Activation of the Raf/MEK/ERK (MAPK) signal transduction cascade by RAS mutations has been found in a variety of human cancers. Mutations of BRAF provide an alternative route for activation of this signalling pathway. To determine the role of mutations in BRAF and KRAS2 in the neoplastic progression of Barrett's adenocarcinoma, we analysed both genes for common mutations. After microdissection, DNA of 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n ¼ 29 low-grade intraepithelial neoplasia (LGIN) and n ¼ 27 high-grade intraepithelial neoplasia (HGIN)), 30 Barrett's mucosa without neoplasia and normal squamous, as well as gastric epithelium, were analysed for BRAF and KRAS2 mutation. Activating BRAF mutations were identified in 2/19 Barrett's adenocarcinomas (11%) and in 1/27 HGIN (4%). KRAS2 mutations were found in four out of 19 (21%) Barrett's adenocarcinomas examined and in three cases of HGIN (11%). In LGIN as well as in normal gastric or oesophageal mucosa, neither BRAF nor KRAS2 mutations were detected. All lesions with KRAS2 mutations had an intact BRAF gene. The status of mismatch-repair proteins was neither related to BRAF nor KRAS2 mutations. These data indicate that RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas. We conclude that the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma.

Objective: Acute respiratory dysfunction (ARD) can occur after acute type A aortic dissection, but relatively little is known about ARD in such patients. This study aims to analyse the clinical impact of ARD after surgery for acute type A aortic dissection and to assess possible treatment options. Methods: We reviewed our institutional database to identify patients who underwent surgery for acute type A dissection between October 1994 and January 2008 (n = 276). Postoperative ARD was defined as oxygenation impairment (PaO 2 /FiO 2 <150) that occurred within 72 h of surgery and was not related to other documented causes of acute respiratory failure. Results: A total of 37 patients (13%) (27 male, mean age 60.7 AE 11 years) experienced ARD after surgery for acute type A dissection. Intensive care unit stay was significantly longer for patients with ARD than those without (18 AE 11 days vs 7.5 AE 6 days, respectively, p < 0.0001). However, hospital mortality was not significantly different between groups (16% for ARD patients vs 19% for patients without ARD, p = 0.6). Logistic regression analysis identified preoperative multiple malperfusion as the only risk factor for ARD (OR 3.2, 95% confidence interval (C.I.): 2.2-4.9). Peak C-reactive protein levels were significantly higher in ARD patients (17.7 AE 6.7 vs 9.6 AE 5.4 mg dl À1 , p = 0.04). Prone positioning ventilation was performed in 15 patients (40%) with severely impaired oxygenation and resulted in an immediate increase in mean oxygenation index from 71.6 AE 8.8 to 138 AE 92.6 ( p < 0.001). There was a tendency towards a shorter total time of mechanical ventilation (355 AE 188 h vs 433 AE 318 h, p = 0.2) and shorter ICU stay (405 AE 198 h vs 505 AE 265 h, p = 0.2) in the prone positioning subgroup. Conclusions: ARD is a relatively common complication of surgery for acute type A dissection and is associated with increased morbidity and resource utilisation. Patients with preoperative malperfusion are at increased risk for development of ARD. Prone positioning is a viable treatment option that significantly improves pulmonary oxygenation. #

We conclude that most Barrett's intraepithelial neoplasms contain genetic and/or epigenetic INK4a-ARF alterations. Methylation of p16INK4a appears to be the most frequent epigenetic defect in the neoplastic progression of Barrett's tumourigenesis.

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