Outcomes of endoscopic retrograde cholangiography and percutaneous transhepatic biliary drainage in liver transplant recipients with a Roux-en-Y biliary-enteric anastomosis.

Backgrounds/Aims: Data regarding outcomes of endoscopic retrograde cholangiography (ERC) in liver transplant (LT) recipients with biliary-enteric (BE) anastomosis are limited. We report outcomes of ERC and percutaneous transhepatic biliary drainage (PTBD) as first-line therapies in LT recipients with BE anastomosis. Methods: All LT recipients with Roux-BE anastomosis from 2001 to 2020 were divided into ERC and PTBD subgroups. Technical success was defined as the ability to cannulate the bile duct. Clinical success was defined as the ability to perform cholangiography and therapeutic interventions. Results: A total of 36 LT recipients (25 males, age 53.5 ± 13 years) with Roux-BE anastomosis who underwent biliary intervention were identified. The most common indications for a BE anastomosis were primary sclerosing cholangitis (n = 14) and duct size mismatch (n = 10). Among the 29 patients who initially underwent ERC, technical success and clinical success were achieved in 24 (82.8%) and 22 (75.9%) patients, respectively. The initial endoscope used for the ERC was a single balloon enteroscope in 16 patients, a double balloon enteroscope in 7 patients, a pediatric colonoscope in 5 patients, and a conventional reusable duodenoscope in 1 patient. Among the 7 patients who underwent PTBD as the initial therapy, six (85.7%) achieved technical and clinical success (p = 0.57). Conclusions: In LT patients with Roux-BE anastomosis requiring biliary intervention, ERC with a balloon-assisted enteroscope is safe with a success rate comparable to PTBD. Both ERC and PTBD can be considered as first-line therapies for LT recipients with a BE anastomosis.

Germline Cancer Susceptibility Gene Testing in Unselected Patients with Hepatobiliary Cancers: A Multi-Center Prospective Study.

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a >80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers. PREVENTION RELEVANCE: Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.

Clinical Impact of Pathogenic Germline Variants in Pancreatic Cancer: Results From a Multicenter, Prospective, Universal Genetic Testing Study.

INTRODUCTION: To report the prevalence and outcomes of unselected pancreatic cancer (PC) patients with pathogenic/likely pathogenic germline variants (PGVs) detected using a universal testing approach. METHODS: We undertook a prospective, multisite study of germline sequencing using a >80 gene next-generation sequencing platform among 250 patients with PC (not selected for age or family history of cancer) between April 1, 2018, and March 31, 2020. Demographic, tumor characteristics, and clinical outcomes were compared between PGV carriers and noncarriers. RESULTS: Of 250 patients, the mean age was 65 years (SD 8.7), 56% was male, 83.6% was White, and 65.6% had advanced disease (stages III and IV). PGVs were found in 15.2% (N = 38) of patients, and 2 patients had more than 1 PGV. Variants of uncertain significance were found in 44.4% (N = 111). Family history of cancer (odds ratio: 2.36, 95% confidence interval: 1.14-5.19, P = 0.025) was associated with a higher risk of PGV. In a median follow-up of 16.5 months, the median overall survival was 16.8 months in PGV carriers compared with 16.5 months in noncarriers (hazard ratio: 0.51, 95% confidence interval: 0.25-1.01, P = 0.05). Higher levels of carbohydrate antigen 19-9 and advanced disease stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, and RAD51C. DISCUSSION: Universal multigene panel testing in PC reveals that 1 in 6 patients are carriers of PGV. Multigene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling.

Adipose saturation reduces lipotoxic systemic inflammation and explains the obesity paradox.

Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context of dietary patterns of the countries from which the studies originated. Increased severity was noted in leaner populations with a higher proportion of unsaturated fat intake. In mice, greater hydrolysis of unsaturated visceral triglyceride caused worse organ failure during pancreatitis, even when the mice were leaner than those having saturated triglyceride. Saturation interfered with triglyceride's interaction and lipolysis by pancreatic triglyceride lipase, which mediates organ failure. Unsaturation increased fatty acid monomers in vivo and aqueous media, resulting in greater lipotoxic cellular responses and organ failure. Therefore, visceral triglyceride saturation reduces the ensuing lipotoxicity despite higher adiposity, thus explaining the obesity paradox.

Interobserver Agreement for Classifying Post-liver Transplant Biliary Strictures in Donation After Circulatory Death Donors.

INTRODUCTION: Biliary strictures are a common complication of donation after circulatory death (DCD) liver transplantation (LT) and require multiple endoscopic retrograde cholangiopancreatography (ERCP) procedures. Three classification systems, based on cholangiograms, have been proposed for categorizing post-LT biliary strictures. We examined the interobserver agreement for each of the three classifications. METHODS: DCD LT recipients from 2012 through March 2017 undergoing ERCP for biliary strictures were included in the study. Initial cholangiograms delineating the entire biliary tree prior to endoscopic intervention were selected. One representative cholangiogram was selected from each ERCP. Five interventional endoscopists independently viewed each anonymized cholangiogram and classified the post-LT stricture according to each of the three classification systems. The Ling classification proposes four types of post-LT strictures based on their location. The Lee classification proposes four classes based on location and number of intrahepatic strictures. The binary system classifies strictures into anastomotic or non-anastomotic types. The Krippendorff's alpha reliability estimate was used to grade the strength of agreement as "poor," "fair," "moderate," "good," or "excellent" for values between 0-0.20, 0.21-0.4, 0.41-0.6, 0.61-0.08, and 0.81-1, respectively. RESULTS: One hundred DCD LT recipients (age 57.07 ± 8.8 years; 71 males) were initially evaluated. Of these, 49 patients who underwent 206 ERCP procedures for biliary strictures were included in the analysis. One hundred thirty-nine cholangiograms were selected and subsequently classified by five endoscopists. Interobserver agreement for post-LT biliary strictures was 0.354 for Ling classification (fair agreement), 0.405 for Lee classification (fair agreement), and 0.421 for the binary classification (moderate agreement). The binary classification provided the least amount of detail regarding the location and number of biliary strictures. DISCUSSION: The currently available classification systems for assessing post-LT biliary strictures have sub-optimal interobserver agreement. A better-designed classification system is needed for categorizing post-LT biliary strictures.

Fine-needle aspiration of pancreatic cystic lesions: a randomized study with long-term follow-up comparing standard and flexible needles.

BACKGROUND: Pancreatic cystic lesions (PCLs) are increasingly found on cross-sectional imaging, with the majority having a low risk for malignancy. The added value of fine-needle aspiration (FNA) in risk stratification remains unclear. We evaluated the impact of three FNA needles on diagnostic accuracy, clinical management, and the ability to accrue fluid for tumor markers. METHODS: A multicenter prospective trial randomized 250 patients with PCLs ≥ 13 mm 2:1:1 to 19G Flex, 19G, and 22G needles with crossover for repeated FNA procedures. Diagnostic accuracy was established at 2-year follow-up, with the final diagnosis from surgical histopathology or consensus diagnosis by experts based sequentially on clinical presentation, imaging, and aspirate analysis in blinded review. RESULTS: Enrolled patients (36 % symptomatic) had PCLs in the head (44 %), body (28 %), and tail (26 %). Percentage of cyst volume aspirated was 78 % (72 % - 84 %) for 19G Flex, 74 % (64 % - 84 %) for 22G, and 73 % (63 % - 83 %) for 19G (P = 0.84). Successful FNA was significantly higher for 19G Flex (89 % [82 % - 94 %]) and 22G (82 % [70 % - 90 %]) compared with 19G (75 % [63 % - 85 %]) (P = 0.02). Repeated FNA was required more frequently in head/uncinate lesions than in body and tail (P < 0.01). Diagnostic accuracy of the cyst aspirate was 84 % (73 % - 91 %) against histopathology at 2-year follow-up (n = 79), and 77 % (70 % - 83 %) against consensus diagnosis among nonsurgical cases (n = 171). Related serious adverse events occurred in 1.2 % (0.2 % - 3.5 %) of patients. CONCLUSIONS: Our study results demonstrate a statistically significant difference among the three needles in the overall success rate for aspiration, but not in the percentage of cyst volume aspirated. Flexible needles may be particularly valuable in sampling cystic PCLs in the pancreatic head/uncinate process.

Recommendations for the Operation of Endoscopy Centers in the setting of the COVID-19 pandemic - World Endoscopy Organization guidance document.

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) is the etiologic agent causing the disease Corona Virus Disease 19 (COVID-19), resulting in a worldwide pandemic. Non-emergent endoscopy services have been disrupted as incidence and hospitalizations were rising. It is anticipated that the peak incidence may be leveling off in many parts of the world, but there is a concern for resurgence of the virus activity. Thus, it is important for endoscopy units to have plans in place during peak times of the epidemic and when resuming endoscopic services as the pandemic wanes. The global endoscopy community is faced with the challenge of providing care during this time. The WEO-COVID guidance task force has provided this resource document based on the current evidence and consensus opinion. These World Endoscopy Organization (WEO) recommendations are meant to guide endoscopists worldwide, should be interpreted in light of specific clinical conditions and resource availability and may not apply in all situations. This guidance document does not supersede the need to check for all local regulations and legislations.

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation.

Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure.

Molecular Inhibitor of QSOX1 Suppresses Tumor Growth In Vivo.

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion in vitro and in vivo, we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis. High throughput screening using a QSOX1-based enzymatic assay revealed multiple potential QSOX1 inhibitors. One of the inhibitors, known as "SBI-183," suppresses tumor cell growth in a Matrigel-based spheroid assay and inhibits invasion in a modified Boyden chamber, but does not affect viability of nonmalignant cells. Oral administration of SBI-183 inhibits tumor growth in 2 independent human xenograft mouse models of renal cell carcinoma. We conclude that SBI-183 warrants further exploration as a useful tool for understanding QSOX1 biology and as a potential novel anticancer agent in tumors that overexpress QSOX1.

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.

Outcomes of endoscopic therapy in donation after cardiac death liver transplant biliary strictures.

BACKGROUND: Biliary strictures after donation-after-cardiac-death (DCD) liver transplantation (LT) require multiple endoscopic retrograde cholangiopancreatographies (ERCP). The outcomes of endoscopic dilation and maximal stenting are not well-characterized in this high-risk population. METHODS: DCD LT recipients who underwent LT and ERCP from 2012-2018 were selected. Anastomotic and non-anastomotic strictures were treated with balloon dilation and maximal stenting. A successful stent-free trial was defined as absence of biochemical, clinical or imaging evidence of strictures on follow-up exceeding 6 months. Adverse events were defined as unplanned admission or inpatient evaluation within 7 days of ERCP. RESULTS: Forty-nine DCD LT recipients underwent ERCP and 34 patients were diagnosed with strictures (20 anastomotic). Stent-free trial was successful in 27 patients. Adverse events occurred after 20 ERCPs. Patients with anastomotic strictures required fewer stents (1.43 ± 1.37 vs 2.63 ± 1.66; P < 0.001), shorter procedure and fluoroscopy times (34.15 ± 20.9 vs 59.6 ± 30.7 minutes, P < 0.001; 5.99 ± 7.4 vs 14.73 ± 10.74 minutes, P < 0.001), fewer relapses (10% vs 57%, P = 0.003), shorter intervals between initial ERCP and stent-free success (136.9 ± 118.3 vs 399.56 ± 234.7; P = 0.003), and between LT and stent-free success (227.8 ± 171.9 vs 464.1 ± 224.6 days; P = 0.005) compared to non-anastomotic strictures. CONCLUSION: Endoscopic dilation and maximal stenting resolves biliary strictures in DCD LT recipients with sustained success and relatively few adverse events.

Familial pancreatic cancer risk: a population-based study in Utah.

INTRODUCTION: Pancreas adenocarcinoma (PC) has an undefined hereditary component. We quantified the familial risk of PC among relatives of patients diagnosed with PC and stratified it based on anatomic location of PC and age and sex of the proband. METHODS: This is a retrospective, population-based, case-control study of PC diagnosed in Utah between 1980 and 2011. The Utah population database and cancer registry were used to identify index patients with PC. The risk of PC in first-degree relatives (FDRs), second-degree relatives (SDRs), and first cousins (FCs) of probands was compared with randomly selected sex- and age-matched population controls. RESULTS: A total of 4,095 patients and 40,933 controls were identified. The relative risk (RR) of PC was 1.76 (95% CI 1.35-2.29) in FDRs, 1.42 (95% CI 1.18-1.7) in SDRs and 1.08 (95% CI 0.95-1.23) in FCs of probands compared to relatives of PC-free controls. The RR were elevated in FDRs (1.96, 95% CI 1.45-2.65), SDRs (1.54, 95% CI 1.19-1.98) and FCs (1.18, 95% CI 1.0-1.64) of female probands. Among probands diagnosed as < 65 years, RR was 2.12 (95% CI 1.37-3.28) in FDRs, 1.94 (95% CI 1.44-2.62) in SDRs, and 1.28 (95% CI 1.0-1.64) in FCs. Overall, the RR for PC was elevated in FDRs regardless of the anatomic location of PC. DISCUSSION: There is an increased risk of PC in FDR and more distant relatives of patients with PC. Relatives of female patients with PC and patients diagnosed at age < 65 years are at a significantly increased risk of PC.

ASGE principles of endoscopic training.

This White Paper shares guidance on the important principles of training endoscopy teachers, the focus of an American Society for Gastrointestinal Endoscopy (ASGE)/World Endoscopy Organization Program for Endoscopic Teachers and Leaders of Endoscopic Training held at the ASGE Institute for Training and Technology. Key topics included the need for institutional support and continuous skills development, the importance of consensus and consistency in content and approach to teaching, the role of conscious competence and content breakdown into discreet steps in effective teaching, defining roles of supervisors versus instructors to ensure teaching consistency across instructors, identification of learning environment factors and barriers impacting effective teaching, and individualized training that incorporates effective feedback and adapts with learner proficiency. Incorporating simulators into endoscopy teaching, applying good endoscopy teaching principles outside the endoscopy room, key principles of hands-on training, and effective use of simulators and models in achieving specific learning objectives were demonstrated with rotations through hands-on simulator stations as part of the program. A discussion of competency-based assessment was followed by live sessions in which attendees applied endoscopy teaching principles covered in the program. Conclusions highlighted the need for the following: formal training of endoscopy teachers to a level of conscious competence, incorporation of formal training structures into existing training curricula, intentional teaching preparation, feedback to trainees and instructors alike aimed at improving performance, and competency-based trainee assessment. The article is intended to help motivate individuals who play a role in training other endoscopists to develop their teaching abilities, promote discussions about endoscopy training, and engage both endoscopy trainers and trainees in a highly rewarding learning process that is in the best interest of patients.

ASGE EndoVators Summit: simulators and the future of endoscopic training.

Interest in the use of simulation for acquiring, maintaining, and assessing skills in GI endoscopy has grown over the past decade, as evidenced by recent American Society for Gastrointestinal Endoscopy (ASGE) guidelines encouraging the use of endoscopy simulation training and its incorporation into training standards by a key accreditation organization. An EndoVators Summit, partially supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, (NIH) was held at the ASGE Institute for Training and Technology from November 19 to 20, 2017. The summit brought together over 70 thought leaders in simulation research and simulator development and key decision makers from industry. Proceedings opened with a historical review of the role of simulation in medicine and an outline of priority areas related to the emerging role of simulation training within medicine broadly. Subsequent sessions addressed the summit's purposes: to review the current state of endoscopy simulation and the role it could play in endoscopic training, to define the role and value of simulators in the future of endoscopic training and to reach consensus regarding priority areas for simulation-related education and research and simulator development. This white paper provides an overview of the central points raised by presenters, synthesizes the discussions on the key issues under consideration, and outlines actionable items and/or areas of consensus reached by summit participants and society leadership pertinent to each session. The goal was to provide a working roadmap for the developers of simulators, the investigators who strive to define the optimal use of endoscopy-related simulation and assess its impact on educational outcomes and health care quality, and the educators who seek to enhance integration of simulation into training and practice.

Endoscopic Ultrasound-Guided Ablation of Liver Tumors.

"Endoscopic ultrasound (EUS)-guided ablative therapies have advanced significantly and have led to experimental applications in locations that have been difficult to image and/or reach with percutaneous approaches, such as the caudate and left lobe of the liver. EUS-guided treatments of the liver are under development. The literature has shown that many percutaneous ablative techniques are readily adaptable for EUS. In this review, the authors discuss the current developments on EUS-guided ablation of liver tumors, including injection of sclerosants, thermal therapy, and EUS-guided portal injection of chemotherapy."