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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Syndromic and sporadic fundic gland polyps are morphologically indistinguishable but may arise via different pathogenetic mechanisms involving mutations of the adenomatous polyposis coli (APC) and its downstream target beta-catenin genes. Although a higher frequency of dysplasia has been reported in syndromic forms, the risk of developing invasive carcinoma is exceedingly low. The current study was designed to investigate whether syndromic and sporadic fundic gland polyps differ in protein expression of a number of genes that are thought to be important in the control of neoplastic transformation. A total of 262 fundic gland polyps, including 155 syndromic polyps obtained from 35 patients with familial adenomatous polyposis or Gardner's syndrome and 107 sporadic polyps randomly selected from 45 patients with gastroesophageal reflux disease or Barrett's esophagus, were included in this study. Immunohistochemical evaluation showed that loss of immunoreactivity to the antibody against the carboxyl terminus of the APC protein, presumably resulting from APC gene mutations, was more frequent in syndromic than in sporadic cases (40% versus 6.7%, P<0.001). However, immunostaining failed to show aberrant nuclear localization of beta-catenin, a protein regulated by APC, in any of the polyps, irrespective of syndromic or sporadic types. Instead, positive membranous staining for beta-catenin was observed in all the cases. In addition, the expression characteristics of 2 other proteins, c-Myc and cyclin D1, whose genes have been reported to be transcriptionally regulated by the APC/beta-catenin pathway, were similar in these two types of polyps. Furthermore, all cases, including those harboring dysplasia, showed negative nuclear staining for p53 and positive nuclear staining for retinoblastoma (RB). Taken together, these data show a lack of dysregulation in the APC/beta-catenin signaling pathway and in the expression of p53 and RB in fundic gland polyps despite a high frequency of somatic mutations of the APC and beta-catenin genes reported in these polyps. These findings may explain at least in part why fundic gland polyps show a negligible malignant potential even in the presence of dysplasia.
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PMID:Immunohistochemical evaluation of adenomatous polyposis coli, beta-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps. 1501 89

Gastric cancer has been declining for more than half a century, whereas the incidence of oesophageal cancer is increasing rapidly. The histopathological subtype is also changing with a predominance of oesophageal adenocarcinoma compared with squamous carcinoma. The reasons for these epidemiological changes are not clear, although population-based data have implicated gastro-oesophageal reflux disease as a risk factor. In susceptible individuals reflux of duodeno-gastric contents can lead to the development of a columnar-lined oesophagus, commonly called Barrett's oesophagus. This can then progress to adenocarcinoma via a metaplasia-dysplasia-carcinoma sequence. At the current time, the mortality from oesophageal adenocarcinoma exceeds 80% at 5 years. Therefore, endoscopic surveillance programmes have been generally recommended for patients with Barrett's oesophagus in an attempt to detect early, curable lesions. Unfortunately these programmes are cumbersome and costly and have not yet been proved to reduce population mortality. In order to improve patient outcomes we need to be able to identify patients at high risk and to understand the triggers for disease progression. There is mounting evidence that there is an underlying genetic susceptibility to Barrett's oesophagus and oesophageal adenocarcinoma. However, this is likely to be as a result of multiple low penetrance susceptibility genes which have yet to be identified. Once patients are identified as having Barrett's oesophagus their chance for developing adenocarcinoma is in the order of 0.5%-1% per year. The histological assessment of dysplasia as a predictor of cancer development is highly subjective. Therefore multiple, specific somatic mutations in the tissue have been investigated as potential biomarkers. The most promising markers to date are the presence of aneuploidy, loss of heterozygosity of p53 and cyclin D1 overexpression. However, a study of evolutionary relationships suggest that mutations occur in no obligate order. Combinatorial approaches are therefore being advocated which include genomic profiling or the use of a panel of molecular markers in order to define the common molecular signatures that can then be used to predict malignant progression. An alternative approach would be to use markers for the final common pathway following genetic instability, which is the loss of proliferative control. We have demonstrated an increase in the expression of a novel proliferation marker, Mcm2, which occurs during the malignant progression of Barrett's oesophagus. These Mcm2-expressing cells are detectable on the surface, and hence a cytological approach may be applicable. In view of the role of reflux components in the pathogenesis of Barrett's oesophagus the effect of acid and bile on the cell phenotype have been studied. These studies have demonstrated that pulsatile acid and bile exposure induce cell proliferation. The mechanism for the hyperproliferative response appears to involve p38 mitogen activated protein kinase (MAPK) pathways as well as protein kinase C (PKC) and cyclo-oxygenases. A clinical implication of the laboratory studies is that suppression of acid and bile may need to be profound in order to suppress cell proliferation and, by inference, ultimately prevent the development of dysplasia. There is some support for this concept from short-term clinical studies, and a large randomised chemoprevention trial is being instigated which will evaluate the effect of proton pump inhibitors with or without aspirin. Given the epidemic increase in oesophageal adenocarcinoma and the dismal 5-year mortality rate, a radical approach is necessary to prevent cancer development in individuals with pre-malignant lesions.
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PMID:Genetics and prevention of oesophageal adenocarcinoma. 1564 81

Many histologic changes have been described in the esophageal squamous mucosa in patients with gastroesophageal reflux disease (GERD), including dilated intercellular spaces, balloon cells, intrapapillary vessel dilation, elongated papillae, basal cell hyperplasia, acanthosis, intraepithelial eosinophils, Langerhans cells, and p53 protein overexpression. To define a set of histologic changes that are invariably reflux associated, we examined the histologic changes in esophageal specimens from normal controls, patients with GERD, patients without GERD but with a suspicion of other pathology, and patients with esophageal carcinoma. We also examined biopsy specimens from sites with differing endoscopic features, including cloudy white and reddened mucosa. A definitive set of reflux-associated histologic changes could not be defined from the small number of biopsy specimens examined in the present study. Histologic changes indicative of GERD are likely to be found somewhere in the esophagus in all patients with GERD, but these changes are nonspecific. A set of histologic changes that are invariably reflux associated may exist, but these changes are nonspecific. To develop a set of characteristic reflux-associated features, endoscopists may perform targeted biopsies from several sites with various endoscopic features and at different stages of disease.
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PMID:Is there a set of histologic changes that are invariably reflux associated? 1567 11

Barrett's esophagus (BE) represents the most serious histological consequence of gastroesophageal reflux disease (GERD) that develops in 5-10% of patients with GERD. Given that BE is the only known precursor to esophageal adenocarcinoma (EA), a systematic endoscopic biopsy protocol can detect EAs at an early stage. However, endoscopic and histopathological evaluation of BE are not adequate for effective screening of high risk patients. Therefore, molecular abnormalities associated with BE have been considered as surrogate markers and their use as such is proposed. Flow cytometry is the most useful adjunct to histology, and ploidy status of BE is an independent risk factor. Cyclin D1 overexpression is inversely correlated with survival in EA. C-erbB2 (+) patients have poorer prognosis. High plasma adenomatous polyposis coli levels correlate with reduced patient survival. p53 expression allows patient risk for EA stratification. Nuclear factor-kappaB overexpression inversely correlates with good response to adjuvant chemotherapy and radiotherapy in EA. Patients with cyclooxygenase-2 overexpression have reduced survival rates. Increased E-cadherin staining is associated with shorter survival in EA patients who received chemoradiotherapy. Finally, existing data cannot rule out a correlation between EA and colorectal tumors. Seventeen BE molecular alterations yielded noteworthy clinical implications. Apart from endoscopy and histology, these data allow for better risk stratification for patients with BE and for more efficient and timely therapeutic approaches.
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PMID:New molecular concepts of Barrett's esophagus: clinical implications and biomarkers. 1585 73

Carcinogenesis in Barrett's esophagus involves the accumulation of DNA abnormalities that enable cells to 1) provide their own growth signals; 2) ignore growth-inhibitory signals; 3) avoid apoptosis; 4) replicate without limit; 5) sustain angiogenesis; and 6) invade and proliferate in unnatural locations. This report reviews recent publications describing molecular abnormalities in Barrett's esophagus that could lead to the acquisition of these key physiologic hallmarks of malignancy. Some recent reports suggest that the gastroesophageal reflux of acid and bile can activate molecular pathways that promote proliferation and interfere with apoptosis in Barrett's metaplastic cells. Inactivation of the p16 and p53 tumor suppressor genes through promoter methylation, gene mutation, or loss of heterozygosity appears to be important for carcinogenesis in Barrett's esophagus. Finally, this report discusses recent data regarding the role of the Cdx2 gene in the development of esophageal intestinal metaplasia.
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PMID:Barrett's esophagus: a molecular perspective. 1591 75

Barrett's esophagus is a premalignant condition and remains the number one risk factor for developing adenocarcinoma. Gastro-esophageal reflux disease is a strong risk factor for both esophageal adenocarcinoma and the precancerous lesion Barrett's esophagus. Both of these conditions are related to the reflux of acid and bile into the esophagus. This results in inflammation and cell damage which initiates a sequence of events termed the metaplasia-dysplasia sequence in which the squamous epithelium is replaced by columnar epithelium exhibiting increasing degrees of dysplasia and overt malignancy. The underlying disease mechanisms remain unclear, but tumor suppression genes (p53, p16, APC) and, oncogenes (K-ras, cyclin D1, c-erb-2) seem to cause the malignant transformation of Barrett's esophagus, and the genetic or epigenetic alterations of these genes have been reported.
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PMID:[Carcinogenesis of Barrett's esophagus]. 1610 Dec 21

The development and progression of Barrett's epithelium are accompanied with the acquisition of many molecular changes of the oesophageal mucosa. Gastro-oesophageal reflux and inflammation cause the oxidative stress and free-radical generations, which result in the expression of oxidative-stress-related genes and the induction of DNA damage. The development of Barrett's epithelium follows a metaplasia-dysplasia-adenocarcinoma sequence, characterized by the accumulation of many genetic and epigenetic alterations, which are seen in carcinogenesis. Abnormalities in the expression of tumor suppressor genes, such as p53, p16, APC, and a number of molecules involved in cell proliferation, apoptosis or angiogenesis are observed. These genetic alterations affecting the cancer hallmarks provide a better understanding of the etiology and pathogenesis of the disease.
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PMID:[Molecular events associated with Barrett's oesophagus]. 1610 Dec 22

Barrett's esophagus is the result of chronic injury which is usually caused by gastroesophageal reflux. NF-kappaB is expressed in the reflux esophagitis. Specialized columnar epithelium (SCE) is characteristic of Barrett's esophagus and has a malignant predisposition. SCE expresses Cdx1 and Cdx2. Adenocarcinoma in Barrett's esophagus is believed to develop through the metaplasia-dysplasia-carcinoma sequence. P53, beta-catenin, PPARgamma, and estrogen receptor beta are closely related to the development of esophageal carcinogenesis.
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PMID:[Expression of transcription factor in Barrett's esophagus]. 1610 Dec 23

Barrett's esophagus (BE) is a metaplastic disorder in which specialized columnar epithelium replaces healthy squamous epithelium (intestinal metaplasia). Even though its pathophysiology and the steps of its neoplastic progression are not completely understood, BE can be considered as a complication of gastroesophageal reflux disease (GERD). Given that esophageal adenocarcinoma, which is continually increasing in the Western world, still has a poor prognosis and suffers from late diagnosis, and because BE is a precancerous lesion, there is a strong need for good molecular markers of malignant progression in Barrett's metaplasia (BM). The aim of this review is to examine the published data regarding the role that assessment of p53 may play in the management of BE, trying to understand if it may be a useful marker to early diagnose BE malignant transformation.
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PMID:p53 and the malignant progression of Barrett's esophagus. 1611 Apr 81

Over the past three decades, there has been a marked change in the epidemiology of esophageal malignancy, with an increasing incidence of esophageal adenocarcinoma. The reasons for this are largely unknown and remain controversial, but several lifestyle risk factors have been proposed, including gastroesophageal reflux disease (GERD). It is hypothesized that chronic GERD results in acute mucosal injury, promotes cellular proliferation, and induces specialized columnar metaplasia (Barrett esophagus). Progression of Barrett esophagus to invasive adenocarcinoma is reflected histologically by the metaplasia-dysplasia-carcinoma sequence. Dysplasia is widely regarded as the precursor of invasive cancer, and high-grade dysplasia in Barrett epithelium is frequently associated with esophageal adenocarcinoma. Although several molecular alterations have been described in Barrett esophagus, it is anticipated that relatively few will prove to be clinically useful. To date, biomarkers which currently appear to predict the progression of Barrett esophagus to invasive malignancy include aneuploidy, loss of heterozygosity of 17p (implicating the p53 tumor suppressor gene), and cyclin D1 protein overexpression, and with further validation, will most likely be incorporated into routine clinical practice. It is anticipated that models incorporating objective scores of sociodemographic and lifestyle risk factors (ie, age, gender, body mass index), severity of reflux symptoms, endoscopic and histologic findings, and an assessment of a panel of biomarkers will be developed to further define subsets of patients with Barrett esophagus at increased risk for malignant progression, thereby permitting the development of more rational endoscopic surveillance and screening programs.
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PMID:Epidemiology and molecular biology of Barrett esophagus. 1642 34


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