Victoria P. Tan

Epidemiology of colorectal cancer in Asia.

The prevalence of colorectal cancer is increasing in Asia. However, the age‐standardized rate has reached a plateau in some countries. Some studies have shown a male predominance difference and increasing risk in the elderly, but not in the younger population. ‘Right shifting’ of colorectal cancer, not accountable by difference in age or the indications for endoscopic examination, has also been noted. Westernized diet is associated with colorectal cancer, but controversy remains on how it causes colorectal cancer. Alcohol consumption, obesity, diabetes mellitus, consumption of red and processed meat and cigarette smoking are linked to bowel cancer epidemiologically. Only high dietary calcium has a consistent negative (or ‘protective’) effect. The efficacy of fish oil, vitamin D, soy, phytoestrogens, folate, methionine, riboflavin and vitamin B6 has not been established. Aspirin and non‐steroidal anti‐inflammatory drugs use decrease risk of colorectal cancer after 5–10 years of use. There is no evidence for a detrimental effect of proton pump inhibitors or benefit of statins in colorectal cancer. In conclusion, there is a rising trend and prevalence of colorectal cancer in Asia. Dietary modification or supplementation may not be effective in preventing colorectal cancer. Surveillance of colorectal cancer in high‐risk groups, according to current recommendation, is probably most effective.

Rabeprazole Is Effective in Treating Laryngopharyngeal Reflux in a Randomized Placebo-Controlled Trial

BACKGROUND & AIMS There is controversy about the efficacy of treating patients with laryngopharyngeal reflux (LPR) using proton pump inhibitors (PPIs). We assessed the effects of high doses of the PPI rabeprazole in patients with LPR. METHODS Patients with LPR symptoms were assigned randomly to receive rabeprazole (20 mg, twice daily, n = 42) or placebo (n = 40) for 12 weeks. All patients completed symptom questionnaires; these provided demographic information and the reflux symptom index before, during, and 6 weeks after cessation of treatment. Videolaryngostroboscopy was used to document the laryngeal findings and determine the reflux finding score. RESULTS Twenty-four patients (57.1%) in the rabeprazole group and 27 patients (67.5%) in the placebo group had pH-documented LPR. The total reflux symptom index score decreased significantly in the group given rabeprazole, compared with patients given placebo, at weeks 6 and 12, but not at week 18. However, there were no significant differences in reflux finding scores between the rabeprazole and placebo groups at any of the time points. CONCLUSIONS Twelve weeks of treatment with rabeprazole (20 mg, twice daily) significantly improved reflux symptoms, compared with placebo, in patients with LPR. Relapse of symptoms was observed 6 weeks after stopping PPI therapy, indicating the requirement for longer treatment duration in patients with LPR.

Impact of genetic and acquired alteration in cytochrome P450 system on pharmacologic and clinical response to clopidogrel

Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce subsequent cardiac events in patients with acute coronary syndrome or coronary artery stenting. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 (CYP) enzyme system. The genes encoding CYP enzymes are polymorphic. Recent data demonstrated patients carrying a genetic variant of CYP enzymes (e.g. CYP2C19) would have a higher rate of ischemic events than non-carriers due to an attenuation of the pharmacokinetic and pharmacodynamic responses to clopidogrel. Furthermore, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is commonly prescribed to patients because of the increased risk of bleeding with dual antiplatelet therapy. PPIs are extensively metabolized by the cytochrome P450 system and have been associated with decreased antiplatelet activity of clopidogrel. In this review, we will discuss the impact of CYP450 enzymes genetic variation and CYP450 pathway drug-drug interactions in pharmacological and clinical response to clopidogrel.

Four and a half LIM protein 2 (FHL2) negatively regulates the transcription of E-cadherin through interaction with Snail1

E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT.

Risk and management of upper gastrointestinal bleeding associated with prolonged dual-antiplatelet therapy after percutaneous coronary intervention

Prolonged dual-antiplatelet therapy with aspirin and clopidogrel is mandatory after drug-eluting stent implantation because of the potential increased risk of late stent thrombosis. The concern regarding prolonged antiplatelet therapy is the increased risk of bleeding. Gastrointestinal bleeding is the most common site of bleeding and presents a serious threat to patients due to the competing risks of gastrointestinal hemorrhage and stent thrombosis. Currently, there are no guidelines and little evidence on how best to manage these patients who are at high risk of morbidity and mortality from both the bleeding itself and the consequences of achieving optimum hemostasis by interruption of antiplatelet therapy. Managing gastrointestinal bleeding in a patient who has undergone recent percutaneous coronary intervention requires balancing the risk of stent thrombosis against further catastrophic bleeding. Close combined management between gastroenterologist and cardiologist is advocated to optimize patient outcomes.

XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification

The role of X chromosome‐linked inhibitor of apoptosis protein (XIAP)‐associated factor 1 (XAF1) in mediating apoptosis has been reported but the underlying mechanism remains unclear. The present study was designed to examine the putative interaction between XAF1 and p53 and the functional importance of this interaction in regulation of apoptosis in human gastric and colon cancer cells. We first identified XAF1 as a novel target gene of p53 by the chromatin immunoprecipitation (CHIP) assay and demonstrated that wild‐type p53, but not mutant p53, down‐regulated XAF1 at both mRNA and protein levels, which acted mostly under the condition of high expression of XAF1 and was associated with the physical interaction between p53 and the XAF1 promoter. We also found that the over‐expression of XAF1 led to activation of wild‐type p53 via post‐translational modification in cells with or without DNA damage, which resulting in p53 nuclear accumulation and its increased transcriptional activity and enhancing p53‐dependent apoptosis. These findings suggest that a potential novel feedback loop exists between XAF1 and wild‐type p53.

Variability in response to clopidogrel: how important are pharmacogenetics and drug interactions?

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel.

Venous and arterial disease in inflammatory bowel disease

Awareness is increasing that risk of venous thromboembolism and development of atherosclerosis is elevated in patients with some chronic inflammatory diseases. This review aimed to examine the risk of vascular disease in patients with inflammatory bowel disease (IBD) and to identify potential pathogenic mechanisms and therapeutic approaches. An extensive literature search was conducted using MEDLINE database, Cochrane Library and international conference abstracts for studies pertaining to venous and arterial thromboembolism in adult IBD patients. There is a 1.1–3.6 fold risk of venothromboembolism in IBD, affecting 0.55–6.15% of patients. Risks are increased during a flare or with chronically active inflammation. Evidence is building that there may be a modestly increased risk of arterial disease overall, despite evidence that traditional risk factors may be reduced. Multiple pathogenic factors have been identified including endothelial dysfunction, inflammation‐mediated calcium deposition in the media of arteries, hyperhomocysteinemia, platelet activation, and altered coagulation and fibrinolysis. The key to active and preventive therapy is to effectively treat inflammation. Recommendations for prophylaxis of venothromboembolism have followed guidelines where they exist and have been extrapolated from studies of other at‐risk conditions, as have those for arterial disease, where screening for risk factors and actively treating abnormalities is encouraged. In conclusion, patients with IBD are at considerably increased risk of venothromboembolism and probably of arterial disease, in particular mesenteric ischemia and ischemic heart disease. Increased penetration of gaps between this knowledge and clinical therapeutic action to prevent thromboembolic events into IBD clinical practice is needed.

Adenovirus-mediated down-regulation of X-linked inhibitor of apoptosis protein inhibits colon cancer

Our previous studies and those of others have indicated that X-linked inhibitor of apoptosis protein (XIAP) holds promise as a target gene in colon cancer gene therapy. In this study, we constructed an adenoviral vector to deliver small hairpin RNA (shRNA) against XIAP (XIAP-shRNA) into colon cancer cells and tested its therapeutic efficacy in vitro and in vivo. We first confirmed an overexpression of XIAP in colon cancer cells and human cancer tissues. We then designed XIAP-small interfering RNA (siRNA) and confirmed the knockdown effect of these siRNAs in colon cancer cells. The sequences of the effective siRNAs were converted into shRNA and then packed into replication-deficient adenoviral vectors using BLOCK-iT Adenoviral RNAi Expression System to generate Adv-XIAP-shRNA. Infection of HT29 and HCT116 cells with Adv-XIAP-shRNA led to enhanced caspase-3 activity, which was associated with increased apoptosis and reduced cell proliferation. The therapeutic effect of Adv-XIAP-shRNA was then tested in xenograft tumors in nude mice. We showed that treatment of the xenograft tumors derived from HCT116 cells with Adv-XIAP-shRNA resulted in a retardation of tumor growth, which was associated with enhanced apoptosis, increased caspase-3 activity, and reduced expression of proliferating cell nuclear antigen in the tumor tissues. Treatment of xenograft tumors with Adv-XIAP-shRNA did not affect the expressions of inflammatory cytokines in tumor-bearing mice. Thus, Adv-XIAP-shRNA–mediated down-regulation of XIAP exerts a therapeutic effect in colon cancer by promoting apoptosis and inhibiting proliferation of colon cancer cells, and the antitumor effect of Adv-XIAP-shRNA was unlikely to be related to virus-induced immune response. [Mol Cancer Ther 2009;8(9):2762–70]

Gastric Cancer Chemoprevention: The Current Evidence

Chemoprevention may form the cornerstone in the management of gastric adenocarcinoma of the future. Helicobacter pylori eradication and aspirin and/or nonsteroidal anti-inflammatory drug therapy have emerged as front-runner chemotherapeutic agents due to the putative pathogenic mechanisms that they address. Before a population-based chemopreventive strategy can be recommended on a large scale, randomized controlled trials with follow-up of more than 10 years of these 2 agents in populations at high gastric adenocarcinoma risk is urgently awaited.