha) induction play a critical role in ischemia-reperfusion-induced intestinal inflammation. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of inflammatory responses. The aim of the present study was to determine whether pioglitazone, a specific PPAR-gamma ligand, can ameliorate reperfusion-induced intestinal injury in rats, and whether the agent can inhibit the increase in neutrophil accumulation associated with TNF-alpha expression. Intestinal damage was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 30 min followed by reperfusion. Reperfusion after 30 min ischemia resulted in an increase in luminal protein concentrations with levels reaching a maximum after 60 min of reperfusion. In contrast, pretreatment with pioglitazone 2 h before ischemia inhibited the increase in luminal protein concentrations after 60 min reperfusion in a dose-dependent manner (1-30 mg/kg). The increase in tissue-associated myeloperoxidase activity, an index of neutrophil infiltration, after reperfusion was significantly inhibited by pretreatment with pioglitazone. Pioglitazone also inhibited increases in intestinal TNF-alpha protein and mRNA expression determined by ELISA and RT-PCR, respectively. In conclusion, activation of PPAR-gamma may represent a novel approach to the treatment of intestinal inflammation induced by ischemia-reperfusion.

We evaluated arterial infusion chemotherapy for unresectable metastatic liver tumor using FDG-PET and CT. A 72-year-old female patient with multiple metastatic liver tumors of rectal cancer was treated by arterial infusion chemotherapy. The tumor size decreased by chemotherapy, but there was a high uptake lesion of FDG. Three months later, tumor ingrowth was detected. FDG produces images of regional glycolytic activity, and it is a useful method of assessment of tumor viability after chemotherapy in patients with cancer.