Incidence of and risk factors for upper gastrointestinal complications in patients taking low-dose aspirin in Japan.

BACKGROUND/AIMS: Low-dose aspirin is widely used for the prevention of cardiovascular and cerebrovascular diseases. However, administration of low-dose aspirin is associated with an increased risk of upper gastrointestinal complications, such as upper gastrointestinal erosions, ulcers and bleeding. The aim of this study was to clarify the prevalence and various clinical factors of upper gastrointestinal complications associated with low-dose aspirin treatment. METHODOLOGY: A total of 1213 patients taking low-dose aspirin were evaluated with upper endoscopic examinations. We studied retrospectively the incidence of and risk factors for upper gastrointestinal complications associated with low-dose aspirin use. RESULTS: Of the 1213 patients taking low-dose aspirin, 598 patients and 72 patients were found to have gastroduodenal erosions (57.3%) and peptic ulcers (5.9%), respectively. Of these 72 peptic ulcers, 27 were diagnosed as hemorrhagic ulcers. Previous ulcer history was identified as a risk factor for peptic ulcer and upper gastrointestinal bleeding during low-dose aspirin therapy. Upper gastrointestinal symptoms and no use of gastroprotective agents were also identified as risk factors for peptic ulcers. In this study, the use of a histamine-2 receptor antagonist was indicated as a protective factor for peptic ulcers. CONCLUSIONS: Low-dose aspirin therapy is associated with an increased risk of developing upper gastrointestinal complications. Administration of a histamine-2 receptor antagonist was effective for the prevention of low-dose aspirin induced peptic ulcers.

Management of acute lower intestinal bleeding: what bowel preparation should be required for urgent colonoscopy?

BACKGROUND/AIMS: The management of acute intestinal bleeding is not standardized. The aim of this study was to determine the most suitable method of bowel preparation for urgent colonoscopy. METHODOLOGY: One hundred and forty patients admitted with acute lower intestinal bleeding (ALIB) to our Hospital (April 1998 to March 2004) were studied. The preparation for colonoscopy consisted, usually, of oral administration of polyethylene glycol (PEG)-salt solution. For elderly patients or for those suspected of bleeding from a sigmoid colon lesion, colonoscopy was performed following glycerin enemas or water enemas. For patients with a suspected rectal lesion or soon after undergoing a polypectomy, colonoscopy was performed without any of the above procedures. RESULTS: Ischemic colitis was the most common cause of bleeding. The overall cecal completion ratio was 41%, compared with 74% in the PEG group. The percentage of those in whom colonoscopy was impossible (poor preparation) was 16% overall, compared with 5% in the PEG group. Endoscopic hematemesis were performed successfully for 26 patients who were mainly postpolypectomy cases or had rectal ulcers. CONCLUSIONS: In urgent colonoscopy, the preparation with PEG-salt solution may improve the patient's outcome. In postpolypectomy patients and those with rectal ulcers preparation was not always needed.

Inhibition of peroxisome proliferator-activated receptor gamma promotes tumorigenesis through activation of the beta-catenin / T cell factor (TCF) pathway in the mouse intestine.

Although peroxisome proliferator-activated receptor gamma (PPARgamma) is strongly expressed in the intestinal epithelium, the role of PPARgamma in intestinal tumorigenesis has not yet been elucidated. To address this issue, we investigated the effect of PPARgamma inhibition and its mechanism on intestinal tumorigenesis using a selective antagonist, T0070907. We treated Apc(Min/+) mice and carcinogen-induced colon cancer model C57BL/6 mice with T0070907 and counted the number of spontaneous polyps and aberrant crypt foci and observed cell proliferation and beta-catenin protein in the colon epithelium. To investigate its mechanism, the changes of beta-catenin/TCF (T cell factor) transcriptional activity and location of beta-catenin induced by T0070907 were investigated in the colon cancer cell lines. T0070907 promoted polyp formation in the small intestine of Apc(Min/+) mice and aberrant crypt foci in the colon of C57BL/6 mice. PPARgamma inhibition promoted cell proliferation and increased expressions of the c-myc and cyclin D1 genes and the beta-catenin protein in the colon epithelium. In vitro, cell proliferation was promoted, but it was inhibited by the transfection of dominant-negative Tcf4. T0070907 increased beta-catenin/TCF transcriptional activity and beta-catenin protein in the cytsol and nucleus, but relatively decreased it on the cell membrane. PPARgamma antagonist promotes tumorigenesis in the small intestine and colon through stimulation of epithelial cell proliferation. beta-Catenin contributes to the promotion of tumorigenesis by PPARgamma antagonist due to activation of TCF/LEF (lymphoid enhancer factor) transcriptional factor.

Inhibition of peroxisome proliferator-activated receptor gamma activity suppresses pancreatic cancer cell motility.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that has been implicated in the carcinogenesis and progression of various solid tumors, including pancreatic carcinomas. We aimed to clarify the role of this receptor in pancreatic cell motility in vitro and in metastasis in vivo. Cell motility was examined by assaying transwell migration and wound filling in Capan-1 and Panc-1 pancreatic cancer cells, with or without the PPARgamma-specific inhibitor T0070907. A severe combined immunodeficiency xenograft metastasis model was used to examine the in vivo effect of PPARgamma inhibition on pancreatic cancer metastasis. In both transwell-migration and wound-filling assays, inhibition of PPARgamma activity suppressed pancreatic cell motility without affecting in vitro cell proliferation. Inhibition of PPARgamma also suppressed liver metastasis in vivo in metastatic mice. In PPARgamma-inhibited cells, p120 catenin accumulation was induced predominantly in cell membranes, and the Ras-homologous GTPases Rac1 and Cdc42 were inactive. Inhibition of PPARgamma in pancreatic cancer cells decreased cell motility by altering p120ctn localization and by suppressing the activity of the Ras-homologous GTPases Rac1 and Cdc42. Based on these findings, PPARgamma could function as a novel target for the therapeutic control of cancer cell invasion or metastasis.

Adenosquamous carcinoma of the pancreas associated with humoral hypercalcemia of malignancy (HHM).

We report a rare case of adenosquamous carcinoma of the pancreas associated with humoral hypercalcemia of malignancy (HHM) in which parathyroid hormone-related protein (PTH-rP) was identified as the causative factor of hypercalcemia. A 72-year-old Japanese man was admitted to our institution complaining of fever and abdominal pain. Abdominal computed tomography demonstrated a large tumor in the body of the pancreas, with multiple liver metastases. Both serum calcium and PTH-rP levels were elevated. No accumulation was observed on bone scan with technetium-99. The patient died of pneumonia 3 months after admission. Autopsy demonstrated that the neoplasm in the pancreas showed an abrupt histological transition from adenocarcinoma to squamous cell carcinoma. PTH-rP was identified in the primary pancreatic tumor cells by immunohistochemical examination and a reverse-transcription polymerase chain reaction (RTPCR) method. We concluded that PTH-rP was the causative factor of the HHM, based on the laboratory data, immunohistochemical examination, and messenger RNA (mRNA) expression. This is a very rare report of adenosquamous cell carcinoma of the pancreas associated with HHM.

Metformin suppresses intestinal polyp growth in ApcMin/+ mice.

Metformin is a biguanide derivative that is widely used in the treatment of diabetes mellitus. One of the pharmacological targets of metformin is adenosine monophosphate-activated protein kinase (AMPK). We investigated the effect of metformin on the suppression of intestinal polyp formation in Apc(Min/+) mice. Administration of metformin (250 mg/kg) did not reduce the total number of intestinal polyp formations, but significantly reduced the number of intestinal polyp formations larger than 2 mm in diameter in Apc(Min/+) mice. To examine the indirect effect of metformin, the index of insulin resistance and serum lipid levels in Apc(Min/+) mice were assessed. These factors were not significantly attenuated by the treatment with metformin, indicating that the suppression of polyp growth is not due to the indirect drug action. The levels of tumor cell proliferation as determined by 5-bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemical staining, and apoptosis, via transferase deoxytidyl uridine end labeling staining, in the polyps of metformin-treated mice were not significantly different in comparison to those of control mice. Gene expression of cyclin D1 and c-myc in intestinal polyps were also not significantly different between those two groups. In contrast, metformin activated AMPK in the intestinal polyps, resulting in the inhibition of the activation of mammalian target of rapamycin, which play important roles in the protein synthesis machinery. Metformin suppressed the polyp growth in Apc(Min/+) mice, suggesting that it may be a novel candidate as a chemopreventive agent for colorectal cancer.

Expression of adiponectin receptors, AdipoR1 and AdipoR2, in normal colon epithelium and colon cancer tissue.

Adiponectin is secreted by adipocytes and is a key hormone responsible for insulin sensitization. Recent studies have shown that plasma adiponectin is decreased in patients with breast, endometrial and gastric cancer. However, the effect of adiponectin on colorectal carcinogenesis is controversial. It is now well known that the adiponectin receptor exists in two isoforms, adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). We examined the expression of the adiponectin receptors on normal colon mucosa and colon cancer tissues in a human study using real-time RT-PCR, Western blotting and immunohistochemical staining. Adiponectin receptors, AdipoR1/AdipoR2, were expressed in normal colon epithelial and colon cancer cells. Furthermore, laser microdissection was performed to confirm our results. These results suggest that adiponectin may exert some effects on normal colon epithelium or colon cancer cells directly through adiponectin receptors. Further studies are required to elucidate the function of the AdipoRs activated by adiponectin and the downstream mechanisms of AdipoRs in colon cancer cells.

Peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses colonic epithelial cell turnover and colon carcinogenesis through inhibition of the beta-catenin/T cell factor (TCF) pathway.

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor superfamily member, plays a major role in lipid metabolism and insulin sensitivity. We investigated the role of PPARgamma in colonic epithelial cell turnover and carcinogenesis in colon because PPARgamma is strongly expressed in colonic epithelium. Administration of PPARgamma agonists suppressed epithelial cell turnover in mice. Expression level of beta-catenin protein, a key molecule in carcinogenesis, was increased in mouse colon treated with PPARgamma ligands. A direct interaction between beta-catenin and PPARgamma in cultured cell lines and colonic epithelium in mice was observed. Ligand-activated PPARgamma ligand directly interacts with beta-catenin, retaining it in the cytosol and reducing beta-catenin/T cell factor (TCF) transcriptional activity that is functionally important on aberrant crypt foci (ACF) formation. PPARgamma hetero-deficiency promoted the induction of ACF, but had no effect on the incidence of colonic polyps. These results indicate that PPARgamma regulates colonic epithelial cell turnover via direct interactions with beta-catenin, resulting in inhibition of beta-catenin-mediated transcriptional pathways that are involved in promoting cell proliferation. Our findings suggest that PPARgamma plays a role as a physiological regulator of colonic epithelial cell turnover and consequently predisposition to the development of colon cancer in early stage.

5-aminosalicylic acid given in the remission stage of colitis suppresses colitis-associated cancer in a mouse colitis model.

PURPOSE: The risk of colorectal cancer is increased in patients with inflammatory bowel diseases, especially those with ulcerative colitis (UC). Although 5-aminosalicylic acid (5-ASA) is widely used in the treatment of UC to suppress the colitic inflammation, no studies have been conducted to examine the chemopreventive effect of 5-ASA, given in the remission phase of colitis, against colitis-associated cancer using animal models. We therefore investigated the possible inhibition by peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and 5-ASA of colitis-associated colon carcinogenesis in a mouse model. EXPERIMENTAL DESIGN: A dextran sodium sulfate/azoxymethane-induced mouse colon cancer model was used, and the chemopreventive effects of 5-ASA and PPARgamma ligands, given in the remission phase of colitis, against colitis-related colon carcinogenesis, were evaluated. RESULTS: The number of neoplasms in the mice treated with 5-ASA was significantly lower than that in the control mice. In addition, the size of the neoplasms in treated mice was also significantly smaller than that in the control mice. In contrast, no significant suppression in the number or size of the tumors was observed in the mice treated with PPARgamma ligands. The proliferating cell nuclear antigen-labeling index in the tumor cells of the 5-ASA-treated mice was significantly smaller than that in the control, indicating that 5-ASA reduced tumor cell proliferation. CONCLUSION: Our results revealed that 5-ASA given in the remission phase of colitis significantly suppressed the development of colitis-associated cancer in a mouse model, which indicates the clinical importance of adopting chemopreventive strategies even in UC patients in remission.

Life style-related diseases of the digestive system: gene expression in nonalcoholic steatohepatitis patients and treatment strategies.

Nonalcoholic steatohepatitis (NASH) is a subset of nonalcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. We analyzed the expression profiles of approximately 50,000 genes and biological pathways in NASH patients in comparison with simple steatosis patients by using the analytical technique of GSEA (Gene Set Enrichment Analysis) by DNA microarrays. Although expressions of various genes were altered, GSEA showed clearly lower expression of nuclear receptors, including the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway. In a preliminary study we therefore investigated the therapeutic effect of low-dose pioglitazone (15 mg/day per body for 24 weeks), a synthetic ligand for PPARgamma, in 12 NASH patients. A decrease in aminotransferase (ALT) values to within the normal range was observed in 7 (58.3%) of the patients, and because the dose of pioglitazone was lower than that ordinarily used, no side effects, such as fatigue, lower extremity edema, or weight gain, were observed. In conclusion, the results confirmed involvement of the PPARgamma pathway in NASH and the therapeutic utility of a PPARgamma ligand.

Life style-related diseases of the digestive system: colorectal cancer as a life style-related disease: from carcinogenesis to medical treatment.

Life style-related diseases are associated with an increased risk of colorectal cancer (CRC). Recently, an association has been demonstrated between obesity and CRC. CRC has been associated with markers of insulin or glucose control, and insulin resistance might be the unifying mechanism by which several risk factors affect colorectal carcinogenesis. We evaluated the association between the number of aberrant crypt foci (ACF) and obesity, insulin resistance, hyperlipidemia, and other factors of life style-related disease. As a result, age, body mass index (BMI), waist circumference, and visceral fat obesity were significantly associated with the number of ACF. These results suggest that visceral fat obesity is an important target for CRC prevention. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily and is highly expressed in CRC. PPARgamma ligand administration for 1 to 8 months significantly reduced the number of ACF in human subjects. PPARgamma ligand is a promising candidate as a chemopreventive agent. Further investigation is needed to elucidate these mechanisms.

Inhibition of peroxisome proliferator-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties.

Esophageal cancer is difficult to treat because of its rapid progression, and more effective therapeutic approaches are needed. The PPARgamma is a nuclear receptor superfamily member that is expressed in many cancers. PPARgamma expression is a feature of esophageal cancer cell lines, and in the present investigation, the PPARgamma antagonists T0070907 and GW9662 could induce loss of invasion but could not induce growth reduction or apoptosis at low concentrations (< 10 mM). A high concentration of antagonists (50 microM) inhibited cell growth and induced apoptosis, but these effects did not explain our result at the low concentration. Morphological change, decreased expression of the cell signaling pathway and inhibition of cancer cell invasion were observed in the low concentration. This suggested that PPARgamma antagonists inhibited esophageal cancer cell invasion as well as cell adherence, most likely due to alteration in the FAK-MAPK pathway, and this was independent of apoptosis. These results suggested that PPARgamma plays an important role in cancer cell invasion and that it might be a novel target for therapy of esophageal cancer.