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1.  Racial Differences in Measures of Obesity and Risk of Colon Adenoma 
Obesity (Silver Spring, Md.)  2011;20(3):673-677.
Obesity is an established risk factor for several malignancies. However, the specific measurement of obesity most relevant to colon neoplasia is still debated, and evidence has suggested gender and racial differences in this measurement. In this study, we sought to compare which measurement—BMI, waist circumference (WC), waist-to-hip ratio (WHR) or waist-to-height ratio (WHtR)—is most strongly associated with development of colon adenomas, a precursor of colon cancer, and to investigate differences in this association between racial groups. We confirmed the strong association between WHR, as a measure of central obesity, and development of colon neoplasia. In our overall analysis, patients in the highest WHR quartile showed a substantial increase in risk of colon adenomas compared to patients in the lowest WHR quartile (odds ratio (OR) = 1.82, 95% confidence interval (CI): 1.12–2.71, Ptrend = 0.0017). In stratified analyses, we noted that strongly associated obesity measures in European Americans were WC (OR = 2.38, 95% CI = 1.45–3.92, Ptrend = 0.0004) and BMI (OR = 2.18, 95% CI = 1.37–3.49, Ptrend = 0.0015), whereas in African Americans, WHR was the strongest and the only obesity measure statistically significantly associated with adenoma risk (OR = 2.12, 95% CI = 1.05–4.30, Ptrend = 0.025). Our data highlight the importance of obesity in the development of early colon neoplasia and suggest substantial racial differences in the measures of obesity most strongly associated with risk of colon adenomas.
PMCID: PMC4301956  PMID: 21996657
3.  Phase II and pharmacokinetic trial of rebeccamycin analog in advanced biliary cancers 
Advanced cancers of the bile duct and gallbladder carry an ominous prognosis. Rebeccamycin analogue (RA) is a novel antitumor antibiotic where phase I trials suggested clinical efficacy in patients with biliary cancers.
The primary objective was to determine the response rate to RA in patients with advanced gallbladder and bile duct tumors. Secondary endpoints were survival and pharmacokinetic characterization. RA was given at a dose 165 mg/(m2 day) × 5 days every 3 weeks.
Forty-six patients were enrolled. Nine patients were removed from study before their first planned imaging study for response. Two patients had partial responses and 16 had stable disease. On an intent-to-treat analysis the median survival was 6.3 months. A >20% drop in CA 19.9 was seen in 43% of patients with initial high levels. Grade 4 neutropenia and thrombocytopenia were seen in 35 and 5% of patients, respectively. Febrile neutropenia occurred in 16% of patients. The pharmacokinetic profile of this trial closely resembles those of prior phase I trials. Measured biliary concentrations of RA were as much as 100× greater than simultaneous plasma concentration.
Although RA has a response rate of 5% in advanced biliary cancers, it is associated with significant numbers of patients experiencing prolonged stable disease. Biliary concentrations of RA are significantly greater than plasma concentrations.
PMCID: PMC4220168  PMID: 19399502
Biliary cancer; Gallbladder cancer; Phase II trial
4.  Feasibility, Safety, Acceptability and Yield of Office-based, Screening Transnasal Esophagoscopy 
Gastrointestinal endoscopy  2012;75(5):945-953.e2.
Endoscopic screening for esophageal neoplasia can identify patients eligible for early intervention for pre-cancerous lesions. Unsedated transnasal esophagoscopy may provide an efficient and accurate endoscopic assessment with fewer risks and less cost compared to conventional upper endoscopy.
To assess the feasibility, safety, acceptability and yield of unsedated transnasal esophagoscopy in a primary care population.
Multi-center, prospective, cross-sectional study.
Two outpatient tertiary centers.
General medical clinic population between the ages of 40 and 85.
Unsedated, office-based transnasal esophagoscopy.
Main outcomes measurements
1) Procedure yield, 2) Completeness of examination, 3) Procedure length, 4) Adverse events and complications, 5) Choking, gagging, pain or anxiety during the examination, and 6) Overall tolerability
Four hundred and twenty-six participants (mean age 55.8 ± 9.5, 43% male) enrolled in the study, and 422 (99%) completed the examination. Mean examination time was 3.7 ± 1.8 minutes. There were no serious adverse events and 12 participants (2.8%) reported minor complications. Participants reported minimal choking, gagging, pain or anxiety. The examination was well tolerated by most participants. Overall, 38% of subjects had an esophageal finding that changed management (34% erosive esophagitis, 4% Barrett’s esophagus).
Nonrandomized study; tertiary centers only; self-selected population with a large proportion reporting esophageal symptoms.
Unsedated transnasal esophagoscopy is a feasible, safe, and well-tolerated method to screen for esophageal disease in a primary care population. Endoscopic findings are common in this patient population.
PMCID: PMC4154478  PMID: 22425272
Barrett’s esophagus; endoscopy; screening; transnasal; esophageal cancer
5.  Association of Barrett’s Esophagus With Type II Diabetes Mellitus: Results From a Large Population-based Case-Control Study 
Central obesity could increase the risk for Barrett’s esophagus (BE) and esophageal adenocarcinoma by mechanical and/or metabolic mechanisms, such as hyperinsulinemia. We performed an epidemiologic study to determine whether prior type 2 diabetes mellitus (DM2) is associated with BE.
We performed a population-based case-control study using the General Practice Research Database, a UK primary care database that contains information on more than 8 million subjects, to identify cases of BE (using previously validated codes; n = 14,245) and matched controls without BE (by age, sex, enrollment date, duration of follow-up evaluation, and practice region by incidence density sampling; n = 70,361). We assessed the association of a prior diagnosis of DM2 with BE using conditional univariate and multivariable regression analysis. Confounders assessed included smoking, obesity measured by body mass index (BMI), and gastroesophageal reflux disease.
BE cases were more likely than controls to have smoked (52.4% vs 49.9%), have a higher mean BMI (27.2 vs 26.9), and a higher prevalence of DM2 than controls (5.8% vs 5.3%). On multivariable analysis, DM2 was associated with a 49% increase in the risk of BE, independent of other known risk factors (odds ratio, 1.49; 95% confidence interval, 1.16–1.91). This association was stronger in women than men. Results remained stable with sensitivity analyses.
In a large population-based case-control study, DM2 was a risk factor for BE, independent of obesity (as measured by BMI) and other risk factors (smoking and gastroesophageal reflux disease). These data suggest that metabolic pathways related to DM2 should be explored in BE pathogenesis and esophageal carcinogenesis.
PMCID: PMC3865768  PMID: 23591277
Visceral Obesity; Insulin Resistance; Esophageal Adenocarcinoma; Epidemiology
6.  Immediate Unprepped Hydroflush Colonoscopy for Severe Lower GI Bleeding: A Feasibility Study 
Gastrointestinal endoscopy  2012;76(2):367-373.
Urgent colonoscopy is not always the preferred initial intervention in severe lower GI bleeding due to the need for a large volume of oral bowel preparation, the time required for administering the preparation, and concern regarding adequate visualization.
To evaluate feasibility, safety, and outcomes of immediate unprepped hydroflush colonoscopy for severe lower gastrointestinal bleeding.
Prospective feasibility study of immediate colonoscopy after tap-water enema without oral bowel preparation, aided by water jet pumps and mechanical suction devices in patients admitted to the intensive care unit with a primary diagnosis of severe lower gastrointestinal bleeding
Tertiary referral center
Main outcome measurements
Primary outcome measurement was the percentage of colonoscopies where the preparation permitted satisfactory evaluation of the entire length of the colon suspected to contain the source of bleeding. Secondary outcome measurements were visualization of a definite source of bleeding, length of hospital and ICU stays, re-bleeding rates, and transfusion requirements.
Thirteen procedures were performed in 12 patients. Complete colonoscopy to the cecum was performed in 9/13 patients (69.2 %). However, endoscopic visualization was felt to be adequate to definitively or presumptively identify the source of bleeding in all procedures, with no colonoscopy repeated due to inadequate preparation. A definite source of bleeding was identified in 5/13 procedures (38.5%). Median length of ICU stay was 1.5 days and hospital stay was 4.3 days. Recurrent bleeding during the same hospitalization, requiring repeat endoscopy, surgery or angiotherapy was seen in 3/12 patients (25%).
Uncontrolled feasibility study of selected patients.
Immediate unprepped hydroflush colonoscopy in patients with severe lower GI bleeding is feasible with the hydroflush technique.
PMCID: PMC4121432  PMID: 22658390
7.  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
8.  Use of prototype two-channel endoscope with elevator enables larger lift-and-snare endoscopic mucosal resection in a porcine model 
Gastroenterology Report  2014;2(1):54-57.
Background: Flat and depressed lesions are becoming increasingly recognized in the esophagus, stomach, and colon. Various techniques have been described for endoscopic mucosal resection (EMR) of these lesions.
Aims: To evaluate the efficacy of lift-grasp-cut EMR using a prototype dual-channel forward-viewing endoscope with an instrument elevator in one accessory channel (dual-channel elevator scope) as compared to standard dual-channel endoscopes.
Methods: EMR was performed using a lift-grasp-cut technique on normal flat rectosigmoid or gastric mucosa in live porcine models after submucosal injection of 4 mL of saline using a dual-channel elevator scope or a standard dual-channel endoscope. With the dual-channel elevator scope, the elevator was used to attain further lifting of the mucosa. The primary endpoint was size of the EMR specimen and the secondary endpoint was number of complications.
Results: Twelve experiments were performed (six gastric and six colonic). Mean specimen diameter was 2.27 cm with the dual-channel elevator scope and 1.34 cm with the dual-channel endoscope (P = 0.018). Two colonic perforations occurred with the dual-channel endoscope, vs no complications with the dual-channel elevator scope.
Conclusions: The increased lift of the mucosal epithelium, through use of the dual-channel elevator scope, allows for larger EMR when using a lift-grasp-cut technique. Noting the thin nature of the porcine colonic wall, use of the elevator may also make this technique safer.
PMCID: PMC3920991  PMID: 24760237
endoscopic mucosal resection; endoscopic polypectomy; gastric cancer
9.  Esomeprazole and 325 mg/d Aspirin Reduce Tissue Concentrations of Prostaglandin E2 in Patients with Barrett’s Esophagus 
Gastroenterology  2012;143(4):917-926.e1.
Background & Aims
Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett’s esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled phase II trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin E2 (PGE2) in patients with BE with no dysplasia or low-grade dysplasia.
Participants were recruited through the multi-center Cancer Prevention Network and randomly assigned to groups that were given esomeprazole (40 mg, twice daily) in combination with an aspirin placebo (once daily) (Arm A; n=42), with 81 mg aspirin (once daily) (Arm B; n=63), or with 325 mg aspirin (once daily) (Arm C; n=63) for 28 days. We collected esophageal biopsies before and after the intervention period, to determine the absolute change in mean concentrations of PGE2 (the primary endpoint).
Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentrations of PGE2 was reduced by 67.6±229.68 pg/mL in Arm A, was reduced by 123.9±284.0 pg/mL in Arm B (P=.10 vs Arm A), and was reduced by 174.9 ±263.62 pg/mL in Arm C (P=.02 vs Arm A).
In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE2 patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients.
PMCID: PMC3458136  PMID: 22796132
esophageal cancer; NSAIDs; inflammation; esophagus
10.  EUS compared with endoscopy plus transabdominal US in the initial diagnostic evaluation of patients with upper abdominal pain 
Gastrointestinal endoscopy  2010;72(5):967-974.
Primary upper endoscopy (EGD) and transabdominal US (TUS) are often performed in patients with upper abdominal pain.
Primary: Determine whether the combination of EGD and EUS was equivalent to EGD plus TUS in the diagnostic evaluation of upper abdominal pain. Secondary: Compare EUS versus TUS in detecting abdominal lesions, and compare EGD by using an oblique-viewing echoendoscope versus the standard, forward-viewing endoscope in detecting mucosal lesions.
Prospective, paired design.
Six academic endoscopy centers.
This study involved patients with upper abdominal pain referred for endoscopy.
All patients had EGD, EUS, and TUS. The EGD was done using both an oblique-viewing echoendoscope and the standard, forward-viewing endoscope (randomized order) by two separate endoscopists in a blinded fashion, followed by EUS. TUS was performed within 4 weeks of EGD/EUS, also in a blinded fashion. Follow-up: telephone interviews and chart reviews.
Main Outcome Measurements
Diagnose possible etiology of upper abdominal pain and detect clinically significant lesions.
A diagnosis of the etiology of upper abdominal pain was made in 66 of 172 patients (38%). The diagnostic rate was 42 of 66 patients (64%) for EGD plus EUS versus 41 of 66 patients (62%) for EGD plus TUS, which was statistically equivalent (McNemar test; P = .27). One hundred ninety-eight lesions were diagnosed with either EUS or TUS. EUS was superior to TUS for visualizing the pancreas (P < .0001) and for diagnosing chronic pancreatitis (P = .03). Two biliary stones were detected only by EUS. Two hundred fifty-one mucosal lesions were similarly diagnosed with EGD with either the standard, forward-viewing endoscope or the oblique-viewing echoendoscope (kappa = 0.48 [95% CI, .43-.54]). EGD with the standard, forward-viewing endoscope was preferred for biopsies.
No cost analysis.
The combination of EGD with EUS is equivalent to EGD plus TUS for diagnosing a potential etiology of upper abdominal pain. EUS is superior to TUS for detecting chronic pancreatitis. EGD combined with EUS should be considered in the first-line diagnostic evaluation of patients with upper abdominal pain.
PMCID: PMC3775486  PMID: 20650452
11.  Association of insulin and insulin-like growth factors with Barrett’s oesophagus 
Gut  2011;61(5):665-672.
It is postulated that high serum levels of insulin and insulin growth factor 1 (IGF-1) mediate obesity-associated carcinogenesis. The relationship of insulin, IGF-1 and IGF binding proteins (IGFBP) with Barrett’s oesophagus (BO) has not been well examined.
Serum levels of insulin and IGFBPs in patients with BO were compared with two separate control groups: subjects with gastro-oesophageal reflux disease (GORD) and screening colonoscopy controls. Fasting insulin, IGF-1 and IGFBPs were assayed in the serum of BO cases (n = 135), GORD (n = 135) and screening colonoscopy (n = 932) controls recruited prospectively at two academic hospitals. Logistic regression was used to estimate the risk of BO.
Patients in the highest tertile of serum insulin levels had an increased risk of BO compared with colonoscopy controls (adjusted OR 2.02, 95% CI 1.15 to 3.54) but not compared with GORD controls (adjusted OR 1.55, 95% CI 0.76 to 3.15). Serum IGF-1 levels in the highest tertile were associated with an increased risk of BO (adjusted OR 4.05, 95% CI 2.01 to 8.17) compared with the screening colonoscopy control group but were not significantly different from the GORD control group (adjusted OR 0.57, 95% CI 0.27 to 1.17). IGFBP-1 levels in the highest tertile were inversely associated with a risk of BO in comparison with the screening colonoscopy controls (adjusted OR 0.11, 95% CI 0.05 to 0.24) but were not significantly different from the GORD control group (adjusted OR 1.04, 95% CI 0.49 to 2.16). IGFBP-3 levels in the highest tertile were inversely associated with the risk of BO compared with the GORD controls (OR 0.36, 95% CI 0.16 to 0.81) and also when compared with the colonoscopy controls (OR 0.40, 95% CI 0.20 to 0.79).
These results provide support for the hypothesis that the insulin/IGF signalling pathways have a role in the development of BO.
PMCID: PMC3669672  PMID: 21930730
12.  Barrett’s esophagus and the risk of obstructive sleep apnea: a case–control study 
BMC Gastroenterology  2013;13:82.
Prior studies suggest that obstructive sleep apnea may be associated with gastroesophageal reflux disease, a strong risk factor for Barrett’s esophagus. The goals of this pilot case–control study were to determine whether Barrett’s esophagus patients have an increased likelihood of obstructive sleep apnea and to determine whether nocturnal gastroesophageal reflux symptoms affect the relationship between Barrett’s esophagus and obstructive sleep apnea risk.
Patients with Barrett’s esophagus completed the Berlin Questionnaire, a validated survey instrument identifying subjects at high risk for obstructive sleep apnea. Two outpatient control groups were recruited: 1) EGD Group, subjects matched to Barrett’s esophagus cases by age, race, and gender with esophagogastroduodenoscopy negative for Barrett’s esophagus; and 2) Colonoscopy Group, patients getting colonoscopy. Rates of scoring at high risk for obstructive sleep apnea were compared. Respondents were also questioned regarding severity of their typical gastroesophageal reflux symptoms and presence of nocturnal gastroesophageal reflux symptoms.
The study included 287 patients (54 Barrett’s esophagus, 62 EGD, and 171 colonoscopy subjects). Barrett’s esophagus patients were slightly older than colonoscopy patients and more obese. 56% (n = 30) of Barrett’s esophagus subjects scored at high risk for obstructive sleep apnea, compared with 42% (n = 26) of EGD subjects (OR 1.73, 95% CI [0.83, 3.62]) and 37% (n = 64) of colonoscopy patients (OR 2.08, 95% CI [1.12, 3.88]). The association between Barrett’s esophagus and scoring at high risk for obstructive sleep apnea compared with colonoscopy patients disappeared after adjusting for age. Barrett’s esophagus patients reported more severe typical heartburn and regurgitation symptoms than either control group. Among all subjects, patients with nocturnal reflux symptoms were more likely to score at high risk for obstructive sleep apnea than patients without nocturnal reflux.
In this pilot study, a high proportion of Barrett’s esophagus subjects scored at high risk for obstructive sleep apnea. Having Barrett’s esophagus was associated with more severe gastroesophageal reflux symptoms, and nocturnal reflux symptoms were associated with scoring at high risk for obstructive sleep apnea. The need for obstructive sleep apnea screening in Barrett’s esophagus patients with nocturnal gastroesophageal reflux symptoms should be further evaluated.
PMCID: PMC3668164  PMID: 23663216
Barrett’s esophagus; Gastroesophageal reflux disease; Obesity; Obstructive sleep apnea
13.  Insulin Resistance, Central Obesity and Risk of Colorectal Adenomas 
Cancer  2011;118(7):1774-1781.
Increasing evidence supports insulin resistance (IR) as the underpinning of the obesity-colorectal neoplasia link. The homeostasis model assessment-IR (HOMA-IR) is a widely accepted index of evolving hyperinsulinemia and early IR. Studies of the relationship between HOMA-IR and colorectal adenomas are limited. Therefore, we sought to determine the associations of HOMA-IR and central obesity [waist-to-hip ratio (WHR)] with risk of colorectal adenomas in a screening colonoscopy-based study.
We have collected lifestyle information and fasting blood samples from 1,222 participants (320 incident adenoma cases and 902 without adenomas) prior to their screening colonoscopies. Unconditional logistic regression models were used to assess risk associations.
In multivariate analysis of participants (n=1,093) reporting no anti-diabetic medication use, those in the top quartile of WHR were twice as likely (OR = 2.18, 95% CI = 1.33 – 3.57, p-trend = 0.003), and those in the top quartile of HOMA-IR were 63% more likely (OR = 1.63, 95% CI = 1.09 – 2.44, p-trend = 0.01), to have adenomas compared to those in the bottom quartiles. Stratified analysis revealed a statistically significant interaction between HOMA-IR and gender (p-interaction = 0.04) with the association largely limited to men: compared to those in the bottom tertile, men in the top tertile of HOMA-IR were twice more likely to have adenomas (OR = 2.11, 95% CI=1.18–3.78, p-trend=0.01).
Our results support central obesity and insulin resistance, particularly in men, as important risk factors for the development of early colorectal neoplasia.
PMCID: PMC3262947  PMID: 22009143
colorectal adenomas; insulin resistance; central obesity; cross-sectional study
14.  Aberrant Vimentin Methylation Is Characteristic of Upper Gastrointestinal Pathologies 
We have previously established aberrant DNA methylation of Vimentin exon-1 (VIM methylation) as a common epigenetic event in colon cancer and as a biomarker for detecting colon neoplasia. We now examine VIM methylation in neoplasia of the upper gastrointestinal tract.
Using a quantitative real-time Methylation-Specific PCR assay we tested for VIM methylation in archival specimens of esophageal and gastric neoplasia.
We find that acquisition of aberrant VIM methylation is highly common in these neoplasms, but largely absent in controls. The highest frequency of VIM methylation was detected in lesions of the distal esophagus, including 91% of Barrett’s esophagus (BE, n=11), 100% of high grade dysplasia (HGD, n=5), and 81% of esophageal adenocarcinoma (EAC, n=26), but absent in controls (n=9). VIM methylation similarly was detected in 87% of signet ring (n=15) and 53% of intestinal type gastric cancers (n=17). Moreover, in tests of cytology brushings VIM methylation proved detectable in 100% of BE cases (n=7), 100% of HGD cases (n=4), and 83% of EAC cases (n=18), but was absent in all controls (n=5).
These findings establish aberrant VIM methylation as a highly common epigenetic alteration in neoplasia of the upper gastrointestinal tract, and demonstrate that Barrett’s esophagus, even without dysplasia, already contains epigenetic alterations characteristic of adenocarcinoma.
These findings suggest VIM methylation as a biomarker of upper gastrointestinal neoplasia with potential for development as molecular cytology in esophageal screening.
PMCID: PMC3454489  PMID: 22315367
Barrett’s Esophagus; Esophageal Cancer; Gastric Cancer; Vimentin; Methylation
15.  Variation In Age At Cancer Diagnosis In Familial Versus Non-Familial Barrett’s Esophagus 
Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study we determine whether cancers develop at an earlier age in multiplex Familial Barrett’s Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC).
Information on BE/EAC risk factors and family history was collected from probands at eight tertiary care academic hospitals. Age of cancer diagnosis and other risk factors were compared between non-familial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds.
The study included 830 non-familial, 274 duplex and 41 multiplex FBE kindreds with 274, 133 and 43 EAC and 566, 288 and 103 BE cases, respectively. Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (p = 0.0186). Median age of cancer diagnosis was significantly younger in multiplex compared to duplex and non-familial kindreds (57 vs. 62 vs. 63 yrs, respectively, p = 0.0448). Mean body mass index (BMI) was significantly lower in multiplex kindreds (p = 0.0033) as was smoking (p < 0.0001), and reported regurgitation (p = 0.0014).
Members of multiplex FBE kindreds develop EAC at an earlier age compared to non-familial EAC cases. Multiplex kindreds do not have a higher proportion of common risk factors for EAC, suggesting that this aggregation might be related to a genetic factor.
These findings indicate that efforts to identify susceptibility genes for BE and EAC will need to focus on multiplex kindreds.
PMCID: PMC3275661  PMID: 22178570
Esophageal adenocarcinoma; Barrett’s esophagus; genetics; family history
16.  The MicroRNAs, MiR-31 and MiR-375, as Candidate Markers in Barrett's Esophageal Carcinogenesis 
Genes, chromosomes & cancer  2012;51(5):473-479.
There is a critical need to identify molecular markers that can reliably aid in stratifying esophageal adenocarcinoma (EAC) risk in patients with Barrett's esophagus. MicroRNAs (miRNA/miR) are one such class of biomolecules. In the present cross-sectional study, we characterized miRNA alterations in progressive stages of neoplastic development, i.e., metaplasia–dysplasia–adenocarcinoma, with an aim to identify candidate miRNAs potentially associated with progression. Using next generation sequencing (NGS) as an agnostic discovery platform, followed by quantitative real-time PCR (qPCR) validation in a total of 20 EACs, we identified 26 miRNAs that are highly and frequently deregulated in EACs (≥4-fold in >50% of cases) when compared to paired normal esophageal squamous (nSQ) tissue. We then assessed the 26 EAC-derived miRNAs in laser microdissected biopsy pairs of Barrett's metaplasia (BM)/nSQ (n = 15), and high-grade dysplasia (HGD)/nSQ (n = 14) by qPCR, to map the timing of deregulation during progression from BM to HGD and to EAC. We found that 23 of the 26 candidate miRNAs were deregulated at the earliest step, BM, and therefore noninformative as molecular markers of progression. Two miRNAs, miR-31 and –31*, however, showed frequent downregulation only in HGD and EAC cases suggesting association with transition from BM to HGD. A third miRNA, miR-375, showed marked downregulation exclusively in EACs and in none of the BM or HGD lesions, suggesting its association with progression to invasive carcinoma. Taken together, we propose miR-31 and –375 as novel candidate microRNAs specifically associated with early- and late-stage malignant progression, respectively, in Barrett's esophagus.
PMCID: PMC3547654  PMID: 22302717
17.  DNA methylation profiling in Barrett's esophagus and esophageal adenocarcinoma reveals unique methylation signatures and molecular subclasses 
Epigenetics  2011;6(12):1403-1412.
Barrett's esophagus (BE) is a metaplastic process whereby the normal stratified, squamous esophageal epithelium is replaced by specialized intestinal epithelium. Barrett's is the only accepted precursor lesion for esophageal adenocarcinoma (EAC), a solid tumor that is rapidly increasing in incidence in western countries. BE evolves into EAC through intermediate steps that involve increasing degrees of dysplasia. Current histologic criteria are quite subjective and the clinical behavior of BE is highly variable and difficult to predict using these standards. It is widely believed that molecular alterations present in BE and EAC will provide more precise prognostic and predictive markers for these conditions than the current clinical and histologic features in use. In order to further define molecular alterations that can classify unique groups of BE and EAC, we utilized methylation microarrays to compare the global gene methylation status of a collection of normal squamous, BE, BE + high-grade dysplasia (HGD), and EAC cases. We found distinct global methylation signatures, as well as differential methylation of specific genes, that discriminated these histological groups. We also noted high and low methylation epigenotypes among the BE and EAC cases. Additional validation of those CpG sites that distinguished BE from BE + HGD and EAC may lead to the discovery of useful biomarkers with potential clinical applications in the diagnosis and prognosis of BE and EAC.
PMCID: PMC3256330  PMID: 22139570
Barrett's esophagus; esophageal adenocarcinoma; DNA methylation; methylation microarray
18.  Prevalence of Barrett's Esophagus in first degree relatives of patients with esophageal adenocarcinoma 
Aim of this study is to determine the prevalence of Barrett's Esophagus (BE) in first degree relatives of patients with esophageal adenocarcinoma (EAC) and Barrett's' high grade dysplasia (HGD).
After Institutional Review board approval first degree relatives of patients with EAC/HGD underwent unsedated ultrathin trans-nasal endoscopy (UUTNE) with biopsy. BE was suspected if any salmon colored epithelial tongues were seen above the gastro-esophageal junction. A diagnosis of BE was made only if biopsy from these areas confirmed columnar lined epithelium with intestinal metaplasia.
From 23 families 47 first degree relative underwent UUTNE and one patient underwent routine upper endoscopy with sedation as part of this study. The mean age of cases was 44.4 yrs. All patients tolerated the procedure well and there were no procedure related complications. BE was suspected in 16 (34%) patients and confirmed in 13/16 (27.7%) patients. There was 4 long segment (> 3cm) and 9 short segment (<3 cm) of BE.
There is a significantly higher than expected prevalence of BE in first degree relatives of EAC/HGD patients. This should be taken in to consideration to develop further screening guidelines. Further work is need to confirm these findings. Un-sedated trans-nasal endoscopy is a safe and well-tolerated method for BE screening.
PMCID: PMC3189338  PMID: 21617543
Barrett's esophagus; prevalence; trans-nasal endoscopy; esophageal adenocarcinoma
19.  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
20.  Motion artifacts associated with in vivo endoscopic OCT images of the esophagus 
Optics Express  2011;19(21):20722-20735.
3-D optical coherence tomography (OCT) has been extensively investigated as a potential screening and/or surveillance tool for Barrett’s esophagus (BE). Understanding and correcting motion artifact may improve image interpretation. In this work, the motion trace was analyzed to show the physiological origin (respiration and heart beat) of the artifacts. Results showed that increasing balloon pressure did not sufficiently suppress the physiological motion artifact. An automated registration algorithm was designed to correct such artifacts. The performance of the algorithm was evaluated in images of normal porcine esophagus and demonstrated in images of BE in human patients.
PMCID: PMC3495872  PMID: 21997082
(110.4500) Optical coherence tomography; (170.2150) Endoscopic imaging; (100.3010) Image reconstruction techniques
21.  Durability of Radiofrequency Ablation in Barrett’s Esophagus with Dysplasia 
Gastroenterology  2011;141(2):460-468.
Background & Aims
Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett’s esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE.
We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events.
After 2 years, 101/106 patients had complete eradication of all dysplasia (95%) and 99/106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51/52 (98%) and intestinal metaplasia was eradicated in 51/52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50/54 (93%) and intestinal metaplasia was eradicated in 48/54 (89%). After 3 years, dysplasia was eradicated in 55/56 of subjects (98%) and intestinal metaplasia was eradicated in 51/56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4/119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1/181 pt-yrs (0.55%/pt-yr); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1/73 pt-yrs (1.37%/pt-yr).
In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.
PMCID: PMC3152658  PMID: 21679712
esophagus; cancer; prevention; endoscopic therapy
22.  Small bowel capsule endoscopy in patients with cardiac pacemakers and implantable cardioverter defibrillators: Outcome analysis using telemetry review 
AIM: To determine if there were any interactions between cardiac devices and small bowel capsules secondary to electromagnetic interference (EMI) in patients who have undergone small bowel capsule endoscopy (SBCE).
METHODS: Authors conducted a chart review of 20 patients with a cardiac pacemaker (CP) or implantable cardioverter defibrillator (ICD) who underwent continuous electrocardiographic monitoring during their SBCE from 2003-2008. authors searched for unexplained electrocardiogram (ECG) findings, changes in CP and ICD set parameters, any abnormality in transmitted capsule data, and adverse clinical events.
RESULTS: There were no adverse events or hemodynamically significant arrhythmias reported. CP and ICD set parameters were preserved. The majority of ECG abnormalities were also found in pre- or post- SBCE ECG tracings and the CP behavior during arrhythmias appeared appropriate. Two patients seemed to have episodes of undersensing by the CP. However, similar findings were documented in ECGs taken outside the time frame of the SBCE. One patient was observed to have a low signal encountered from the capsule resulting in lack of localization, but no images were lost.
CONCLUSION: Capsule-induced EMI remains a possibility but is unlikely to be clinically important. CP-induced interference of SBCE is also possible, but is infrequent and does not result in loss of images transmitted by the capsule.
PMCID: PMC3309898  PMID: 22442746
Small bowel capsule endoscopy; Cardiac pacemakers; Implantable cardioverter defibrillators; Electromagnetic interference; Telemetry review
23.  Biopsy depth after radiofrequency ablation of dysplastic Barret's esophagus 
Gastrointestinal endoscopy  2010;72(3):490-496.e1.
After endoscopic radiofrequency ablation (RFA) of dysplastic Barrett's esophagus (BE), endoscopic biopsy samples are obtained to assess response to therapy. Whether these biopsies are of adequate depth to assess efficacy is unknown.
To compare the depth of endoscopic biopsy samples after RFA with those of untreated controls and to determine the prevalence of subepithelial structures in endoscopic biopsy fragments.
Secondary analysis of the AIM Dysplasia Trial, a multicenter, randomized, sham-controlled study.
Nineteen treatment centers.
Subjects with dysplastic BE, either status post RFA or ablation naïve (sham).
Main Outcome Measurements
The proportion of biopsy samples demonstrating subepithelial structures, stratified by tissue type (columnar vs squamous) in sham- and RFA-treated subjects.
A total of 5648 biopsy fragments were analyzed from 113 subjects (78 RFA, 35 sham; mean 50.0 fragments per subject). Most fragments (4653, 82.4%) contained subepithelium. Squamous biopsy samples from RFA and sham subjects demonstrated subepithelium at similar rates (78.4% vs 79.1%, respectively, P = not significant [NS]). Columnar biopsy samples from RFA and sham subjects also included subepithelium at similar rates (99.0% vs 98.8%, respectively, P = NS). Regardless of treatment assignment, more columnar than squamous biopsy samples demonstrated subepithelium (98.8% vs 78.5%, P < .001).
Biopsy samples were not individually mounted.
In both squamous and columnar tissue, endoscopic biopsy samples after RFA were as likely to demonstrate subepithelium as untreated controls. Almost 80% of all biopsy samples were adequate to evaluate for subsquamous intestinal metaplasia. The primary determinant of biopsy depth is the type of epithelium that underwent biopsy, with squamous less likely to yield subepithelium than columnar. Biopsy samples after RFA appear to be of adequate depth to assess response to therapy.
PMCID: PMC3093936  PMID: 20598302
24.  Endoscopically guided spectral-domain OCT with double-balloon catheters 
Optics Express  2010;18(16):17364-17372.
Fourier-domain optical coherence tomography (OCT) and balloon-based catheters have furthered the potential of OCT as a real-time surveillance tool for Barrett’s esophagus (BE). However, a balloon catheter, which expands the esophagus and centers the catheter, applies direct pressure on the esophagus. This may affect the tissue appearance and the ability to detect dysplasia in BE. To study this effect, we propose a double-balloon catheter to allow imaging with and without balloon-tissue contact. A system design based on a spectral-domain OCT platform is reported and validated by acquisition of high quality, volumetric images of swine esophagus in vivo.
PMCID: PMC3408909  PMID: 20721123
(110.4500) Optical Coherence Tomography; (170.2150) Endoscopic imaging
25.  Screening for Barrett’s Esophagus 
Barrett’s esophagus (BE) increases the risk for development of esophageal adenocarcinoma. Because of the rapid rise in incidence of esophageal adenocarcinoma, screening for BE with subsequent surveillance when found has been proposed as a method of early detection. Sedated endoscopy, however, is too expensive for wide spread screening. As a result, other techniques including unsedated transnasal esophagoscopy and capsule esophagoscopy have been proposed to expand screening programs.
PMCID: PMC2906782  PMID: 20657789

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