Detection of Barrett's neoplasia with a near-infrared fluorescent heterodimeric peptide.

BACKGROUND: Esophageal adenocarcinoma (EAC) is a molecularly heterogeneous disease with poor prognosis that is rising rapidly in incidence. We aimed to demonstrate specific binding by a peptide heterodimer to Barrett's neoplasia in human subjects. METHODS: Peptide monomers specific for EGFR and ErbB2 were arranged in a heterodimer configuration and labeled with IRDye800. This near-infrared (NIR) contrast agent was topically administered to patients with Barrett's esophagus (BE) undergoing either endoscopic therapy or surveillance. Fluorescence images were collected using a flexible fiber accessory passed through the instrument channel of an upper gastrointestinal endoscope. Fluorescence images were collected from 31 BE patients. A deep learning model was used to segment the target (T) and background (B) regions. RESULTS: The mean target-to-background (T/B) ratio was significantly greater for high grade dysplasia (HGD) and EAC versus BE, low grade dysplasia (LGD), and squamous epithelium. At a T/B ratio of 1.5, sensitivity and specificity of 94.1 % and 92.6 %, respectively, were achieved for the detection of Barrett's neoplasia with an area under the curve of 0.95. No adverse events attributed to the heterodimer were found. EGFR and ErbB2 expression were validated in the resected specimens. CONCLUSIONS: This "first-in-human" clinical study demonstrates the feasibility of detection of early Barrett's neoplasia using a NIR-labeled peptide heterodimer.

Small Intestinal Bacterial Overgrowth Is Common in Chronic Pancreatitis and Associates With Diabetes, Chronic Pancreatitis Severity, Low Zinc Levels, and Opiate Use.

OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) is often present in patients with chronic pancreatitis (CP) with persistent steatorrhea, despite pancreatic enzyme replacement therapy. Overall prevalence of SIBO, diagnosed by glucose breath test (GBT), varies between 0% and 40% but 0%-21% in those without upper gastrointestinal (GI) surgery. We investigated the prevalence and nonsurgical independent predictors of SIBO in CP without upper GI surgery. METHODS: Two hundred seventy-three patients ≥18 years old had a presumptive diagnosis of CP and a GBT between 1989 and 2017. We defined CP by Mayo score (0-16) ≥4 and a positive GBT for SIBO by Rome consensus criteria and retrospectively collected data for 5 a priori variables (age, opiates, alcohol use, diabetes mellitus (DM), gastroparesis) and 41 investigational variables (demographics, GI symptoms, comorbidities, CP etiologies and cofactors, CP symptom duration, Mayo score and nondiabetes components, and biochemical variables). RESULTS: Ninety-eight of 273 patients had definite CP and 40.8% had SIBO. Five of 46 variables predicted SIBO: opiates, P = 0.005; DM, P = 0.04; total Mayo score, P < 0.05; zinc, P = 0.005; and albumin, P < 0.05). Multivariable analysis of 3 noncorrelated variables identified zinc level (odds ratio = 0.0001; P = 0.03) as the sole independent predictor of SIBO (model C-statistic = 0.89; P < 0.001). DISCUSSION: SIBO, diagnosed by GBT, occurs in 40.8% of patients with CP without upper GI surgery. In patients with CP, markers of more severe CP (low zinc level, DM and increased Mayo score) and opiate use should raise clinical suspicion for SIBO, particularly in patients with persistent steatorrhea or weight loss despite pancreatic enzyme replacement therapy.

Preoperative predictors of choledocholithiasis in patients presenting with acute calculous cholecystitis.

BACKGROUND AND AIMS: Markedly increased liver chemistries in patients presenting with acute calculous cholecystitis (AC) often prompt an evaluation for concomitant choledocholithiasis (CDL). However, current guidelines directing the workup for CDL fail to address this unique population. The aims of this study are to define the range of presenting laboratory values and imaging findings in AC, develop a model to predict the presence of concurrent CDL, and develop a management algorithm that can be easily applied on presentation. METHODS: We conducted a retrospective review of patients presenting with AC to a large tertiary hospital over a 3.5-year period. CDL was defined as common bile duct (CBD) stone(s), sludge, or debris seen on any of the following studies: US, CT, magnetic resonance imaging/MRCP, EUS, ERCP, or intraoperative cholangiogram. A multivariable model to predict CDL was developed on 70% of the patients and validated on the remaining 30%. RESULTS: A total of 366 patients were identified and 65 (17.8%) had concurrent CDL. Univariable analysis was used to predict CDL and demonstrated statistically significant odds ratios for transaminases >3 times the upper limit of normal, alkaline phosphatase (AlkPhos) above normal, lipase >3 times the upper limit of normal, total bilirubin ≥1.8 mg/dL, and CBD diameter >6 mm. In the validation cohort, an optimal model containing alanine transaminase (ALT) >3 times the upper limit of normal, abnormal AlkPhos, and CBD diameter >6 mm was found to have an area under the receiver operating curve of 0.91. When 0 or 1 risk factors were present, 98.6% of patients did not have CDL. When all 3 risk factors were present, 77.8% were found to have CDL. CONCLUSIONS: The prevalence of CDL is high among patients with AC. When a validated model is used, application of cutoffs for ALT, AlkPhos, and CBD diameter can effectively triage patients with low and high likelihood for CDL to surgery or ERCP, respectively.

Detection of Sessile Serrated Adenomas in the Proximal Colon Using Wide-Field Fluorescence Endoscopy.

BACKGROUND & AIMS: Many cancers in the proximal colon develop via from sessile serrated adenomas (SSAs), which have flat, subtle features that are difficult to detect with conventional white-light colonoscopy. Many SSA cells have the V600E mutation in BRAF. We investigated whether this feature could be used with imaging methods to detect SSAs in patients. METHODS: We used phage display to identify a peptide that binds specifically to SSAs, using subtractive hybridization with HT29 colorectal cancer cells containing the V600E mutation in BRAF and Hs738.St/Int cells as a control. Binding of fluorescently labeled peptide to colorectal cancer cells was evaluated with confocal fluorescence microscopy. Rats received intra-colonic 0.0086 mg/kg, 0.026 mg/kg, or 0.86 mg/kg peptide or vehicle and morbidity, mortality, and injury were monitored twice daily to assess toxicity. In the clinical safety study, fluorescently labeled peptide was topically administered, using a spray catheter, to the proximal colon of 25 subjects undergoing routine outpatient colonoscopies (3 subjects were given 2.25 µmol/L and 22 patients were given 76.4 µmol/L). We performed blood cell count, chemistry, liver function, and urine analyses approximately 24 hours after peptide administration. In the clinical imaging study, 38 subjects undergoing routine outpatient colonoscopies, at high risk for colorectal cancer, or with a suspected unresected proximal colonic polyp, were first evaluated by white-light endoscopy to identify suspicious regions. The fluorescently labeled peptide (76.4 µmol/L) was administered topically to proximal colon, unbound peptide was washed away, and white-light, reflectance, and fluorescence videos were recorded digitally. Fluorescence intensities of SSAs were compared with those of normal colonic mucosa. Endoscopists resected identified lesions, which were analyzed histologically by gastrointestinal pathologists (reference standard). We also analyzed the ability of the peptide to identify SSAs vs adenomas, hyperplastic polyps, and normal colonic mucosa in specimens obtained from the tissue bank at the University of Michigan. RESULTS: We identified the peptide sequence KCCFPAQ and measured an apparent dissociation constant of Kd = 72 nM and an apparent association time constant of K = 0.174 min-1 (5.76 minutes). During fluorescence imaging of patients during endoscopy, regions of SSA had 2.43-fold higher mean fluorescence intensity than that for normal colonic mucosa. Fluorescence labeling distinguished SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. The peptide had no observed toxic effects in animals or patients. In the analysis of ex vivo specimens, peptide bound to SSAs had significantly higher mean fluorescence intensity than to hyperplastic polyps. CONCLUSIONS: We have identified a fluorescently labeled peptide that has no observed toxic effects in animals or humans and can be used for wide-field imaging of lesions in the proximal colon. It distinguishes SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. This targeted imaging method might be used in early detection of premalignant serrated lesions during routine colonoscopies. ClinicalTrials.gov ID: NCT02156557.

Specialist Endoscopists Are Associated with a Decreased Risk of Incomplete Polyp Resection During Endoscopic Mucosal Resection in the Colon.

BACKGROUND: Endoscopic experience is known to correlate with outcomes of endoscopic mucosal resection (EMR), particularly complete resection of the polyp tissue. Whether specialist endoscopists can protect against incomplete polypectomy in the setting of known risk factors for incomplete resection (IR) is unknown. AIMS: We aimed to characterize how specialist endoscopists may help to mitigate the risk of IR of large sessile polyps. METHODS: This is a retrospective cohort study of patients who underwent EMR at the University of Michigan from January 1, 2006, to November 15, 2015. The primary outcome was endoscopist-reported polyp tissue remaining at the end of the initial EMR attempt. Specialist endoscopists were defined as endoscopists who receive tertiary referrals for difficult colonoscopy cases and completed at least 20 EMR colonic polyp resections over the study period. RESULTS: A total of 257 patients with 269 polyps were included in the study. IR occurred in 40 (16%) cases. IR was associated with polyp size ≥ 40 mm [adjusted odds ratio (aOR) 3.31, 95% confidence interval (CI) 1.38-7.93], flat/laterally spreading polyps (aOR 2.61, 95% CI 1.24-5.48), and difficulty lifting the polyp (aOR 11.0, 95% CI 2.66-45.3). A specialist endoscopist performing the initial EMR was protective against IR, even in the setting of risk factors for IR (aOR 0.13, 95% CI 0.04-0.41). CONCLUSIONS: IR is associated with polyp size ≥ 40 mm, flat and/or laterally spreading polyps, and difficulty lifting the polyp. A specialist endoscopist initiating the EMR was protective of IR.

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.).

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.

Endoscopic Transpapillary Gallbladder Stent Placement Is Safe and Effective in High-Risk Patients Without Cirrhosis.

BACKGROUND: Endoscopic transpapillary gallbladder stent (ETGS) placement is a proposed minimally invasive alternative to cholecystectomy in high-risk patients with symptomatic gallbladder disease. AIMS: To describe the safety and efficacy of ETGS placement in 29 consecutive patients without cirrhosis. METHODS: A retrospective analysis of consecutive ETGS cases from 2005 to 2013 at a referral center was undertaken. RESULTS: The mean age was 70 years (range 40-91), and 62 % were hospitalized. The most common indication for ETGS was acute calculus cholecystitis (52 %). Comorbidities precluding cholecystectomy included advanced cancer (45 %), severe cardiopulmonary disease (21 %), and advanced age/frailty (17 %). Eighty-six percent of the patients had an ASA class of III or IV, and the Charlson comorbidity index was >3 in 55 %. An ETGS was successfully placed in 22 patients (76 %) with 18 being successful on the first attempt. A percutaneous rendezvous approach was required to obtain cystic duct access in six patients (21 %). During a mean follow-up of 376 days, a sustained clinical response was noted in 90 % of the patients with a stent placed. No peri-procedural complications were noted. However, two patients developed delayed complications of abdominal pain and cholangitis. Six patients were alive with their original stent still in place at a mean follow-up of 2.5 years. CONCLUSIONS: ETGS is an effective and safe alternative to cholecystectomy in high-risk patients. Technical success can be facilitated by a percutaneous rendezvous technique. Our data and those of others suggest that scheduled stent exchanges may not be required unless a clinical change occurs.

Flexible fiber cholangioscope for detection of near-infrared fluorescence.

Video 1Flexible fiber cholangioscope for detection of near-infrared fluorescence.

Possible biliary disease: diagnostic performance of high-spatial-resolution isotropic 3D T2-weighted MRCP.

PURPOSE: To retrospectively assess the diagnostic performance of magnetic resonance cholangiopancreatography (MRCP) performed by using a high-spatial-resolution isotropic three-dimensional (3D) fast-recovery fast spin-echo (FSE) sequence with parallel imaging for the evaluation of possible biliary disease. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board; informed consent was waived. Ninety-five patients (58 female, 37 male; mean age, 51 years; range, 15-91 years) underwent MRCP by using the respiratory-triggered isotropic 3D fast-recovery FSE sequence and endoscopic or percutaneous direct visualization between March 2003 and June 2007. Two independent readers evaluated the MRCP images for strictures, dilatation, and intraductal filling defects. Sensitivity, specificity, and interobserver agreement (kappa statistics) were determined. RESULTS: The respective sensitivity and specificity for strictures, dilatation, and intraductal filling defects (all choledocholithiasis) were 86% (40 of 47) and 94% (45 of 48), 98% (57 of 58) and 100% (37 of 37), and 68% (19 of 28) and 97% (65 of 67) for reader 1 and 88% (41 of 47) and 94% (45 of 48), 96% (56 of 58) and 100% (37 of 37), and 75% (21 of 28) and 99% (66 of 67) for reader 2. The sensitivity for stones larger than 3 mm was 94% (15 of 16) for reader 1 and 100% (16 of 16) for reader 2, whereas the sensitivity for stones 3 mm or smaller was 33% (four of 12) for reader 1 and 42% (five of 12) for reader 2. Agreement between readers was good to excellent, with kappa values of 0.76, 0.85, and 0.98 for strictures, dilatation, and choledocholithiasis, respectively. CONCLUSION: MRCP by using the respiratory-triggered isotropic 3D fast-recovery FSE sequence with parallel imaging demonstrates excellent diagnostic capabilities for possible biliary disease, although it is limited for stones 3 mm or smaller in size.