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The role of EUS in managing asymptomatic pancreatic cystic lesions (PCLs) remains unresolved. We retrospectively evaluated EUS in risk stratification of PCLs when adhering to the most recent AGA guidelines. Asymptomatic PCLs that were evaluated by EUS from January 2014 to December 2014 were retrospectively reviewed including associated cytology, fluid analysis, and relevant surgical pathology. Cross-sectional imaging reports were reviewed blindly by an expert radiologist using AGA risk stratification terminology. Accepted imaging high-risk features (HRF) included cyst diameter > 3 cm, dilated upstream pancreatic ducts, and a solid component in the cyst. We reviewed 125 patients who underwent EUS. Expert review of cross-sectional imaging resulted in a different interpretation 25% of the time including 1 malignant cyst. Ninety-three patients (75%) had no HRFs on cross-sectional imaging; 28 patients (22%) were diagnosed with 1 HRF and 4 patients (3%) had 2 HRFs. Adhering to AGA guidelines using 2 HRF as threshold for use of EUS, the diagnosis of malignant and high-risk premalignant lesions (including pancreatic adenocarcinoma, mucinous cystadenoma, neuroendocrine tumors, and IPMN with dysplasia) had a 40% sensitivity and 100% specificity. Had EUS been utilized based on a threshold of 1 HRF on imaging, malignant and high-risk premalignant lesions would have been identified with 80% sensitivity and 95% specificity. By adding EUS to radiographic imaging, the specificity for detecting carcinomas (p = 0.0009) and detection of all premalignant lesions (p = 0.003) statistically improved. Furthermore, EUS allowed 14 patients (11%) to avoid further surveillance by lowering their risk stratification. EUS remains an essential risk stratification modality for incidental PCLs. Current guideline suggestions of its utility may be too stringent. Our study justifies expert radiology review when managing PCLs. Further studies are required to identify the optimal approach to PCL management.

Background and Aims Minimum EUS and ERCP volumes that should be offered per trainee in “high quality” advanced endoscopy training programs (AETPs) are not established. We aimed to define the number of procedures required by an “average” advanced endoscopy trainee (AET) to achieve competence in technical and cognitive EUS and ERCP tasks to help structure AETPs. Methods American Society for Gastrointestinal Endoscopy (ASGE)-recognized AETPs were invited to participate; AETs were graded on every fifth EUS and ERCP examination using a validated tool. Grading for each skill was done using a 4-point scoring system, and learning curves using cumulative sum analysis for overall, technical, and cognitive components of EUS and ERCP were shared with AETs and trainers quarterly. Generalized linear mixed-effects models with a random intercept for each AET were used to generate aggregate learning curves, allowing us to use data from all AETs to estimate the average learning experience for trainees. Results Among 62 invited AETPs, 37 AETs from 32 AETPs participated. Most AETs reported hands-on EUS (52%, median 20 cases) and ERCP (68%, median 50 cases) experience before starting an AETP. The median number of EUS and ERCPs performed per AET was 400 (range, 200-750) and 361 (range, 250-650), respectively. Overall, 2616 examinations were graded (EUS, 1277; ERCP-biliary, 1143; pancreatic, 196). Most graded EUS examinations were performed for pancreatobiliary indications (69.9%) and ERCP examinations for ASGE biliary grade of difficulty 1 (72.1%). The average AET achieved competence in core EUS and ERCP skills at approximately 225 and 250 cases, respectively. However, overall technical competence was achieved for grade 2 ERCP at about 300 cases. Conclusion The thresholds provided for an average AET to achieve competence in EUS and ERCP may be used by the ASGE and AETPs in establishing the minimal standards for case volume exposure for AETs during their training. (Clinical trial registration number: NCT02509416.)

Background and aims: Adenoma detection rate (ADR) and cecal withdrawal time (CWT) have been identified as measures of colonoscopy quality. This study evaluates the impact of monitoring these measures on provider performance. Methods: Six blinded gastroenterologists practicing at a Veterans Affairs Medical Center were prospectively monitored over 9 months. Data for screening, adenoma surveillance, and fecal occult blood test positive (FOBT +) indicated colonoscopies were obtained, including exam preparation quality, cecal intubation rate, CWT, ADR, adenomas per colonoscopy (APC), and adverse events. Metrics were continuously monitored after a period of informed CWT monitoring and informed CWT + ADR monitoring. The primary outcome was impact on ADR and APC. Results: A total of 1671 colonoscopies were performed during the study period with 540 before informed monitoring, 528 during informed CWT monitoring, and 603 during informed CWT + ADR monitoring. No statistically significant impact on ADR was noted across each study phase. Multivariate regression revealed a trend towards fewer adenomas removed during the CWT monitoring phase (OR = 0.79; 95 %CI 0.62 – 1.02, P = 0.065) and a trend towards more adenomas removed during the CWT + ADR monitoring phase when compared to baseline (OR = 1.26; 95 %CI 0.99 – 1.61, P = 0.062). Indication for examination and provider were significant predictors for higher APC. Provider-specific data demonstrated a direct relationship between high ADR performers and increased CWT. Conclusions: Monitoring quality metrics did not significantly alter colonoscopy performance across a small heterogeneous group of providers. Non-significant trends towards higher APC were noted with CWT + ADR monitoring. Providers with a longer CWT had a higher ADR. Further studies are needed to determine the impact of monitoring on colonoscopy performance.

Primary sclerosing cholangitis (PSC) is a complex, chronic, and progressive fibroinflammatory destructive cholestatic biliary disease. The exact etiology and pathogenesis are unknown and possibly related to an enhanced immune-mediated response and reaction in the biliary system. PSC is closely associated with inflammatory bowel disease and specifically, ulcerative colitis. It can be characterized by both intrahepatic and extrahepatic bile duct stricturing and dilation. Clinical manifestations include abnormal liver tests, jaundice, pruritus, and fatigue. At more advanced stages, PSC can progress to cirrhosis and posttransplant disease recurrence is not uncommon. PSC is associated with an increased risk of cholangiocarcinoma and is an independent risk factor for colorectal cancer in patients with concomitant inflammatory bowel disease. Cholangiography is the mainstay of PSC diagnosis. Improved noninvasive biliary imaging has shifted the role of endoscopic retrograde cholangiopancreatography from disease diagnosis to management of complications, including dominant biliary strictures, bile duct stones, and assisting in the differentiation of benign vs malignant strictures. The role of additional endoscopic modalities, including endoscopic ultrasound, direct cholangioscopy, and probe-based confocal laser endomicroscopy is evolving. At the present time, medical treatment options are limited and the role of endoscopy is mainly supportive.

Pancreaticobiliary stenting is an efficacious and safe method to address biliary manifestations of benign and malignant disease. Removal of pancreaticobiliary prostheses is necessary for most patients with benign disease and for those suffering from stent-related adverse events, including stent occlusion and migration. The key principles of stent retrieval are optimizing patient safety; ensuring complete removal of the foreign body; maintaining intraductal access, when necessary; and thoroughly assessing for iatrogenic injury and resolution of the original indication for stent placement. This chapter will review the indications, timing, and techniques of biliary and pancreatic stent retrieval, as well as introduce the subject of lumen-apposing metal stent removal.

34 Question: A 35-yearold woman presented to the emergency department with a 1-day history of right lower quadrant pain. Her past medical historywasnotable foran omphalocele (requiring multiple abdominal surgeries as an infant) and antiphospholipid syndrome with multiple deep vein thromboses and pulmonary emboli. The patient described the abdominal pain as constant without radiation and unrelated to food intake. She denied any nausea, vomiting, fevers, chills, change in bowels, bleeding, or urinary symptoms. Laboratory data were unremarkable. Coronal and cross-sectional cuts from abdominal computed tomography (CT) are shown in Figures A and B, respectively. What is the diagnosis? Look on page 323 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

Background & Aims It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. Methods We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. Results By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). Conclusions In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416 .

Background Omega-3 fatty acids (ω-3 FA) have been demonstrated to have anti-inflammatory properties, postulated to occur through several principal mechanisms, including (1) displacement of arachidonic acid from the cellular membrane; (2) shifting of prostaglandin E2 and leukotriene B4 production; and (3) molecular level alterations including decreased activation of nuclear factor kappa B and activator protein-1. An additional regulator that is likely associated is the production of nitric oxide (NO) by nitric oxide synthetase. NO is a short-lived free radical involved in many biological functions. However, excessive NO production can lead to complications, suggesting that decreased NO production is a potential target for some inflammatory diseases. We hypothesized that pretreating with an ω-3 FA lipid emulsion would decrease the production of NO in macrophages and that this effect would occur through alterations in inducible nitric oxide synthetase (iNOS). Materials and methods Greiss reagent was used to assess NO production in RAW 264.7 macrophages following ω-3 or ω-6 FA treatment alone or in combination with lipopolysaccharide (LPS) stimulation for 12 h/24 h. iNOS levels were determined by Western blot. Tumor necrosis factor-alpha levels were determined by enzyme-linked immunosorbent assay. Results Following LPS-stimulation, ω-3 FA pretreatment at 12 and 24 h produced significantly less NO (P Conclusion These experiments demonstrate that, in addition to other anti-inflammatory effects, ω-3 FA lipid emulsions also significantly lower NO production in LPS-stimulated macrophages through altered iNOS protein expression.

Background Omega-3 fatty acids (n-3 FA) demonstrate significant anti-inflammatory properties thought to occur through three principal mechanisms; (1) displacement of arachidonic acid from the cellular membrane, (2) differential prostaglandin E 2 (PGE 2 ) and LTB 4 production, and (3) molecular level alterations such as diminished nuclear factor kappa B and AP-1 activation. Recently, n-3 FA have been demonstrated to significantly decrease nitric oxide (NO) production in a lipopolysaccharide (LPS)-stimulated MΦ model. We hypothesized that decreased NO production by n-3 FA occurs through inhibition of cyclooxygenase-2 (COX-2) derived PGE 2 and that repletion of the system with PGE 2 would obliterate these effects. Selective COX-2 inhibitor (L-748,731) experiments and separate PGE 2 repletion studies were used to test this hypothesis. Methods NO production was assessed following 24 h with or without LPS/PGE 2 in the presence of n-3 FA, L-748,731 (a selective COX-2 inhibitor), or combination (n-3 FA + L-748,731) treatment. Western blots were used to assess inducible NO synthase protein expression. Results Independently or in the presence of LPS, treatment with a COX-2 inhibitor significantly increased NO production compared with control, n-3 FA, and combination treatment. NO production in combination treatment is slightly increased compared to n-3 FA treatment. In control cells treated with LPS, PGE 2 repletion resulted in a significant decrease in NO. All other treatment groups repleted with PGE 2 demonstrated no significant alterations in NO production. Inducible NO synthase protein expression levels were similar to NO production across all treatments. Conclusion These experiments disproved our original hypothesis that the decrease in NO production associated with n-3 FA treatment occurs through a COX-2 derived PGE 2 dependent mechanism. Eliminating COX-2 derived PGE 2 by a selective inhibitor actually increased NO production. Exogenous PGE 2 repletion did not restore the system. Therefore, mechanisms other than n-3 FA associated alterations in COX-2 derived PGE 2 are likely involved in decreasing NO production in LPS stimulated MΦ.

Little is known about the change in risk conferred by family history of colorectal cancer (CRC) as a person ages. We evaluated the effect of family history on CRC incidence and mortality after 55 years of age, when the risk of early onset cancer had passed.We collected data from participants in the randomized, controlled Prostate, Lung, Colorectal and Ovarian cancer screening trial of flexible sigmoidoscopy versus usual care (55-74 years old, no history of CRC), performed at 10 US centers from 1993 to 2001. A detailed family history of colorectal cancer was obtained at enrollment, and subjects were followed for CRC incidence and mortality for up to 13 years.Among 144,768 participants, 14,961 subjects (10.3%) reported a family of CRC. Of 2090 incident cases, 273 cases (13.1%) had a family history of CRC; among 538 deaths from CRC, 71 (13.2%) had a family history of CRC. Overall, family history of CRC was associated with an increased risk of CRC incidence (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.50; P.0001) and increased mortality (HR, 1.31; 95% CI, 1.02-1.69; P = .03). Subjects with 1 first degree relative (FDR) with CRC (n = 238; HR, 1.23; 95% CI, 1.07-1.42) or ≥2 FDRs with CRC (n = 35; HR, 2.04; 95% CI, 1.44-2.86) were at increased risk for incident CRC. However, among individuals with 1 FDR with CRC, there were no differences in risk based on age at diagnosis in the FDR (for FDR60 years of age: HR, 1.27; 95% CI, 0.97-1.63; for FDR 60-70 years of age: HR, 1.33; 95% CI, 1.06-1.62; for FDR70 years of age: HR, 1.14; 95% CI, 0.93-1.45; P trend = .59).After 55 years of age, subjects with 1 FDR with CRC had only a modest increase in risk for CRC incidence and death; age of onset in the FDR was not significantly associated with risk. Individuals with ≥2 FDRs with CRC had continued increased risk in older age. Guidelines and clinical practice for subjects with a family history of CRC should be modified to align CRC testing to risk. ClinicalTrials.gov number, NCT00002540.

Emodin is a commonly used traditional herbal treatment in China, including use for pancreatic malignancy. In this study, the potential for emodin to inhibit pancreatic cancer cell proliferation was examined using 4 human pancreatic adenocarcinoma cell lines: Mia Paca-2, BxPC-3, Panc-1, and L3.6pl. WST-1 proliferation, propidium iodide flow cytometry cell cycle analysis, and poly-ADP-ribose polymerase (PARP) Western blot analysis were performed. Forty-eight-hour treatment with 50 muM emodin inhibited proliferation in Mia Paca-2 cells by 42%, BxPc-3 by 38%, L3.6pl by 56%, and Panc-1 by 18% (all P.01). In three-fourths of the cell lines, emodin treatment resulted in an increase (from 4.7% to 22%) in the cell population number in apoptosis when measured by flow cytometric analysis. Mia Paca-2 revealed a significant PARP cleavage product when compared with control. These feasibility experiments provide initial evidence that emodin exerts an antiproliferative effect, likely through apoptosis induction-related mechanism(s), that is reproducible in various human pancreatic cancer cell lines.

Transcription profiling of placentomes derived from somatic cell nuclear transfer (SCNT, n = 20), in vitro fertilization (IVF, n = 9), and artificial insemination (AI, n = 9) at or near term development was performed to better understand why SCNT and IVF often result in placental defects, hydrops, and large offspring syndrome (LOS). Multivariate analysis of variance was used to distinguish the effects of SCNT, IVF, and AI on gene expression, taking into account the effects of parturition (term or preterm), sex of fetus, breed of dam, breed of fetus, and pathological finding in the offspring (hydrops, normal, or other abnormalities). Differential expression of 20 physiologically important genes was confirmed with quantitative PCR. The largest effect on placentome gene expression was attributable to whether placentas were collected at term or preterm (i.e., whether the collection was because of disease or to obtain stage-matched controls) followed by placentome source (AI, IVF, or SCNT). Gene expression in SCNT placentomes was dramatically different from AI ( n = 336 genes; 276 >2-fold) and from IVF ( n = 733 genes; 162 >2-fold) placentomes. Functional analysis of differentially expressed genes (DEG) showed that IVF has significant effects on genes associated with cellular metabolism. In contrast, DEG associated with SCNT are involved in multiple pathways, including cell cycle, cell death, and gene expression. Many DEG were shared between the gene lists for IVF and SCNT comparisons, suggesting that common pathways are affected by the embryo culture methods used for IVF and SCNT. However, the many unique gene functions and pathways affected by SCNT suggest that cloned fetuses may be starved and accumulating toxic wastes due to placental insufficiency caused by reprogramming errors. Many of these genes are candidates for hydrops and LOS.

Pancreatic cancer-gemcitabine (GEM) chemoresistance has been demonstrated to be associated with enhanced NF-kB activation and antiapoptotic protein synthesis. The well-known capacity of omega-3 fatty acids (n-3 FAs) to inhibit NF-kB activation and promote cellular apoptosis has the potential to restore or facilitate gemcitabine chemosensitivity.Four pancreatic cancer cell lines (MIA PaCa-2, BxPC-3, PANC-1, and L3.6), each with distinct basal NF-kB and differing GEM sensitivity profiles, were administered: 100 uM of (1) n-3FA, (2) n-6FA, (3) GEM, (4) n-3FA + GEM, or (5) n-6FA + GEM for 24 and 48 hours. Proliferation was assessed using the WST-1 assay. To define the mechanism(s) of altered proliferation, electron mobility shift assay for NF-kB activity, western blots of phoshoStat3, phosphoIkappaB, and poly(ADP-ribose) polymerase (PARP) cleavage were performed in the MIA PaCa-2 cell line.All cell lines demonstrated a time/dose-dependent inhibition of proliferation in response to n-3FA. For MIA PaCa-2 cells, n-3FA and n-3FA + GEM treatment resulted in reduction of I-kB phosphorylation and NF-kB activation when compared with n-6FA control. n-3FA and combination treatment also significantly decreased Stat3 phosphorylation, whereas GEM alone had no effect. n-3FAs and n-3FA + GEM groups demonstrated increased PARP cleavage, mirroring NF-kB activity and Stat3 phosphorylation.n-3 FA treatment is specifically associated with inhibition of proliferation in these four pancreatic cell lines irrespective of varied gemcitabine resistance. An experimental paradigm to screen for potential contributory mechanism(s) in altered pancreatic cancer cellular proliferation was defined, and using this approach the co-administration of n-3 FA with GEM inhibited GEM-induced NF-kB activation and restored apoptosis in the MIA PaCa-2 cell-line.

Omega-3 (omega-3) fatty acids have been clinically and experimentally associated with the amelioration of chronic and acute inflammation; however, the mechanisms for these observations have not been well defined. During the past decade, laboratories of nutrition and inflammation have demonstrated that the anti-inflammatory activities of omega-3 fatty acids occur at least in part through the inhibition of macrophage-elaborated tumor necrosis factor production and through inactivation of the nuclear factor-kappaB signaling pathway subsequently altering proinflammatory cytokine transcription. These observations led to further experiments that support a role for omega-3 fatty acids in the restoration of apoptosis in various chemoresistant tumor models through a similar inactivation of the nuclear factor-kappaB signaling pathway. The potential for nutritional modulation of host inflammation has been an ongoing and expanding area of investigation. An increased emphasis has been placed on the potential for diet and dietary supplements to serve as modulators of host response to disease, injury, and infection.