Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells.

Despite the high prevalence of chronic gastritis caused by Helicobacter pylori, the gastric mucosa has received little investigative attention as a unique immune environment. Here, we analyzed whether retinoic acid (RA), an important homeostatic factor in the small intestinal mucosa, also contributes to gastric immune regulation. We report that human gastric tissue contains high levels of the RA precursor molecule retinol (ROL), and that gastric epithelial cells express both RA biosynthesis genes and RA response genes, indicative of active RA biosynthesis. Moreover, primary gastric epithelial cells cultured in the presence of ROL synthesized RA in vitro and induced RA biosynthesis in co-cultured monocytes through an RA-dependent mechanism, suggesting that gastric epithelial cells may also confer the ability to generate RA on gastric dendritic cells (DCs). Indeed, DCs purified from gastric mucosa had similar levels of aldehyde dehydrogenase activity and RA biosynthesis gene expression as small intestinal DCs, although gastric DCs lacked CD103. In H. pylori-infected gastric mucosa, gastric RA biosynthesis gene expression was severely disrupted, which may lead to reduced RA signaling and thus contribute to disease progression. Collectively, our results support a critical role for RA in human gastric immune regulation.

Outcomes after implementing a tailored endoscopic step-up approach to walled-off necrosis in acute pancreatitis.

BACKGROUND: The aim of the study was to compare the outcomes of patients with pancreatic or peripancreatic walled-off necrosis by endoscopy using the conventional approach versus an algorithmic approach based on the collection size, location and stepwise response to intervention. METHODS: This was an observational before-after study of consecutive patients managed over two time intervals. In the initial period (2004-2009) symptomatic patients with walled-off necrosis underwent conventional single transmural drainage with placement of two stents and a nasocystic catheter, followed by direct endoscopic necrosectomy, if required. In the later period (2010-2013) an algorithmic approach was adopted based on size and extent of the walled-off necrosis and stepwise response to intervention. The main outcome was treatment success, defined as a reduction in walled-off necrosis size to 2 cm or less on CT after 8 weeks. RESULTS: Forty-seven patients were treated in the first interval and 53 in the second. There was no difference in patient demographics, clinical or walled-off necrosis characteristics and laboratory parameters between the groups, apart from a higher proportion of women and Caucasians in the later period. The treatment success rate was higher for the algorithmic approach compared with conventional treatment (91 versus 60 per cent respectively; P < 0·001). On multivariable logistic regression, management based on the algorithm was the only predictor of treatment success (odds ratio 6·51, 95 per cent c.i. 2·19 to 19·37; P = 0·001). CONCLUSION: An algorithmic approach to pancreatic and peripancreatic walled-off necrosis, based on the collection size, location and stepwise response to intervention, resulted in an improved rate of treatment success compared with conventional endoscopic management.

Utility of double-balloon enteroscopy in patients with left ventricular assist devices and obscure overt gastrointestinal bleeding.

Obscure overt gastrointestinal bleeding (OGIB) is a challenge in patients with left ventricular assist devices (LVADs). We evaluated the utility and safety of double-balloon enteroscopy (DBE) in patients with LVADs in an observational consecutive-patient cohort from a single tertiary referral center. Ten patients with LVADs underwent thirteen DBEs for obscure OGIB. The first OGIB event necessitating DBE occurred after a mean of 512 ± 363 days of LVAD support. All patients underwent DBE, eleven anterograde and two retrograde, with a mean insertion depth 176 ± 85 cm. Diagnostic yield was 69 % with the primary bleeding lesion most frequently found in the mid-bowel. The most common lesions were arteriovenous malformations. Therapeutic yield with argon plasma coagulation (APC), epinephrine injection, and/or hemoclip placement was 89 %. There were no procedure-related complications. DBE in patients with LVADs has good diagnostic yield and high therapeutic yield for obscure OGIB and is safe and well tolerated.

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.

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.

Therapeutic and interventional endoscopy for gastrointestinal bleeding.

INTRODUCTION: Gastrointestinal (GI) bleeding remains a common clinical problem encountered by every emergency room and trauma physician. Endoscopy remains the main approach to the diagnosis and therapy of GI bleeding. OBJECTIVES: To present the modern endoscopic approach for GI bleeding. METHODS: Narrative review based on our expertise and inclusion of classic articles dealing with interventional and therapeutic GI endoscopy. RESULTS: GI hemorrhage is now classified as upper, middle, and lower GI bleeding. Upper GI bleeding is defined as hemorrhage originating from the oropharynx to the ligament of Treitz (or papilla of Vater), middle GI bleeding occurs distal to the papilla of Vater to the terminal ileum, and lower GI bleeding is defined as bleeding distal to the ileocecal valve, including the entire colon and anorectum. Endoscopic methods used to diagnosed and treat GI bleeding include esophagogastroduodenoscopy, duodenoscopy, capsule endoscopy, double- and single-balloon enteroscopy, spiral enteroscopy, and colonosocopy. CONCLUSIONS: This is the first review paper dedicated to endoscopic therapy for bleeding involving any part of the luminal GI tract (i.e., esophagus, stomach, small bowel, and colon). Modern endoscopy permits the investigation and treatment of the majority of conditions affecting the entire hollow GI tract.

The economics of upper gastrointestinal bleeding in a US managed-care setting: a retrospective, claims-based analysis.

OBJECTIVE: To assess 12-month healthcare resource utilization and costs associated with upper gastrointestinal (UGI) bleeding events. METHODS: Patients hospitalized with a UGI bleeding event were identified in US national health-plan claims data (1999-2003) and propensity matched to control patients without UGI bleeding in the same health plan. Matching criteria included age, gender, index date, Charlson Comorbidity Index score, geographic region, and prior medical utilization. RESULTS: A total of 9,033 UGI-bleed patients and 579,018 control patients met the inclusion criteria, yielding 4,651 matched pairs. After matching, differences between the UGI bleed and general population cohorts remained for office visits, ER visits, and ER costs during the 6-month baseline period prior to the index date. During the 12 months following the index date, both UGI-related healthcare utilization and total healthcare, medical, and pharmacy costs incurred by the UGI-bleed cohort were significantly greater (p< 0.0001) than those incurred by the general population cohort (mean of $20,405 vs. 3,652), even after excluding the initial hospitalization costs (mean of $11,228 vs. 3,652). Costs were primarily due to inpatient hospitalizations (mean of $13,059 for the UGI-bleed cohort vs. $729 for the general population cohort) and ambulatory services (mean of $4,037 for the UGI-bleed cohort vs. $1,537 for the general population cohort). Sixteen percent of the UGI-bleed cohort had a GI-related hospitalization, and about 40% of total costs occurred after the initial hospitalization. CONCLUSIONS: Patients with UGI bleeds experienced significantly higher (p< 0.0001) 12-month health-resource utilization and costs than patients without UGI bleeds. This study provides empirical evidence of the long-term economic burden associated with UGI bleeding. Interpretation of the results should take into account the lack of available information in claims data that could have an effect on study outcomes, such as particular clinical and disease-specific parameters that are not mitigated by propensity score and comorbidity index matching. In addition, this study is limited by the intensive demographic matching that was done between the two cohorts, which may have eliminated the sickest UGI patients and the healthiest general health-plan population patients.

A randomized trial comparing endoscopic stenting to a sham procedure for chronic pancreatitis.

BACKGROUND: A number of studies support the use of endoscopically placed pancreatic duct (PD) stents to decrease pain in chronic pancreatitis (CP). Nevertheless, flaws in study design have prevented experts from reaching a consensus. PURPOSE: (1) Evaluate the efficacy of PD stenting to ameliorate abdominal pain in patients with CP and ductal strictures; (2) evaluate the placebo response rate from sham endoscopic therapy; (3) compare pain medication usage, healthcare utilization, psychological distress, and quality of life before and after endoscopic stenting; (4) prospectively evaluate the durability of the response. METHODS: Patients with typical abdominal pain, imaging confirmation of CP and endoscopic retrograde cholangiopancreatography (ERCP) confirmation of PD stricture will complete questionnaires to assess quality of life, psychological distress, pain intensity/unpleasantness, pain medication usage, and healthcare utilization. Enrolled patients will be randomized to ERCP with sphincterotomy and PD stenting versus sham procedure. Pain level and medication usage will be assessed weekly with telephone interviews. At 6-8 weeks, patients treated with stents will undergo stent removal; those randomized to the sham procedure without significant improvement (<50% reduction in pain score) will cross over to the treatment group; and those randomized to sham procedure who experienced improvement (>50% reduction) will be followed clinically. Patients will be followed in clinic or by phone biannually (up to 3 years). The primary endpoint is improvement in abdominal pain. The secondary endpoints are reduction in narcotic use, healthcare utilization, and work days missed; return to employment; improvement in quality of life and weight gain. RESULTS: Proposed study. LIMITATIONS: Strict inclusion criteria may limit enrollment. CONCLUSION: The proposed study represents the first trial of endoscopic stenting for symptomatic CP and ductal strictures with a credible sham procedure, assessment of multiple dimensions of pain, and psychosocial factors.

Gastrointestinal complications of HIV infection: changing priorities in the HAART era.

It has now been some 25 years since the initial description of AIDS. Following these observations, the epidemiology, natural history and manifestations of this disease have been well characterised. Intense investigation has better characterised HIV, resulting in the development of effective drug therapies to arrest disease progression. These multidrug combinations, termed highly active antiretroviral therapy or HAART, can suppress the viral load to the undetectable range and secondarily halt the destruction of CD4 T lymphocytes. This virological response is associated with a marked improvement in survival and absence of the many complications related to immunodeficiency. For patients who respond to HAART, the current emphasis is on treating side effects from the medications as well as treating other non-AIDS-related disorders. However, given the cost and complexities of these regimens, there are many patients who continue to present with the classic manifestations of AIDS, and, especially in the developing world, we will continue to see these patients for years to come.

Erythromycin prior to endoscopy for acute upper gastrointestinal haemorrhage: a cost-effectiveness analysis.

BACKGROUND: Erythromycin is a potent stimulator of gastrointestinal motility. Recent studies have examined the use of intravenous erythromycin to clear the stomach of blood before oesophago-gastroduodenoscopy (EGD) for acute upper gastrointestinal haemorrhage (UGIH). These studies have shown clinical effectiveness. AIM: To evaluate the cost-effectiveness of this intervention. METHODS: We sought to determine the cost-effectiveness of erythromycin before EGD from the payer's perspective. We found three relevant studies of erythromycin and used these data for the analysis. We obtained costs for intravenous erythromycin and charges for peptic ulcer hospitalization, EGD, surgery, and angiographic embolization. Complication rates were also incorporated from the literature. We implemented a model of health-related quality of life to measure the impact of the intervention. We created a decision-analysis tree and performed a probabilistic sensitivity analysis. RESULTS: A strategy of erythromycin prior to EGD resulted in a cost-effective outcome in a majority of trials using willingness-to-pay figures of USD 0, USD 50,000 and USD 100,000 per quality-adjusted life-year (QALY). CONCLUSION: Because of the implications for cost saving and increase in QALY, we would recommend giving erythromycin prior to EGD for UGIH.

Aspirin chemoprevention in patients with increased risk for colorectal cancer: a cost-effectiveness analysis.

BACKGROUND: Aspirin chemoprevention combined with colonoscopy screening is not cost-effective for the general population. However, the cost-effectiveness of aspirin in individuals with prior adenoma resection has not been evaluated. AIM: To evaluate the cost-effectiveness of aspirin chemoprevention alone and in combination with colonoscopy surveillance in patients with prior adenoma resection. METHODS: A model of the natural history of individuals with a history of endoscopic polypectomy was constructed. Four strategies were compared: (i) no intervention, (ii) routine colonoscopy surveillance, (iii) aspirin chemoprevention alone, and (iv) aspirin therapy combined with colonoscopy. RESULTS: Compared with no intervention, all other strategies were more costly but were associated with gains in years of life saved. Aspirin chemoprevention alone was associated with a gain of 0.0092 years, whereas routine colonoscopic surveillance and combination strategy were associated with further gains in years of life saved (0.0124 and 0.0138 years, respectively). Compared with no intervention, the incremental cost-effectiveness ratio of routine colonoscopy surveillance was $78,226 per year of life saved, and the incremental cost-effectiveness ratio of combination aspirin and colonoscopy was $60,942 per year of life saved. CONCLUSION: Aspirin chemoprevention combined with colonoscopic surveillance in post-polypectomy patients may be considered a cost-effective strategy.