Comorbidities Drive the Majority of Overall Mortality in Low-Risk Mucinous Pancreatic Cysts Under Surveillance.

BACKGROUND & AIMS: The Charlson Comorbidity Index (CACI) has been suggested as a tool to determine comorbidity burden and guide management for patients with mucinous pancreatic cysts (Intrapapillary Mucinous Neoplasms and Mucinous Cystic Neoplasms), but has not been studied well among "low-risk" mucinous pancreatic cysts i.e. without worrisome features (WF) and high-risk stigmata (HRS). This study sought to determine the comorbidity burden among surveillance population of low-risk pancreatic cysts and provide their follow-up mortality outcomes. METHODS: A single center study retrospectively reviewed a prospective pancreatic cyst database and included individuals with low-risk cysts undergoing serial imaging during 2016. Electronic medical records were reviewed to determine their baseline age-adjusted CACI (age-CACI). After 4 years, their progression to WF, disease specific (pancreatic malignancy-related, DSM), extra-pancreatic (EPM), and overall mortalities (OM) were determined using Kaplan-Meir Survival Analysis. RESULTS: 502 individuals underwent prospective surveillance. The study included 440 individuals with low-risk suspected or presumed mucinous cysts and excluded 50 and 12 individuals with WF and HRS respectively. Over a median follow-up of 56 months, 12 WF progressions, 2 DSMs, 42 EPMs, and 44 OMs were observed. Baseline age-CACI had good predictive capacity for 4-year EPM (Area-Under Curve: 0.87; p< .0001). The median age-CACI of 4 enabled cohort stratification into Low (age-CACI <4) and High CACI (age-CACI ≥4) groups. A significantly higher OM (p< .001) was observed among the High CACI group as compared to the Low CACI group. CONCLUSION: Through real-time application of CACI to patient outcomes, our analysis supports incorporation of this comorbidity assessment tool in making shared surveillance decisions among low-risk pancreatic cyst population.

Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms.

BACKGROUND: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a "universal" NET biomarker, is considered controversial as a circulating biomarker of BPNEN. AIM: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study. MATERIAL AND METHODS: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISATM kit (EuroDiagnostica). RESULTS: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45-0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26-37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11-16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression). CONCLUSIONS: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

Sedation During Endoscopy in Patients with Cirrhosis: Safety and Predictors of Adverse Events.

BACKGROUND: Sedation during endoscopy in cirrhotic patients is typically via moderate sedation, most commonly using a combination of a benzodiazepine (i.e., midazolam) and narcotic (i.e., fentanyl) or with propofol using monitored anesthesia care (MAC). Here, we examined the safety of moderate sedation and MAC in patients with cirrhosis. METHODS: This retrospective cohort study of cirrhotic patients undergoing endoscopy from a large academic medical center between 2010 and 2014 examined extensive clinical data including the following: past history, physical findings, laboratory results, and procedural adverse events. Adverse events were defined a priori and included hypoxia, hypotension, bleeding, and death. RESULTS: We identified 2618 patients with cirrhosis who underwent endoscopic procedures; the mean age was 56 years, 36% were female, the mean Child-Pugh score was 9.3 (IQR: 8, 11), and Charlson Comorbidity Index score was 3.2 (IQR: 1, 4); 1157 had MAC; and 1461 had moderate sedation. There was no difference in the frequency of adverse events in MAC and moderate sedation groups, with a total of 15 adverse events (7/1157 MAC and 8/1461 moderate sedation). The most common procedure performed was esophagogastroduodenoscopy (EGD, n = 1667) and was associated with 10 adverse events. Overall, adverse events included bradycardia (1), hypoxia (7), bleeding (5), laryngospasm (1), and perforation (1). The frequency was similar for EGD, ERCP, and colonoscopy-each at a rate of 0.6%. CONCLUSIONS: Adverse events in cirrhotic patients undergoing endoscopy appeared to be similar with moderate sedation or MAC, and the frequency was the same for different types of procedures.

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease.

BACKGROUND: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript "liquid biopsy" (NETest) in BPC for diagnosis and monitoring of the disease status. AIM: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study. MATERIAL AND METHODS: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means ± SD. RESULTS: NETest levels were significantly increased in BPC (45 ± 25) versus controls (9 ± 8; p < 0.0001). The area under the ROC curve was 0.96 ± 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 ± 32) and LCNEC (28 ± 7). NETest accurately distinguished progressive (61 ± 26) from stable disease (35.5 ± 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 ± 21) and SCC (12 ± 11) and benign disease (IPF) (18 ± 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25-0.31). CONCLUSIONS: Elevated -NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression.

Trends in the timing of inpatient ERCP relative to cholecystectomy: a nationwide database studied longitudinally.

BACKGROUND AND AIMS: ERCP has largely replaced common bile duct exploration for therapy of common bile duct pathology, yet its use as a purely diagnostic test has declined. Among inpatients, we hypothesized that timing between ERCP and cholecystectomy (CCY) has changed. The objectives were to measure temporal trends in the timing between inpatient ERCP and CCY and to examine factors associated with delays. METHODS: We used the National Inpatient Sample between 1998 and 2013 to classify admissions for gallstone-related diagnoses undergoing inpatient CCY and ERCP by timing relative to CCY: within (±) 1 day, ≥2 days before, and ≥2 days after. Logistic regression and Poisson regression were used to determine pattern utilization and association of ERCP timing on hospital length of stay. RESULTS: Between 1998 and 2013, the proportion of admissions for CCY associated with same-stay ERCP increased (14.5% in 1998 to 17.3% in 2013, P < .001), and approximately two-thirds of ERCPs were performed within 1 day of CCY. After adjusting for covariates, the mean adjusted length of stay remained significantly shorter for patients who underwent CCY within 1 day of ERCP (5.13 vs 7.48 days for ERCP ≥2 days before and vs 7.41 days for ERCP ≥2 days after, P < .001). CONCLUSIONS: Use of inpatient ERCP in conjunction with CCY has increased minimally between 1998 and 2013, whereas length of stay has decreased. ERCPs performed within 1 day of CCY were associated with shorter hospital length of stay, suggesting delays between inpatient procedures should be minimized unless medical comorbidities preclude it.

Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass.

BACKGROUND AND AIMS: The obesity epidemic has led to increased use of Roux-en-Y gastric bypass (RYGB). These patients have an increased incidence of pancreaticobiliary diseases, yet standard ERCP is not possible because of surgically altered gastroduodenal anatomy. Laparoscopy-assisted ERCP (LA-ERCP) has been proposed as an option, but supporting data are derived from single-center small case series. Therefore, we conducted a large multicenter study to evaluate the feasibility, safety, and outcomes of LA-ERCP. METHODS: This is a retrospective cohort study of adult patients with RYGB who underwent LA-ERCP in 34 centers. Data on demographics, indications, procedure success, and adverse events were collected. Procedure success was defined when all the following were achieved: reaching the papilla, cannulating the desired duct, and providing endoscopic therapy as clinically indicated. RESULTS: A total of 579 patients (median age, 51; 84% women) were included. Indication for LA-ERCP was biliary in 89%, pancreatic in 8%, and both in 3%. Procedure success was achieved in 98%. Median total procedure time was 152 minutes (interquartile range [IQR], 109-210), with a median ERCP time of 40 minutes (IQR, 28-56). Median hospital stay was 2 days (IQR, 1-3). Adverse events were 18% (laparoscopy related, 10%; ERCP related, 7%; both, 1%) with the clear majority (92%) classified as mild/moderate, whereas 8% were severe and 1 death occurred. CONCLUSIONS: Our large multicenter study indicates that LA-ERCP in patients with RYGB is feasible with a high procedure success rate comparable with that of standard ERCP in patients with normal anatomy. The ERCP-related adverse events rate is comparable with conventional ERCP, but the overall adverse event rate was higher because of the added laparoscopy-related events.

How much pain relief do patients expect after cholecystectomy?

BACKGROUND: Cholecystectomy is a common operation, increasingly performed, in the USA, for "functional gall bladder disorder" (FGBD). Outcomes of these surgeries are uncertain. In planning a study of FGBD, we needed to define the best outcome measures. METHODS: We sought the opinions of patients (52 with FGBD and 100 with stones for comparison) coming to cholecystectomy. They were asked to respond in four ways about the minimum benefit they would count as "success." RESULTS: We found that most patients do not expect cholecystectomy to relieve their pain-related disability completely, regardless of the presence or absence of stones. CONCLUSIONS: Future studies of the success of surgery should use patient-centered outcome assessments, such as PGIC (patient's global impression of change), in addition to objective measures of the impact of treatment on key symptoms, such as pain.

An assessment of existing risk stratification guidelines for the evaluation of patients with suspected choledocholithiasis.

BACKGROUND: Prior studies have demonstrated that existing risk stratification guidelines for the evaluation of suspected choledocholithiasis lack accuracy, leading to the overutilization of endoscopic retrograde cholangiopancreatography (ERCP). The aim of our study was to evaluate the performance characteristics of published guidelines in predicting choledocholithiasis and to determine the impact of laboratory trends on diagnostic accuracy. METHODS: We identified patients with suspected choledocholithiasis hospitalized over a 5-year period (2009-2014) at a tertiary care academic medical center. Among eligible patients, we assessed the performance characteristics of the American Society for Gastrointestinal Endoscopy (ASGE) guidelines predicting the presence of choledocholithiasis, confirmed by endoscopic ultrasound, magnetic resonance cholangiography, ERCP, or intra-operative cholangiography. We also evaluated whether a second set of liver function tests improved the accuracy of the guidelines. RESULTS: On presentation, 71 of the 173 eligible patients (41.4 %) met ASGE high-probability criteria for choledocholithiasis. Of these, only 39 (54.9 %) were found to have a choledocholithiasis on confirmatory testing. Conversely, of the 102 patients (58.6 %) who were classified as low or intermediate probability, 32 (31.4 %) had choledocholithiasis. Overall, the accuracy of the guidelines was 63 % (sensitivity 54.9 %; specificity 68.6 %). Incorporating a second set of laboratory tests did not improve accuracy (62.7 %), and a significant decline in liver function tests did not reliably predict spontaneous stone passage. CONCLUSIONS: Existing guidelines performed suboptimally for predicting choledocholithiasis in our patient population, similar to other validation studies. These findings further underscore the importance of developing alternate risk stratification tools for choledocholithiasis, aiming to minimize unnecessary diagnostic ERCP.

Endoscopic ultrasound (EUS) and the management of pancreatic cancer.

Pancreatic cancer is one of the leading causes of cancer-related mortality in western countries. Early diagnosis of pancreatic cancers plays a key role in the management by identification of patients who are surgical candidates. The advancement in the radiological imaging and interventional endoscopy (including endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography and endoscopic enteral stenting techniques) has a significant impact in the diagnostic evaluation, staging and treatment of pancreatic cancer. The multidisciplinary involvement of radiology, gastroenterology, medical oncology and surgical oncology is central to the management of patients with pancreatic cancers. This review aims to highlight the diagnostic and therapeutic role of EUS in the management of patients with pancreatic malignancy, especially pancreatic ductal adenocarcinoma.

Rectal indometacin dose escalation for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography in high-risk patients: a double-blind, randomised controlled trial.

BACKGROUND: Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients. METHODS: In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete. FINDINGS: Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients-76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1·19, 95% CI 0·87-1·61; p=0·32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients-six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0·79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0·25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up. INTERPRETATION: Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP. FUNDING: American College of Gastroenterology.

Emerging techniques and efficacy of endoscopic esophageal reconstruction and lumen restoration for complete esophageal obstruction.

BACKGROUND AND STUDY AIMS: Complete esophageal obstruction (CEO) is a rare occurrence characterized by progressive esophageal stricture, which eventually causes lumen obliteration. With recent advances in flexible endoscopy, various innovative techniques exist for restoring luminal continuity. The primary aim of this study was to assess the efficacy and safety of patients undergoing combined antegrade-retrograde endoscopic dilation for CEO at our institution. The secondary aim was to review and highlight emerging techniques, outcomes, and adverse events after endoscopic treatment of CEO. PATIENTS AND METHODS: Our electronic endoscopy database was retrospectively reviewed to identify patients who underwent combined antegrade and retrograde endoscopy for CEO. Patient and procedural data collected included gender, age, technical success, pre- and post-dysphagia scores, and adverse events. RESULTS: Six patients (67 % male, mean age 71.6 years [range 63 - 80]) underwent technically successful esophageal reconstruction with combined antegrade-retrograde endoscopy. All patients noted improvement in dysphagia with mean pre-procedure dysphagia score of 4 reduced to 1.33 (range 0 - 3) post-procedure. There were no adverse events and mean follow-up time was 17.3 months (range 3 - 48). CONCLUSIONS: Combined antegrade and retrograde endoscopic therapy for CEO is feasible and safe. We present our experience with endoscopic management of complete esophageal obstruction, and highlight emerging techniques, outcomes and adverse events related to this minimally invasive modality.

Adjunctive radiofrequency ablation for the endoscopic treatment of ampullary lesions with intraductal extension (with video).

BACKGROUND AND STUDY AIMS: Catheter-based radiofrequency ablation (RFA) delivered during endoscopic retrograde cholangiopancreatography (ERCP) may represent a viable treatment option for intraductal extension of ampullary neoplasms, however, clinical experience with this modality is limited. After ampullary resection, 4 patients with intraductal extension underwent adjunctive RFA of the distal bile duct. All patients received a temporary pancreatic stent to reduce the risk of pancreatitis, as well as a plastic biliary stent to prevent biliary obstruction. Three patients were treated for adenoma and 1 for adenoma with a focus of adenocarcinoma. During a short follow-up period, 3 patients experienced complete eradication of the target lesion, whereas the patient with a focus of adenocarcinoma had progression to overt invasive cancer. There were no immediate adverse events. One patient developed a post-RFA bile duct stricture, which has required additional endoscopic therapy. Catheter-based RFA of ampullary lesions that extend up the bile duct is technically feasible. Additional research is necessary to understand the risks and long-term benefits of this technique.

Sphincter of Oddi Manometry: Reproducibility of Measurements and Effect of Sphincterotomy in the EPISOD Study.

BACKGROUND/AIMS: The reproducibility of sphincter of Oddi manometry (SOM) measurements and results of SOM after sphincterotomy has not been studied sufficiently. The aim of our study is to evaluate the reproducibility of SOM and completeness of sphincter ablation. METHODS: The recently published Evaluating Predictors and Interventions in sphincter of Oddi dysfunction (EPISOD) study included 214 subjects with post-cholecystectomy pain, and fit the criteria of sphincter of Oddi dysfunction type III. They were randomized into 3 arms, irrespective of manometric findings: sham (no sphincterotomy), biliary sphincterotomy, and dual (biliary and pancreatic). Thirty-eight subjects had both biliary and pancreatic manometries performed twice, at baseline and at repeat endoscopic retrograde cholangiopancreatography after 1-11 months. Sham arm was examined to assess the reproducibility of manometry, and the treatment arms to assess whether the sphincterotomies were complete (elevated pressures were normalized). RESULTS: Biliary and pancreatic measurements were reproduced in 7/14 (50%) untreated subjects. All 12 patients with initially elevated biliary pressures in biliary and dual sphincterotomy groups normalized after biliary sphincterotomy. However, 2 of 8 subjects with elevated pancreatic pressures in the dual sphincterotomy group remained abnormal after pancreatic sphincterotomy. Paradoxically, normal biliary pressures became abnormal in 1 of 15 subjects after biliary sphincterotomy, and normal pancreatic pressures became abnormal in 5 of 15 patients after biliary sphincterotomy, and in 1 of 9 after pancreatic sphincterotomy. CONCLUSIONS: Our data suggest that SOM measurements are poorly reproducible, and question whether we could adequately perform pancreatic sphincterotomy.