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A large body of evidence from epidemiological and preclinical studies have shown that nonsteroideal anti-inflammatory drugs (NSAIDs) have a chemopreventive effect on gastrointestinal cancers and, more specifically, in colorectal cancer. This review highlights recent advances in our understanding of the role of NSAIDs in colorectal cancer prevention and adjuvant treatment. Moreover, we have focused on randomized controlled studies assessing their efficacy to prevent adenoma recurrence and reduction of colorectal cancer incidence and mortality but also their gastrointestinal and cardiovascular side effects. Among NSAIDs, almost the unique agent with potential use as chemopreventive agent is aspirin at low dose since it has both no cardiovascular and low gastrointestinal risk. Furthermore, since aspirin has shown efficacy in secondary prevention of cardiovascular diseases, this drug carries a particular attractive intervention for selected populations. Nevertheless, before it can be prescribed, further studies are necessary to define some important questions, specially the most appropriate dose and time of aspirin use and the population who may benefit from it. [ABSTRACT FROM AUTHOR]

A large body of evidence from basic science, epidemiologic observations and population-based studies demonstrates that aspirin, as well as other non-steroidal anti-inflammatory drugs, has a chemopreventive effect on several cancer types and, more specifically, in CRC. This protective effect includes prevention of adenoma recurrence and reduction of CRC incidence and mortality. Although the protective effect appears to depend on the dose and the drug, the most important factor is the duration of exposure. However, the lowest effective dose, treatment duration, specific target populations, and effects on survival have not been defined yet. More important, data on the risk–benefit profile for cancer prevention are insufficient and, accordingly, no definitive recommendation can be made at present. In this article, besides reviewing current knowledge of the mechanisms involved in aspirin-based CRC chemoprevention, we will be focused on randomized controlled studies assessing its efficacy in high-, moderate- and average-risk populations. [Copyright &y& Elsevier]

Background & Aims: Whether low-dose aspirin (acetylsalicylic acid [ASA]) produces intestinal damage is controversial. Our aim was to determine whether the small bowel is damaged by low-dose ASA on a short-term basis. Methods: Twenty healthy volunteers (age range, 19–64 years) underwent video capsule endoscopy (VCE), fecal calprotectin, and permeability tests (sucrose and lactulose/mannitol [lac/man] ratio) before and after ingestion of 100 mg of enteric-coated ASA daily for 14 days. Video capsule images were assessed by 2 independent expert endoscopists, fully blinded to the treatment group, by using an endoscopic scale. Results: Post-ASA VCE detected 10 cases (50%) with mucosal damage not apparent in baseline studies (6 cases had petechiae, 3 had erosions, and 1 had bleeding stigmata in 2 ulcers). The median baseline lac/man ratio (0.021; range, 0.011–0.045) increased after ASA use (0.036; range, 0.007–0.258; P = .08), and the post-ASA lac/man ratio was above the upper end of normal (>0.025) in 10 of 20 volunteers (vs baseline, P < .02). The median baseline fecal calprotectin concentration (6.05 μg/g; range, 1.9–79.2) also increased significantly after ASA use (23.9 μg/g; range, 3.1–75.3; P < .0005), with 3 patients having values above the cutoff (>50 μg/g). Five of 10 subjects with abnormal findings at VCE also had lac/man ratios above the cutoff. Median baseline sucrose urinary excretion (70.0 mg; range, 11.8–151.3) increased significantly after ASA administration (107.0 mg; range, 22.9–411.3; P < .05). Conclusions: The short-term administration of low-dose ASA is associated with mucosal abnormalities of the small bowel mucosa, which might have implications in clinical practice. [Copyright &y& Elsevier]

Abstract: Background: Previous studies have reported a potential genetic predisposition to NSAID-related upper gastrointestinal (GI) bleeding. Objective: This study evaluated whether there was an association between 2 polymorphisms-the platelet glycoprotein (GP) IIIa PlA1/A2 polymorphism and the 27-bp VNTR (variable number of tandem repeats) polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene-and a risk for nonvariceal upper GI bleeding in Spanish patients taking low-dose aspirin for secondary prophylaxis of vascular occlusive diseases. Methods: Genotyping for the 2 polymorphisms was performed in patients hospitalized for upper GI bleeding associated with the use of low-dose aspirin between September 1998 and October 2000, and race-, age-, and sex-matched controls who were taking low-dose aspirin but had no history of upper GI bleeding. To ascertain allele frequencies in a healthy population, genotyping was also performed in an unmatched group of blood donors. Results: The study included 88 white patients (65 men, 23 women; mean age, 67.5 years) with an episode of upper GI bleeding, 108 matched controls with no history of upper GI bleeding (79 men, 29 women; mean age, 65.9 years), and 158 blood-donor controls (109 men, 49 women; mean age, 53.4 years). No significant differences were found between cases and controls in terms of genotype, carriage, or allele frequency of the GPIIIa PlA1/A2 polymorphism. However, after adjustment for confounding variables, logistic regression analysis indicated an association between carriage of the eNOS “a” allele and a reduced risk of upper GI bleeding (odds ratio [OR] ＝ 0.39; 95％ CI, 0.18-0.85; P ＝ 0.018). In this model, treatment with ni-trovasodilators (OR ＝ 0.28; 95％ CI, 0.12-0.66; P ＝ 0.004) and use of antisecretory drugs (OR ＝ 0.15; 95％ CI, 0.05-0.47; P ＝ 0.001) were also identified as protective factors. Helicobacter pylori infection (OR ＝ 3.07; 95％ CI, 1.23-7.70; P ＝ 0.017), alcohol consumption (OR ＝ 5.04; 95％ CI, 1.86-13.70; P ＝ 0.001), and a history of peptic ulcer (OR ＝ 13.41; 95％ CI, 3.78-47.64; P ＜ 0.001) were identified as risk factors for upper GI bleeding. Conclusion: In this small, selected population of individuals taking low-dose aspirin for secondary prevention, carriage of the “a” allele of the eNOS gene was associated with a decreased risk for upper GI bleeding. [Copyright &y& Elsevier]

Abstract: Accumulating evidence suggests that COX-2-derived prostaglandin E2 (PGE2) plays an important role in esophageal adenocarcinogenesis. Recently, PGE2 receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE2 signals in esophageal adenocarcinoma, we investigated the role of EP receptors using a human Barrett''s-derived esophageal adenocarcinoma cell line (OE33). OE33 cells expressed COX-1, COX-2, EP1, EP2 and EP4 but not EP3 receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP3 downregulation. Endogenous PGE2 production was mainly due to COX-2, since this was significantly suppressed with COX-2 inhibitors (NS-398 and SC-58125), but not COX-1 inhibitors (SC-560). Cell proliferation (3H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP1 antagonist SC-51322, AH6809 (EP1/EP2 antagonist), and the EP4 antagonist AH23848B, but was not affected by exogenous PGE2. However, treatment with the selective EP2 agonist Butaprost or 16,16-dimethylPGE2 significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE2 on migration was attenuated when cells were first treated with EP1 and EP4 antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma. [Copyright &y& Elsevier]

Abstract: We aimed to evaluate the influence of Helicobacter pylori infection and IL-1/TNF gene polymorphisms on interleukin (IL)-1β and tumor necrosis factor (TNF)-α gastric mucosal production. IL-1β and TNF-α levels in homogenized biopsy specimens taken from the antrum and corpus of 81 patients were measured by enzyme-linked immunosorbent assay. Genomic DNA was typed for the IL1B-511, IL1B+3954, variable number of tandem repeat (VNTR) IL1RN, TNFA-308, TNFA-238, LTA NcoI, and LTA Bsi gene polymorphisms by polymerase chain reaction, restriction fragment length polymorphism, and TaqMan assays. H. pylori infection and CagA/VacA antibody status were determined by Western blot. IL-1β and TNF-α protein levels were significantly higher in the gastric antrum of patients infected with H. pylori compared with uninfected patients [9.54 (5.07–16.28) vs. 4.55 (3.69–8.28) pg IL-1β/mg protein, p = 0.004, and 1.5 (0.7–2.71) vs. 0.63 (0.3–1.26) pg TNF-α/mg protein, p = 0.001]. Among H. pylori-infected individuals, carriers of the IL1RN*2 allele had significantly higher antrum mucosal IL-1β levels than noncarriers [15.97 (9.59–26.6) vs. 10.08 (7.72–13.33), p = 0.008]. No association between gastric mucosal TNF-α levels and genotypes of the TNFA and LTA gene polymorphisms was reported. Our results indicate that the VNTR polymorphism of the IL1RN gene influences IL-1β gastric mucosal production in patients infected with H. pylori. [Copyright &y& Elsevier]

Abstract: Colorectal cancer (CRC) is one of the most common neoplasms and a leading cause of death related to cancer worldwide. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent autosomal dominant predisposition to the development of CRC, accounting for approximately 2.5% of the total CRC burden in Spain. Genomic rearrangements in the MSH2 and MLH1 genes have been reported to account for an important proportion of the mutation spectrum in HNPCC, and DNA dosage techniques have been developed facilitating molecular screening of such deletions/duplications. We screened for MSH2 and MLH1 genomic rearrangements by multiplex ligation-dependent probe amplification (MLPA) in 142 Spanish patients at risk for HNPCC prior to the exon-by-exon mutation scanning and found a deletion encompassing exons 9–16 of MSH2 and a duplication encompassing exons 11–16 of MSH2, both only in one case. These results showed that MSH2/MLH1 rearrangements in Spanish patients at risk for HNPCC seem to be a less frequent mutational event than in other populations. [Copyright &y& Elsevier]