Efficacy of submucosal injection of different solutions inclusive blood components on mucosa elevation for endoscopic resection.

BACKGROUND: Endoscopic resection has become the standard treatment for noninvasive gastrointestinal malignancies. In flat mucosal tumors, normal saline is frequently used for submucosal fluid injection in order to reduce the risk of complications during endoscopic resection. Recent studies have demonstrated longer-lasting mucosa elevation by injection of agents such as hyaluronic acid or glyceol, rather than normal saline. We investigated the efficacy of different blood components in comparison with other solutions for use as a submucosal fluid cushion. METHODS: Normal saline, sodium hyaluronate, glyceol, hydroxyethyl starch, serum, plasma, and whole blood were evaluated for their effectiveness in creating a submucosal cushion. One milliliter of each solution was injected into the submucosa of 5 × 5 cm specimens of resected porcine stomach. Mucosa elevation was measured before and up to 60 minutes after injection. RESULTS: The shortest duration of mucosa elevation was observed after injection of normal saline, glyceol, and 0.125% hyaluronic acid. A significantly longer duration was obtained after injection of hydroxyethyl starch, 0.25% and 0.5% hyaluronic acid, serum, and plasma. However, whole blood generated a longer-lasting mucosa elevation than all other agents. CONCLUSION: The results of the current study suggest that whole blood is more effective in generating long-lasting mucosa elevation than any other commonly used solution. Because autologous blood is readily available at almost no cost, this seems to be an optimal agent for creating the mucosa elevation needed for endoscopic resection. Further in vivo studies in humans are needed to clarify the potential role of autologous blood for long-lasting endoscopic mucosa resection or endoscopic submucosal dissection.

Differential effects of PPARgamma activation by the oral antidiabetic agent pioglitazone in Barrett's carcinoma in vitro and in vivo.

BACKGROUND AND PURPOSE: The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcription factor regulating genes involved in adipogenesis, glucose homeostasis and cell differentiation. Moreover, PPARgamma has been demonstrated to control proliferation and apoptosis in various cancer cells. We investigated the biological effects of PPARgamma activation by the oral antidiabetic agent pioglitazone in Barrett's adenocarcinoma cells in vitro and in vivo. RESULTS: PPARgamma mRNA and protein were overexpressed in endoscopic biopsies of Barrett's epithelium and the human Barrett's adenocarcinoma cancer cell line OE33 as compared to normal esophagus and stomach and the esophageal squamous epithelium cancer cell line Kyse-180. PPARgamma activation by pioglitazone in OE33 cells in vitro led to reduced cell growth by induction of apoptosis. Effects of systemic PPARgamma activation by the thiazolidinedione pioglitazone on tumor cell proliferation and apoptosis were then assessed in vivo in nude mice bearing transplantable Barrett's adenocarcinomas derived from OE33 cells. Unexpectedly, enhanced growth of OE33 derived transplantable adenocarcinomas was observed in Balb/c nu/nu mice upon systemic pioglitazone treatment due to increased cell proliferation. CONCLUSION: These results indicate that PPARgamma is involved in the molecular pathogenesis of Barrett's adenocarcinoma formation and growth. However, activation of PPARgamma exerts differential effects on growth of Barrett's adenocarcinoma cells in vitro and in vivo emphasizing the importance of additional cell context specific factors and systemic metabolic status for the modulation of PPARgamma action in vivo.

Selenium supplementation enhances low selenium levels and stimulates glutathione peroxidase activity in peripheral blood and distal colon mucosa in past and present carriers of colon adenomas.

Selenoproteins such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR), and selenoprotein P (SePP) contain molecular selenium in form of selenocysteines within their active center. They are involved in the defense of reactive oxygen species, which otherwise may cause DNA damage and alterations of protein function. Selenium intake has been linked to colon carcinogenesis in epidemiological and interventional studies. In a double-blinded, placebo-controlled trial, we demonstrate that carriers of colon adenomas present with low basal serum levels of selenium and plasma glutathione peroxidase (pGPx) activity before treatment, but both parameters can be normalized by interventional selenium supplementation. GPx activity in colon mucosa was enhanced in the verum group, albeit this had only borderline significance. No change of activity was observed for mucosal TrxR activity on selenium supplementation. In summary, our results confirm the existence of low selenium levels in patients prone to colon adenomas and show that by selenium supplementation this can be normalized. If prospective trials confirm that selenium supplementation reduces colon cancer incidence rates, it may be concluded that selenium supplementation should be recommended for patients at risk.

A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency.

Epidemiological data, animal studies and interventional studies provide evidence for a potential chemopreventive effect of selenium during development of colorectal cancer. The human glycoprotein Selenoprotein P (SeP) contains up to 50% of plasma selenium content. SeP is expressed in the gastrointestinal tract and the liver, where its expression is downregulated by various proinflammatory cytokines (Il1beta, TGFbeta, IFNgamma). Previously, we have demonstrated dramatically reduced SeP expression in human colon adenomas. Here, we have identified a complex (A)4-C-(A)4-GG-(A)8-GCT-(TC)5-(T)17 (bp -429 to bp - 477) repeat structure within the SeP promoter and we have analysed this regulatory DNA sequence with respect to polymorphisms, genomic instability and functional relevance to promoter activity. As opposed to the (TC)5 variant we identified a novel (TC)3 polymorphism within this repeat in the general population, which conferred significantly reduced basal promoter activity to reporter gene constructs in HepG2 cells. Allelic distribution of this (TC)(n) element was similar in colon carcinoma patients and healthy controls. Additionally, we observed genetic instability within the (T)17 repeat motif in colon cancers of the mutator phenotype. This instability of the (T)17 repeat had no effect on basal promoter activity in reporter gene assays. In conclusion, we characterised a complex repeat structure within the SeP promoter that may be of functional relevance to SeP gene expression. Further studies on the effect of different SeP promoter genotypes on SeP protein expression and disease susceptibility are needed.