Distinct Serum Immune Profiles Define the Spectrum of Acute and Chronic Pancreatitis From the Multicenter Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) Study.

BACKGROUND & AIMS: Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis. METHODS: Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57). RESULTS: A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status. CONCLUSIONS: Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.

Pancreatitis pain quality changes at year 1 follow-up, but GP130 remains a biomarker for pain.

BACKGROUND/OBJECTIVES: Debilitating abdominal pain is a common symptom affecting patients with chronic pancreatitis (CP). CP pain is dynamic due to multiple underlying mechanisms. The objective of this study was to 1) evaluate changes in pain phenotype at one year follow-up and 2) validate putative pain biomarkers in a prospective cohort study. METHODS: The Neuropathic and Nociceptive PROMIS-PQ questionnaires were used to classify pain for participants with in the PROCEED study. Putative serum biomarkers were measured via immunoassay. RESULTS: At enrollment, 17.6 % (120/681) subjects with CP reported no pain in the previous year. Of those, 29 % experienced pain during the 1 yr follow-up whereas 18 % of those with pain prior to enrollment reported no pain during the 1 yr follow-up period. Of the 393 subjects with PROMIS-PQ data at enrollment, 212 also had follow-up data at 1 yr. Approximately half (53.3 %) of those individuals changed pain phenotype between baseline and follow-up. At 1 yr, serum TGFß1 level was negatively correlated with nociceptive T-scores (p = 0.006). GP130 was significantly correlated with both nociceptive (p = 0.012) and neuropathic T-scores (p = 0.043) at 1 yr, which is consistent with the previously published findings. CONCLUSIONS: The positive association between TGFß1 and pain is not maintained over time, suggesting it is a poor pain biomarker. However, serum GP130 is a consistent biomarker for mixed-type pain in CP. Preclinical studies show that targeting TGFß1 or IL-6 (ligand for GP130) is sufficient to inhibit CP pain supporting further investigation of this as a potential therapeutic target.

Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study.

OBJECTIVE: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). METHODS: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. RESULTS: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CONCLUSION: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.

Lumen-apposing metal stents with or without coaxial plastic stent placement for the management of pancreatic fluid collections.

BACKGROUND AND AIMS: Coaxial double-pigtail plastic stent (DPPS) placement is often performed within lumen-apposing metal stents (LAMSs) for drainage of pancreatic fluid collections (PFCs) to prevent adverse events (AEs) such as stent occlusion and bleeding. This study compares the safety and outcomes of LAMSs alone versus LAMSs with coaxial DPPSs for PFC management. METHODS: Patients undergoing drainage of a PFC with LAMSs were retrospectively identified and categorized as LAMS or LAMS/DPPS based on initial drainage strategy. The AE rate, AE type, and clinical success were extracted by chart review. RESULTS: One hundred eighty-five individuals (83 LAMS, 102 LAMS/DPPS) were identified. No significant differences were found in rates of clinical success (75.9% LAMS vs 69.6% LAMS/DDPS, P = .34) or overall AEs (15.7% LAMS vs 15.7% LAMS/DPPS, P = .825). CONCLUSIONS: In this comparative single-center study, placement of a coaxial DPPS for drainage of PFCs with LAMSs did not affect rates of AEs or clinical success.

A Protocolized Management of Walled-Off Necrosis (WON) Reduces Time to WON Resolution and Improves Outcomes.

BACKGROUND AND AIMS: Patients with infected or symptomatic walled-off necrosis (WON) have high morbidity and health care utilization. Despite the recent adoption of nonsurgical treatment approaches, WON management remains nonalgorithmic. We investigated the impact of a protocolized early necrosectomy approach compared with a nonprotocolized, clinician-driven approach on important clinical outcomes. METHODS: Records were reviewed for consecutive patients with WON who underwent a protocolized endoscopic drainage with a lumen-apposing metal stent (cases), and for patients with WON treated with a lumen-apposing metal stent at the same tertiary referral center who were not managed according to the protocol (control subjects). The protocol required repeat cross-sectional imaging within 14 days after lumen-apposing metal stent placement, with regularly scheduled endoscopic necrosectomy if WON diameter reduction was <50%. Control patients were treated according to their clinician's preference without an a priori strategy. Inverse probability of treatment weighting-adjusted analysis was used to evaluate the influence of being in the protocolized group on time to resolution. RESULTS: A total of 24 cases and 47 control subjects were included. There were no significant differences in baseline characteristics. Although numbers of endoscopies and necrosectomies were similar, cases had lower adverse event rates, shorter intensive care unit stay, and required nutritional support for fewer days. On matched multivariate Cox regression, cases had earlier WON resolution (hazard ratio, 5.73; 95% confidence interval, 2.62-12.5). This was confirmed in the inverse probability of treatment weighting-adjusted analysis (hazard ratio, 3.4; 95% confidence interval, 1.92-6.01). CONCLUSIONS: A protocolized strategy resulted in faster WON resolution compared with a discretionary approach without the need for additional therapeutic interventions, and with a better safety profile and decreased health care utilization.

Association of Chronic Pancreatitis Pain Features With Physical, Mental, and Social Health.

BACKGROUND AND AIMS: Pain is a cardinal symptom of chronic pancreatitis (CP). Using Patient-Reported Outcomes Measurement Information System (PROMIS) measures, we characterized physical and mental health and symptom profiles of a well-defined cohort of individuals with CP and compared them with control subjects. Among patients with CP, we also examined associations between pain (intensity, temporal nature) and PROMIS symptom profiles and the prevalence of clinically significant psychological comorbidities. METHODS: We analyzed baseline data in 488 CP patients and 254 control subjects enrolled in PROCEED (Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies), an ongoing longitudinal cohort study. Participants completed the PROMIS-Global Health, which captures global physical and mental health, and the PROMIS-29 profile, which captures 7 symptom domains. Self-reported pain was categorized by severity (none, mild-moderate, severe) and temporal nature (none, intermittent, constant). Demographic and clinical data were obtained from the PROCEED database. RESULTS: Pain was significantly associated with impairments in physical and mental health. Compared with participants with no pain, CP participants with severe pain (but not mild-moderate pain) had more decrements in each PROMIS domain in multivariable models (effect sizes, 2.54-7.03) and had a higher prevalence of clinically significant depression, anxiety, sleep disturbance, and physical disability (odds ratios, 2.11-4.74). Similar results were noted for constant pain (but not intermittent pain) for PROMIS domains (effect sizes, 4.08-10.37) and clinically significant depression, anxiety, sleep disturbance and physical disability (odds ratios, 2.80-5.38). CONCLUSIONS: Severe and constant pain are major drivers for poor psychological and physical health in CP. Systematic evaluation and management of psychiatric comorbidities and sleep disturbance should be incorporated into routine management of patients with CP. (ClinicalTrials.gov, Number: NCT03099850).

Novel classification system for walled-off necrosis: a step toward standardized nomenclature and risk-stratification framework.

BACKGROUND AND AIMS: The optimal therapeutic approach for walled-off necrosis (WON) is not fully understood, given the lack of a validated classification system. We propose a novel and robust classification system based on radiologic and clinical factors to standardize the nomenclature, provide a framework to guide comparative effectiveness trials, and inform the optimal WON interventional approach. METHODS: This was a retrospective analysis of patients who underwent endoscopic management of WON by lumen-apposing metal stent placement at a tertiary referral center. Patients were classified according to the proposed QNI classification system: quadrant ("Q"), represented an abdominal quadrant distribution; necrosis ("N"), denoted by the percentage of necrosis of WON; and infection ("I"), denoted as positive blood culture and/or systemic inflammatory response syndrome reaction with a positive WON culture. Two blinded reviewers classified all patients according to the QNI system. Patients were then divided into 2 groups: those with a lower QNI stratification (≤2 quadrants and ≤30% necrosis; group 1) and those with a higher stratification (≥3 quadrants, 2 quadrants with ≥30% necrosis, or 1 quadrant with >60% necrosis and infection; group 2). The primary outcome was mean time to WON resolution. Secondary procedural and clinical outcomes between the groups were compared. RESULTS: Seventy-one patients (75% men) were included and stratified by the QNI classification; group 1 comprised 17 patients and group 2, 54 patients. Patients in group 2 had a higher number of necrosectomies, longer hospital stays, and more readmissions. The mean time to resolution was longer in group 2 than in group 1 (79.6 ± 7.76 days vs 48.4 ± 9.22 days, P = .02). The mortality rate was higher in group 2 (15% vs 0%, P = .18). CONCLUSIONS: Despite the heterogeneous nature of WON in severe acute pancreatitis, a proposed QNI system may provide a standardized framework for WON classification to inform clinical trials, risk-stratify the disease course, and potentially inform an optimal management approach.

High Prevalence of Osteopathy in Chronic Pancreatitis: A Cross-sectional Analysis From the PROCEED Study.

BACKGROUND & AIMS: Chronic pancreatitis (CP) is associated with osteopathy (osteoporosis or osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP. METHODS: We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression model with forward selection to identify risk factors for osteopathy. RESULTS: The majority of subjects had osteopathy on DXA scan (56.0%; 17.0% osteoporosis; 39.0% osteopenia). Subjects with osteopathy had a higher prevalence of traumatic (40.0% vs 26.4%; P = .02) and spontaneous fractures (3.9% vs 0; P = .04). On multivariate analysis, older age (odds ratio [OR], 1.29 per 5 years; 95% confidence interval [CI], 1.15-1.45), female sex (OR, 3.08; 95% CI, 1.75-5.43), white race (OR, 2.68; 95% CI, 1.20-6.01), and underweight body mass index category (OR, 7.40; 95% CI, 1.56-34.99) were associated with higher probability of osteopathy. There were no significant associations between osteopathy and other patient and disease-related features of CP. CONCLUSION: In the largest study of patients with CP who underwent DXA screening, the majority had osteopathy. There are overlapping risk factors with osteopathy in the general population, but the high prevalence in men and younger women supports the need for future investigations into the mechanisms of bone loss in CP. CLINICALTRIALS: gov number, NCT03099850.

Prospective Study Assessing Impact of Ethylene Oxide Sterilization on Endoscopic Ultrasound Image Quality.

BACKGROUND & AIMS: Duodenoscope-associated transmission of infections has raised questions about efficacy of endoscope reprocessing using high-level disinfection (HLD). Although ethylene oxide (ETO) gas sterilization is effective in eradicating microbes, the impact of ETO on endoscopic ultrasound (EUS) imaging equipment remains unknown. In this study, we aimed to compare the changes in EUS image quality associated with HLD vs HLD followed by ETO sterilization. METHODS: Four new EUS instruments were assigned to 2 groups: Group 1 (HLD) and Group 2 (HLD + ETO). The echoendoscopes were assessed at baseline, monthly for 6 months, and once every 3 to 4 months thereafter, for a total of 12 time points. At each time point, review of EUS video and still image quality was performed by an expert panel of reviewers along with phantom-based objective testing. Linear mixed effects models were used to assess whether the modality of reprocessing impacted image and video quality. RESULTS: For clinical testing, mixed linear models showed minimal quantitative differences in linear analog score (P = .04; estimated change, 3.12; scale, 0-100) and overall image quality value (P = .007; estimated change, -0.12; scale, 1-5) favoring ETO but not for rank value (P = .06). On phantom testing, maximum depth of penetration was lower for ETO endoscopes (P < .001; change in depth, 0.49 cm). CONCLUSIONS: In this prospective study, expert review and phantom-based testing demonstrated minimal differences in image quality between echoendoscopes reprocessed using HLD vs ETO + HLD over 2 years of clinical use. Further studies are warranted to assess the long-term clinical impact of these findings. In the interim, these results support use of ETO sterilization of EUS instruments if deemed clinically necessary.

Impact of trimodality sampling on detection of malignant biliary strictures compared with patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: Malignant biliary strictures can be difficult to diagnose, with up to 20% considered indeterminate after initial tissue sampling. This study aimed to determine the performance characteristics of transpapillary biopsy sampling (TPB) and fluorescence in situ hybridization (FISH) in isolation or in combination with standard brush cytology (BC) in patients who received trimodality sampling for biliary strictures. METHODS: This single-center retrospective cohort study included patients with biliary strictures undergoing ERCP with trimodality sampling between September 2014 and April 2019. Performance characteristics for each diagnostic test alone and in combination were calculated. RESULTS: Two hundred four patients underwent trimodality biliary sampling, including 104 (51.0%) with malignancy. The diagnostic sensitivity for malignancy with BC (17.3%) significantly improved with dual modality (BC+FISH, 58.7%; BC+TPB, 40.4%) or trimodality sampling (68.3%; P < .001 for all comparisons). Trimodality sampling improved diagnostic sensitivity for malignancy compared with BC+FISH (P = .002) and BC+TPB (P < .001). There was no statistically significant difference in the sensitivity of trimodality sampling in detecting cholangiocarcinoma (79.7%) compared with pancreatic cancer (62.5%; P = .1). Among 57 patients with primary sclerosing cholangitis (PSC), the sensitivity of detecting biliary malignancy (n = 20) was 20% for BC and significantly improved with the addition of FISH (80%; P < .001) but not with TPB (35.0%; P = .25). Trimodality sampling did not further improve diagnostic sensitivity (85%) over BC+FISH (80%) for malignancy in the setting of PSC (P = 1). CONCLUSIONS: Trimodality sampling improves the diagnostic sensitivity for the detection of malignant biliary strictures with no significant difference in sensitivity for cholangiocarcinoma compared with pancreatic cancer. However, in patients with PSC, trimodality sampling was not superior to BC+FISH.

Endoscopic Ultrasound/Fine Needle Aspiration Is Effective for Lymph Node Staging in Patients With Cholangiocarcinoma.

BACKGROUND AND AIMS: Presence of malignant regional lymph nodes (MRLNs) precludes curative oncological resection or liver transplantation for cholangiocarcinoma (CCA). Limited data support the utility of endoscopic ultrasound (EUS)/fine needle aspiration (FNA) for detection of MRLNs in extrahepatic CCA, but there are no data for its role in intrahepatic CCA (iCCA). The aim of this study is to evaluate the staging impact of EUS for CCA, including analysis by subtype. APPROACH AND RESULTS: We identified consecutive patients with CCA who underwent EUS staging at a single tertiary care center from October 2014 to April 2018. Among this cohort, we abstracted clinical demographic, radiographical, procedural, cytopathological, and surgical data. STATA 15 software was used for comparative analysis calculations (StataCorp LP, College Station, TX). The study cohort included 157 patients; 24 (15%), 124 (79%), and 9 (6%) with intrahepatic, perihilar, and distal CCA, respectively. EUS was able to identify regional lymph nodes (RLNs) in a higher percentage of patients compared to cross-sectional imaging (86% vs. 47%; P < 0.001). FNA was performed in 133 (98.5%) patients with RLNs, with a median of three passes per node. EUS-FNA identified MRLN in 27 of 31 (87.1%) patients ultimately found to have MRLNs. For iCCA, EUS detected a higher percentage of RLN compared to cross-sectional imaging (83% vs. 50%; P = 0.048), with MRLNs identified in 4 (17%) patients. Among the entire cohort, identification of at least one MRLN by EUS was associated with lower median survival (353 vs. 1,050 days; P < 0.001) and increased risk of death (hazard ratio = 4.1; P < 0.001). CONCLUSIONS: EUS-FNA is effective for identifying MRLN in patients with CCA, and should be routinely incorporated into staging of all CCA subtypes given the impact of MRLN on prognosis and management decisions.

Transpapillary gallbladder stent placement for long-term therapy of acute cholecystitis.

BACKGROUND AND AIMS: Select patients with acute cholecystitis (AC) are poor candidates for cholecystectomy. ERCP-guided transpapillary gallbladder (GB) drainage (ERGD) is one modality for nonoperative management of AC in these patients. Our primary aim was to evaluate long-term success of destination ERGD. Secondary aims were the rate of technical and clinical success, number of repeat procedures, rate of adverse events, and risk factors for recurrent AC. METHODS: Consecutive patients with AC who were not candidates for cholecystectomy underwent ERGD with attempted transpapillary GB plastic double-pigtail stent placement at a tertiary hospital from January 2008 to December 2019. Long-term success was defined as no AC after ERGD until 6 months, death, or reintervention. Technical success was defined as placement of at least 1 transpapillary stent into the GB and clinical success as resolution of AC symptoms with discharge from the hospital. RESULTS: Long-term success was achieved in 95.9% of patients (47/49), technical success in 96% (49/51), and clinical success 100% in those with technical success. Mild adverse events occurred in 5.9% (n = 3). Mean follow-up was 453 days after ERGD (range, 18-1879). A trend toward longer time to recurrence of AC was seen in patients with 2 rather than 1 GB stent placed (P = .13), and more repeat procedures were performed when a single stent was placed (P = .045). CONCLUSIONS: ERGD with transpapillary GB double-pigtail stent placement is a safe and effective long-term therapy for poor surgical candidates with AC. Risk factors for recurrence include stent removal and single-stent therapy. Double-stent therapy is not always technically feasible but may salvage failed single-stent therapy or recurrence after elective stent removal and may therefore be the preferred treatment modality.

Impact of disconnected pancreatic duct syndrome on endoscopic ultrasound-guided drainage of pancreatic fluid collections.

BACKGROUND: Endoscopic intervention for pancreatic fluid collections (PFCs) with disconnected pancreatic duct syndrome (DPDS) has been associated with failures and increased need for additional endoscopic and non-endoscopic interventions. The primary aim of this study was to determine the outcomes of endoscopic ultrasound (EUS)-guided transmural drainage of PFCs in patients with DPDS. METHODS: In patients undergoing EUS-guided drainage of PFCs from January 2013 to January 2018, demographic profiles, procedural indications and details, adverse events, outcomes, and subsequent interventions were retrospectively collected. Overall treatment success was determined by PFC resolution on follow-up imaging or stent removal without recurrence. RESULTS: EUS-guided drainage of PFCs was performed in 141 patients. DPDS was present in 57 of them (40 %) and walled-off necrosis was the most frequent type of PFC (55 %). DPDS was not associated with lower clinical success, increased number of repeat interventions, or increased time to PFC resolution. Patients with DPDS were more likely to be treated with permanent transmural plastic double-pigtail stents (odds ratio [OR] 6.4; 95 % confidence interval [CI] 2.5 - 16.5; P < 0.001). However, when stents were removed, DPDS was associated with increased PFC recurrence after stent removal (OR 8.0; 95 %CI 1.2 - 381.8; P = 0.04). CONCLUSIONS: DPDS frequently occurs in patients with PFCs but does not negatively impact successful resolution. DPDS is associated with increased PFC recurrence after stent removal.

Gastrointestinal endoscopy experience of surgical trainees throughout rural Africa.

BACKGROUND: Gastrointestinal endoscopy (GIE) is not routinely accessible in many parts of rural Africa. As surgical training expands and technology progresses, the capacity to deliver endoscopic care to patients improves. We aimed to describe the current burden of gastrointestinal (GI) disease undergoing GIE by examining the experience of surgical training related to GIE. METHODS: A retrospective review was conducted on GIE procedures performed by trainees with complete case logs during 5-year general surgery training at Pan-African Academy of Christian Surgeons (PAACS) sites. Cases were classified according to diagnosis and/or indication, anatomic location, intervention, adverse events, and outcomes. Comparisons were performed by institutional location and case volumes. Analysis was performed for trainee self-reported autonomy by post-graduate year and case volume experience. RESULTS: Twenty trainees performed a total of 2181 endoscopic procedures. More upper endoscopies (N = 1,853) were performed than lower endoscopies (N = 325). Of all procedures, 546 (26.7%) involved a cancer or mass, 267 (12.2%) involved a report of blood loss, and 452 (20.7%) reported pain as a component of the diagnosis. Interventions beyond biopsy were reported in 555 (25%) procedures. Esophageal indications predominated the upper endoscopies, particularly esophageal cancer. Trainees in high-volume centers and in East Africa performed more interventional endoscopy and procedures focused on esophageal cancer. Procedure logs documented adverse events in 39 cases (1.8% of all procedures), including 16 patients (0.8%) who died within 30 days of the procedure. Self-reported autonomy improved with both increased endoscopy experience and post-graduate year. CONCLUSIONS: GIE is an appropriate component of general surgery residency training in Africa, and adequate training can be provided, particularly in upper GI endoscopy, and includes a wide variety of endoscopic therapeutic interventions.

Methylated DNA in Pancreatic Juice Distinguishes Patients With Pancreatic Cancer From Controls.

BACKGROUND & AIMS: Precursors of pancreatic cancer arise in the ductal epithelium; markers exfoliated into pancreatic juice might be used to detect high-grade dysplasia (HGD) and cancer. Specific methylated DNA sequences in pancreatic tissue have been associated with adenocarcinoma. We analyzed these methylated DNA markers (MDMs) in pancreatic juice samples from patients with pancreatic ductal adenocarcinomas (PDACs) or intraductal papillary mucinous neoplasms (IPMNs) with HGD (cases), and assessed their ability to discriminate these patients from individuals without dysplasia or with IPMNs with low-grade dysplasia (controls). METHODS: We obtained pancreatic juice samples from 38 patients (35 with biopsy-proven PDAC or pancreatic cystic lesions with invasive cancer and 3 with HGD) and 73 controls (32 with normal pancreas and 41 with benign disease), collected endoscopically from the duodenum after secretin administration from February 2015 through November 2016 at 3 medical centers. Samples were analyzed for the presence of 14 MDMs (in the genes NDRG4, BMP3, TBX15, C13orf18, PRKCB, CLEC11A, CD1D, ELMO1, IGF2BP1, RYR2, ADCY1, FER1L4, EMX1, and LRRC4), by quantitative allele-specific real-time target and signal amplification. We performed area under the receiver operating characteristic curve analyses to determine the ability of each marker, and panels of markers, to distinguish patients with HGD and cancer from controls. MDMs were combined to form a panel for detection using recursive partition trees. RESULTS: We identified a group of 3 MDMs (at C13orf18, FER1L4, and BMP3) in pancreatic juice that distinguished cases from controls with an area under the receiver operating characteristic value of 0.90 (95% CI, 0.83-0.97). Using a specificity cut-off value of 86%, this group of MDMs distinguished patients with any stage of pancreatic cancer from controls with 83% sensitivity (95% CI, 66%-93%) and identified patients with stage I or II PDAC or IPMN with HGD with 80% sensitivity (95% CI, 56%-95%). CONCLUSIONS: We identified a group of 3 MDMs in pancreatic juice that identify patients with pancreatic cancer with an area under the receiver operating characteristic value of 0.90, including patients with early stage disease or advanced precancer. These DNA methylation patterns might be included in algorithms for early detection of pancreatic cancer, especially in high-risk cohorts. Further optimization and clinical studies are needed.

Significance of peripheral eosinophilia for diagnosis of IgG4-related disease in subjects with elevated serum IgG4 levels.

OBJECTIVES: In this study, we aim to assess the diagnostic utility of elevated serum IgG4 (sIgG4) concentration alone and in combination with peripheral eosinophilia (PE) for IgG4-related disease (IgG4-RD). METHODS: From the Mayo Clinic, Rochester electronic medical record database we identified 409 patients with above normal levels of sIgG4 (reference range 121-140 mg/dL) who had sIgG4 measured to differentiate IgG4-RD from another disease. RESULTS: Among 409 patients with any elevation in sIgG4 levels, 129 (31.5%) had a definite diagnosis of IgG4-RD. The prevalence of PE increased with increasing sIgG4 levels and was more likely to be seen in subjects with IgG4-RD vs. non-IgG4-RD at ≥1X (n = 35/120, 29.2% vs. n = 23/258, 8.9%; p < 0.001), ≥2X (n = 23/64, 35.9% vs. n = 5/54,9.3%; p = 0.001) and ≥3X (n = 18/42, 42.9% vs. n = 0/9, 0%; p = 0.015) of sIgG4 upper limit of normal (ULN), respectively. After adjusting for gender and age, sIgG4 levels ≥ 2X ULN with PE as a predictor, had a higher positive predictive value in predicting IgG4-RD (72.2% vs. 65.9%) with an Area Under the Receiver Operatic Characteristic Curve (AUC) of 0.776, compared to sIgG4 ≥ 2X ULN without PE predictor (AUC = 0.74), p = 0.016. PE, sIgG4≥2X ULN, male gender, and age independently predicted the disease with odds ratio of 4.89 (95% CI:2.51-9.54), 3.78 (95% CI:2.27-6.28), 2.78 (95% CI:1.55-4.97), and 1.03 (95% CI:1.02-1.05), respectively. CONCLUSION: Even in subjects in whom IgG4-RD is suspected, only a minority (∼30%) with elevated sIgG4 levels have IgG4-RD. sIgG4 by itself is more specific at higher levels, though never diagnostic. PE increases with increasing sIgG4 and adds diagnostic value at higher sIgG4 levels.

Clinical impact of celiac ganglia metastasis upon pancreatic ductal adenocarcinoma.

BACKGROUND: Pre-operative staging of pancreatic adenocarcinoma guides clinical decision making. Limited data indicate that metastasis to celiac ganglia (CG) correlates with poor prognosis. We investigated feasibility and safety of endoscopic ultrasound fine needle aspiration (EUS-FNA) detection of CG metastasis and its impact upon tumor stage, resectability, and survival in pancreatic ductal adenocarcinoma (PDAC). PATIENTS: We reviewed our prospectively maintained EUS and cytopathology databases to identify patients with FNA proven CG metastasis in patients with PDAC from 2004 to 2017. Clinical demographics, EUS, CT, MRI, cytopathology, cancer stage, and resectability data were analyzed. Survival of PDAC patients with CG metastasis was compared to the expected survival of PDAC patients of similar stage as reported by the United States National Cancer Database. RESULTS: Twenty-one patients with PDAC [median age 73 (IQR63-78); 14 (67%) female)], had CG metastasis confirmed by cytopathologic assessment. CG metastasis resulted in tumor upstaging relative to other EUS findings and cross sectional imaging findings in 12 (57%) and 15 (71%) patients, and converted cancers from resectable to unresectable relative to EUS and cross sectional imaging in 7 (37%) and 7 (37%) patients, respectively. In patients with PDAC, the survival of patients with CG metastasis was not significantly different from the overall survival (hazard ratio 0.71; 95% confidence interval 0.44, 1.13; p = 0.15). CONCLUSIONS: EUS-FNA may safely identify CG metastases. While CG metastasis upstaged and altered the resectability status among this cohort of patients with PDAC, the survival data with regard to PDAC suggest that this may be misguided.

Cholangioscopy Biopsies Improve Detection of Cholangiocarcinoma When Combined with Cytology and FISH, but Not in Patients with PSC.

BACKGROUND AND AIMS: Single-operator cholangioscopy (SOC) has been suggested to be a cost-effective strategy for the detection of cholangiocarcinoma (CCA). The aim of this study is to compare the performance characteristics of SOC-guided biopsies and transpapillary biopsies with standard sampling techniques for the detection of CCA. METHODS: A retrospective cohort study of patients undergoing SOC between 1/2007 and 10/2018 at a single academic center was performed. Demographic, procedural, and outcomes data were recorded and analyzed using STATA 14.0. Sensitivity comparison between diagnostic tests was performed using exact McNemar test exclusively among patients with CCA. Two-sided p value < 0.05 was considered statistically significant. RESULTS: Ninety-two patients were included; 36 (39.1%) with primary sclerosing cholangitis (PSC), 41 (44.6%) with CCA, and median follow-up was 15.1 months. In the overall cohort, brush cytology demonstrated a sensitivity of 44.7% and increased with the addition of FISH (56.8%; p = 0.12), FISH with SOC-guided biopsy (71.4%; p = 0.03), and FISH with transpapillary biopsy (64.5%; p = 0.01). However, in patients with PSC, there was no significant improvement in sensitivity with the addition of SOC-guided biopsy or transpapillary biopsy in addition to FISH when compared to brush cytology. There was no difference in the rates of overall adverse events (14% vs. 23.2%; p = 0.27) or infection (3% vs. 4%; p = 0.83) in patients with and without PSC. CONCLUSIONS: SOC-guided and transpapillary biopsies improve sensitivity for the detection of cholangiocarcinoma in combination with other ERCP-based techniques compared to brush cytology alone. However, while safe, these modalities do not significantly improve the sensitivity for the detection of malignancy in PSC patients.

An innovative technique using a percutaneously placed guidewire allows for higher success rate for ERCP compared to balloon enteroscopy assistance in Roux-en-Y gastric bypass anatomy.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is technically challenging in Roux-en-Y gastric bypass (RYGB). Current approaches either have high failure rate, are resource intensive, or invasive. OBJECTIVE: To describe successful adoption of an old technique for performance of ERCP in patients with RYGB anatomy employing enteroscopy with the assistance of a percutaneously placed guidewire, which facilitates both reaching and cannulating the major papilla. METHOD: A retrospective cohort study in a tertiary-care center. We included patients with RYGB from 2015 to 2017 who underwent ERCP. We compared success rate and adverse events between rendezvous guidewire-assisted (RGA) and balloon-assisted enteroscopy (BAE) ERCP techniques. RESULTS: Thirty patients with RYGB underwent 62 ERCPs. The mean age was 62.2 ± 11 years with female predominance 83.3%. The procedures were performed using BAE 43/62 (69.3%), RGA 13/62 (21%), gastrostomy tube 5/62 (8.1%), and colonoscope 1/62 (1.6%). In patients with a native papilla (n = 37 ERCPs), clinical success rate with BAE was 36.8% compared to 100% with RGA (P < 0.001). There was no significant difference in bleeding (P = 0.17), post-ERCP pancreatitis (P = 0.4), or luminal perforation (P = not estimated) between the two techniques in native papilla. The mean procedure time with the RGA was significantly shorter than successful BAE with mean difference: 33 min (95% CI 8-57 min, P = 0.01). Twenty-five ERCPs were performed in eight patients with non-native papilla. BAE success rate in non-native papilla was 95.8%. The mean procedure time of the BAE in non-native papilla was 111 ± 60 min. Native papillae were associated with a significantly higher BAE failure rate compared to non-native papillae (OR: 12; 95% CI 1.44-99.7, P = 0.02). CONCLUSION: In patients with RYGB, RGA appears to be highly successful and safe in achieving clinical success for patients with native papilla as compared to BAE.

Accuracy of Endoscopic Ultrasound Imaging in Distinguishing Celiac Ganglia From Celiac Lymph Nodes.

BACKGROUND & AIMS: Endoscopic ultrasound (EUS) allows visualization of celiac lymph nodes (CLNs) and celiac ganglia (CG). Reliably distinguishing these structures is important for tumor staging and CG ablative therapies. We aimed to evaluate the accuracy of EUS in distinguishing CLNs from CG using a strict cytopathology reference standard. We also determined the rate of detection of CLN and CG by conventional cross-sectional imaging. METHODS: From EUS and cytopathology databases, we identified all patients who underwent EUS-FNA of a presumed CLN or CG from October 1, 2004, through March 1, 2017, and compared the findings with those from cytology (reference standard). Indeterminate cytology results were re-reviewed. EUS imaging (ie, index test) results were compared with those from the reference standard. An expert radiologist re-reviewed computed tomography and magnetic resonance images from 100 lesions, from 94 randomly selected patients with a reference standard, to determine the rates of CLN and CG detection. RESULTS: A total of 504 patients (mean age, 63.4 ± 13.2 years; 292 men) underwent a median of 7 EUS-FNA passes (range, 1-13) for a total of 566 lesions perceived to be either a CLN or CG; the cytology reference standard was available for 521 lesions (92.1%). When we excluded indeterminate cytology results, the EUS accurately identified 281/286 CLNs (98.3%) and 166/186 CGs (89.2%), for an overall accuracy of 447/472 (94.7%). EUS-FNA distinguished CG from CLNs with a 93.3% sensitivity, 93.7% specificity, a positive predictive value of 96.2%, and a negative predictive value of 89.2%. Of 100 lesions in 94 patients randomly selected for a second expert radiology review, computed tomography and magnetic resonance imaging detected 59/67 CLNs (88.1%) and 13/33 CG (39.4%). CONCLUSION: EUS accurately distinguishes CLNs from CG. EUS might therefore be used to increase the accuracy of tumor staging, to select tumor stage-appropriate therapy, and to guide CG-ablative therapies.