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Malignant biliary strictures are caused by pancreatobiliary cancer and other metastatic malignancies. Most of them are unresectable at diagnosis with a dismal prognosis. Various new ablation methods have been introduced. Of them, ERCP-guided intraductal radiofrequency ablation (ID-RFA) appears to be the most promising minimally invasive endoscopic treatment by delivering a high-frequency alternating current to the target tissue, leading to coagulative necrosis. Thus far, many studies have provided evidence that ERCP-guided ID-RFA is a safe, feasible, and effective treatment modality for stent patency and overall survival. Compared to other ablation treatments, ERCP-guided ID-RFA has several advantages, including ease of delivery, controlled application of thermal energy, low cost, and fewer systemic side effects with an acceptable safety profile. Therefore, ERCP-guided ID-RFA can be considered an adjunctive treatment for the palliation of unresectable malignant biliary strictures. On the other hand, the decision of local ablation treatment should be individualized by multidisciplinary team support due to the lack of comparative studies.

Pancreatobiliary malignancy is relatively rare; however, it remains one of the most lethal malignancies and has a dismal prognosis. Endoscopic retrograde cholangiopancreatography (ERCP)-guided intraductal radiofrequency ablation (ID-RFA) is a promising, minimally invasive treatment for unresectable malignant biliary strictures by delivering high-frequency alternating current to the target tissue, leading to coagulative necrosis. Recent studies have provided evidence that ERCP-guided ID-RFA is a safe, well-tolerated, and effective adjunctive treatment in terms of stent patency as well as overall survival. Compared with other local treatments, such as photodynamic therapy, ERCP-guided ID-RFA has advantages, including ease of delivery, controlled application of thermal energy, low cost, and fewer systemic side effects, with an acceptable safety profile. ERCP-guided ID-RFA has been proposed as an attractive endobiliary ablative therapy and is regarded to be an adjuvant method for the palliative care of patients with unresectable malignant biliary strictures. However, due to the ongoing lack of comparative studies, the choice of local ablative therapy remains, in each case, an individual decision by the multidisciplinary team.

Purpose Repeating endoscopic retrograde cholangiopancreatography (ERCP) in patients with recurrent common bile duct (CBD) stones is problematic in many ways. Choledochoduodenostomy (CDS) and choledochojejunostomy (CJS) are 2 surgical treatment options for recurrent CBD stones, and each has different advantages and disadvantages. The aim of this study was to compare the 2 surgical options in terms of the recurrence rate of CBD stones after surgical treatment. Methods This retrospective multicenter study included all patients who underwent surgical treatment due to recurrent CBD stones that were not effectively controlled by medical treatment and repeated ERCP between January 2006 and March 2015. We collected data from chart reviews and medical records. A recurrent CBD stone was defined as a stone found 6 months after the complete removal of a CBD stone by ERCP. Patients who underwent surgery for other reasons were excluded. Results A total of 27 patients were enrolled in this study. Six patients underwent CDS, and 21 patients underwent CJS for the rescue treatment of recurrent CBD stones. The median follow-up duration was 290 (180-1,975) days in the CDS group and 1,474 (180-6,560) days in the CJS group (P = 0.065). The postoperative complications were similar and tolerable in both groups (intestinal obstruction; 2 of 27, 7.4%; 1 in each group). CBD stones recurred in 4 patients after CDS (4 of 6, 66.7%), and 3 patients after CJS (3 of 21, 14.3%) (P = 0.010). Conclusion CJS may be a better surgical option than CDS for preventing further stone recurrence in patients with recurrent CBD stones.

Radiofrequency ablation (RFA) has been regarded as an established technique to treat various diseases such as hepatocellular carcinoma, renal cell carcinoma and Barret’s esophagus. Although the application of RFA in the pancreas has been limited due to increased risk of adverse events, endoscopic ultrasound-guided RFA (EUS-RFA) has generated interest as a novel minimally invasive treatment modality which combines real-time visualization with a precise localization of the treatment procedure. For over a decade, the optimization of RFA devices have made EUS-RFA relatively safe, and several studies have supported its feasibility. However, there is insufficient evidence to suggest the appropriate indications and to describe long-term outcomes of EUS-RFA for various pancreatic neoplasms such as pancreatic neuroendocrine tumor, ductal adenocarcinoma, and cystic lesions. Therefore, this review focuses on the technical aspects and clinical applications of EUS-RFA for each pancreatic disease.

A gallbladder (GB) polyp is an elevation of the GB mucosa that protrudes into the GB lumen. GB polyps have an estimated prevalence of 0.3-9.5% and can be divided into neoplastic (true) polyps and nonneoplastic polyps (pseudopolyps). Pseudopolyps are most commonly cholesterol polyps but also include focal adenomyomatosis and inflammatory polyps with no malignant potential. Neoplastic polyps, however, can be benign or malignant. Benign polyps are most commonly adenomas, while malignant polyps are usually adenocarcinoma. Transabdominal ultrasonography is the main radiological modality used for diagnosing and surveilling GB polyps. On the other hand, because it is difficult to diagnose GB polyps before surgery, alternative imaging modalities, such as endoscopic ultrasound, are being further evaluated. The current guidelines recommend cholecystectomy for GB polyps ≥ 10 mm in size as well as suboptimal sized GB polyps (6-9 mm) with other risk factors, including age >50, sessile, and symptoms. The quality of the evidence behind this practice is relatively low. Therefore, this review identifies the current gaps in the available evidence and guidelines and introduces methods that can help make decisions regarding patients who require a cholecystectomy or follow-up.

Backgrounds and aim Multiple insertions of self-expandable metal stents (SEMS) for advanced malignant hilar obstruction (MHO) are now considered to be an effective palliative method for adequate drainage of liver volume. However, the efficacy of endoscopic reintervention in technically and clinically successful bilateral SEMS is limited. This study investigated the endoscopic revision efficacy in patients who underwent bilateral SEMS in MHO. Methods Primary endoscopic revision using plastic or metal stents or an alternative percutaneous approach followed by secondary endoscopic revision was performed in patients who underwent clinically successful deployment of bilateral SEMS. The primary outcome was a technical success. Secondary outcomes were clinical success, adverse events, and patency duration after reintervention. Results A total of 55 patients (83.3%) out of 66 enrolled patients underwent reintervention: primary endoscopic reintervention (n = 47) and secondary endoscopic revision following percutaneous drainage (n = 8). Intended technical success rates of primary and secondary endoscopic reintervention were 93.6% (44/47) and 87.5% (7/8), respectively (P = 0.47). Clinical success rates were 72.3% and 50%, respectively (P = 0.23). Stent malfunction rate after reintervention was 48.9% (23/47) and 37.5% (3/8) (P = 0.70) during follow up, and median cumulative stent patency duration was 119 and 55 days, respectively (log-rank P = 0.68). Stent patent rate after reintervention was not different according to the time interval. In univariate and multivariate analysis for stent patency duration-related factors after reintervention, there were no meaningful factors. Conclusion Primary endoscopic reintervention for bilateral SEMS in MHO was feasible technically and clinically. However, there were no statistically meaningful factors for stent patency duration after reintervention.

A number of different conditions can lead to a bile duct stricture. These strictures are particularly common after biliary operations, including living-donor liver transplantation. Endoscopic and percutaneous methods have high success rates in treating benign biliary strictures. However, these conventional methods are difficult to manage when a guidewire cannot be passed through areas of severe stenosis or complete obstruction. Magnetic compression anastomosis has emerged as an alternative nonsurgical treatment method to avoid the mortality and morbidity risks of reoperation. The feasibility and safety of magnetic compression anastomosis have been reported in several experimental and clinical studies in patients with biliobiliary and bilioenteric strictures. Magnetic compression anastomosis is a minimally traumatic and highly effective procedure, and represents a new paradigm for benign biliary strictures that are difficult to treat with conventional methods.

Biliary drainage is necessary to improve the survival or quality of life of patients with malignant biliary obstruction. In the past, surgery was the primary treatment for biliary drainage, but recently, endoscopic or percutaneous stent implantation has been recognized as the main treatment. Various materials and structures have been devised and developed to increase the patency of the biliary stent. In the development of these stents, drug-eluting biliary stents with an anti-tumoral agent (DES) have emerged to increase the stent patency period by chemically inhibiting tumor growth in the stent through the change of the coating material. The DESs have been proved to be stable through several animal and clinical trials, but their effectiveness has not been demonstrated. We will discuss the development process, problems, and future directions of DES that has been clinically applied.

OBJECTIVES Successful biliary cannulation is a prerequisite and important component of endoscopic retrograde cholangiopancreatography, but conventional cannulation methods (CCMs) have a postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) rate of 14.1% in patients at high risk for PEP. The aim of this study was to evaluate the effectiveness and safety of needle-knife fistulotomy (NKF), compared with a CCM, when used for primary biliary access in patients at high risk for developing PEP. METHODS A total of 207 patients with one or more risk factors for PEP were prospectively enrolled. The patients were randomly allocated to one of 2 groups according to the primary biliary cannulation technique (NKF or CCM). We compared biliary cannulation success rates, cannulation and procedure times, and the incidence of adverse events, including PEP, between the groups. RESULTS The mean number of PEP risk factors was similar between the groups (NKF, 2.2 ± 1.0; CCM, 2.2 ± 0.9). PEP occurred in 8 patients in the CCM group and in no patients in the NKF group (9.2% vs 0%, P < 0.001). The rates of other adverse events did not differ between the groups. The biliary cannulation success rate was high in the NKF group, but relatively low in the CCM group, possibly because of the stringent failure criteria aimed at reducing PEP. However, the mean cannulation and total procedural times were longer in the NKF group than in the CCM group. DISCUSSION NKF is an effective and safe procedure to gain primary biliary access in patients at high risk for developing PEP. ClinicalTrials.gov, NCT02916199.

Simple Summary Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features of GB-NENs with those of adenocarcinomas (ADCs) of the GB. Among 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinoma (NEC), and 1 patient had large-cell NEC. At initial presentation, all patients had advanced stages of cancer, with extensive local extension and/or distant metastasis. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer (AJCC) stage, age, sex, and operation status, there was no difference in the overall survival or PFS between AJCC stage-matched patients with GB-NEC or GB-ADC. In conclusion, GB-NEC is difficult to diagnose early and has a prognosis similar to that of GB-ADC. Abstract Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features, disease progression, management, and prognosis of patients with GB-NENs with those of patients with GB-adenocarcinomas (ADCs). A total of 21 patients with GB-NENs and 206 patients with GB-ADCs, treated at three tertiary medical centers between January 2010 and December 2020, were enrolled. Of the 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinomas (NECs), and 1 patient had large-cell NEC. All patients presented with advanced stages of cancer with extensive local extension and/or distant metastasis and non-specific symptoms. Tumor-node-metastasis stage IIIB and IV (A/B) tumors were found in 6 and 15 (1/14) patients, respectively. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer stage, age, sex, and operation status, 19 pairs of patients were included. Compared with stage-matched patients with GB-ADC, patients with GB-NEC had similar overall survival and PFS. However, as GB-NEC is rarely diagnosed early, further studies investigating methods for the early diagnosis and improvement in the survival of patients with GB-NEC are needed.

BACKGROUND AND AIM Endoscopic ultrasound (EUS) is the most accurate diagnostic modality for polypoid lesions of the gallbladder (GB), but is limited by subjective interpretation. Deep learning-based artificial intelligence (AI) algorithms are under development. We evaluated the diagnostic performance of AI in differentiating polypoid lesions using EUS images. METHODS The diagnostic performance of the EUS-AI system with ResNet50 architecture was evaluated via three processes: training, internal validation, and testing using an AI development cohort of 1039 EUS images (836 GB polyps and 203 gallstones). The diagnostic performance was verified using an external validation cohort of 83 patients and compared with the performance of EUS endoscopists. RESULTS In the AI development cohort, we developed an EUS-AI algorithm and evaluated the diagnostic performance of the EUS-AI including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. For the differential diagnosis of neoplastic and non-neoplastic GB polyps, these values for EUS-AI were 57.9%, 96.5%, 77.8%, 91.6%, and 89.8%, respectively. In the external validation cohort, we compared diagnostic performances between EUS-AI and endoscopists. For the differential diagnosis of neoplastic and non-neoplastic GB polyps, the sensitivity and specificity were 33.3% and 96.1% for EUS-AI; they were 74.2% and 44.9%, respectively, for the endoscopists. Besides, the accuracy of the EUS-AI was between the accuracies of mid-level (66.7%) and expert EUS endoscopists (77.5%). CONCLUSIONS This newly developed EUS-AI system showed favorable performance for the diagnosis of neoplastic GB polyps, with a performance comparable to that of EUS endoscopists.

(1) Background: Pancreatic cancer is a high devastating disease with the lowest survival rate among all common cancers due to difficulties in early diagnosis. The purpose of this study was to identify and characterize the distinct subset of blood cell population elevated in peripheral blood mononuclear cells (PBMC) of pancreatic cancer to evaluate the potential markers for diagnosis of pancreatic cancer, (2) Methods: We analyzed differential gene expression in PBMC from normal individuals and pancreatic cancer patients utilizing transcriptome analysis. Flow cytometry analysis was applied to identify the discrete subset of interleukin-7 receptor (IL-7R) expressing cells in these cells. The expression of IL-7R during tumorigenesis was determined in syngeneic mouse model of pancreatic cancer in vivo, (3) Results: PBMC from pancreatic cancer patients expressed elevated IL-7R mRNA compared to healthy control individuals. IL-7R expressing cells rapidly appeared from the early stages of the onset of tumor formation in syngeneic pancreatic cancer mouse model in vivo. The discrete subset of IL-7R positive cells mainly consist of naïve T, central memory T, and effector memory T cells, (4) Conclusions: Taken together, our present findings suggest that pancreatic cancer patients expressed higher level of IL-7R expression in PBMC that rapidly emerged from the onset of early pancreatic tumor formation in vivo than normal individuals. Thus, it can be used as a novel biological marker for early events of pancreatic cancer development.

Liver transplantation (LT) is a viable treatment for fatal end-stage liver disease. Anastomotic bile leakage and anastomotic stricture are considered as major post-LT complications. Stent insertion by endoscopic retrograde cholangiopancreatography and percutaneous transhepatic biliary drainage is the conventional treatment for post-LT anastomotic biliary stricture. In cases in which these conventional modalities fail, magnet compression anastomosis (MCA) can be applied. We reported a case in which post-LT bile leakage and anastomotic stricture were treated by MCA and using a fully covered self-expandable metal stent (FCSEMS). The FCSEMS was removed 3 months later, at which time the stricture and the leakage had resolved.

Background/Aims Metallic stents designed to relieve malignant biliary obstruction are susceptible to occlusive tumor ingrowth or overgrowth. In a previous report, we described metallic stents covered with paclitaxel-incorporated membrane (MSCPM-I, II) to prevent occlusion from tumor ingrowth via antitumor effect. This new generation paclitaxel-eluting biliary stent is further endowed with sodium caprate (MSCPM-III) for enhanced drug delivery. The purpose of this study is to examine the safety of its drug delivery system in the porcine biliary tract. Methods MSCPM-III (10% [wt/vol] paclitaxel) and covered metal stents (CMSs) were endoscopically inserted in porcine bile ducts in vivo. Histologic biliary changes, levels of paclitaxel released, and various serum analytes (albumin, alkaline phosphate, aspartate transaminase, alanine transaminase, total protein, total bilirubin, and direct bilirubin) were assessed. Results Based on the intensity of reactive inflammation and fibrosis, changes in porcine biliary epithelium secondary to implanted MSCPM-III were deemed acceptable (i.e., safe). Histologic features in the MSCPM-III and CMS groups did not differ significantly. In a related serum analysis, paclitaxel release from MSCPM-III stents was below the limit of detection for 28 days. Biochemical analyses were also similar for the two groups, and no evidence of hepatic or renal toxicity was found in animals receiving MSCPM-III stents. Conclusions In a prototypic porcine trial, this newly devised metal biliary stent incorporating both paclitaxel and sodium caprate appears to be safe in the porcine bile duct.

Backgrounds The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. Methods Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. Results The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups. Conclusions Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans.

Endoscopic ultrasound (EUS) is the most accurate diagnostic modality for polypoid lesions of the gallbladder (GB), but is limited by subjective interpretation. We evaluated the diagnostic performance of deep learning-based artificial intelligence (AI) in differentiating polypoid lesions using EUS images. The diagnostic performance of the EUS-AI system with ResNet50 architecture was evaluated via three processes: training, internal validation, and testing. The diagnostic performance was also verified using an external validation cohort and compared with the performance of EUS endoscopists. In the AI development cohort, the diagnostic performance of EUS-AI including sensitivity, specificity, positive predictive value, negative predictive value and accuracy. For the differential diagnosis of neoplastic and non-neoplastic GB polyps, these values for EUS-AI were 77.8%, 91.6%, 57.9%, 96.5%, and 89.8%, respectively. In the external validation cohort, the differential diagnosis of neoplastic and non-neoplastic GB polyps, these values were 60.3%, 77.4%, 36.2%, 90.2%, and 74.4%, respectively, for EUS-AI; they were 74.2%, 44.9%, 75.4%, 46.2%, and 65.3%, respectively, for the endoscopists. The accuracy of the EUS-AI was between the accuracies of mid-level (66.7%) and expert EUS endoscopists (77.5%). This EUS-AI system showed favorable performance for the diagnosis of neoplastic GB polyps, with a performance comparable to that of EUS endoscopists.

Background/aims Endoscopic retrograde cholangiopancreatography (ERCP) is used as a curative method for choledocholithiasis, but little is known about ERCP for patients with end-stage renal disease (ESRD) on hemodialysis (HD). The aim of the current study was to evaluate the efficacy and safety of ERCP for patients with ESRD on HD and to identify the risk factors of ERCP-related bleeding. Materials and methods The medical records of 61 ESRD patients with choledocholithiasis who underwent ERCP were retrospectively investigated with respect to successful bile duct stone removal and procedure-related adverse events such as pancreatitis, bleeding, and cholangitis. Results For the study subjects, the overall stone removal success rate was 96.7%, and the overall ERCP-related adverse event rate was 21.3% (pancreatitis, 4.9%; bleeding, 13.1%; cholangitis, 6.6%). Endoscopic sphincterotomy (EST) was found to be associated with hemorrhage (p=0.02), and the occurrence of hemorrhage in patients who underwent EST with or without endoscopic papillary balloon dilation (EPBD) was significantly higher than that in patients who underwent EPBD alone (Odds ratio 1.27, 95% confidence interval 1.075-1.493, p=0.02). Conclusion ERCP for ESRD patients was found to be feasible and safe. However, EST was significantly related to hemorrhagic events. EPBD reduced the risk of hemorrhage and was as effective as EST in terms of stone removal.

Objectives Non-surgical methods have high success rates for treating benign biliary strictures (BBSs), but treatment of proximal strictures is difficult. Recent studies have reported that fully covered self-expandable metal stents (FCSEMSs) are useful for treating refractory BBSs. We investigated the efficacy of a short and removable FCSEMS with an anti-migration design for treatment of proximal BBSs. Methods Fully covered self-expandable metal stents were inserted endoscopically in patients with BBSs after living donor liver transplantation (LDLT). Each FCSEMS was initially maintained for 3 months and subsequently exchanged every 3 months until the stricture resolved. Adverse events and stricture recurrence after FCSEMS removal were assessed during follow-up. Results A total of 63 patients with a median age of 57 years were enrolled in this study; 50 were male. The most common underlying disease was hepatocellular carcinoma and the previous operation was LDLT. The mean duration from surgery to diagnosis of stricture was 8.5 months, and the mean stent indwelling time was 4.2 months. The technical success and stricture resolution rate were 100%. The recurrence rate was 23.8% and the adverse event rate was 12.7%. All stents were removable, and asymptomatic stent migration was observed in four patients (6.4%). Conclusions The newly designed FCSEMS is effective in the treatment of proximal BBSs after LDLT.

Many genetic and environmental factors are involved in the pathogenesis of the formation of gallbladder (GB) stones. GB stone is divided into cholesterol gallstone, black pigment stone, and brown pigment stone. Each stone has different pathogenesis. Treatment of GB stone is divided into surgical and medical treatment according to the presence of biliary colic. Laparoscopic cholecystectomy is standard in symptomatic GB stone patients with definite biliary colic. However, medical treatment may be helpful in patients without surgical indication. The treatment of gallstone in pregnant patients is the same as general gallstone treatment, but it is essential to extend the length of pregnancy and control pain as much as possible. Recently, there have been studies that attempted prophylactic medical treatment due to the increase in the frequency of cholesterol gallstone due to rapid weight loss. This chapter demonstrates the pathogenesis and treatment of GB stones in various conditions.

This study compared the efficacy of a percutaneous transhepatic cholangioscopy (PTCS) catheter and a fully covered self-expandable metal stent (FCSEMS) for maintaining biliary tract patency after magnetic compression anastomosis (MCA).This study included patients with completely obstructed benign biliary stricture (BBS), which was resolved by MCA and subsequent insertion of a PTCS catheter or FCSEMS. We compared the restenosis-free time after removal of the PTCS catheter or FCSEMS, and the rate of complications.A total of 49 patients were analyzed. The mean ages of the patients in these groups were 50.1 and 49.6 years, respectively. The predisposing conditions causing complete BBS were liver transplantation (n = 38), abdominal surgery (n = 10) and trauma (n = 1). The mean indwelling durations were 176 and 128 days in the PTCS catheter and FCSEMS groups, respectively. The mean follow-up duration after removal of the PTCS catheter and FCSEMS were 2259 and 680.5 days, respectively. Three patients in the PTCS group and three patients in the FCSEMS group experienced stricture relapse. The mean duration between recurrence and stent removal were 924 and 265 days, respectively, and the numbers of stricture-free days did not differ significantly between the two groups. The adverse event rate did not differ significantly between the PTCS and FCSEMS groups (50% vs. 24.2%, respectively).FCSEMSs have an efficacy and safety similar to those of PTCS catheters for maintaining biliary tract patency after MCA, but are more convenient for patients.

Biliary drainage for malignant hilar strictures includes endoscopic and percutaneous approaches. In general, endoscopic drainage is the first approach for Bismuth types I and II, while percutaneous drainage is recommended for Bismuth types III and IV. However, a multidisciplinary approach involving an endoscopist and radiologist is needed for a far-advanced malignant hilar stricture, and endoscopic and percutaneous drainage can be used in a complementary manner.

Endoscopic and percutaneous methods have high success rates for the treatment of benign biliary stricture. However, patients in whom a guidewire cannot be passed through a refractory stricture or a complete obstruction are difficult to treat using conventional methods. Magnetic compression anastomosis (MCA) has emerged as a non-surgical alternative method to avoid the risks of mortality and morbidity associated with re-operation. The feasibility and safety of MCA have been verified experimentally and clinically in patients with biliobiliary and bilioenteric anastomoses. However, no pre-MCA assessment modality predictive of the outcomes is yet available, nor is a universally effective method of magnet delivery, which hampers identification of patients for whom MCA is available. Various experimental and human studies aiming to overcome these limitations are underway. Such works will improve our understanding of MCA, which has been trialed in various medical fields. Upon further development, MCA may be expected to be minimally traumatic and highly effective and may become a new-paradigm method for the treatment of benign strictures that are difficult to resolve using conventional methods.

Preoperative evaluation of biliary strictures is problematic because of the risk of failing to detect a malignant tumor and the potential sequelae of unnecessary surgery in patients with strictures of benign origin. A stricture whose cause cannot be determined despite endoscopy, hematology, and imaging, including histological examination, is defined as an indeterminate biliary stricture. Imaging modalities—such as magnetic resonance imaging, magnetic resonance cholangiopancreatography, and multidetector computed tomography—play an important role in assessing the location, extent, length, and mass of the stricture. Early diagnosis of malignant strictures enables timely surgical intervention and administration of an appropriate chemotherapy regimen. However, no definitive diagnosis of malignant or benign strictures has been established. This chapter focuses on the causes of biliary strictures, and the blood tests, imaging studies, and endoscopic techniques that facilitate their diagnosis.

Various etiologies can result in bile duct stricture. In particular, it is a major complication after a biliary operation, such as living-donor liver transplantation. However, despite the development of endoscopic and percutaneous therapies, no treatment protocol has yet been established for complete bile duct obstruction or severe bile duct stricture. Several studies have succeeded in recanalization of biliary strictures using magnets. This new treatment technique has been proven to be effective and safe for complete bile duct obstructions or severe bile duct strictures that cannot be treated using conventional methods. In this chapter, we discuss the development of magnetic compression anastomosis and detail the treatment methods and results.

Biliary-tract complications, such as biliary strictures, anastomotic leaks, choledocholithiasis, and biliary casts, can occur after liver transplantation (LT). Of these complications, biliary strictures are regarded as an Achilles’ heel. Recently, treatment of anastomotic biliary stricture (ABS) has transitioned from conventional surgical revision to a nonsurgical treatment modality. Endoscopic serial balloon dilatation and/or multiple plastic stent replacements are highly effective and are now regarded as the first-line treatments. However, if the patient has undergone anastomosis by means of a hepaticojejunostomy, percutaneous treatment is performed. With recent technological advances and the rendezvous method, the clinical success rates of endoscopic and percutaneous ABS treatments have increased, but these methods fail in some patients who have total obstruction of anastomotic stricture. For these patients, magnetic compression anastomosis (MCA) has been suggested as an alternative method. Animal and human studies have demonstrated the safety and efficacy of MCA, and advancements in these nonsurgical methods have increased the clinical success rate of ABS. This review focuses on ABSs that develop after LT and discusses the clinical results of various nonsurgical methods and future directions.

Common bile duct (CBD) stone is a biliary disease with an increasing incidence in Korea. Many advances have been made in diagnosis and treatment according to the development of imaging equipment and various devices to diagnose and treat CBD stones. The Korean Society for Pancreatobiliary Association has developed clinical practice guidelines for the diagnosis and treatment of CBD stones to assist clinicians in their management. The guidelines were divided into three parts: evaluation of CBD stones, endoscopic management of CBD stones, and endoscopic management of difficult and recurrent CBD stones. The purpose of this review is to summarize and present the diagnosis and treatment guidelines for CBD stones established in Korea.

Background and Aims Endobiliary brushings are routinely used in the diagnosis, treatment, and prognostication of biliary strictures. However, standard Papanicolaou (Pap) staining has a low sensitivity in this setting, and the accuracy of brush cytology has not been established for indeterminate strictures. We therefore evaluated the diagnostic merit of methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence (IF) staining in such cytologic specimens. Methods During ERCP, endobiliary brushings were obtained from patients with extrahepatic biliary strictures prospectively enrolled at 6 tertiary hospitals. Using liquid-based cytologic preparations of these samples, we performed Pap and MARS1 IF staining. Results In total, 240 patients were eligible; of these, we compared the Pap and MARS1 IF staining results of 218 (malignant, 157; benign, 61). By conventional Pap staining, the diagnoses were distributed as follows: malignant, 55; suspicious of malignancy, 60; atypical, 45; negative for malignancy, 58. MARS1 IF staining was strongly positive in malignant biliary stricture but not so in specimens negative for malignancy. The diagnostic parameters (sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of the MARS1 IF (93.6%, 96.7%, 98.7%, 85.5%, and 94.5%, respectively) and conventional Pap (73.2%, 100%, 100%, 59.2%, and 80.7%, respectively) staining methods differed significantly (P Conclusions The high sensitivity and accuracy of MARS1 IF staining enabled the detection of malignancy in patients with biliary strictures. Further prospective studies are needed to validate our findings. (Clinical trial registration number: NCT03708445 .)

Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study Background: There are several things needed to be resolved for successful efficacy when NK cell therapy is applied for solid tumor; improvement of NK cell invasion into tumor, activation and production of a large number of NK cells, etc. Basically, in human, NK cell number is relatively small compared to other immune cells such as T cell and the number becomes severely low when NK cell is obtained from cancer patients. For these reasons, allogeneic NK cell has been used for clinical studies against various cancer types. Recently, we also have finished a phase1 study of allogeneic NK cell therapy for cholangiocarcinoma, enrolling 9 patients at inoperable and no chemotherapy favorable stage due to side effects. Four of nine patients (44%) showed SD (stable disease) after six NK cell injections and no severe AE (adverse event) was found. In this following phase 2a study, to bring out immuno-synergetic effect of NK cell therapy against the inoperably advanced bile duct cancer, we have designed a combinatorial protocol with using Pembrolizumab. Methods: Enrollment of 40 bile duct cancer patients has been finished for a combinatorial study of allogeneic NK cell therapy with Pembrolizumab at two different sites in Korea (ClinicalTrials gov, NCT03937895). Patients were eligible for the enrollment when they were inoperable and no chemotherapy favorable stage due to side effects, and also when they had PD-L1-positive score. For treatment, the most favorable method for highly activated allogeneic NK cell production has been determined from our previous study, resulting that 3x106 NK cells per kg are injected for each dose along with Pembrolizumab injection. Pembrolizumab (200mg) was given every 3 weeks for up to 9 times and NK cell injection was given for up to 18 times during the maximum injection period of Pembrolizumab. Results: Six patients (pts) were first enrolled for the pilot combinatorial study, dosing 6 times of NK cells and 3 times of Pembrolizumab. The result showed no severe AE from the injections. Among the five pts finished the injections, 2 pts showed SD (Stable Disease) and continued the treatment, being enrolled into the Phase 2a in which 34 more pts were enrolled. Among the 20 pts finished 6 NK cell and 3 Pembrolizumab injections (1st RECIST), 65% of pts showed SD. When 12 NK cell and 6 Pembrolizumab injections finished (2nd RECIST), pts had 40% and 20% of SD and PR (Partial remission). Of the 3 pts at 3rd RECIST (18 NK cell and 9 Pembrolizumab), 1 and 2 pts showed SD and PR, respectively. Finding pts experienced AE, a total of 6 AEs has been reported: no treatment-related AE, one grade 3 (Encephalopathy), and five grade 1-2 with common AE. In a recent safety and efficacy study of pembrolizumab alone (10mg/kg, every 2 weeks for up to 2 years) with 28 pts of advanced bile duct cancer showing PD-L1 expression, 17% pts showed PR, 17% pts and 52% had SD and PD (progressive disease), respectively. Although our study is still ongoing, continuing the combinatorial treatment gives rise to PR, suggesting that NK cell therapy with Pembrolizumab shows an immuno-synergetic effect for the cancer. Biomarker experiments with the injected NK cells supports our finding and we will discuss this at presentation. Citation Format: Yong Yoon Chung, Seung Woo Park, Jung-Min Im, Da-Kyung Yoo, Hyo-Cheon Cheon, Jae-Eun Kim, Kyeong-Pill Lim, Eun-Hee Yang, Hye-Jin choi, Hyo-Sun Chung, Seo-Yeon Kim, Ju-Yong Lee, In-Hye Jung, Seung Min Bang, Moon Jae Chung, Sung Ill Jang, Jae Hee Cho, Hee Seung Lee, Jung Youp Park, Jung Hyun Jo. Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT171.

Background/Aims A drug-eluting stent for unresectable malignant biliary obstruction was developed to increase stent patency by preventing tumor ingrowth. The safety and efficacy of a new generation of metallic stents covered with a paclitaxel-incorporated membrane using a Pluronic® mixture (MSCPM-II) were compared prospectively with those of covered metal stents (CMSs) in patients with malignant biliary obstructions. Methods This study was initially designed as a prospective randomized trial but was closed early because of a high incidence of early occlusion. Therefore, the data were analyzed using the intent-to-treat method. A total of 72 patients with unresectable distal malignant biliary obstructions were prospectively enrolled. Results The two groups did not differ significantly in basic characteristics and mean follow-up period (MSCPM-II 194 days vs CMS 277 days, p=0.063). Stent occlusion occurred in 14 patients (35%) who received MSCPM-II and in seven patients (21.9%) who received CMSs. Stent patency and survival time did not significantly differ between the two groups (p=0.355 and p=0.570). The complications were mild and resolved by conservative management in both groups. Conclusions There were no significant differences in stent patency or patient survival in MSCPM-II and CMS patients with malignant biliary obstructions.

Background and Aim Palliative endoscopic or percutaneous biliary drainage is used for unresectable advanced hilar cancer (HC). The best option for drainage in Bismuth type III or IV HC has not been established. The aims of this study are to identify factors predictive of endoscopic stenting failure and evaluate the effectiveness of rescue percutaneous stenting in patients with advanced HC. Methods Data from 110 patients with inoperable advanced HC were retrospectively reviewed. All received bilateral self-expandable metallic stents. Patients were divided into three groups: I, successful initial endoscopic stenting; II, unsuccessful initial endoscopic stenting, followed by percutaneous stenting; and III, initial percutaneous stenting. We analyzed clinical results and radiologic tumor characteristics. Results Baseline characteristics and clinical outcomes of all groups were similar, except the hospital stay was longer in group III than group I. Technical success rate was higher in groups II and III (100%) than in group I (72.4%). The functional success rate, stent patency time, patient survival time, and complication rate were similar between groups. Endoscopic stenting failed because of guide-wire passage failure (n = 12) or stent passage failure (n = 7). The only factor significantly associated with endoscopic failure was a smaller left intrahepatic duct–common bile duct angle. Conclusions As clinical outcomes were generally similar between approaches, percutaneous stenting is recommended for patients with Bismuth type III or IV advanced HC. Acute left intrahepatic duct–common bile duct angulation predicts endoscopic stenting failure. If endoscopic stenting fails, immediate conversion to the percutaneous approach is a necessary and effective rescue method.

Background: Recently, there has been an increase in clinical success rates using nonsurgical methods to resolve anastomotic biliary strictures (ABSs) that develop after liver transplantation (LT). However, some strictures are particularly refractory and cannot be completely resolved by an endoscopic or percutaneous procedure. Consequently, the aim of this study was to examine the feasibility and efficacy of using a newly designed fully covered self-expandable metal stent (FCSEMS) to resolve refractory ABS. Methods: A total of 35 patients with an ABS that developed after LT, but could not be resolved by an endoscopic or percutaneous procedure, were included in this study. FCSEMSs were positioned endoscopically and removed after 2–3 months. After stent removal, the patients were followed to assess complications, including re-stenosis. Results: The mean period from LT to stricture was 13.7 months, and the mean duration of the stricture was 31.8 months. The type and mean number of procedures previously attempted were endoscopic retrograde cholangiopancreatography (ERCP) (9.1 ± 5.1) in 19 patients and percutaneous transhepatic biliary drainage (9.2 ± 4.8) in 16 patients. All patients had successful FCSEMS insertions and removals; the mean stent indwelling time was 3.2 months. The mean follow-up period was 18.7 months (range: 6.4–37.8 months). Stricture recurrence was observed in 6 of 29 patients (recurrence rate: 20.7%). The anastomotic stricture resolved with the FCSEMS insertion in 29 of 35 patients (clinical success rate: 82.9%). Conclusions: The newly designed FCSEMS is a potentially feasible and effective treatment for anastomotic strictures that develop after LT but are not amenable to treatment by conventional procedures.

Background and aim Although endoscopic papillary large balloon dilation (EPLBD) has been widely used to facilitate the removal of difficult common bile duct stones, however, the outcomes have not yet been investigated in terms of the diameter of the balloon used. We aimed to compare the clinical outcomes between EPLBD using smaller (12-15 mm, S-EPLBD) and larger balloons (> 15 mm, L-EPLBD). Methods Six hundred seventy-two patients who underwent EPLBD with or without endoscopic sphincterotomy for common bile duct stone removal were enrolled from May 2004 to August 2014 at four tertiary referral centers in Korea. The outcomes, including the initial success rate, the success rate without endoscopic mechanical lithotripsy, the overall success rate, and adverse events between S-EPLBD and L-EPLBD groups, were retrospectively compared. Results The initial success rate, the success rate without mechanical lithotripsy, the overall success rate, and the overall adverse events were not significantly different between the two groups. The rate of severe-to-fatal adverse events was higher in the L-EPBLD group than in the S-EPLBD group (1.6% vs 0.0%, 0.020). One case of severe bleeding and two cases of fatal perforation occurred only in the L-EPLBD group. In the multivariate analysis, the use of a > 15-mm balloon was the only significant risk factor for severe-to-fatal adverse events (>0.005, 23.8 [adjusted odds ratio], 2.6-214.4 [95% confidence interval]). Conclusions L-EPLBD is significantly related to severe-to-fatal adverse events compared with S-EPLBD for common bile duct stone removal.

Identifying malignant biliary strictures using endobiliary brushing cytology specimens is important for treatment decision-making and prognosis prediction. The sensitivity of brushing cytology specimens based on Papanicolaou (Pap) staining is low, which hampers accurate diagnosis of indeterminate strictures. Here, we assessed the diagnostic value of immunohistochemical (IHC) and immunofluorescence (IF) staining for methionyl-tRNA synthetase 1 (MARS1).Endobiliary brushing cytology specimens were obtained during ERCP from 80 patients with an extrahepatic biliary stricture. Pap and MARS1 IF staining were performed on liquid-based cytology slides derived from these specimens. Sections of bile duct adenocarcinoma and normal bile duct tissue were obtained from 45 patients who underwent surgery for malignant biliary stricture, and MARS1 levels were evaluated by IHC staining.MARS1 IF staining was applied to brushing cytology specimens, and the results showed strong signals in malignant biliary structures but not in the negative for malignancy specimens. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 70.4%, 96.2%, 97.4%, 56.8%, and 78.8%, respectively, for conventional Pap staining and 98.1%, 96.1%, 98.1%, 96.2%, and 97.5%, respectively, for MARS1 IF (P .0001). When IHC staining was used, MARS1 was detected in 45 bile duct adenocarcinoma sections but not in 15 normal bile duct sections. Moreover, MARS1 mRNA and protein levels were significantly higher in bile duct adenocarcinoma sections according to polymerase chain reaction and Western blot, respectively.The high sensitivity and accuracy of MARS1 IF staining enabled detection of malignancy in patients with indeterminate biliary stricture. Further prospective studies are needed to validate our findings. (Clinical trial registration number: KCT 0003285.).

Background: Successful biliary cannulation is a prerequisite and important component of endoscopic retrograde cholangiopancreatography (ERCP), but conventional cannulation methods (CCMs) have a post-ERCP pancreatitis (PEP) rate of 14.1% in patients at high risk for PEP. The aims of this study were to evaluate the effectiveness and safety of needle-knife fistulotomy (NKF), compared with a CCM, when used for primary biliary access in patients at high risk for developing PEP. Methods: A total of 207 patients with one or more risk factors for PEP were prospectively enrolled. The patients were randomly allocated to one of two groups according to the primary biliary cannulation technique (NKF or CCM). We compared biliary cannulation success rates, cannulation and procedure times, and the incidence of adverse events, including PEP, between the groups. Findings: The mean number of PEP risk factors was similar between the groups (NKF, 2.2 ± 1.0; CCM, 2.2 ± 0.9). PEP occurred in eight patients in the CCM group and in no patients in the NKF group (9.2% vs. 0%, p < 0.001). The rates of other complications did not differ between the groups. The biliary cannulation success rate was higher in the NKF group than in the CCM group (97.9% vs. 89.7%, p = 0.005). The mean cannulation time and total procedure time were longer in the NKF group than in the CCM group. Interpretation: NKF is an effective and safe procedure to gain primary biliary access in patients at high risk for developing PEP. Trial registration number: ClinicalTrials.gov, NCT02916199. Funding Statement: The authors state: "None." Declaration of Interests: The authors state: "None." Ethics Approval Statement: The study was approved by the institutional review boards of each institution (Approval number: 3-2017-0092).

Biliary dyspepsia presents as biliary colic in the absence of explanatory structural abnormalities. Causes include gallbladder dyskinesia, sphincter of Oddi dysfunction, biliary tract sensitivity, microscopic sludges, and duodenal hypersensitivity. However, no consensus treatment guideline exists for biliary dyspepsia. We investigated the effects of medical treatments on biliary dyspepsia. We retrospectively reviewed the electronic medical records of 414 patients who had biliary pain and underwent cholescintigraphy from 2008 to 2018. We enrolled patients who received litholytic agents and underwent follow-up scans after medical treatment. We divided the patients into the GD group (biliary dyspepsia with reduced gallbladder ejection fraction [GBEF]) and the NGD group (biliary dyspepsia with normal GBEF). We compared pre- and post-treatment GBEF and symptoms. Among 57 patients enrolled, 40 (70.2%) patients had significant GBEF improvement post-treatment, ranging from 34.4 ± 22.6% to 53.8 ± 26.8% (P

Background Endoscopic papillary large balloon dilation (EPLBD) without prior endoscopic sphincterotomy (EST) produces excellent outcomes for the treatment of large common bile duct (CBD) stones. However, it remains unclear how the outcomes of EPLBD alone compare with those of EPLBD with EST. In this study, we assessed the safety and therapeutic outcomes of EPLBD with vs. without EST for the removal of large bile duct stones. Methods This prospective, multicenter study was conducted on 200 patients with bile duct stones of ≥ 10 mm in diameter. Patients were randomly assigned to an EPLBD alone group (n = 100) or an EPLBD with EST group (n = 100). These two groups were compared with respect to overall procedure-related adverse events, overall stone removal success rate, number of endoscopic sessions required for complete stone removal, need for mechanical lithotripsy, and total procedure time. Results The incidence of adverse events was not significantly different between the groups (EPLBD alone vs. EPLBD with EST: overall adverse events 6 % vs. 4 %, P = 0.75; pancreatitis 1 % vs. 3 %, P = 0.62). Overall success (P = 0.35), initial success (P = 0.28), and the need for mechanical lithotripsy (P = 0.39) were also similar between groups. Median total procedure time tended to be greater in the EPLBD alone group (20.5 minutes) than in the EPLBD with EST group (18 minutes; P = 0.08). Conclusion The therapeutic outcomes and adverse events of EPLBD alone for the removal of large bile duct stones were comparable to those of EPLBD with EST.

Biliary stents are used to facilitate the drainage of bile into the digestive tract, most often in the palliation of malignant biliary obstruction, but also in benign conditions such as biliary fistulas or benign biliary strictures. Temporary multiple double-pigtail biliary stenting is a safe method for treating large, difficult common bile duct (CBD) stones in elderly patients; it helps reduce stone size and facilitates successful duct clearance. We report a new technique for retrieving two tangled plastic biliary stents using rendezvous endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic biliary drainage.

Biliary drainage in malignant biliary obstruction improves patient survival and quality of life. Although bypass surgery was historically the main method of treating malignant biliary obstruction, stent insertion using endoscopy or interventional radiology is currently recognized as the first-line of treatment. Biliary stents have undergone various modifications in terms of material and structure, with the aim of increasing stent patency. One such modification is the antitumor-agent-eluting stent, which is intended to suppress tumor ingrowth through chemical changes in the membrane. Another modified stent is the antireflux stent, which physically prevents the reflux of food by using an antireflux valve. Although the safety of these modified stents has been demonstrated in both animal and human studies, their efficacy, compared with conventional stents, remains unknown. Although the development of these functional stents is challenging, their potential is promising. Effort is necessary to increase stent patency, which requires much modification and development, to prolong patient survival.

Ampullary neuroendocrine tumor is rare but requires total resection for treatment. Traditionally, pancreatic duodenal resection has been recommended for treatment of ampullary neuroendocrine tumor. Because of the morbidity and mortality associated with surgical resection, endoscopic papillectomy is increasingly used in selected cases with low grade, no metastasis, and no invasion of the pancreatic or bile duct. We present a case of an ampullary neuroendocrine tumor which was successfully and completely resected via endoscopic papillectomy. Endoscopic papillectomy can be a viable alternative for the resection of neuroendocrine tumor at the major duodenal papilla in cases with high surgical risks. Korean J Pancreatobiliary 2014;19(4):204-209

Endoscopic and percutaneous procedures have shown high success rates when used to treat benign biliary stricture. However, cases in which a guidewire cannot be passed through a refractory stricture or a complete obstruction are difficult to treat using conventional methods. Magnetic compression anastomosis (MCA) has emerged as a non-surgical alternative avoiding operational mortality and morbidity. The feasibility and safety of MCA have been experimentally and clinically verified in cases of biliobiliary and bilioenteric anastomosis. However, no pre-MCA assessment modality capable of predicting outcomes is as yet available, and no universally effective magnet delivery method has as yet been established, rendering it difficult to identify patients for whom MCA is appropriate. Various experimental studies seeking to overcome these limitations are underway. Such work will improve our in-depth understanding of MCA, which has been trialed in various fields. Upon further development, MCA may become a ground-breaking option for treatment of benign strictures that are difficult to resolve using conventional methods, and MCA may be expected to be minimally traumatic and highly effective. The aim of the present study was to discuss the current status of MCA and the direction of MCA development by reviewing clinical and experimental MCA data.

Metastatic carcinoma that causes appendicitis is extremely rare. To our knowledge, metastatic cholangiocarcinoma in the appendix has been reported in only 1 case in the English literature. We report herein the case of an 87-year-old woman who presented with abdominal pain and jaundice. Advanced cholangiocellular carcinoma and a proximal appendiceal mass with appendicitis were detected on contrast-enhanced computed tomography and positron emission tomography/computed tomography. After elective laparoscopic appendectomy and wedge resection of the cecum, pathologic results revealed metastatic adenocarcinoma from extrahepatic cholangiocellular carcinoma in the appendix.