Activation of Wnt signalling promotes development of dysplasia in Barrett's oesophagus.

Barrett's oesophagus is a precursor of oesophageal adenocarcinoma, via intestinal metaplasia and dysplasia. Risk of cancer increases substantially with dysplasia, particularly high-grade dysplasia. Thus, there is a clinical need to identify and treat patients with early-stage disease (metaplasia and low-grade dysplasia) that are at high risk of cancer. Activated Wnt signalling is critical for normal intestinal development and homeostasis, but less so for oesophageal development. Therefore, we asked whether abnormally increased Wnt signalling contributes to the development of Barrett's oesophagus (intestinal metaplasia) and/or dysplasia. Forty patients with Barrett's metaplasia, dysplasia or adenocarcinoma underwent endoscopy and biopsy. Mice with tamoxifen- and ß-naphthoflavone-induced expression of activated ß-catenin were used to up-regulate Wnt signalling in mouse oesophagus. Immunohistochemistry of ß-catenin, Ki67, a panel of Wnt target genes, and markers of intestinal metaplasia was performed on human and mouse tissues. In human tissues, expression of nuclear activated ß-catenin was found in dysplasia, particularly high grade. Barrett's metaplasia did not show high levels of activated ß-catenin. Up-regulation of Ki67 and Wnt target genes was also mostly associated with high-grade dysplasia. Aberrant activation of Wnt signalling in mouse oesophagus caused marked tissue disorganization with features of dysplasia, but only selected molecular indicators of metaplasia. Based on these results in human tissues and a mouse model, we conclude that abnormal activation of Wnt signalling likely plays only a minor role in initiation of Barrett's metaplasia but a more critical role in progression to dysplasia.

A comparison of POSSUM and GPS models in the prediction of post-operative outcome in patients undergoing oesophago-gastric cancer resection.

BACKGROUND: There is some evidence that a patient's pre-operative condition influences short-term and long-term post-operative outcomes. The aim of the present study is to compare the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) and modified Glasgow prognostic score (mGPS) models in the prediction of post-operative outcome, both short term and long term, in patients undergoing resection of oesophago-gastric cancer. PATIENTS AND METHODS: Patients who underwent curative resection for oesophago-gastric cancer from January 2005 to May 2009 and who had data to score the POSSUM, P-POSSUM, O-POSSUM and mGPS models were included in the study. Observed morbidity and mortality rates were compared with predicted outcome in different risk groups. Both short-term outcome and long-term survival were recorded. RESULTS: Observed morbidity was 49%, whereas POSSUM predicted post-operative morbidity in 60%, giving an overall standardised morbidity ratio of 0.82. Only male sex [hazard ratio (HR) 3.61, 95% confidence interval (CI) 1.38-9.46, P = 0.009] and POSSUM physiology score (HR 2.13, 95% CI 1.11-4.08, P = 0.023) were independently associated with post-operative morbidity. The post-operative mortality rates predicted by POSSUM, P-POSSUM and O-POSSUM were 16.5, 5.8 and 9.9%, respectively, giving a standardised mortality ratio of 0.25, 0.71 and 0.42. Only mGPS (HR 1.96, 95% CI 1.09-3.54, P = 0.025) and tumour-node-metastasis (TNM) stage (HR 2.21, 95% CI 1.44-3.38, P < 0.001) were independently associated with cancer-specific survival. CONCLUSIONS: The POSSUM physiology score was useful in predicting post-operative morbidity, and the mGPS was useful in predicting cancer-specific survival, in patients undergoing surgery for oesophago-gastric cancer.

Persistent elevation of C-reactive protein following esophagogastric cancer resection as a predictor of postoperative surgical site infectious complications.

BACKGROUND: Infectious complications, particularly in the form of anastomotic leaks (ALs) or surgical site infections (SSIs), represent a serious morbidity after esophagogastric cancer resections. Therefore, early detection is of paramount importance. Although markers of the systemic inflammatory response, including C-reactive protein (CRP) and white cell count (WCC), have been used in this regard, their relative predictive value is unclear. The aim of the present study was to examine serial postoperative WCC, albumin, and CRP and their diagnostic accuracy in case of infectious complications. PATIENTS AND METHODS: White cell count, albumin, and CRP were routinely measured postoperatively for 7 days in 136 consecutive patients who had undergone esophagogastric cancer resection. All postoperative complications were recorded. The diagnostic accuracy of the WCC, albumin, and CRP values were analyzed by receiver operating characteristics curve analysis with surgical site and remote infectious complications as outcome measures. RESULTS: Fifty-four (40%) patients developed infectious complications, and 17 of them developed an AL. CRP was significantly higher from postoperative day (POD) 3 onward in those patients who developed an AL. On POD 3, a threshold reading of 180 mg/l was associated with development of an AL, providing a sensitivity of 82% and a specificity of 63%. On POD 4, the same CRP threshold of 180 mg/l provided 71% sensitivity and 83% specificity. CONCLUSIONS: Postoperative CRP measurements on PODs 3 and 4 are clinically useful in predicting surgical site infectious complications, in particular an AL, after resection for esophagogastric cancer.

Comparison of the prognostic value of tumour- and patient-related factors in patients undergoing potentially curative resection of oesophageal cancer.

BACKGROUND: Evidence is increasing that elevated systemic inflammation is associated with poor survival in patients with oesophageal carcinoma. However, it is not yet established if any specific component of systemic inflammatory response is a better predictor of cancer survival. The aim of the present study was to compare the predictive value of selected markers of systemic inflammation in patients who undergo surgical resection of oesophageal cancer. METHODS: One hundred twelve patients who underwent potentially curative resection for oesophageal carcinoma, including type I and type II tumours of the gastro-oesophageal junction (Siewert and Stein in Dis Esophagus 9:173-182, 1996), between 1996 and 2008 were included in the study. Patients had laboratory measurement of white cells, neutrophils, lymphocytes, platelet counts, albumin, and C-reactive protein. Glasgow Prognostic Score (mGPS), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and metastatic lymph node ratio (LNR) were calculated. RESULTS: On multivariate analysis, only the LNR (HR 2.87, 95% CI 1.99-4.15, p < 0.001) and the mGPS (HR 4.31, 95% CI 2.20-8.45, p < 0.001) were independently associated with cancer-specific survival in oesophageal cancer. An elevated mGPS was associated with high white cell count (p < 0.05) and poorer survival (p = 0.001). CONCLUSION: The present study indicates that the mGPS, an acute-phase protein-based prognostic score, better predicts cancer survival compared with the cellular components of systemic inflammation in patients with oesophageal carcinoma.

Photodynamic therapy for Barretts' adenocarcinoma associated with an Angelchik device.

We present a novel case of an elderly patient with a Barrett's adenocarcinoma in the presence of an Angelchik prosthesis. We aim to draw attention to issues relating to metaplastic Barretts' oesphagus and its adenocarcinoma complications and highlight relevant issues in multimodal endoscopic management and palliation using photodynamic therapy in the presence of the device.

Comparison of the prognostic value of tumour and patient related factors in patients undergoing potentially curative resection of gastric cancer.

BACKGROUND: There is increasing evidence that the patient-related systemic inflammatory response is a powerful prognostic factor. The aim of the present study was to compare the prognostic value of selected markers of the systemic inflammatory response in patients undergoing resection of gastric cancer. METHODS: One hundred twenty patients undergoing resection of gastric cancer, had measurements of various systemic inflammatory markers in addition to tumor-related factors. From these, the modified Glasgow Prognostic Score (mGPS), neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and metastatic lymph node ratio were calculated. RESULTS: On multivariate analysis, only the ratio of positive to total lymph nodes (hazard ratio, 2.29%; 95% confidence interval, 1.57%-3.33%; P < .001) and the mGPS (hazard ratio, 2.23%; 95% confidence interval, 1.40%-3.54%; P = .001) were independently associated with cancer-specific survival in patients with gastric cancer. An increase in the mGPS was associated with a higher neutrophil/lymphocyte ratio (P < .05) and poorer survival (P < .001). CONCLUSIONS: The present study indicates that the mGPS, an acute-phase, protein-based prognostic score, is a superior predictor of cancer survival compared with the cellular components of the systemic inflammatory response in patients undergoing resection of gastric cancer.