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1.  Associations of Diabetes Mellitus, Insulin, Leptin, and Ghrelin With Gastroesophageal Reflux and Barrett's Esophagus 
Gastroenterology  2013;145(6):1237-44.e1-5.
Background & Aims
Insulin and leptin have proliferative and anti-apoptotic effects. Ghrelin promotes gastric emptying and secretion of growth hormone and inhibits inflammation. We assessed whether diabetes mellitus and serum levels of insulin, leptin, and ghrelin are associated with gastroesophageal reflux disease (GERD) and Barrett's esophagus.
We conducted a case-control study in 822 men undergoing colorectal cancer screening who were recruited to also undergo upper endoscopy. We identified 70 with Barrett's esophagus; 80 additional men with Barrett's esophagus were recruited shortly after their clinical diagnoses. Serum levels of insulin, leptin, and ghrelin were assayed in all 104 fasting men with Barrett's esophagus without diabetes and 271 without diabetes or Barrett's esophagus. Logistic regression was used to estimate the effects of diabetes and levels of insulin, leptin, and ghrelin on GERD and Barrett's esophagus.
Among men with GERD, diabetes was inversely associated with Barrett's esophagus (adjusted odds ratio [OR] = 0.383; 95% confidence interval [CI]: 0.179–0.821). Among nondiabetics, hyperinsulinemia was positively associated with Barrett's esophagus, but the association was attenuated by adjustment for leptin and ghrelin. Leptin was positively associated with Barrett's esophagus, adjusting for obesity, GERD, and levels of insulin and ghrelin (OR for 3rd vs 1st tertile = 3.25; 95% CI: 1.29–8.17); this association was stronger in men with GERD (P = .01 for OR heterogeneity). Ghrelin was positively associated with Barrett's esophagus (OR for an increment of 400 pg/mL = 1.39; 95% CI: 1.09–1.76), but inversely associated with GERD (OR for 3rd vs 1st tertile = 0.364; 95% CI: 0.195–0.680).
Based on a case-control study, leptin was associated with Barrett's esophagus, particularly in men with GERD. Serum insulin level was associated with Barrett's esophagus, but might be mediated by leptin. Serum ghrelin was inversely associated with GERD, as hypothesized, but positively associated with Barrett's esophagus, contrary to our hypothesis. Additional studies are needed in men and women to replicate these findings.
PMCID: PMC3914630  PMID: 23999171
Insulin; Leptin; Ghrelin; Gastroesophageal Reflux
2.  A survey of expert follow-up practices after successful endoscopic eradication therapy for Barrett's esophagus with high-grade dysplasia and intramucosal adenocarcinoma 
Gastrointestinal endoscopy  2013;78(5):696-701.
Despite the increasing number of patients undergoing endoscopic therapy for Barrett's esophagus (BE) with high-grade dysplasia (HGD) or intramucosal cancer (IMC), there are few data to guide clinical decision making and research initiatives in the area of posttreatment follow-up.
We aimed to define expert practice patterns regarding follow-up after endoscopic treatment of BE with HGD and IMC.
Electronic survey.
Forty-eight endoscopists in the United States with expertise in BE endotherapy based on high-impact publications and national reputation.
A 21-item Web-based survey inquiring about post-BE endotherapy follow-up practices.
Of 48 expert endoscopists, 42 completed the survey. After successful treatment of BE with HGD or IMC, all experts perform surveillance upper endoscopy, most commonly at 3-month intervals in the first posttreatment year, every 6 months during the second year, and annually thereafter. None of the experts perform surveillance EUS after treatment of HGD, and only 19% perform EUS after treatment of IMC. After cancer eradication, only 36% of experts refer patients for CT, and 24% refer patients for positron emission tomography. Thirty-eight percent of experts refer patients for a surgical opinion when IMC extends into the muscularis mucosa; 100% refer when IMC extends into submucosa.
Not a consensus document; only U.S. experts included.
This study reports the follow-up practices of expert endoscopists after successful endotherapy for BE with HGD and IMC. Additional research is necessary to establish optimal surveillance intervals, the role of follow-up EUS, CT, and positron emission tomography, as well as the surgical implications of low-risk IMC extending into the muscularis mucosa.
PMCID: PMC3961573  PMID: 23711553
3.  Self-expanding metal stents (SEMS) provide superior outcomes compared to plastic stents for pancreatic cancer patients undergoing neoadjuvant therapy 
Neoadjuvant therapy is increasingly utilized for pancreatic cancer patients to decrease tumor burden in anticipation of later surgical resection. However, infectious complications such as life threatening cholangitis may occur for those with biliary obstruction. We hypothesized that placement of metal rather than plastic stents in such patients results in lower rates of stent-related complications, leading to improved clinical outcomes.
Retrospective cohort of pancreatic cancer patients treated by the University of Michigan Multidisciplinary Pancreatic Cancer Destination Program between January 2005 and June 2010. Only patients undergoing neoadjuvant therapy with one or more biliary stents placed for malignant obstruction were studied. Time to stent complication was compared between metal and plastic stents. The complication rate was estimated as the ratio of complications to total stent exposure time and 95% confidence intervals were calculated.
52 patients met inclusion criteria. A total of 113 stents were placed in 52 patients (70 plastic, 43 metal). The complication rate was almost 7 times higher with plastic stents, 0.20 (95% CI, 0.14-0.30), than with metal stents, 0.03 (95% CI, 0.01-0.06). Moreover, the rate of hospitalization for stent-related complications was 3-fold higher in the plastic stent group than the metal stent group. The first quartile estimate of time to stent complication was almost 5 times longer for metal than for plastic stents (44 vs. 200 days) (P<0.0001).
Compelling evidence indicates that self-expanding metal, not plastic stents should be used for malignant biliary obstruction in patients undergoing neoadjuvant therapy for pancreatic cancer.
PMCID: PMC3492479  PMID: 23205306
Pancreatic cancer; jaundice; chemotherapy; bile duct stents
4.  Does Rectal Indomethacin Eliminate the Need for Prophylactic Pancreatic Stent Placement in Patients Undergoing High-Risk ERCP? Post hoc Efficacy and Cost-Benefit Analyses Using Prospective Clinical Trial Data 
A recent large-scale randomized controlled trial (RCT) demonstrated that rectal indomethacin administration is effective in addition to pancreatic stent placement (PSP) for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. We performed a post hoc analysis of this RCT to explore whether rectal indomethacin can replace PSP in the prevention of PEP and to estimate the potential cost savings of such an approach.
We retrospectively classified RCT subjects into four prevention groups: (1) no prophylaxis, (2) PSP alone, (3) rectal indomethacin alone, and (4) the combination of PSP and indomethacin. Multivariable logistic regression was used to adjust for imbalances in the prevalence of risk factors for PEP between the groups. Based on these adjusted PEP rates, we conducted an economic analysis comparing the costs associated with PEP prevention strategies employing rectal indomethacin alone, PSP alone, or the combination of both.
After adjusting for risk using two different logistic regression models, rectal indomethacin alone appeared to be more effective for preventing PEP than no prophylaxis, PSP alone, and the combination of indomethacin and PSP. Economic analysis revealed that indomethacin alone was a cost-saving strategy in 96% of Monte Carlo trials. A prevention strategy employing rectal indomethacin alone could save approximately $150 million annually in the United States compared with a strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP.
This hypothesis-generating study suggests that prophylactic rectal indomethacin could replace PSP in patients undergoing high-risk ERCP, potentially improving clinical outcomes and reducing healthcare costs. A RCT comparing rectal indomethacin alone vs. indomethacin plus PSP is needed.
PMCID: PMC3947644  PMID: 23295278
5.  A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis 
The New England Journal of Medicine  2012;366(15):1414-1422.
Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP).
In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights.
A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P = 0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P = 0.03).
Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; number, NCT00820612.)
PMCID: PMC3339271  PMID: 22494121
6.  The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage 
Arthritis Research & Therapy  2013;15(Suppl 3):S5.
NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks.
PMCID: PMC3891010  PMID: 24267413
7.  Esophageal Adenocarcinoma Incidence in Individuals With Gastroesophageal Reflux: Synthesis and Estimates From Population Studies 
Recent advances in the management of Barrett's esophagus may kindle enthusiasm for screening for esophageal adenocarcinoma (EAC). Symptoms of gastroesophageal reflux disease (GERD) are recognized as relative risks for EAC. However, the absolute incidence of EAC in specific populations with GERD is unknown. We aimed to estimate the symptom-, age-, and sex-specific incidences of EAC, and place these incidences in the perspective of other cancers for which screening is endorsed.
A Markov computer model utilizing published and publicly available data was created to estimate the age- and sex-specific incidences of EAC in American white non-Hispanics with GERD symptoms.
The incidence of EAC in men younger than 50 years with GERD symptoms is very low (for instance, at the age of 35 years, incidence = 1.0/100,000), and their incidence of colorectal cancer is relatively much higher (for instance, at the age of 35 years, incidence of colorectal cancer is 6.7-fold greater). The incidence of EAC in older men with weekly GERD symptoms is substantial (for instance, at the age of 70 years, incidence = 60.8/100,000 person-years), but their incidence of colorectal cancer is at least threefold greater. The incidence of EAC in women with GERD is extremely low, and similar to that of breast cancer in men (for instance, 3.9/100,000 person-years at the age of 60 years).
Screening for EAC should not be performed in men younger than 50 years or in women because of very low incidences of cancer, regardless of the frequency of GERD symptoms. In white men with weekly GERD over the age of 60 years, the incidence of EAC is substantial, and might warrant screening if that practice is particularly accurate, safe, effective, and inexpensive.
PMCID: PMC3901355  PMID: 21139576
8.  Clinical yield of diagnostic ERCP in orthotopic liver transplant recipients with suspected biliary complications 
Background and aims
Diagnostic endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed for the evaluation of biliary complications after orthotopic liver transplantation (OLT). This practice is contrary to national trends towards reserving ERCP for therapeutic purposes. Our aim was to evaluate the clinical yield and complications of diagnostic ERCP in OLT recipients.
In this retrospective study, 165 OLT recipients who underwent ERCP between 1/2006 and 12/2010 at the University of Michigan were divided into 2 groups: 1) therapeutic ERCP group (T-ERCP) if they met pre-specified criteria that suggested a high likelihood of endoscopic intervention, and 2) diagnostic ERCP group (D-ERCP) if they had a clinical suspicion of biliary disease but did not meet any criteria. The two groups were compared with regard to the proportion of subjects in each group who underwent a high-yield ERCP, defined as a procedure that resulted in a clinically important intervention that modified disease course.
66.3% of diagnostic ERCPs were classified as high-yield, compared to 90.1% of therapeutic ERCPs (p<0.001). Serious complications were infrequent in both groups. A survey of practitioners caring for OLT recipients suggested that the rate of high-yield D-ERCP seen in this study is congruent with that considered acceptable in clinical practice.
Although T-ERCP was more likely to reveal a pathologic process requiring intervention, diagnostic ERCP appears to be an acceptable clinical strategy in OLT recipients because of the high likelihood of a high-yield study and the low rate of serious complications.
PMCID: PMC3900243  PMID: 22888069
All appear in the title
9.  EUS and pancreatic cyst fluid analysis: Is the juice worth the aqueeze? 
PMCID: PMC3397625  PMID: 22811851
10.  Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON) 
Heart  2011;97(10):797-802.
To determine whether once-daily esomeprazole 40 mg or 20 mg compared with placebo reduces the incidence of peptic ulcers over 26 weeks of treatment in patients taking low-dose acetylsalicylic acid (ASA) and who are at risk for ulcer development.
Multinational, randomised, blinded, parallel-group, placebo-controlled trial.
Cardiology, primary care and gastroenterology centres (n=240).
Helicobacter pylori-negative patients taking daily low-dose ASA (75–325 mg), who fulfilled one or more of the following criteria: age ≥18 years with history of uncomplicated peptic ulcer; age ≥60 years with either stable coronary artery disease, upper gastrointestinal symptoms and five or more gastric/duodenal erosions, or low-dose ASA treatment initiated within 1 month of randomisation; or age ≥65 years. All patients were ulcer-free at study entry.
Once-daily, blinded treatment with esomeprazole 40 mg, 20 mg or placebo for 26 weeks.
Main outcome measures
The primary end point was the occurrence of endoscopy-confirmed peptic ulcer over 26 weeks.
A total of 2426 patients (52% men; mean age 68 years) were randomised. After 26 weeks, esomeprazole 40 mg and 20 mg significantly reduced the cumulative proportion of patients developing peptic ulcers; 1.5% of esomeprazole 40 mg and 1.1% of esomeprazole 20 mg recipients, compared with 7.4% of placebo recipients, developed peptic ulcers (both p<0.0001 vs placebo). Esomeprazole was generally well tolerated.
Acid-suppressive treatment with once-daily esomeprazole 40 mg or 20 mg reduces the occurrence of peptic ulcers in patients at risk for ulcer development who are taking low-dose ASA.
Clinical trial registration number identifier: NCT00441727.
PMCID: PMC3088470  PMID: 21415072
Peptic ulcer; esomeprazole; acetylsalicylic acid; cardiovascular risk management; clinical trials
11.  Maintenance treatment with esomeprazole following initial relief of non-steroidal anti-inflammatory drug-associated upper gastrointestinal symptoms: the NASA2 and SPACE2 studies 
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 (COX-2) inhibitors, cause upper gastrointestinal (GI) symptoms that are relieved by treatment with esomeprazole. We assessed esomeprazole for maintaining long-term relief of such symptoms. Six hundred and ten patients with a chronic condition requiring anti-inflammatory therapy who achieved relief of NSAID-associated symptoms of pain, discomfort, or burning in the upper abdomen during two previous studies were enrolled and randomly assigned into two identical, multicentre, parallel-group, placebo-controlled studies of esomeprazole 20 mg or 40 mg treatment (NASA2 [Nexium Anti-inflammatory Symptom Amelioration] and SPACE2 [Symptom Prevention by Acid Control with Esomeprazole] studies; identifiers NCT00241514 and NCT00241553, respectively) performed at various rheumatology, gastroenterology, and primary care clinics. Four hundred and twenty-six patients completed the 6-month treatment period. The primary measure was the proportion of patients with relapse of upper GI symptoms, recorded in daily diary cards, after 6 months. Relapse was defined as moderate-to-severe upper GI symptoms (a score of more than or equal to 3 on a 7-grade scale) for 3 days or more in any 7-day period. Esomeprazole was significantly more effective than placebo in maintaining relief of upper GI symptoms throughout 6 months of treatment. Life-table estimates (95% confidence intervals) of the proportion of patients with relapse at 6 months (pooled population) were placebo, 39.1% (32.2% to 46.0%); esomeprazole 20 mg, 29.3% (22.3% to 36.2%) (p = 0.006 versus placebo); and esomeprazole 40 mg, 26.1% (19.4% to 32.9%) (p = 0.001 versus placebo). Patients on either non-selective NSAIDs or selective COX-2 inhibitors appeared to benefit. The frequency of adverse events was similar in the three groups. Esomeprazole maintains relief of NSAID-associated upper GI symptoms in patients taking continuous NSAIDs, including selective COX-2 inhibitors.
PMCID: PMC1866019  PMID: 17391505
12.  Practical approaches to minimizing gastrointestinal and cardiovascular safety concerns with COX-2 inhibitors and NSAIDs 
Arthritis Research & Therapy  2005;7(Suppl 4):S23-S29.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective in treating the pain and inflammation associated with osteoarthritis and rheumatoid arthritis, but it is well recognized that these agents are associated with substantial gastrointestinal toxicity. Treatment guidelines suggest that patients with one or more risk factors for NSAID associated ulcers should be prescribed preventive treatment. However, well over 80% of such patients may not receive an appropriate therapeutic intervention. Multiple strategies are available to reduce the risk for NSAID associated gastrointestinal complications. First, risk may be reduced by using non-NSAID analgesics. Second, use of the minimum effective dose of the NSAID may reduce risk. Third, co-therapy with a proton pump inhibitor or misoprostol may be desirable in at-risk patients. Use of cyclo-oxygenase-2 inhibitors may also reduce the risk for gastrointestinal events, although this benefit is eliminated in patients who receive aspirin, and cyclo-oxygenase-2 inhibitors may increase cardiovascular adverse events. The optimal management of NSAID related gastrointestinal complications must be based on the individual patient's risk factors for gastrointestinal and cardiovascular disease, as well as on the efficacy and tolerability of both the NSAID and accompanying gastroprotective agent.
PMCID: PMC2833978  PMID: 16168078
13.  Decision Analytic Modeling and NSAID Gastropathy 
PMCID: PMC1495468  PMID: 10886479

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