s-1743 and Esophageal-Neoplasms

Oesophageal cancer is on the rise and often present in an advanced state. Advances in surgical techniques, chemotherapy and radiotherapy have not changed the prognosis of oesophageal cancer over the last 20 years. With the unravelling of molecular biology of carcinogenesis in the oesophagus, there is a need for a paradigm shift from cancer treatment to prevention. Barrett's oesophagus is the commonest pre-malignant condition for development of oesophageal adenocarcinomas and is eminently suitable for the study of chemoprevention strategies. Now in its third year, the AspECT trial is the biggest, multicentre, randomised controlled clinical trial looking at the long-term chemoprevention effect of esomeprazole with or without aspirin. More than 85% of the participants tolerated the medications at the initial intended doses, and the drop-out rate has been 7%; the interim analysis is due in 2011.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Clinical Trials as Topic; Esomeprazole; Esophageal Neoplasms; Humans

Patients with dysplasia in Barrett's esophagus (BE) have a considerable risk of developing esophageal adenocarcinoma (EAC). The mucosal expression of the pro-inflammatory angiotensin II receptor type 1 (AT1R) is elevated in these patients, suggesting a role in carcinogenesis. The purpose of this study was to determine whether interference with the renin-angiotensin system (RAS) would influence downstream markers of carcinogenesis.. Endoscopic mucosal biopsies from BE patients with low-grade dysplasia (LGD) were sampled before and after a three-week period of RAS-interfering treatment. Thirty patients were randomly allocated to enalapril (ACE inhibitor, 5 mg od), candesartan (AT1R antagonist, 8 mg od), or no drug. The expression of 12 proteins known to be associated with RAS and carcinogenesis was assessed using western blot.. We found altered expression of several proteins after enalapril treatment (decreased: NFκB, p = .043; NLRP3, p = .050; AMACR, p = .017; and caspase 3, p = .025; increased: p53, p = .050). Candesartan treatment was associated with increased iNOS expression (p = .033). No significant changes were seen in the no-drug group.. Interference with angiotensin II formation was associated with altered expression of inflammation- and carcinogenesis-related proteins. The present results speak in favor of involvement of angiotensin II in BE dysplasia, but the role of AT1R should be investigated further.

Topics: Adenocarcinoma; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Barrett Esophagus; Benzimidazoles; Biomarkers, Tumor; Biphenyl Compounds; Enalapril; Endoscopy; Esomeprazole; Esophageal Neoplasms; Female; Humans; Hyperplasia; Male; Middle Aged; Neoplasm Proteins; Nitric Oxide Synthase Type II; Precancerous Conditions; Prospective Studies; Proton Pump Inhibitors; Renin-Angiotensin System; Risk Factors; Sweden; Tertiary Care Centers; Tetrazoles

To compare the diagnostic accuracy of conventional versus virtual microscopy for the diagnosis of Barrett's neoplasia.. Sixty-one biopsies from 35 ASPirin Esomeprazole ChemopreventionTrial (AspECT) trial patients were given a Barrett's neoplasia score (1-5) by a panel of five pathologists using conventional microscopy. Thirty-three biopsies positive for neoplasia were digitized and rescored blindly by virtual microscopy. Diagnostic reliability was compared between conventional and virtual microscopy using Fleiss' kappa. There was substantial reliability of diagnostic agreement (κ = 0.712) scoring the 61 biopsies and moderate agreement scoring the subgroup of 33 'positive' biopsies with both conventional microscopy (κ = 0.598) and virtual microscopy (κ = 0.436). Inter-observer diagnostic agreement between two pathologists by virtual microscopy was substantial (κ = 0.76). Comparison of panel consensus neoplasia scores between conventional and virtual microscopy was almost perfect (κ = 0.8769). However, with virtual microscopy there was lowering of the consensus neoplasia score in nine biopsies.. Diagnostic agreement with virtual microscopy compares favourably with conventional microscopy in what is recognized to be a challenging area of diagnostic practice. However, this study highlights possible limitations for this method in the primary diagnostic setting.

Topics: Anti-Ulcer Agents; Aspirin; Barrett Esophagus; Disease Progression; Esomeprazole; Esophageal Neoplasms; Esophagoscopy; Humans; Microscopy; Observer Variation; Reproducibility of Results; Telepathology; User-Computer Interface

Topics: Aspirin; Barrett Esophagus; Esomeprazole; Esophageal Neoplasms; Humans; Proton Pump Inhibitors

Topics: Child, Preschool; Endoscopy, Digestive System; Enteral Nutrition; Esomeprazole; Esophageal Neoplasms; Esophagus; Female; Focal Dermal Hypoplasia; Humans; Immunohistochemistry; Papilloma; Proton Pump Inhibitors; Stomach

Neoadjuvant treatment plays a crucial role in the therapy of advanced esophageal cancer. However, response to radiochemotherapy varies widely. Proton pump inhibitors (PPIs) have been demonstrated to impact on chemotherapy in a variety of other cancers. We analyzed the impact of PPI treatment on esophageal cancer cell lines, and investigated mechanisms that mediate the effect of PPI treatment in this tumour.. We investigated the effect of esomeprazole treatment on cancer cell survival, adhesion, migration and chemotherapy in human adeno-(OE19) and squamous-cell-carcinoma (KYSE410) cell lines. Furthermore, we investigated the effect of PPI treatment on intra-/extracellular pH and on expression of resistance-relevant miRNAs.. Esomeprazole significantly inhibited tumour cell survival (in a dose-dependent manner), adhesion and migration in both tumour subtypes. Furthermore, esomeprazole augmented the cytotoxic effect of cisplatin and 5-FU in both tumour subtypes. Surprisingly, PPI treatment led to a significant increase of intracellular pH and a decrease of the extracellular pH. Finally, we found esomeprazole affected expression of resistance-relevant miRNAs. Specifically, miR-141 and miR-200b were upregulated, whereas miR-376a was downregulated after PPI treatment in both tumour types.. Our study demonstrates for the first time that PPIs impact on tumour cell survival, metastatic potential and sensitivity towards chemotherapy in esophageal cancer cell lines. Furthermore, we observed that in this tumour entity, PPIs do not lead to intracellular acidification, but affect the expression of resistance-relevant miRNAs.

Topics: Adenocarcinoma; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Esomeprazole; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; MicroRNAs; Neoplasm Invasiveness; Proton Pump Inhibitors

There is a controversy as to whether gastroesophageal reflux disease (GERD) exists as a spectrum of disease severity or as a categorial disease in three distinct groups: nonerosive (NERD) and erosive reflux disease (ERD) and Barrett's esophagus (BE). Aim of the study was to assess progression or regression of GERD over 2 yr in a large cohort of patients (N = 3,894) under routine clinical care in Germany, Austria, and Switzerland (ProGERD study).. Patients with predominant heartburn, with or without esophagitis, were recruited and classified according to endoscopic status at baseline, i.e., NERD, erosive reflux disease-Los Angeles (ERD-LA) grade A/B and ERD-LA grade C/D, and BE. After an initial treatment with esomeprazole, they were followed, regardless of their response. Medical therapy or endoscopy was initiated at the discretion of their primary care physician, in line with routine care. At 2 yr, endoscopy with biopsy was performed according to the protocol.. After 2 yr, 25% of patients who had NERD at baseline progressed to LA A/B and 0.6% to LA C/D; 1.6% of patients who had LA A/B progressed to LA C/D and 61% regressed to NERD; 42% of patients who had LA C/D regressed to LA A/B and 50% regressed to NERD (all figures exclude patients with confirmed BE at baseline). At 2 yr, 22% of patients had been off medication for at least 3 months. Patients with ERD-LA grade C/D were at greatest risk of developing BE: 5.8% compared with 1.4% for ERD-LA grade A/B and 0.5% for NERD.. GERD does not seem to be a categorial disease. Progression and regression between grades was observed in this large cohort of patients under routine clinical care.

Topics: Barrett Esophagus; Disease Progression; Esomeprazole; Esophageal Neoplasms; Esophagitis; Esophagoscopy; Female; Follow-Up Studies; Gastroesophageal Reflux; Humans; Male; Middle Aged; Prospective Studies