Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers.

BACKGROUND: Altered DNA repair may be associated with aggressive tumour biology and impact upon response to chemotherapy and radiotherapy. We investigated whether expression of human AP endonuclease (APE1), a key multifunctional protein involved in DNA BER, would impact on clinicopathological outcomes in ovarian, gastro-oesophageal, and pancreatico-biliary cancer. METHODS: Formalin-fixed human ovarian, gastro-oesophageal, and pancreatico-biliary cancers were constructed into TMAs. Expression of APE1 was analysed by IHC and correlated to clinicopathological variables. RESULTS: In ovarian cancer, nuclear APE1 expression was seen in 71.9% (97 out of 135) of tumours and correlated with tumour type (P=0.006), optimal debulking (P=0.009), and overall survival (P=0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% (16 out of 46) of tumours were positive in the nucleus and this correlated with shorter overall survival (P=0.005), whereas cytoplasmic localisation correlated with tumour dedifferentiation (P=0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% (32 out of 72) of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P=0.007), vascular invasion (P=0.05), and poorly differentiated tumours (P=0.068). A trend was noticed with advanced stage (P=0.077). CONCLUSIONS: Positive clinicopathological correlations of APE1 expression suggest that APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. METHODS AND RESULTS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). CONCLUSIONS: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.

Biomarkers of response to therapy in oesophago-gastric cancer.

Cancer of the oesophagus, gastro-oesophageal junction (GOJ) and stomach remains a major health problem worldwide. The evidence base for the optimal management of patients with operable oesophago-gastric cancer is evolving. Accepted approaches include preoperative chemotherapy followed by surgery (oesophageal cancer), chemo-radiotherapy alone (oesophageal cancer) and perioperative chemotherapy (gastric and gastro-oesophageal adenocarcinomas). The underlying principles behind neoadjuvant therapy are to improve resectability of the tumour by tumour shrinkage/downstaging and to treat occult metastatic disease as early as possible. The response rate to cytotoxic therapy is about 40% in oesophago-gastric cancer. Available evidence suggests that a favourable histopathological response to cytotoxic therapy may be a useful positive predictive marker in oesophago-gastric cancer. However, the ability to predict tumour response in routine clinical practice is difficult and is an area of intense investigation. There is evolving evidence for the role of predictive biomarkers in cancer in general and oesophago-gastric cancer in particular. We provide an overview on the current status of radiological and biological predictive biomarkers. We have focussed on clinical translational investigations and, where appropriate, provided pre-clinical insights. Whether predictive markers will be routinely incorporated in clinical practice remains to be seen as biomarker research is expensive and the data generated from these investigations are complex. It is clear that a concerted international effort between academia and industry is critical if personalised medicine as a practical reality for our cancer patients is to be realised.

Synchronous carotid endarterectomy and off-pump coronary bypass: an updated, systematic review of early outcomes.

OBJECTIVES: To update our previous systematic review of outcomes following synchronous carotid endarterectomy (CEA) and off-pump coronary artery bypass grafting (OFF-CABG). DESIGN: A systematic review of operative risks reported in published studies of synchronous CEA plus OFF-CABG procedures. RESULTS: We identified 12 eligible studies, including data on 324 synchronous CEA plus OFF-CABG procedures. Operative mortality was 1.5% (95% confidence interval (CI): 0.3-2.8), the risk of death or ipsilateral stroke was 1.6% (0.4-2.8%), risk of death or any stroke was 2.2% (95% CI: 0.7-3.7) and the risk of death, stroke or myocardial infarction was 3.6% (95% CI: 1.6-5.5). CONCLUSIONS: Limited published data on 324 patients suggest that early outcomes after synchronous CEA plus OFFCABG are better than those following staged or synchronous CEA plus CABG where the cardiac procedure was performed on-pump. This may, however, be attributed to publication bias, case selection or the fact that the aorta was not manipulated or cannulated, rather than CEA being primarily responsible for the lower stroke risk. Colleagues with unpublished experience of CEA plus OFF-CABG are encouraged to submit their data to further inform the debate.