In addition to the upper GI tract, NSAIDs can damage the small bowel and the colon. NSAID enteropathy is frequent and may be present in more than 60% of patients taking these drugs long term. In most ...cases, damage is subclinical, including increased mucosal permeability, inflammation, erosions, ulceration, but other more serious clinical outcomes such as anemia, and overall bleeding, perforation, obstruction, diverticulitis and deaths have also been described. The magnitude of these serious outcomes from the lower GI tract is not well defined, but recent data suggest that they may be as frequent and severe as upper GI complications. Contrary to what happens in the upper GI tract, treatment and prevention of NSAID enteropathy is difficult, since the pathogenic mechanisms are different and not well understood. Among other options, misoprostol, antibiotics, and sulphasalazine have been proved to be effective in animal models, but they have not been properly tested in humans. Selective COX-2 inhibition is emerging as a potential alternative to tNSAIDs in the prevention of damage in the lower GI tract in rheumatologic patients. Preliminary studies in healthy volunteers have shown that these drugs are associated with no or less small bowel damage than tNSAIDs plus PPI, although their long-term effects in patients need to be properly tested. Post hoc analysis of previous outcome studies focused on complications of upper GI tract or cardiovascular events have shown contradictory results. Data from one ongoing trial comparing celecoxib versus diclofenac plus PPI and examining serious outcomes from the whole GI tract will probably provide new insights in this area.
The results of Aspirin prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP) are controversial.
We conducted a biomarker-based clinical study in eight FAP patients ...treated with enteric-coated low-dose Aspirin (100 mg daily for three months) to explore whether the drug targets mainly platelet cyclooxygenase (COX)-1 or affects extraplatelet cellular sources expressing COX-isozymes and/or off-target effects in colorectal adenomas.
In FAP patients, low-dose Aspirin-acetylated platelet COX-1 at Serine529 (>70%) was associated with an almost complete inhibition of platelet thromboxane (TX) B
generation ex vivo (serum TXB
). However, enhanced residual urinary 11-dehydro-TXB
and urinary PGEM, primary metabolites of TXA
and prostaglandin (PG)E
, respectively, were detected in association with incomplete acetylation of COX-1 in normal colorectal biopsies and adenomas. Proteomics of adenomas showed that Aspirin significantly modulated only eight proteins. The upregulation of vimentin and downregulation of HBB (hemoglobin subunit beta) distinguished two groups with high vs. low residual 11-dehydro-TXB
levels, possibly identifying the nonresponders and responders to Aspirin.
Although low-dose Aspirin appropriately inhibited the platelet, persistently high systemic TXA
and PGE
biosynthesis were found, plausibly for a marginal inhibitory effect on prostanoid biosynthesis in the colorectum. Novel chemotherapeutic strategies in FAP can involve blocking the effects of TXA
and PGE
signaling with receptor antagonists.
Colonic diverticular disease is common in Western countries and its prevalence increases with age. The large majority of patients (80–85%) will remain entirely asymptomatic throughout their life. In ...symptomatic cases, most patients will have diverticulosis without inflammation while the remainder will have diverticulitis with or without complications. About 1–2% will require hospitalization and 0.5% will require surgery. Factors predicting the development of symptoms remain to be identified. However, it is generally recognized that diverticular disease is probably related to complex interactions between colon structure, intestinal motility, diet, and genetic features. Epidemiologic studies have demonstrated an association between diverticulosis and diets that are low in fiber and high in refined carbohydrates. Although the causes of symptom development are still unclear, it is thought that previous episodes of intestinal inflammation may play a role. Changes in intestinal microflora could be one of the putative mechanisms responsible for low-grade inflammation. In patients with uncomplicated diverticulosis, a diet abundant in fruit and vegetables is recommended. The current therapeutic approaches in preventing recurrence of symptoms are based on nonabsorbable antibiotics, mesalazine, and/or probiotics. Cyclic rifaximin administration seems to be an adequate approach to relieving symptoms and preventing acute diverticulitis in patients with symptomatic diverticulosis.
Two recent genome‐wide association studies in Asians have reported the association between the PSCA (prostate stem cell antigen) rs2294008C>T gene polymorphism and two Helicobacter pylori ...infection‐related diseases such as gastric cancer (GC) and duodenal ulcer (DU). Since rs2294008 allele frequencies differ notably among ethnicities, we aimed to assess the role of rs2294008 on the susceptibility to GC and DU in a Caucasian population in Spain. Moreover, the relevance of rs2294008 on GC prognosis was evaluated. Genomic DNA from 603 Spanish patients with primary GC, 139 with DU and 675 healthy controls was typed for the PSCA rs2294008C>T polymorphism by PCR‐TaqMan assays. H. pylori infection odds ratio (OR): 8.27; 95% confidence interval (CI): 3.45–15.33 and nonsteroidal anti‐inflammatory drugs (OR: 6.54; 95% CI: 3.19–12.43) were identified as independent risk factors for DU whereas the rs2294008T allele was associated with reduced risk of developing the disease (OR: 0.52; 95% CI: 0.33–0.82). Infection with CagA strains (OR: 2.10; 95% CI: 1.63–2.34), smoking (OR: 1.93; 95% CI: 1.54–2.61), family history of GC (OR: 2.83; 95% CI: 2.01–3.83), and the rs2294008T allele (OR: 1.46; 95% CI: 1.07–1.99) were associated with increased risk of GC. Interestingly, the association with the rs2294008T allele was restricted to noncardia GC (OR: 1.43; 95% CI: 1.12–1.82), particularly of the diffuse histotype (OR: 1.59; 95% CI: 1.16–1.92). Finally, Cox regression analysis identified the rs2294008T variant as a prognosis factor associated with worse overall survival in patients with diffuse‐type GC (hazard ratio: 1.85; 95% CI: 1.12–3.06). From these results we conclude that the PSCA rs2294008 polymorphism is involved in the susceptibility to GC and DU, as well as in the prognosis of the diffuse‐type of GC in Caucasians.
What's new?
Susceptibility to Helicobacter pylori infection‐related disease differs by ethnic group, and there are vast divergences in disease outcome, specifically for duodenal ulcer (DU) and gastric cancer (GC). Those differences may be explained in part by genetic variations, including differences in allele frequencies of rs2294008, a polymorphism of the PSCA gene. In this study of a Spanish Caucasian population, the rs2294008 T allele was found to be associated with increased GC risk, particularly diffuse‐type GC, and with reduced DU risk. A significant link was uncovered between the rs2294008 T allele and worse overall survival in patients with diffuse‐type GC.
Abstract Diverticular disease represents the most common disease affecting the colon in the Western world. Most cases remain asymptomatic, but some others will have symptoms or develop complications. ...The aims of treatment in symptomatic uncomplicated diverticular disease are to prevent complications and reduce the frequency and intensity of symptoms. Fibre, probiotics, mesalazine, rifaximin and their combinations seem to be usually an effective therapy. In the uncomplicated diverticulitis, outpatient management is considered the optimal approach in the majority of patients, and oral antibiotics remain the mainstay of treatment. Admission to hospital and intravenous antibiotic are recommended only when the patient is unable to intake food orally, affected by severe comorbidity or does not improve. However, inpatient management and intravenous antibiotics are necessary in complicated diverticulitis. The role of surgery is also changing. Most diverticulitis-associated abscesses can be treated with antibiotics and/or percutaneous drainage and emergency surgery is considered only in patients with acute peritonitis. Finally, patient related factors, and not the number of recurrences, play the most important role in selecting recipients of elective surgery to avoid recurrences.
Recent studies have reported an association between cytokine gene polymorphisms and GC risk. However, results are inconsistent among studies from different geographic regions and ethnic groups. Our ...goal was to evaluate the influence of Helicobacter pylori (H. pylori) infection and host genetic factors on GC susceptibility in a population of Spanish white GC patients.
DNA from 404 unrelated patients with GC and 404 sex- and age-matched healthy controls was typed for several functional polymorphisms in pro- (IL-1B, TNFA, LTA, IL-12p40) and anti-inflammatory (IL-4, IL-1RN, IL-10, TGFB1) genes by PCR, RFLP, and TaqMan assays. H. pylori infection and CagA/VacA antibody status were also determined by western blot serology.
Logistic regression analysis identified H. pylori infection with cagA strains (OR 2.54, 95% CI 1.77-3.66), smoking habit (OR 1.91, 95% CI 1.25-2.93), and positive family history of GC (OR 3.67, 95% CI 2.01-6.71) as independent risk factors for GC. None of the cytokine gene polymorphisms analyzed in this study were associated with susceptibility to GC development, whether GC patients were analyzed as a group or categorized according to anatomic location or histological subtype. Some simultaneous combinations of proinflammatory genotypes reportedly associated with greater GC risk yielded no significant differences between patients and controls.
Our results show that, at least in some white populations, the contribution of the cytokine gene polymorphisms evaluated in this study (IL-1B, IL-1RN, IL-12p40, LTA, IL-10, IL-4, and TGF-B1) to GC susceptibility may be less relevant than previously reported.
Variations in DNA repair genes have been reported as key factors in gastric cancer (GC) susceptibility but results among studies are inconsistent. We aimed to assess the relevance of DNA repair gene ...polymorphisms and environmental factors to GC risk and phenotype in a Caucasian population in Spain. Genomic DNA from 603 patients with primary GC and 603 healthy controls was typed for 123 single nucleotide polymorphisms in DNA repair genes using the Illumina platform. Helicobacter pylori infection with CagA strains (odds ratio (OR): 1.99; 95% confidence interval (CI): 1.55-2.54), tobacco smoking (OR: 1.77; 95% CI: 1.22-2.57), and family history of GC (OR: 2.87; 95% CI: 1.85-4.45) were identified as independent risk factors for GC. By contrast, the TP53 rs9894946A (OR: 0.73; 95% CI: 0.56-0.96), TP53 rs1042522C (OR: 0.76; 95% CI: 0.56-0.96), and BRIP1 rs4986764T (OR: 0.55; 95% CI: 0.38-0.78) variants were associated with lower GC risk. Significant associations with specific anatomopathological GC subtypes were also observed, most notably in the ERCC4 gene with the rs1799801C, rs2238463G, and rs3136038T variants being inversely associated with cardia GC risk. Moreover, the XRCC3 rs861528 allele A was significantly increased in the patient subgroup with diffuse GC (OR: 1.75; 95% CI: 1.30-2.37). Our data show that specific TP53, BRIP1, ERCC4, and XRCC3 polymorphisms are relevant in susceptibility to GC risk and specific subtypes in Caucasians.
Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to ...characterize the associations at the genome and transcriptome level. We performed a fine‐mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10−04) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10−09). On chromosome 5p13 we found cis‐eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10−11). On chromosome 8q24 we observed cis‐eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10−47). In addition, we found trans‐eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10−09). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk‐conferring GC pathomechanisms.
Genetic variants at chromosome 5p13 and 8q24 contribute to gastric cancer (GC) risk. Expression quantitative trait loci (eQTLs) involving PTGER4 (5p13), PSCA (8q24), and MBOAT7 may act as underlying pathomechanisms.
Genetic factors influencing the prognosis of gastric adenocarcinoma (GAC) are not well known. Given the relevance of cytokines and other pro-inflammatory mediators in cancer progression and ...invasiveness, we aimed to assess the prognostic role of several functional cytokine and cyclooxygenase gene polymorphisms in patients with GAC.
Genomic DNA from 380 Spanish Caucasian patients with primary GAC was genotyped for 23 polymorphisms in pro-inflammatory (IL1B, TNFA, LTA, IL6, IL12p40), anti-inflammatory (IL4, IL1RN, IL10, TGFB1) cytokine, and cyclooxygenase (PTGS1 and PTGS2) genes by PCR, RFLP and TaqMan assays. Clinical and histological information was collected prospectively. Survival curves were estimated by the Kaplan-Meier method and compared using the log rank test. Outcome was determined by analysis of Cox proportional hazards, adjusting for confounding factors.
The median follow-up period and median overall survival (OS) time were 9.9 months (range 0.4-120.3) and 10.9 months (95% CI: 8.9-14.1), respectively. Multivariate analysis identified tumor stages III (HR, 3.23; 95% CI:2-5.22) and IV (HR, 5.5; 95% CI: 3.51-8.63) as independent factors associated with a significantly reduced OS, whereas surgical treatment (HR: 0.44; 95%CI: 0.3-0.6) was related to a better prognosis of the disease. Concerning genetic factors, none of the 23 polymorphisms evaluated in the current study did influence survival. Moreover, no gene-environment interactions on GAC prognosis were observed.
Our results show that, in our population, the panel of selected pro- and anti-inflammatory cytokine, and cyclooxygenase gene polymorphisms are not relevant in determining the prognosis of gastric adenocarcinoma.
SUMMARY
The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma has increased in Western countries in recent decades. The aim of this study is to describe the changes in incidence and ...prevalence of BE diagnosis, dysplasia, and adenocarcinoma development in BE patients in a South‐European Mediterranean area. Retrospective population‐based analyses of endoscopy and pathology reports from 1976 to 2001 was performed. Data from patients with diagnosis of BE and/or esophageal carcinoma were collected. The study period was divided in four quartiles for statistical calculations; parametric and nonparametric tests were used. A 6.9‐fold increase was found in the diagnosis of long‐segment BE from the first to the fourth quartile, and a 9.3‐fold increase in short‐segment BE from 1995 to 2000, in contrast to a much smaller increase of 1.9‐fold increase in the number of upper gastrointestinal endoscopies. The adjusted incidence of BE diagnosis increased from 0.73 to 9.73 cases/100 000 (first to fourth quartile, respectively) and the adjusted prevalence from 6.51 to 76.04 cases/100 000 (1985–2001). The incidence of dysplasia was 2.13% per year (95% confidence interval: 0.05–11.3%) − 1.78% for low‐grade dysplasia and 0.36% for high‐grade dysplasia – giving a total incidence of 1 per 47 patient‐years. The incidence of adenocarcinoma during follow‐up was 0.48% per year (95% confidence interval: 0.006–2.62%), for an incidence of 1 per 210 patient‐years. Nineteen patients with BE (14 long‐segment BE, 5 short‐segment BE) were diagnosed with esophageal adenocarcinoma, with eight being diagnosed during endoscopic surveillance. Only 14 (8%) adenocarcinoma patients diagnosed during the study period had a history of BE. BE diagnosis has dramatically increased over recent decades in our population, unrelated to an increase in endoscopies. Progression to low‐grade dysplasia and adenocarcinoma is rare. Surveillance may have a low impact on the survival of adenocarcinoma patients in Southern Europe.
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