Clinical Outcomes of Follow-Up Observation After Endoscopic Submucosal Dissection for Esophageal Squamous Cell Carcinoma Invading the Muscularis Mucosa Without Lymphovascular Involvement.

BACKGROUND: The therapeutic approach after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) diagnosed as pathological T1a-muscularis mucosa (pT1a-MM) without lymphovascular involvement (LVI) remains uncertain. We aimed to determine whether observation after ESD is acceptable for patients without LVI showing pT1a-MM cancer. METHODS: We retrospectively registered 566 ESCC patients who were treated with ESD at ten institutions between January 2007 and December 2015. Of those, 447 cases showing pT1a-epithelium/lamina propria mucosa (EP/LPM) without LVI and vertical margin (VM) (EP/LPM group), and 41 cases showing pT1a-MM without LVI and VM (MM group) were analyzed in this investigation. The clinical outcomes were assessed between the groups. RESULTS: The 5 year cumulative incidence of metastatic recurrence was 0.5% and 3.3% in the EP/LPM and MM groups, respectively (P = 0.121). Two cases showing pT1a-EP/LPM and one showing pT1a-MM experienced lymph node recurrence. The 5 year cumulative incidence of local recurrence was 1.5% and 3.8% in the EP/LPM and MM groups, respectively (P = 0.455). The 5 year disease-specific survival (DSS) rate was 99.3% and 96.6% in the EP/LPM and MM groups, respectively (P = 0.118), whereas the 5 year overall survival rate was significantly higher in the EP/LPM group than in the MM group (92.6% versus 81.1%, respectively; P = 0.021). CONCLUSIONS: As regards metastatic recurrence and DSS, ESCC patients with pT1a-MM without LVI showed favorable outcomes that were equivalent to those with pT1a-EP/LPM, even when they were not treated with additional therapy after ESD.

[A case report:the progress of fascioliasis from hepatic phase to biliary phase].

This is a case report of fascioliasis that progressed from the hepatic to the biliary phases over 2 years. A woman in her late 60s ate Zingiber mioga from the field, which was followed by abdominal pain that occurred 1 month later. Although CT and MRI studies revealed an increase in blood eosinophils as well as multiple hepatic nodules, they vanished quickly. After 2 years, an MRCP study revealed multiple flat lesions, which were diagnosed as adult fascioliasis. Definitive diagnosis was provided by enzyme-labeled antibody method using fasciola-specific antigen. Triclabendazole was administered once to complete the treatment.

Clinical Outcomes of Vonoprazan-Treated Patients after Endoscopic Submucosal Dissection for Gastric Neoplasms: A Prospective Multicenter Observation Study.

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.

Mucosa-Associated Microbiota in the Gastrointestinal Tract of Healthy Japanese Subjects.

BACKGROUND: The importance of microbiota infiltrating the gut mucus layer has been reported in the pathogenesis of various gastrointestinal and systemic diseases. However, little is known about the mucosa-associated microbiota (MAM) in healthy subjects. The present study aimed to clarify the characteristics of the gastrointestinal MAM from the oral cavity to the rectum in healthy Japanese subjects. METHODS: Seventeen healthy subjects were enrolled. In this study, 5 mucosa samples from the upper gut (intraoral, mid-esophagus, gastric corpus, gastric antrum, and duodenum) and 7 from the lower gut (ileum, cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum) were collected with a brush under endoscopic examination. MAM profiles of each sample were analyzed by 16S-rRNA V3-V4 gene sequences. RESULTS: Collecting mucosa samples by brushing provided sufficient material for MAM profiling without causing adverse effects. The upper and lower gut MAM profiles differed significantly (p < 0.0001). In the upper and lower gut, the intra- and inter-individual MAM profiles were significantly different (p = 0.0008 and p < 0.0001 respectively). CONCLUSIONS: The MAM profiles of the upper and lower gut were significantly different. The inter-individual differences in MAM were remarkable compared to the intra-individual differences.

Higher Levels of Streptococcus in Upper Gastrointestinal Mucosa Associated with Symptoms in Patients with Functional Dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is associated with poor health-related quality of life. Recent evidence suggests that the main pathogenesis suspect is the gut mucosa-associated microbiota (MAM). However, little is known about the MAM in FD subjects. The aim of this study was to clarify the relationship between upper gastrointestinal symptoms in FD and the characteristics of the gastrointestinal MAM. SUMMARY: Five mucosa samples from the upper gut (intraoral, mid-esophagus, gastric body, gastric antrum, and descending portion of the duodenum) were collected with a brush under endoscopic examination from FD and healthy control subjects. MAM profiles of each sample were analyzed by 16S-rRNA -V3-V4 gene sequences. Questionnaire was used to assess gastrointestinal symptoms in FD. Between FD and healthy control subjects, although the comparison of MAM α-diversity showed no significant differences, the structure of MAM (ß-diversity) was clearly different. Only the phylum Firmicutes was increased in FD compared to healthy control subjects in all sites of the upper gut. At the genus level, Streptococcus was significantly increased in all sites in the upper gut in FD. The relative abundance of Streptococcus was positively correlated with upper gastrointestinal symptoms in each upper gut group. Furthermore, the relative abundance of OTU 90 was positively correlated with upper gastrointestinal symptoms in all sites in the upper gut in FD. Key Messages: Streptococcus is a bacterium strongly correlated with upper gastrointestinal symptoms in FD.

Blue laser imaging-bright improves the real-time detection rate of early gastric cancer: a randomized controlled study.

BACKGROUND AND AIMS: Blue laser imaging-bright (BLI-bright) has shown promise as a more useful tool for detection of early gastric cancer (EGC) than white-light imaging (WLI). However, the diagnostic performance of BLI-bright in the detection of EGC has not been investigated. We aimed to compare real-time detection rates of WLI with that of BLI-bright for EGC. METHODS: This was a prospective, randomized, controlled study in 2 Japanese academic centers. We investigated 629 patients undergoing follow-up endoscopy for atrophic gastritis with intestinal metaplasia or surveillance after endoscopic resection of EGC. Patients were randomly assigned to receive primary WLI followed by BLI-bright or primary BLI-bright followed by WLI. The real-time detection rates of EGC were compared between primary WLI and primary BLI-bright. RESULTS: There were 298 patients in each group. The real-time detection rate of EGC with primary BLI-bright was significantly greater than that with primary WLI (93.1% vs 50.0%; P = .001). Primary BLI-bright had a significantly greater ability to detect EGCs in patients with a history of endoscopic resection for EGC, no Helicobacter pylori infection in the stomach after eradication therapy, lesions with an open-type atrophic border, lesions in the lower third of the stomach, depressed-type lesions, small lesions measuring <10 mm and 10 to 20 mm in diameter, reddish lesions, well-differentiated adenocarcinomas, and lesions with a depth of invasion of T1a. CONCLUSIONS: BLI-bright has a higher real-time detection rate for EGC than WLI. BLI-bright should be performed during surveillance endoscopy in patients at high risk for EGC. (Clinical trial registration number: UMIN000011324.).

Mucus reduction promotes acetyl salicylic acid-induced small intestinal mucosal injury in rats.

BACKGROUND: Acetyl salicylic acid (ASA) is a useful drug for the secondary prevention of cerebro-cardiovascular diseases, but it has adverse effects on the small intestinal mucosa. The pathogenesis and prophylaxis of ASA-induced small intestinal injury remain unclear. In this study, we focused on the intestinal mucus, as the gastrointestinal tract is covered by mucus, which exhibits protective effects against various gastrointestinal diseases. MATERIALS AND METHODS: ASA was injected into the duodenum of rats, and small intestinal mucosal injury was evaluated using Evans blue dye. To investigate the importance of mucus, Polysorbate 80 (P80), an emulsifier, was used before ASA injection. In addition, rebamipide, a mucus secretion inducer in the small intestine, was used to suppress mucus reduction in the small intestine of P80-administered rats. RESULTS: The addition of P80 reduced the mucus and exacerbated the ASA-induced small intestinal mucosal injury. Rebamipide significantly suppressed P80-reduced small intestinal mucus and P80-increased intestinal mucosal lesions in ASA-injected rats, demonstrating that mucus is important for the protection against ASA-induced small intestinal mucosal injury. These results provide new insight into the mechanism of ASA-induced small intestinal mucosal injury. CONCLUSION: Mucus secretion-increasing therapy might be useful in preventing ASA-induced small intestinal mucosal injury.

Transforming growth factor ß1-induced collagen production in myofibroblasts is mediated by reactive oxygen species derived from NADPH oxidase 4.

Intestinal fibrosis with stricture formation is a severe complication of Crohn's disease (CD). Though new therapeutic targets to enable the prevention or treatment of intestinal fibrosis are needed, markers of this condition and the basic mechanisms responsible have not been established. NADPH oxidase (NOX) 4 has already been reported to play a key role in models of fibrogenesis, including that of the lung. However, its importance in intestinal fibrogenesis remains unclear. In this study, we examined the role of NOX4 in collagen production by intestinal myofibroblasts stimulated with transforming growth factor (TGF)-ß1. Using LmcMF cells, an intestinal subepithelial myofibroblast (ISEMF) line, we first examined the induction of collagen production by TGF-ß1. Subsequently, we investigated the role of NOX4 in TGF-ß1-induced collagen I production in these cells using SB525334 (an SMAD2/3 inhibitor), diphenyleneiodonium (an NOX inhibitor), and Nox4 small interfering RNA (siRNA). Production of collagen was assessed with Sirius red staining, and Nox4 expression was measured by quantitative real-time PCR. Reactive oxygen species (ROS) production was determined using DCFDA and fluorescent microscopy. We observed that TGF-ß1 induced collagen production via NOX4 activation and ROS generation in LmcMF cells. Nox4 siRNA and inhibitors of TGF-ß1 receptor and NOX significantly reduced TGF-ß1-induced ROS and collagen production. Thus, in the present study, we revealed that collagen production in ISEMFs is induced via an NOX4-dependent pathway. This work supports a function for NOX4 in intestinal fibrogenesis and identifies it as a potential therapeutic target in recalcitrant fibrotic disorders of CD patients.

Impact of the Charlson comorbidity index and prognostic nutritional index on prognosis in patients with early gastric cancer after endoscopic submucosal dissection.

BACKGROUND AND AIM: With the aging of society, comorbidities or nutritional status are assessed prior to endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). However, it is uncertain which factors are important for predicting prognosis in EGC patients after ESD. Thus, we aimed to evaluate clinical outcomes of ESD for EGC, with respect to comorbidities or nutritional status. METHODS: We carried out a retrospective study involving 708 EGC in 585 patients who were enrolled between April 2007 and March 2012. They were classified into two groups; an elderly (≥80 years) and non-elderly (<80 years) group. Short- and long-term outcomes were evaluated between the groups. RESULTS: There were no significant differences regarding short-term outcomes. Overall survival (OS) rates in the elderly group were significantly lower than those in the non-elderly group (P = 0.001). OS rates in patients with a low (≤2) Charlson comorbidity index (CCI) were significantly higher than those in patients with a high (≥3) CCI, regardless of age. OS rates in patients with a high (≥47.7) prognostic nutritional index (PNI) were significantly higher than those in patients with a low (<47.7) PNI, regardless of age. In multivariate analysis, an Eastern Cooperative Oncology Group performance status (PS) ≥2 (hazard ratio [HR], 95% confidence interval: 3.23, 1.54-6.75), CCI ≥3 (HR 7.88, 4.50-13.80) and PNI <47.7 (HR 3.44, 2.00-5.90) were significantly associated with OS rate (P < 0.01). CONCLUSION: CCI and PNI can be prognostic indicators for non-elderly and elderly patients with EGC after ESD.

Preventive effect of agaro-oligosaccharides on non-steroidal anti-inflammatory drug-induced small intestinal injury in mice.

BACKGROUND AND AIM: Non-steroidal anti-inflammatory drugs (NSAIDs), which are commonly used in clinical medicine, cause erosion, ulcers, and bleeding in the gastrointestinal tract. No effective agent for the prevention and treatment of small intestinal injury by NSAIDs has been established. This study investigates the effects of agaro-oligosaccharides (AGOs) on NSAID-induced small intestinal injury in mice. METHODS: Mice were treated with indomethacin, an NSAID, to induce intestinal injury. The respective degrees of mucosal injury of mice that received AGO and control mice were compared. Heme oxygenase-1 (HO-1) expression using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were measured. The expression of keratinocyte chemoattractant (KC) was measured using qRT-PCR and enzyme-linked immunosorbent assay. RESULTS: AGO administration induced HO-1 expression in mouse small intestinal mucosa. Induction was observed mainly in F4/80 positive macrophages. The increased ulcers score, myeloperoxidase activity, and KC expression by indomethacin were inhibited by AGO administration. Conversely, HO inhibitor cancelled AGO-mediated prevention of intestinal injury. In mouse peritoneal macrophages, AGOs enhanced HO-1 expression and suppressed lipopolysaccharide-induced KC expression. Furthermore, AGOs enhanced the expressions of alternatively activated macrophage markers arginase-1, mannose receptor-1, and chitinase 3-like 3. CONCLUSIONS: Results suggest that oral administration of AGOs prevents NSAID-induced intestinal injury.

The impact of non-steroidal anti-inflammatory drugs on the small intestinal epithelium.

The small intestine has been called as a dark continent of digestive tract and it had been very difficult to diagnose or treat the disease of small intestine. However recent technological development including video capsule endoscopy or balloon-assisted endoscopy has made us to aware the various diseases of small intestine. By using capsule endoscopy, many researchers reported that more than 70% of patients treated continuously with non-steroidal anti-inflammatory drugs (NSAID) exhibit the mucosal damage of small intestine. In some cases, NSAID not only causes mucosal damage but also results in life threatening bleeding from small intestine, which had not been prevented or cured by gastro-protective drug or anti-gastric acid secretion drug administration. Therefore to investigate and identify the effective drug that protects small intestine from mucosal damage is urgently expected. In spite of extensive investigation in clinical field, only a few drugs such as misoprostol, a synthetic prostaglandin E1 analogue, has been reported as an effective one but is not satisfactory enough to fulfill the requirement of patients who suffer from NSAID-induced mucosal damage of small intestine. And now, extensive study is being performed using several gastro-mucoprotective drugs by many researchers. In this review, we introduce the current clinical situation in small intestinal injury of patients under NSAID treatment, and to summarize the molecular mechanism by which NSAID, including acetyl salicylic acid, cause small intestinal damage. In addition, we present results of clinical trials performed so far, and refer the possible preventive method or treatment in the near future.

A case of needle tract seeding with endoscopic findings of progression over time.

An 83-year-old male underwent three transgastric punctures with endoscopic ultrasound-guided fine-needle aspiration for the examination of a pancreatic body tumor. After a diagnosis of resectable pancreatic cancer and undergoing distal pancreatectomy, the patient was administered postoperative adjuvant chemotherapy with oral S-1 for 6 months, and carcinoembryonic antigen and carbohydrate antigen 19-9 levels were bimonthly evaluated. Carbohydrate antigen 19-9 levels continually increased to 4638.1 U/mL at 45 months post-fine-needle aspiration. Endoscopic ultrasound-guided showed a 25 mm low-echoic, irregularly shaped, and heterogeneous tumor with clear margins protruding from the mucosa outside the gastric wall, and biopsy confirmed adenocarcinoma. Since the immunostaining findings of the specimen matched those of the previously resected specimen, needle tract seeding (NTS) due to puncture of the pancreatic cancer was identified as the cause. After a pylorus-preserving gastrectomy at 46 months post-fine-needle aspiration, postoperative chemotherapy initiation, comprising gemcitabine and nab-paclitaxel, was initiated; however, the patient died despite these interventions as he developed multiple peritoneal dissemination. Although rare, the incidence of NTS will increase in the future owing to the expected extended survival in post-pancreatic cancer resection cases. We suggest regular upper gastrointestinal endoscopy and endoscopic ultrasound-guided evaluations for patients who are at risk for NTS can facilitate early detection. Furthermore, it is extremely relevant to share experiences of encountered NTS cases in practice and extend knowledge of its varying endoscopic appearances.

A case of disseminated peritoneal metastases after 2-year conservative treatment for intramucosal colon carcinoma due to a perforation during endoscopic submucosal dissection.

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.

MDR1 is related to intestinal epithelial injury induced by acetylsalicylic acid.

BACKGROUND/AIMS: Although the cytotoxicity of aspirin against the intestinal epithelium is a major clinical problem, little is known about its pathogenesis. We assessed the involvement of Multi Drug Resistance (MDR) 1 in intestinal epithelial cell injury caused by aspirin using MDR1 gene-transfected Caco2 cells. METHODS: Caco2 cells were treated with various concentrations of aspirin for 24 h. After treatment of Caco2 cells with verapamil, a specific inhibitor of MDR1, we assessed the extent of cell injury using a WST-8 assay at 24 h after aspirin-stimulation. We performed the same procedure in MDR1 gene-transfected Caco2 cells. To determine the function of MDR1 in the metabolism of aspirin, flux study was performed using (14)C-labeled aspirin. RESULTS: The level of aspirin-induced cell injury was higher in verapamil-treated Caco2 cells than in control cells and was less serious in MDR1-transfected Caco2 cells than in control vector-transfected cells. The efflux of (14)C-labeled aspirin was higher in verapamil-treated Caco2 cells than in control cells. CONCLUSION: These data suggest that aspirin effux occurs through the MDR1 transporter and that the MDR1 transporter is involved in the pathogenesis of aspirin-induced cell injury.

Hemin ameliorates indomethacin-induced small intestinal injury in mice through the induction of heme oxygenase-1.

BACKGROUND AND AIM: Although non-steroidal anti-inflammatory drugs can induce intestinal injury, the mechanisms are not fully understood, and treatment has yet to be established. Heme oxygenase-1 (HO-1) has recently gained attention for anti-inflammatory and cytoprotective effects. This study aimed to investigate the effects of hemin, an HO-1 inducer, on indomethacin-induced enteritis in mice. METHODS: Enteritis was induced by single subcutaneous administration of indomethacin (10 mg/kg) in male C57BL/6 mice. Hemin (30 mg/kg) was administered by intraperitoneal administration 6 h before indomethacin administration. Mice were randomly divided into four groups: (i) sham + vehicle; (ii) sham + hemin; (iii) indomethacin + vehicle; or (iv) indomethacin + hemin. Enteritis was evaluated by measuring ulcerative lesions. Myeloperoxidase activity was measured as an index of neutrophil accumulation. The mRNA expression of inflammatory cytokines and chemokines, such as tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and keratinocyte chemoattractant, were analyzed by real-time polymerase chain reaction. RESULTS: The area of ulcerative lesions, myeloperoxidase activity, and mRNA expression of inflammatory cytokines and chemokines were significantly increased in mice administrated with indomethacin compared with vehicle-treated sham mice. Development of intestinal lesions, increased levels of myeloperoxidase activities, and mRNA expressions of inflammatory cytokines and chemokines were significantly suppressed in mice treated with hemin compared with vehicle-treated mice. Protective effects of hemin were reversed by co-administration of tin protoporphyrin, an HO-1 inhibitor. CONCLUSIONS: Induction of HO-1 by hemin inhibits indomethacin-induced intestinal injury through upregulation of HO-1. Pharmacological induction of HO-1 may offer a novel therapeutic strategy to prevent indomethacin-induced small intestinal injury.

Acetyl salicylic acid induces damage to intestinal epithelial cells by oxidation-related modifications of ZO-1.

Acetyl salicylic acid (ASA) is one of the most frequently prescribed medications for the secondary prevention of cardiovascular and cerebrovascular events. It has recently been reported to cause small intestinal mucosal injury at a considerably higher rate than previously believed. The aim of this study is to investigate the mechanism by which this occurs using an in vitro small intestine model focusing on the role of oxidative stress and cell permeability. Differentiated Caco-2 exhibits a phenotype similar to human small intestinal epithelium. We measured whether ASA induced the increase of differentiated Caco-2 permeability, the decrease of tight junction protein expression, the production of reactive oxygen species (ROS), and the expression of ROS-modified zonula occludens-1 (ZO-1) protein. In some experiments, Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, a superoxide dismutase mimetic) was used. The nontoxic concentration of ASA decreased transepithelial electrical resistance and increased the flux of fluorescein isothiocyanate-conjugated dextran across Caco-2 in a time-dependent manner. The same concentration of ASA significantly decreased ZO-1 expression among TJ proteins as assessed by Western blot and immunocytochemistry and increased ROS production and the expression of oxidative stress-modified ZO-1 protein. However, MnTMPyP suppressed the ASA-induced increased intercellular permeability and the ASA-induced ROS-modified ZO-1 expression. Our findings indicate that ASA-induced ROS production can specifically modify the expression of ZO-1 protein and induce increased cell permeability, which may ultimately cause small intestinal mucosal injury.

Role and Potential Mechanism of Heme Oxygenase-1 in Intestinal Ischemia-Reperfusion Injury.

Intestinal ischemia-reperfusion (IR) injury is a complex, multifactorial, and pathophysiological condition with high morbidity and mortality, leading to serious difficulties in treatment, especially in humans. Heme oxygenase (HO) is the rate-limiting enzyme involved in heme catabolism. HO-1 (an inducible form) confers cytoprotection by inhibiting inflammation and oxidation. Furthermore, nuclear factor-erythroid 2-related factor 2 (Nrf2) positively regulates HO-1 transcription, whereas BTB and CNC homolog 1 (Bach1) competes with Nrf2 and represses its transcription. We investigated the role and potential mechanism of action of HO-1 in intestinal IR injury. Intestinal ischemia was induced for 45 min followed by 4 h of reperfusion in wild-type, Bach1-deficient, and Nrf2-deficient mice, and a carbon monoxide (CO)-releasing molecule (CORM)-3 was administered. An increase in inflammatory marker levels, nuclear factor-κB (NF-κB) activation, and morphological impairments were observed in the IR-induced intestines of wild-type mice. These inflammatory changes were significantly attenuated in Bach1-deficient mice or those treated with CORM-3, and significantly exacerbated in Nrf2-deficient mice. Treatment with an HO-1 inhibitor reversed this attenuation in IR-induced Bach1-deficient mice. Bach1 deficiency and treatment with CORM-3 resulted in the downregulation of NF-κB activation and suppression of adhesion molecules. Together, Bach1, Nrf2, and CO are valuable therapeutic targets for intestinal IR injury.

[A case of malignant peritoneal mesothelioma treated effectively with cisplatin and gemcitabine].

Peritoneal mesothelioma presents difficulty in early diagnosis and establishment of standard treatment. We report a case of malignant peritoneal mesothelioma treated effectively with cisplatin and gemcitabine. A 53-year-old man, presenting with abdominal fullness and massive ascites was first admitted to our hospital in April, 2006. Although we conducted upper gastrointestinal endoscopy, total colonoscopy, chest-abdominal computed tomography, and FDG-PET, suspected with disseminated metastasis of cancer, we could not detect the original cancer lesion. Then, a diagnostic laparoscopy revealed many gray-colored nodules diffusely in the peritoneum. The peritoneal biopsy demonstrated that tumor cells grow papillarly and show a strongly positive image for calretinin, but a negative image for Ber-EP4. Therefore, we have diagnosed this case as a malignant peritoneal mesothelioma. Treatment with cisplatin 60 mg/m² and intraperitoneal instillation of mitomycin C 10 mg/m² were not so effective. Then, cisplatin 60 mg/m² and gemcitabine 1,000 mg/m² were administered biweekly. The tumor marker decreased remarkably and the massive ascites disappeared. Therefore, the chemotherapy could be done on an outpatient basis.

[A case of rectal GIST treated with imatinib mesylate neoadjuvant therapy to preserve the anus].

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.

A review of the mechanism and prophylaxis of acetyl salicylic acid-induced injury of the small intestine.

Besides the preventive effect of aspirin on cerebrocardiovascular diseases, aspirin has adverse effects, especially on the gastrointestinal system and kidneys. Especially, a recent advancement in endoscopy revealed that aspirin-induced small intestinal mucosal injury is considerably higher than previously believed. However, the mechanism of this phenomenon is not clear yet. Moreover, effective prophylaxis does not exist. First, we investigated the cytotoxic effect of aspirin on the intestinal epithelial cell line in rats at a high concentration, and found that aspirin significantly decreased heat shock protein 70 expression, increased reactive oxygen species production, and increased epithelial cell apoptosis. These phenomena were prevented by the increment of heat shock protein 70 expression. Next, we investigated the effect of a lower concentration of aspirin on epithelial cell permeability, and found that aspirin significantly increased reactive oxygen species production, decreased tight junction protein expression, and increased epithelial permeability. These phenomena were suppressed by an antioxidant. Finally, we investigated the role of intestinal mucus on aspirin-induced mucosal damage using an in vivo model, and found that mucus prevented a high concentration of aspirin-induced mucosal damage. The investigation of chronic users of aspirin revealed that mucus-increasing therapy might be useful for preventing aspirin-induced small intestinal mucosal injury.