False-positive fecal immunochemical test results in colorectal cancer screening and gastrointestinal drug use.

PURPOSE: The study aimed to determine the influence of drug treatments (proton pump inhibitors [PPIs] combined with other drugs) on the false-positive (FP) rate in the fecal immunochemical test (FIT). METHODS: Patients undergoing colonoscopy in the setting of a CRC screening program due to a positive FIT result were included prospectively. Demographic data and drug intake of PPIs, antiplatelet therapy (APA), anticoagulants, selective serotonin reuptake inhibitors (SSRIs), and nonsteroidal anti-inflammatory drugs (NSAIDs) were collected. An FP FIT result was considered normal colonoscopy or with nonneoplastic pathology (NNP). Logistic regression models were used to evaluate the effect of these drugs on the rate of FP FIT results. RESULTS: We included 515 patients, and 59% (304/515) were males. The rate of FP FIT results was 48% (249/515). Study drug use was higher in patients > 60 years old and females than in those < 60 years old and males (p < 0.001 and p = 0.049, respectively). Multivariate logistic regression revealed that female sex (OR = 2.7 95% CI 1.9-3.9), NNP (OR = 1.5 95% CI 1.1-2.2), and the use of any of the study drugs (OR = 1.4 95% CI 0.9-2.0) were independent risk factors for FP FIT results. The risk of FP FIT results was significantly higher in PPI users than in nonusers (OR = 1.8 95% CI 1.1-2.9), specifically when PPIs were combined with other drugs (OR = 2.01 95% CI 1.1-3.6) only in men. CONCLUSION: Female sex, NNP, and PPIs combined with other drugs in males were identified as independent risk factors for FP FIT results.

Quantitative analysis of p16 methylation in Barrett's carcinogenesis.

p16 hypermethylation in Barrett's carcinogenesis has been evaluated in studies which did not take into account sample heterogeneity and yielded qualitative (methylated/unmethylated) instead of accurate quantitative (percentage of CpG methylation) data. We aimed to measure the degree of p16 methylation in pure samples representing all the steps of Barrett's tumorogenesis and to evaluate the influence of sample heterogeneity in methylation analysis. METHODS: 77 paraffin-embedded human esophageal samples were analyzed. Histological grading was established by two pathologists in: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia and adenocarcinoma. Areas of interest were selected by laser-capture microdissection. p16 methylation was quantified by pyrosequencing. An adjacent section of the whole sample was also analyzed to compare methylation data. RESULTS: After microdissection, we obtained 15 samples of squamous epithelium, 36 non-dysplastic Barrett's esophagus, 3 indefinite for dysplasia, 24 low-grade dysplasia, 4 high-grade dysplasia and 12 adenocarcinoma. Squamous epithelium showed the lowest methylation rates: 6% (IQR 5-11) vs. 11%(7-39.50) in negative/indefinite for dysplasia, p<0.01; 10.60%(6-24) in low-grade dysplasia, p<0.05; and 44.50%(9-66.75) in high-grade dysplasia/adenocarcinoma, p<0.01. This latter group also exhibited higher methylation rates than Barrett's epithelium with and without low-grade dysplasia (p<0.05). p16 methylation rates of microdissected and non-microdissected samples did not correlate unless the considered histological alteration comprised >71% of the sample. CONCLUSIONS: p16 methylation is an early event in Barrett's carcinogenesis which increases with the severity of histological alteration. p16 methylation rates are profoundly influenced by sample heterogeneity, so selection of samples is crucial in order to detect differences.

Low-Dose Aspirin Acetylates Cyclooxygenase-1 in Human Colorectal Mucosa: Implications for the Chemoprevention of Colorectal Cancer.

The mechanism of action of low-dose aspirin in the prevention of colorectal cancer (CRC) remains largely hypothetical. We aimed to compare the effects of low-dose aspirin (100 mg/day for 7 days) given to 40 individuals undergoing CRC screening on the extent of cyclooxygenase (COX)-1 acetylation at serine-529 (AceCOX-1), in blood platelets vs. colorectal mucosa, at 7 (group 1) and 24 h (group 2) after dosing. A significantly (P < 0.01) lower %AceCOX-1 was detected in colonic and rectal mucosa (average 64%) vs. platelets (average 75%) in both groups. This effect was associated with an average 46% (P < 0.01) and 35% (P < 0.05) reduction in prostaglandin (PG) E2 levels and phosphorylated S6 (p-S6) levels, respectively. Rectal mucosal levels of p-S6/S6 significantly (P < 0.01) correlated with PGE2 . These findings demonstrate that low-dose aspirin produces long-lasting acetylation of COX-1 and downregulation of p-S6 in human colorectal mucosa, an effect that may interfere with early colorectal carcinogenesis.

IV Spanish Consensus Conference on Helicobacter pylori infection treatment / IV Conferencia Española de Consenso sobre el tratamiento de la infección por Helicobacter pylori

Helicobacter pylori approximately infect 50% of Spanish population and causes chronic gastritis, peptic ulcer and gastric cancer. Until now, three consensus meetings on H.pylori infection had been performed in Spain (the last in 2012). The changes in the treatment schemes, and the increasing available evidence, have justified organizing the IVSpanish Consensus Conference (March 2016), focused on the treatment of this infection. Nineteen experts participated, who performed a systematic review of the scientific evidence and developed a series of recommendation that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. As starting point, this consensus increased the minimum acceptable efficacy of recommended treatments that should reach, or preferably surpass, the 90% cure rate when prescribed empirically. Therefore, only quadruple therapies (with or without bismuth), and generally lasting 14 days, are recommended both for first and second line treatments. Non-bismuth quadruple concomitant regimen, including a proton pump inhibitor, clarithromycin, amoxicillin and metronidazole, is recommended as first line. In the present consensus, other first line alternatives and rescue treatments are also reviewed and recommended

La infección por Helicobacter pylori afecta aproximadamente al 50% de la población española y es causante de la gastritis crónica, la úlcera péptica y el cáncer gástrico. Se han llevado a cabo hasta el momento, en nuestro país, 3 reuniones de Consenso sobre el manejo de la infección por H. pylori (la última de ellas en 2012). Los cambios en los esquemas de tratamiento y la creciente evidencia disponible al respecto han justificado la organización de esta IV Conferencia Española de Consenso en marzo de 2016, centrada en el tratamiento de esta infección. Participaron 19 expertos sobre el tema, que realizaron una búsqueda sistemática de la evidencia científica y elaboraron una serie de recomendaciones que fueron sometidas a un proceso de interacción de votaciones anónimas seriadas mediante metodología Delphi. Para clasificar la evidencia científica y la fuerza de las recomendaciones se utilizó el sistema GRADE. Este consenso establece, como punto de partida, un aumento de la exigencia en la eficacia de los tratamientos recomendados, que deben alcanzar, o preferiblemente superar, el 90% de curación al ser administrados de forma empírica. De este modo, tanto en primera como en segunda línea se recomiendan tratamientos cuádruples con o sin bismuto, generalmente prescritos durante 14 días. El tratamiento cuádruple sin bismuto concomitante, que incluye un inhibidor de la bomba de protones, claritromicina, amoxicilina y metronidazol, se recomienda como primera línea. En el presente consenso se revisan también con detalle otras alternativas de tratamiento tanto de primera línea como de rescate.

The effects of proton pump inhibition on patient-reported severity of dyspepsia when receiving dual anti-platelet therapy with clopidogrel and low-dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial.

BACKGROUND: Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patient-reported outcomes is undetermined. AIM: To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo. METHODS: We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial. RESULTS: Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 ± 0.17 vs. 6.40 ± 0.17, P = 0.001, and 10.61 ± 0.07 vs. 11.00 ± 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 ± 0.35 vs. 7.10 ± 0.37, P = 0.020 for pain intensity; 10.36 ± 0.12 vs. 10.93 ± 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up. CONCLUSIONS: In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline.

Peptic Ulcer Bleeding Risk. The Role of Helicobacter Pylori Infection in NSAID/Low-Dose Aspirin Users.

OBJECTIVES: Helicobacter pylori (H. pylori) infection and NSAID/low-dose aspirin (ASA) use are associated with peptic ulcer disease. The risk of peptic ulcer bleeding (PUB) associated with the interaction of these factors remains unclear. The objective of this study was to determine the risk of PUB associated with the interaction between H. pylori infection and current nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose ASA use. METHODS: This was a case-control study of consecutive patients hospitalized because of PUB. Controls were matched by age, sex, and month of admission. H. pylori infection status was determined in all cases and controls by serology. Drug use was determined by structured questionnaire. Adjusted relative risk (RR) associated with different factors, and the interaction between NSAID/ASA and H. pylori infection was estimated by logistic regression analysis. RESULTS: The study included 666 cases of PUB and 666 controls; 74.3% cases and 54.8% controls (RR: 2.6; 95% confidence interval (CI): 2.0-3.3) tested positive for H. pylori infection; 34.5% of cases had current NSAID use compared with 13.4% of controls (RR: 4.0; 95% CI: 3.0-5.4). Respective proportions for low-dose ASA use were 15.8 and 12%, respectively (RR: 1.9; 95% CI: 1.3-2.7). The RR of PUB for concomitant NSAID use and H. pylori infection suggested an additive effect (RR: 8.0; 95% CI: 5.0-12.8), whereas no interaction was observed with ASA use (RR: 3.5; 95% CI: 2.0-6.1). CONCLUSIONS: NSAID, low-dose ASA use, and H. pylori infection are three independent risk factors for the development of PUB, but there were differences in the interaction effect between low-dose ASA (no interaction) or NSAID (addition) use and H. pylori infection, which may have implications for clinical practice in prevention strategies.

Reappraisal of the clinical pharmacology of low-dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action.

BACKGROUND: Even though the acetylation of platelet cyclooxygenase (COX)-1 at serine-529 is the direct mechanism of action of low-dose aspirin, its antiplatelet effect has been characterized using indirect indexes of COX-1 activity. OBJECTIVES: We performed a clinical study with enteric-coated low-dose aspirin (EC-aspirin), in healthy subjects, to evaluate the effects on the extent and duration of platelet COX-1 acetylation, using a novel proteomic strategy for absolute protein quantification (termed AQUA), as compared with traditional pharmacokinetic and pharmacodynamic parameters. SUBJECTS AND METHODS: In a phase I, single-arm, open-label study of EC aspirin (100 mg day(-1) ) administered to 24 healthy subjects, we compared, over a 24 h-period on day 1 and 7, % platelet acetylated COX-1 (AceCOX-1) with traditional pharmacokinetic and pharmacodynamics [i.e. serum thromboxane (TX) B2 , platelet function by monitoring CEPI(collagen/epinephrine) closure time (CT) using whole-blood PFA-100 and urinary excretion of 11-dehydro-TXB2 ] parameters. RESULTS: Acetylation of platelet COX-1 was measurable before detection of aspirin levels in the systemic circulation and increased in a cumulative fashion upon repeated dosing. After the last dose of EC-aspirin, %AceCOX-1, serum TXB2 and CEPI-CT values were maximally and persistently modified throughout 24 h; they averaged 76 ± 2%, 99.0 ± 0.4% and 271 ± 5 s, respectively. EC-aspirin caused 75% reduction in urinary 11-dehydro-TXB2 excretion. After chronic dosing with aspirin, the pharmacokinetics of acetylsalicylic acid was completely dissociated from pharmacodynamics. CONCLUSIONS: The demonstrated feasibility of quantifying the extent and duration of platelet COX-1 acetylation will allow characterizing the genetic, pharmacokinetic and pharmacodynamic determinants of the inter-individual variability in the antiplatelet response to low-dose aspirin as well as identifying extra-platelet sites of drug action.

Effect of oral anticoagulants on the outcome of faecal immunochemical test.

BACKGROUND: We aimed to evaluate whether oral anticoagulants (OACs) alter faecal immunochemical test (FIT) performance in average-risk colorectal cancer (CRC) screening. METHODS: Individuals aged 50-69 years were invited to receive one FIT sample (cutoff 75 ng ml(-1)) between November 2008 and June 2011. RESULTS: Faecal immunochemical test was positive in 9.3% (21 out of 224) of users of OAC and 6.2% (365 out of 5821) of non-users (P-trend=0.07). The positive predictive value (PPV) for advanced neoplasia (AN) in non-users was 50.4% vs 47.6% in users (odds ratio, 0.70; 95% CI, 0.3-1.8; P=0.5). The PPV for AN in OAC more antiplatelets (aspirin or clopidogrel) was 75% (odds ratio, 2; 95% CI, 0.4-10.8; P=0.4). CONCLUSIONS: Oral anticoagulant did not significantly modify the PPV for AN in this population-based colorectal screening program. The detection rate of advanced adenoma was higher in the combination OAC more antiplatelets.

Guía práctica para el manejo de la hemorragia digestiva alta no varicosa / Clinical practice guidelines for managing nonvariceal upper gastrointestinal bleeding

La hemorragia digestiva alta no varicosa (HDANV) es una emergencia médica frecuente que se asocia a una considerable morbilidad y mortalidad. En los últimos años se han producido importantes avances en el manejo de la HDANV, que han permitido disminuirla recidiva hemorrágica y la mortalidad en estos pacientes. El objetivo del presente documento es ofrecer una guía de manejo de la HDANV eminentemente práctica basada en la evidencia científica y en las recomendaciones de los recientes consensos. Lostres puntos clave del manejo de la HDANV son: a) la reanimación hemodinámica precozy la prevención de las complicaciones de la patología cardiovascular de base, quees frecuente en pacientes con HDANV; b) el tratamiento endoscópico de las lesiones con alto riesgo de recidiva; y c) el uso de inhibidores de la bomba de protones a dosis altas pre y postendoscopia. La combinación de estas medidas permite reducir la recidiva y la mortalidad de la HDANV (AU)

Nonvariceal upper gastrointestinal (GI) bleeding is a common medical emergency associated with appreciable morbidity and mortality. The significant advances made in managing this condition in recent years have reduced the rates of rebleeding and mortality. These clinical guidelines for managing this emergency are intended to be highly practical, evidence-based, and take recent consensus statements into account. The 3 keys to managing nonvariceal upper GIbleeding are a) early restoration of fluids and blood pressure and the prevention of underlying cardiovascular disease, which is common in these patients; b) endoscopy to treat lesions at high risk of rebleeding; and c) medical therapy with high doses of proton pump inhibitors before and after endoscopy. These 3 measures, used in combination, reduce upperGI rebleeding and mortality rates (AU)

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

The aspirin cardiovascular/gastrointestinal risk calculator--a tool to aid clinicians in practice.

BACKGROUND: Assessment of both GI and CV risks vs. the benefits of low-dose aspirin for individual patients can be difficult in clinical practice. AIM: To develop a tool to estimate CV and GI risks to facilitate the clinical decision-making process. METHODS: We constructed risk-ratio estimations and determined the incidence of CV events and upper GI complications according to the presence of different risk factors. For upper GI complications we assumed a baseline incidence of 1 case/1000-persons-year, a twofold increased risk with low-dose aspirin, and estimated a 60% GI risk reduction with proton pump inhibitors (PPI) co-therapy and a 60% risk reduction with H. pylori eradication in patients with a history of peptic ulcer. RESULTS: The calculator can be found at http://www.asariskcalculator.com. In patients with low CV risk the number of GI complications induced by low-dose aspirin may be greater than the number of CV events prevented. In patients with high CV risk, low-dose aspirin is recommended, but the number of GI complications induced may still overcome the CV events saved. The use of PPI reduces the number of complication events induced by low-dose aspirin, but the number of CV events saved may still be offset by the number of GI complications induced in patients at very high GI risk. CONCLUSIONS: There are many clinical situations where the number of potential upper GI complications induced by low-dose aspirin may exceed the number of potentially prevented CV events. A risk calculator should guide physicians in choosing appropriate therapy and maximise the aspirin benefit.

Gastroprotection in low-dose aspirin users for primary and secondary prevention of ACS: results of a cost-effectiveness analysis including compliance.

PURPOSE: Low-dose aspirin (ASA) increases the risk of upper gastrointestinal (GI) complications. Proton pump inhibitors (PPIs) reduce these upper GI side effects, yet patient compliance to PPIs is low. We determined the cost-effectiveness of gastroprotective strategies in low-dose ASA users considering ASA and PPI compliance. METHODS: Using a Markov model we compared four strategies: no medication, ASA monotherapy, ASA+PPI co-therapy and a fixed combination of ASA and PPI for primary and secondary prevention of ACS. The risk of acute coronary syndrome (ACS), upper GI bleeding and dyspepsia was modeled as a function of compliance and the relative risk of developing these events while using medication. Costs, quality adjusted life years and number of ACS events were evaluated, applying a variable risk of upper GI bleeding. Probabilistic sensitivity analyses were performed. RESULTS: For our base case patients using ASA for primary prevention of ACS no medication was superior to ASA monotherapy. PPI co-therapy was cost-effective (incremental cost-effectiveness ratio [ICER] €10,314) compared to no medication. In secondary prevention, PPI co-therapy was cost-effective (ICER €563) while the fixed combination yielded an ICER < €20,000 only in a population with elevated risk for upper GI bleeding or moderate PPI compliance. PPI co-therapy had the highest probability to be cost-effective in all scenarios. PPI use lowered the overall number of ACS. CONCLUSIONS: Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy.

Risk factors associated with a decrease ≥2 g/dL in haemoglobin and/or ≥10% haematocrit in osteoarthritis patients taking celecoxib or a nonselective NSAID plus a PPI in a large randomised controlled trial (CONDOR).

BACKGROUND: Nonsteroidal anti-inflammatory drugs are associated with gastrointestinal (GI) damage. The Celecoxib vs. Omeprazole and Diclofenac for At-Risk Osteoarthritis and Rheumatoid Arthritis Patients (CONDOR) trial showed that a haemoglobin drop ≥2 g/dL adjudicated as either of defined or presumed GI origin was the most frequent component/event for the composite GI primary end point. This adverse event is potentially clinically relevant in long-term NSAID treatment. AIM: To define potential risk factors associated with a decrease in haemoglobin/haematocrit. METHODS: Post hoc analysis of the CONDOR trial was conducted in the intention-to-treat population. Clinically significant blood loss was defined as: (i) a haemoglobin drop ≥2 g/dL and/or a haematocrit drop ≥10%; and (ii) blood loss adjudicated as either of defined or presumed GI origin. Fifteen risk factors were evaluated by stepwise logistic regression. Each factor had to be significant at <0.20 α to be included in the model. RESULTS: A total of 64/3774 (1.7%) osteoarthritis (OA) patients had decreased haemoglobin/haematocrit and were adjudicated to the GI endpoint. Significant risk factors, at the 0.20 α level found to be associated with clinically significant blood loss in OA patients included [odds ratio (80% CI)] baseline C-reactive protein (CRP) levels [2.27 (1.46-3.53)], history of gastritis and history of GI intolerance [1.55 (1.06-2.28)], positive Helicobacter pylori at screening [1.54 (1.07-2.22)], increasing age [1.17 (1.04-1.32)] and body mass index [BMI; 1.03 (1.00-1.06)]. CONCLUSIONS: Monitoring for decreases in haemoglobin should be considered for all OA patients and especially those with an increased age, BMI, history of gastritis and GI intolerance, CRP levels >1 mg/dL and/or positive H. pylori status, as this may affect their clinical management.

Characterization of the prostaglandin E2 pathway in a rat model of esophageal adenocarcinoma.

UNLABELLED: Accumulating evidence indicates that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a key role in esophageal carcinogenesis. A better understanding of the pathway downstream of COX-2 may reveal novel targets for the prevention of esophageal adenocarcinoma (EAC). The objective of this study was to characterize the profile of genes involved in PGE2 metabolism and signaling in an experimental model of EAC. Esophagojejunostomy with gastric preservation was performed in wistar rats to induce gastroduodenal reflux. Rats were sacrificed 2 or 4 months after surgery. Nine non-operated rats were used to obtain normal (control) esophageal tissues. RESULTS: All rats that underwent esophagojejunostomy developed inflammation. In addition, 90% of the animals showed intestinal metaplasia; of those, 40% progressed to AC. This process was accompanied by a significant increase in esophageal PGE2 levels and the induction of both mRNA and protein levels of COX-2, COX-1, prostaglandin E synthase, 15-hydroxyprostaglandin dehydrogenase, and PGE2 receptors EP3, EP4 and especially EP2, which rose to particularly high levels in experimental rats. In addition, exposure to a selective COX-2 inhibitor (SC58125) or an EP1/EP2 antagonist (AH6809), but not an EP4 antagonist (AH23848B), significantly reduced cell proliferation of esophageal explants in 24 hour-organ culture experiments. Our data suggest that, in addition to COX-2, other components of the PGE2 pathway, including COX-1, may play important roles in the development of EAC induced by gastroduodenal reflux in the rat. Although it must be confirmed in vivo, the EP2 receptor may represent a promising selective target in the prevention of Barrett's associated AC.

Haemoglobin decreases in NSAID users over time: an analysis of two large outcome trials.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with clinically significant decreases in haemoglobin dependent and independent of acute bleeding events. AIM: To evaluate the incidence and time to a clinically meaningful decrease in haemoglobin in two double-blind, prospective randomised clinical trials comparing NSAIDs in patients with osteoarthritis (OA) or rheumatoid arthritis (RA). METHODS: In CLASS, patients with OA/RA who were aged ≥ 18 years and required continuous NSAID treatment were included; patients who were Helicobacter pylori positive and/or using aspirin were not excluded. In contrast, in the CONDOR trial, comparing celecoxib alone to diclofenac sustained release (plus omeprazole), patients were aged ≥ 60 years or ≥ 18 years with a history of gastroduodenal ulcer and were H. pylori negative; aspirin or other anti-platelet users were excluded. To make a parallel post hoc analysis we limited our study to 6 months and the populations to only the non-aspirin users in CLASS and those patients receiving either celecoxib or diclofenac. A decrease in haemoglobin of ≥ 2 g/dL defined the primary end point. RESULTS: At 6 months, in the CLASS and CONDOR trials, 1.9% and 2.0% of patients treated with celecoxib and 3.3% and 5.7% of patients treated with diclofenac developed a ≥ 2 g/dL decrease in haemoglobin, respectively, [CLASS: odds ratio (OR) 1.80 (95% confidence interval (CI), 1.22-2.65) and CONDOR: OR 2.93 (95% CI, 2.06-4.15), respectively]. CONCLUSION: IN these two large, independent trials, clinically-meaningful decreases in haemoglobin ≥ 2 g/dL occurred in a relatively similar fashion over time despite differences in trial designs.

A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22.

BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24. METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24. RESULTS: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. CONCLUSIONS: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.

Clinical predictors of poor outcomes among patients with nonvariceal upper gastrointestinal bleeding in Europe.

BACKGROUND: Nonvariceal upper gastrointestinal bleeding (NVUGIB) is a common medical emergency associated with substantial morbidity and mortality. Despite advances in endoscopic and pharmacological treatment during the past two decades, the incidence of mortality associated with NVUGIB has remained relatively constant. AIM: To report outcomes and predictive factors for bleeding continuation/re-bleeding and mortality of NVUGIB in clinical practice in different European countries. METHODS: This observational, retrospective cohort study (NCT00797641; ENERGIB) was conducted in Belgium, Greece, Italy, Norway, Portugal, Spain and Turkey. Eligible patients were hospitalised (new admissions or inpatients), presenting with overt NVUGIB with endoscopy from 1 October to 30 November, 2008. Patients were managed according to routine care, and data regarding bleeding continuation/re-bleeding, pharmacological treatment, surgery and mortality during 30-days after the initial bleed were collected. A multivariate analysis of clinical factors predictive of poor outcomes was conducted. RESULTS: Overall, 2660 patients (64.7% men; mean age 67.7 years) were evaluable. Significant differences across countries in bleeding continuation/re-bleeding (range: 9-15.8%) or death (2.5-8%) at 30 days were explained by clinical factors (number of comorbidities, age > 65 years, history of bleeding ulcers, in-hospital bleeding, type of lesion or type of concomitant medication). Other factors (country, size of hospital, profile of team managing the event, or endoscopic/pharmacological therapy received) did not affect these outcomes. Similar predictors were observed in patients with high-risk stigmata. CONCLUSION: Differences in the outcomes of nonvariceal upper gastrointestinal bleeding in clinical practice across some European countries are explained mainly by patient-related factors, and not by management factors.

The changing face of hospitalisation due to gastrointestinal bleeding and perforation.

BACKGROUND: Temporal changes in the incidence of cause-specific gastrointestinal (GI) complications may be one of the factors underlying changing medical practice patterns. AIM: To report temporal changes in the incidence of five major causes of specific gastrointestinal (GI) complication events. METHODOLOGY: Population-based study of patients hospitalised due to GI bleeding and perforation from 1996 to 2005 in Spain. We report crude rates, and estimate regression coefficients of temporal trends, severity and recorded drug use for five frequent GI events. GI hospitalisation charts were validated by independent review of large random samples. RESULTS: The incidence per 100 000 person-years of hospitalisations due to upper GI ulcer bleeding and perforation decreased over time [from 54.6 and 3.9 in 1996 (R² = 0.944) to 25.8 and 2.9 in 2005 (R² = 0.410) respectively]. On the contrary, the incidence per 100 000 person-years of colonic diverticular and angiodysplasia bleeding increased over time [3.3 and 0.9 in 1996 (R² = 0.443) and 8.0 and 2.6 in 2005 (R² = 0.715) respectively]. A small increasing trend was observed for the incidence per 100 000 person-years of intestinal perforations (from 1.5 to 2.3 events). Based on data extracted from the validation process, recent recorded drug intake showed an increased frequency of anticoagulants with colonic diverticular and angiodysplasia bleeding, whereas NSAID and low-dose aspirin use were more prevalent in peptic ulcer bleeding and colonic diverticular bleeding respectively. CONCLUSIONS: From 1996 to 2005, hospitalisations due to peptic ulcer bleeding and perforation have decreased significantly, whereas the number of cases of colonic diverticular and angiodysplasia bleeding have increased.