Cyrus R. Piraka

A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis

BACKGROUND Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS 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. RESULTS 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). CONCLUSIONS 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; ClinicalTrials.gov number, NCT00820612.).

Targeted Imaging of Esophageal Neoplasia with a Fluorescently Labeled Peptide: First-in-Human Results

A fluorescently labeled peptide enables first-in-human targeted endoscopic imaging of esophageal neoplasia. Fluorescent Peptide Probe for Esophageal Cancer Detecting cancerous tissue isn’t always easy—and it can be particularly difficult for the early stages of esophageal cancer because the new lesions are often flat (versus a bulky tumor, for example) and thus invisible to the naked eye. To confidently detect esophageal adenocarcinoma (EAC), Sturm and colleagues designed a fluorescently labeled synthetic peptide, named ASY*-FITC, that recognizes cancer tissue and allows for in vivo imaging with a clinical endoscope. The cancer-targeting ASY*-FITC peptide was discovered using phage display technology and was found to bind tightly to human EAC cells and tissues ex vivo, but not to normal (squamous) tissue or metaplastic tissue, such as Barrett’s esophagus (BE). The tissues identified as cancerous were confirmed via histology. The authors then took this peptide into 25 patients. The fluorescent peptide was administered as would be expected during clinical exam: sprayed on the suspect area and then imaged with an endoscope. No ASY*-FITC bound to the squamous areas, and only minimal amounts of peptide bound to BE. However, areas of EAC as well as a high-grade dysplasia (HGD) were brightly illuminated and easily detected. The peptide was found to be safe and well tolerated in both humans and animals, and was synthesized according to good manufacturing practices (GMPs), suggesting that translation to a clinical setting will be possible in the near future. Further testing is needed to address optical limitations, such as imaging depth. Nevertheless, this first-in-human study paves the way for detection of HGD and EAC and other neoplasias, potentially without invasive biopsy. Esophageal adenocarcinoma is rising rapidly in incidence and usually develops from Barrett’s esophagus, a precursor condition commonly found in patients with chronic acid reflux. Premalignant lesions are challenging to detect on conventional screening endoscopy because of their flat appearance. Molecular changes can be used to improve detection of early neoplasia. We have developed a peptide that binds specifically to high-grade dysplasia and adenocarcinoma. We first applied the peptide ex vivo to esophageal specimens from 17 patients to validate specific binding. Next, we performed confocal endomicroscopy in vivo in 25 human subjects after topical peptide administration and found 3.8-fold greater fluorescence intensity for esophageal neoplasia compared with Barrett’s esophagus and squamous epithelium with 75% sensitivity and 97% specificity. No toxicity was attributed to the peptide in either animal or patient studies. Therefore, our first-in-human results show that this targeted imaging agent is safe and may be useful for guiding tissue biopsy and for early detection of esophageal neoplasia and potentially other cancers of epithelial origin, such as bladder, colon, lung, pancreas, and stomach.

Is There a Role for Cholangioscopy in Patients with Primary Sclerosing Cholangitis

OBJECTIVES:Assess the role of cholangioscopy in primary sclerosing cholangitis for 1) detection of cholangiocarcinoma using cholangioscopy-assisted biopsy 2) detection of stones not seen on cholangiography 3) stone removal with cholangioscopy-directed lithotripsy.METHODS:Prospective cohort of consecutive patients referred for cholangioscopy to evaluate dominant strictures or stones. A data collection sheet was employed. Follow-up was by chart review/phone contact. Clinical improvement was defined as resolution of jaundice or ≥50% reduction in pain or cholangitis episodes requiring hospitalization.RESULTS:41 patients (30M, 11F) had 60 cholangioscopy procedures (55 per oral, 5 percutaneous). 33/41 (80%) patients underwent 44 tissue sampling events. Histology: positive for extrahepatic cholangiocarcinoma (N = 1), negative/atypical (N = 31), and inadequate (N = 1). Stones were found in 23/41 (56%) patients, of which 7/23 (30%) were missed on cholangiography and detected only by cholangioscopy. 9/23 (39%) underwent cholangioscopy-directed lithotripsy. Stone clearance: complete (N = 10, 7 by cholangioscopy-directed lithotripsy after failed conventional stone extraction); partial (N = 7); and not attempted (N = 6). Median follow-up was 17.0 months (range 1–56). Clinical improvement was achieved in 25/40 (63%). Eight patients have undergone transplant and cholangiocarcinoma was present in the explant of two at 1 and 12 months post-cholangioscopy, respectively.CONCLUSIONS:This is the first series of patients with primary sclerosing cholangitis undergoing cholangioscopy for the evaluation of dominant strictures and cholangioscopy-directed stone therapy with demonstrable clinical benefits. Stones detected by cholangioscopy were missed by cholangiography in nearly one of three patients. Cholangioscopy-directed lithotripsy may be superior to conventional ERCP for achieving complete stone clearance. Despite the use of cholangioscopy, diagnosis of cholangiocarcinoma remains technically challenging.

EUS-guided transesophageal, transgastric, and transcolonic drainage of intra-abdominal fluid collections and abscesses

BACKGROUND The therapeutic role of EUS is evolving. We report our experience with EUS-guided transesophageal, transgastric, and transcolonic drainage of various intra-abdominal fluid collections. OBJECTIVE To determine the technical feasibility and clinical outcomes of EUS-guided drainage. DESIGN Prospective case series. SETTING Academic tertiary referral center. PATIENTS Patients referred for endoscopic drainage of intra-abdominal fluid collections; pancreatic pseudocysts amenable to conventional transgastric or transduodenal drainage were excluded. INTERVENTIONS Single-step EUS-guided drainage of fluid collections by using a therapeutic linear-array echoendoscope with fluoroscopic guidance. MAIN OUTCOME MEASUREMENTS Technical success, relief of symptoms, and procedural complications. RESULTS Nine consecutive patients deemed appropriate for EUS-guided drainage of intra-abdominal fluid collections included transesophageal drainage of pseudocysts (n = 2), transgastric drainage of biloma (n = 2) and upper intra-abdominal abscesses (n = 2), transcolonic drainage of diverticular abscess (n = 1), Crohns abscess (n = 1), and postoperative hematoma (n = 1). Endoscopic drainage was successful in all patients. Confirmation of complete resolution of the target fluid collection and symptom relief was achieved in 8 (89%) of 9 patients. Pneumothorax and mediastinitis developed in 1 patient after transesophageal drainage, which resolved with chest tube and medical therapy. During multiple stent placement, one of the stents was fully deployed into the abscess cavity in 2 patients; both were successfully retrieved either endoscopically (Crohns abscess) or at the time of primary colonic resection (diverticular abscess). LIMITATION Limited number of patients. CONCLUSIONS EUS-guided transenteric drainage of bilomas, hematomas, abscesses, and inflammatory fluid collections is technically feasible and generally results in complete drainage and symptom relief. Procedural complications may be minimized with more experience.

Factors associated with esophageal stricture formation after endoscopic mucosal resection for neoplastic Barrett's esophagus

BACKGROUND EMR for early neoplastic Barretts esophagus is gaining favor over esophagectomy. Esophageal stricture development has been reported as a common complication of EMR, photodynamic therapy, and combination endoscopic therapy. OBJECTIVE To determine clinical and procedural predictors of symptomatic stricture formation after EMR. DESIGN Retrospective analysis. SETTING Tertiary-care referral university hospital. PATIENTS Data were retrospectively reviewed on 73 patients at our institution who underwent EMR monotherapy for Barretts esophagus with high-grade dysplasia or intramucosal cancer since January 2006. INTERVENTION EMR. MAIN OUTCOME MEASUREMENTS Symptomatic esophageal stricture formation. RESULTS Symptomatic esophageal stricture formation was noted in 24.7% of patients undergoing EMR. Stricture formation on univariate analysis was associated with percentage of circumference of esophageal lumen resected, total pieces resected, number of EMR sessions, and tobacco use. A threshold effect was found at 50% of esophageal circumference resected (66.7% vs 27.2% developed strictures above and below the threshold, respectively; P = .004). A 25-pack-year or greater history of tobacco use had a threshold effect on esophageal stricture formation (77.8% vs 7.2% developed strictures above and below the threshold, respectively; P = .02). In multivariate analysis, resection of >50% of the circumference was strongly associated with stricture formation (odds ratio [OR] 4.17; 95% confidence interval [CI], 1.27-13.7). A 25-pack-year or greater history of tobacco use also trended toward stricture formation (OR 3.33; 95% CI, 0.929-12.1). LIMITATIONS Retrospective design, sample size. CONCLUSION Resection of at least 50% of the esophageal mucosal circumference is strongly associated with stricture formation. Patients with strong histories of tobacco use also may be more likely to develop esophageal strictures following EMR.

Prophylactic 5-Fr pancreatic duct stents are superior to 3-Fr stents: a randomized controlled trial.

BACKGROUND Temporary prophylactic pancreatic duct stenting effectively reduces post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk patients, but the optimal stent remains unclear. We compared rate of spontaneous passage, and technical difficulty of placement for 3-Fr and 5-Fr stents. METHODS A randomized controlled trial at a single academic medical center. Patients deemed high risk for PEP randomly received 5-Fr or 3-Fr pancreatic duct stents. Primary outcome was spontaneous stent passage by 2 weeks. Secondary outcomes were ease and time for stent placement, and number of guide wires required for the entire procedure. RESULTS Patients (69 female [89 %]; mean age 44.9 years, standard deviation [SD] 16.8) were randomly assigned to receive 5-Fr (n = 38) and 3-Fr (n = 40) stents. Indications for stenting were similar. Seven patients in the 3-Fr group actually received a 5-Fr stent, and two in the 5-Fr group had a 3-Fr stent. Spontaneous passage or non-passage was confirmed in 64 (83 %). No statistically significant difference in spontaneous passage rates was seen (5-Fr group, 68.4 %; 3-Fr group 75.0 %; P = 0.617). Non-passage rates were 10.5 % (5-Fr group) and 10.0 % (3-Fr group) ( P = 1.00). The study was stopped after a futility analysis for the primary end point. Placement of 5-Fr stents was rated easier, at a mean score of 1.8 (5-Fr) vs. 3.4 (3-Fr), P < 0.001, with a trend towards being faster, 9.2 vs. 11.1 minutes ( P = 0.355). Fewer guide wires were required for 5-Fr stent placement, 1.5 vs. 1.9 ( P = 0.002). PEP rates did not differ ( P = 0.519). CONCLUSION Placement of 5-Fr compared to 3-Fr pancreatic duct stents for PEP prophylaxis is easier, faster, and requires fewer wires. No statistically significant difference in spontaneous passage was found between the two sizes.

Predicting the likelihood of a persistent bile duct stone in patients with suspected choledocholithiasis: accuracy of existing guidelines and the impact of laboratory trends

BACKGROUND Existing guidelines aim to stratify the likelihood of choledocholithiasis to guide the use of ERCP versus a lower-risk diagnostic study such as EUS, MRCP, or intraoperative cholangiography. OBJECTIVE To assess the performance of existing guidelines in predicting choledocholithiasis and to determine whether trends in laboratory parameters improve diagnostic accuracy. DESIGN Retrospective cohort study. SETTING Tertiary-care hospital. PATIENTS Hospitalized patients presenting with suspected choledocholithiasis over a 6-year period. INTERVENTIONS Assessment of the American Society for Gastrointestinal Endoscopy (ASGE) guidelines, its component variables, and laboratory trends in predicting choledocholithiasis. MAIN OUTCOME MEASUREMENTS The presence of choledocholithiasis confirmed by EUS, MRCP, or ERCP. RESULTS A total of 179 (35.9%) of the 498 eligible patients met ASGE high-probability criteria for choledocholithiasis on initial presentation. Of those, 99 patients (56.3%) had a stone/sludge on subsequent confirmatory test. Of patients not meeting high-probability criteria on presentation, 111 (34.8%) had a stone/sludge. The overall accuracy of the guidelines in detecting choledocholithiasis was 62.1% (47.4% sensitivity, 73% specificity) based on data available at presentation. The accuracy was unchanged when incorporating the second set of liver chemistries obtained after admission (63.2%), suggesting that laboratory trends do not improve performance. LIMITATIONS Retrospective study, inconsistent timing of the second set of biochemical markers. CONCLUSION In our cohort of patients, existing choledocholithiasis guidelines lacked diagnostic accuracy, likely resulting in overuse of ERCP. Incorporation of laboratory trends did not improve performance. Additional research focused on risk stratification is necessary to meet the goal of eliminating unnecessary diagnostic ERCP.

Multimodal endoscope can quantify wide-field fluorescence detection of Barrett's neoplasia.

BACKGROUND AND STUDY AIMS To demonstrate the clinical use of a multimodal endoscope with a targeted fluorescently labeled peptide for quantitative detection of Barretts neoplasia. PATIENTS AND METHODS We studied 50 patients with Barretts esophagus using a prototype multimodal endoscope with a fluorescently labeled peptide. Co-registered fluorescence and reflectance images were converted to ratios to correct for differences in distance and geometry over the image field of view. The ratio images were segmented using a unique threshold that maximized the variance between high and low intensities to localize regions of high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). RESULTS Early neoplasia (HGD and EAC) was identified with 94 % specificity and 96 % positive predictive value at a threshold of 1.49. The mean results for HGD and EAC were significantly greater than those for squamous/Barretts esophagus and low grade dysplasia by one-way analysis of variance (ANOVA). The receiver operator characteristic curve for detection of early neoplasia had an area under the curve of 0.884. No adverse events associated with the endoscope or peptide were found. CONCLUSION A multimodal endoscope can quantify fluorescence images from targeted peptides to localize early Barretts neoplasia. (ClinicalTrials.gov number NCT01630798.).

In Vivo Molecular Imaging of Barrett's Esophagus With Confocal Laser Endomicroscopy

Esophageal adenocarcinoma (EAC) arises from Barrett’s esophagus, a columnar metaplasia of the epithelium caused by chronic acid reflux.1 This disease is growing faster than any other type of cancer in Western countries,2 and despite extensive efforts for prevention, the incidence remains high and the 5- year survival rate is poor. Early detection may allow for more effective interventions, and is critical to improving prognosis. Current methods of surveillance with white light endoscopy are limited in effectiveness because pre-malignant lesions (dysplasia) are flat in appearance and difficult to visualize.3 Molecular imaging is an emerging technology that can help physicians guide biopsy by generating image contrast based on unique biological properties tissue.4 Imaging agents that are specific for overexpressed molecular targets can improve diagnosis, staging, intervention, and management of this disease. Early imaging validation is needed to establish safety and evidence of efficacy.5

A survey of expert follow-up practices after successful endoscopic eradication therapy for Barrett's esophagus with high-grade dysplasia and intramucosal adenocarcinoma

BACKGROUND Despite the increasing number of patients undergoing endoscopic therapy for Barretts 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. OBJECTIVES We aimed to define expert practice patterns regarding follow-up after endoscopic treatment of BE with HGD and IMC. DESIGN Electronic survey. SUBJECTS Forty-eight endoscopists in the United States with expertise in BE endotherapy based on high-impact publications and national reputation. INTERVENTION A 21-item Web-based survey inquiring about post-BE endotherapy follow-up practices. RESULTS 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. LIMITATIONS Not a consensus document; only U.S. experts included. CONCLUSIONS 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.