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• W608552401 abstract "Gastro-esophageal reflux disease (GERD) is a relevant health problem worldwide. It impairs patients' quality of life and predisposes to intestinal-like esophageal metaplasia (i.e. Barrett's esophagus, BE), that is recognized as the major risk factor for the development of esophageal adenocarcinoma (Eac).The incidence of Eac has dramatically increased since the mid of the 1970s in the USA and Western countries for unknown reasons, while the prognosis of Eac has only slightly been improved. During the same time potent acid suppressors have been introduced for the treatment of GERD. Nowadays these drugs lead the list of the world best seller drugs with a US$ 8 billion market per year. Some authors have linked the increase of the incidence of Eac with the wide diffusion of acid suppression in the general population and among patients with GERD(1).The risk of Eac in patients with GERD is too low to justify endoscopic surveillance. On the other hand endoscopic surveillance for patients with BE is generally accepted. Clinical evidence is still lacking on the best treatment for BE, in order to minimize the risk for neoplastic progression(2). Pharmacological, surgical and endoscopic therapies have been used, without a clear evidence about the benefit of a treatment on the others (chapter 1).The experimental surgical models of reflux-induced esophageal carcinogenesis can reproduce in laboratory animals the stepwise progression from inflammation to Eac, through BE(3,4). In Chapter 2 we provide a detailed description of the microsurgical technique we used for the reflux induced esophageal carcinogenesis model, in order to increase its reproducibility and minimize the number of animals needed to set up the experiments.Chapter 3 shows the results of a study about the effect of chronic GERD on animal welfare. The main short and long-term clinical complications are analyzed, as well as the significance and prognostic value of two different scoring systems based on clinical parameters. Using these methods, humane endpoints can be defined.A time-course experiment of long-lasting GERD in the rat is presented in chapter 4 with both the histological findings and Cdx2 immunostaining(5). Two types of metaplastic lesions are described: intestinal metaplasia (BE) and multi-layered epithelium (MLE). MLE consists of four to seven layers of cells that appear as basaloid squamous cells in the basal part and columnar cells in the superficial layer. Therefore MLE is a hybrid epithelium in which both squamous and columnar epithelia coexist and is considered a protometaplasia (i.e. a precursor of BE). Consistently with its phenotype, MLE expresses markers of both squamous and columnar differentiation6. The presence of MLE has been associated with reflux(1).Cdx2 is a transcription factor that regulates the expression of differentiation-related molecules and it is specifically involved in intestinal cells commitment. The prevalence of Cdx2 expression (i.e. the prevalence of BE and MLE) increases significantly with time in the study, suggesting a time-dependent relationship between the chemical injury and the severity of the lesions. De novo Cdx2 expression is shown to be an early event among the morphological changes caused by the refluxate, consistently with the results by Pera and collaborators(7), who described Cdx2 immunostaining in the basal cell layer close to esophageal ulcers 16 weeks after surgery.Chapter 5 provides evidence of both esophagitis cystica profunda, metaplasia and Eac in the model in use. Esophagitis cystica profunda has been defined as a highly differentiated mucinous lesion commonly found in the submucosa at the site of surgical anastomosis(8). This entity has to be considered an inflammatory reaction, caused by the surgical insult. On the other side we present an external validation that both intestinal metaplasia (i.e. BE) and true Eac can be obtained using our surgically-induced reflux model.Chapter 6 is an experimental study on the effect of long-term proton pump inhibitor (PPI) treatment in the rat model of reflux-induced esophageal carcinogenesis.Consistently with the literature, describing PPIs as very effective drugs in ulcer healing, ulcers resulted more severe in the placebo group, compared with the PPI group, in our study. Surprisingly, esophagitis cystica profunda was more common among PPI-treated animals. This mucous-producing lesion has been generally described as well differentiated mucinous adenocarcinoma. However, we consider these tumours as inflammatory reactions, consistently with Ten Kate and collaborators(8). Of note, the misinterpretation of those lesions as adenocarcinomas could lead to the false belief that PPI treatment had increased the incidence of adenocarcinoma in the present study. On the contrary, an effect of the drug on the incidence of carcinomas was not demonstrated by our study. Surgical anti-reflux treatments and acid-suppressors in humans aim primarily to relieve symptoms of GERD. Anti-reflux surgery offers the advantage of reducing both acid and bile reflux, which has been shown to act synergistically in the pathogenesis of Barrett’s esophagus(9).On the other hand, PPIs are acid suppressors. The effect of PPIs in preventing or inducing Eac progression in patients with GERD or BE is controversial. In vivo experimental studies of reflux treated with proton pump inhibitor have not revealed a reduction in adenocarcinoma risk(10-12). However using the esophagoduodenostomy model for esophageal reflux in the rat a recent study comparing refluxates of different pH found that non-acidic refluxate increases the occurrence of intestinal metaplasia with dysplasia and EAC while the low-pH gastric juice exerts a protective effect in the presence of duodenal juice(13). Acid has been recently shown to have antiproliferative effects in nonneoplastic Barrett's epithelial cells cultured in vitro and it has been suggested that the prescription of acid suppressors in dosages beyond those required to control GERD symptoms could be detrimental(14).Gastric acid secretion is a complex, tightly regulated, physiological mechanism, with neural, hormonal, paracrine, and intracellular pathways. Gastrin, histamine, acetylcholine are the major stimuli for acid secretion, that is primarily inhibited by somatostatin, and to a lesser extent by cholecystokinin, atrial natriuretic peptide, and nitric oxide(15).PPIs act on the final common pathway of gastric acid secretion, permanently inactivating the H+/K+ ATPase (proton pump) in the parietal cell. The consequent increase in gastric pH removes the negative feedback for gastrin production by G cells. As a consequence, hypergastrinemia develops in patients with GERD treated with PPIs chronically or life-long. Concerns have been expressed about the potential role of gastrin on esophageal carcinogenesis. In vitro studies suggested that BE is sensitive to the proliferative effects of gastrin via its cholecystokinin-type 2/gastrin receptor (CCK-2R)(16). An antiapoptotic role for gastrin through up-regulation of PKB/Akt in BE samples has been recently suggested and the treatment with a CCK-2R antagonist has been shown to reduce the levels of activated PKB/Akt(17). A better understanding of the effect of pathways regulating gastric secretions could lead to new pharmacological strategies to treat gastroesophageal reflux disease." @default.
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• W608552401 date "2012-01-30" @default.
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• W608552401 title "New Insights In Experimental Esophageal Carcinogenesis" @default.
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