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Background and study aims The aim of the current study was to review the outcomes of a large-scale international registry on endoscopic ultrasound-guided gallbladder drainage (EGBD) that encompasses different stent systems in patients who are at high-risk for cholecystectomy. Patients and methods This was a retrospective international multicenter registry on EGBD created by 13 institutions around the world. Consecutive patients who received EGBD for several indications were included. Outcomes include technical and clinical success, unplanned procedural events (UPE), adverse events (AEs), mortality, recurrent cholecystitis and learning curve of the procedure. Results Between June 2011 and November 2017, 379 patients were recruited to the study. Technical and clinical success were achieved in 95.3 % and 90.8 % of the patients, respectively. The 30-day AE rate was 15.3 % and 30-day mortality was 9.2 %. UPEs were significantly more common in patients with EGBD performed for conversion of cholecystostomy and symptomatic gallstones (P Conclusion EGBD was associated with high success rates in this large-scale study. EGBD performed for indications other than acute cholecystitis was associated with higher UPEs. The number of cases required to gain competency with the technique by experienced interventional endosonographers was 25 procedures.

Background/Aims Treatment for cholangitis without common bile duct (CBD) stones has not been established in patients with gallstones. We investigated the usefulness of endoscopic biliary drainage (EBD) without endoscopic sphincterotomy (EST) in patients diagnosed with gallstones and cholangitis without CBD stones by endoscopic retrograde cholangiopancreatography (ERCP) and intraductal ultrasonography (IDUS). Methods EBD using 5F plastic stents without EST was performed prospectively in patients with gallstones and cholangitis if CBD stones were not diagnosed by ERCP and IDUS. After ERCP, all patients underwent laparoscopic cholecystectomy. The primary outcomes were clinical and technical success. The secondary outcomes were recurrence rate of biliary events and procedure-related adverse events. Results Among 187 patients with gallstones and cholangitis, 27 patients without CBD stones according to ERCP and IDUS received EBD using 5F plastic stents without EST. The stents were maintained in all patients until laparoscopic cholecystectomy, and recurrence of cholangitis was not observed. After cholecystectomy, the stents were removed spontaneously in 12 patients and endoscopically in 15 patients. Recurrence of CBD stones was not detected during the follow-up period (median, 421 days). Conclusions EBD using 5F plastic stents without EST may be safe and effective for the management of cholangitis accompanied by gallstones in patients without CBD stones according to ERCP and IDUS.

Introduction Chemo-responsiveness in pancreatic cancer is known to be dependent on fibrosis and vascularity. The purpose of this study was to assess vascular enhancement in advanced pancreatic adenocarcinoma with or without liver metastasis in computed tomography (CT) and to analyze the correlation between enhancement patterns and chemo-responsiveness. Methods Patients were assigned to either a responder group (partial response or stable disease) or a non-responder group (progressive disease) according to chemo-responsiveness assessed by CT before and after gemcitabine-based chemotherapy. Hounsefield unit (HU) was measured in pancreatic mass and the largest metastatic liver mass using region of interest (ROI). HU differences (ΔHU) between arterial and pre-contrast phase were calculated. Results Of the 101 study subjects, 78(77.2%) were assigned to the pancreas responder group {mean ΔHU (±SD), 36.7(±21.6)} and 23(22.8%) to the pancreas non-responder group {mean ΔHU (±SD), 20.6(±9.9)} (p = 0.001 for ΔHUs). Of the 46 study subjects with liver metastasis, 25(54.3%) were assigned to the liver metastasis responder group {mean ΔHU (±SD), 36.9(±21.0} and 21(45.7%) to the liver metastasis non-responder group {mean ΔHU (±SD), 17.1 (±24.0)}, (p = 0.005 for ΔHUs). Conclusion CT determined mass vascular enhancement patterns may predict chemoresponse in advanced pancreatic cancer.

Background and Aim It can be difficult to identify the cause of an enlarged ampulla of Vater (AOV). This study evaluated the accuracy of wire-guided intraduodenal ultrasonography (US) for the differential diagnosis of an enlarged AOV during endoscopic retrograde cholangiopancreatography (ERCP). Patients and Methods Thirty-four patients with enlarged AOVs of unknown cause identified on imaging studies or endoscopic observations underwent wire-guided intraduodenal US using a catheter probe. Results The final diagnoses were malignant or premalignant tumors in 10 patients (29.4%), stones in nine patients (26.5%), inflammation in 14 patients (41.2%), and cyst in one patient (2.9%). The overall diagnostic accuracy of intraduodenal US for enlarged AOVs was 91.2%. The diagnostic accuracies of stones, inflammation, and AOV tumors were 100.0%, 94.1%, and 91.1%, respectively. Conclusions Wire-guided intraduodenal US using a catheter probe is readily applicable during ERCP and may be useful in the differential diagnosis of enlarged ampullary lesions.

Currently available peroral cholangioscopy (POC) is a duodenoscopy-assisted procedure that does not involve directly inserting an endoscope into the biliary tree. A prototype multibending (MB) ultra-slim endoscope has been developed as a dedicated cholangioscope to overcome the technical difficulties of direct POC. In this study, we evaluated the efficacy of the new MB ultra-slim endoscope compared with a conventional ultra-slim endoscope for free-hand insertion of an endoscope into the bile duct for direct POC without the assistance of accessories.Ninety-two patients with biliary disease requiring diagnostic and/or therapeutic direct POC were assigned randomly to groups examined using an MB ultra-slim endoscope (MB group, n=46) versus a conventional ultra-slim endoscope (conventional group, n=46). The primary outcome was the technical success of free-hand insertion of the endoscope during direct POC, defined as successful insertion of the endoscope through the ampulla of Vater and advancement of the endoscope up to the bifurcation or to the obstructed segment of the biliary tree without any accessories within 15 minutes.Free-hand biliary insertion of the endoscope for direct POC was technically successful in 41 patients (89.1%) in the MB group, which was significantly higher than the rate (14 patients, 30.4%) in the conventional group (P .001). The procedure time (mean ± standard deviation) of direct POC using free-hand biliary insertion of the endoscope was significantly shorter in the MB group than in the conventional group (3.2 ± 1.8 vs 6.0 ± 3.0 minutes, P = .004). Adverse events were observed in 3 patients (6.5%) in the MB group and 2 patients (4.3%) in the conventional group (P = .500), all of whom were treated conservatively. The technical success rates of the diagnostic or therapeutic intervention were not significantly different between the 2 groups in patients undergoing successful direct POC.Free-hand biliary insertion of the MB ultra-slim endoscope showed a high technical success rate without severe adverse events and effectively decreased procedure time compared with a conventional ultra-slim endoscope. Direct POC using the MB ultra-slim endoscope can be used for novel diagnostic and therapeutic procedures of the biliary tree without the assistance of another endoscope or accessory. (Clinical trial registration number: NCT02189421.).

A reproducible in vivo swine model of bile duct dilation (BDD) was recently established and reported for the preclinical testing of newly developed biliary devices or endoscopic techniques. The aim of this study is to develop more advanced large animal model which is possible to direct examination of the biliary tree. Six mini pigs were prepared for the study. The BDD models were first made by closure of the ampulla of Vater in all swine. Then endoscopic papillary balloon dilation (EPBD) was performed in the animals. The feasibility of single-operator peroralcholangioscopy without assistance of accessories was evaluated using an ultra-slim upper endoscope in the animals. EPBD could be implemented using a dilation balloon catheter (10 ~ 13.5 mm) in all BDD models (6/6, 100%). The success rate of free-hand direct insertion of an ultra-slim endoscope into the common bile duct (CBD) was 100% (6/6), and access to the common hepatic duct with examination was possible using the direct peroralcholangioscopy in five animals (5/6, 83.3%). None of the animals died. In the cholangioscopic examination, a bile duct polyp and a benign biliary stricture occurred naturally, respectively, in two of six swine. An in vivo swine model of biliary dilatation-based direct peroralcholangioscopy was established. This novel animal model may be useful for the preclinical research of new materials or devices because direct visualization of the biliary tree is feasible. This article is protected by copyright. All rights reserved.

Background and Aim: A major concern about endoscopic snare papillectomy (ESP) is the risk of procedure-related pancreatitis. To maintain pancreatic duct access for stent placement after ESP, wire-guided ESP (WP) was introduced. The aim of the study was to compare post-procedure pancreatitis rates, the success rate of pancreatic stent insertion, and complete resection rates between WP and conventional ESP (CP) procedures. Methods: This was a multi-center, prospective, randomized pilot study. Forty-five patients with ampullary tumors were randomly assigned to a WP group (n = 22) or a CP group (n = 23). In the WP group, a guidewire was placed in the pancreatic duct prior to ESP. A 5-Fr pancreatic stent was passed over the guidewire and placed across the pancreatic duct orifice. Results: Complete resection was achieved in 20 patients (91%) in the WP group and 18 patients (78%) in the CP group (P = 0.414). A pancreatic stent was placed successfully in all patients in the WP group but in only 15 patients (65%) in the CP group (P = 0.004). Post-papillectomy pancreatitis occurred in four (18%) patients in the WP and three (13%) patients in the CP groups (P = 0.960). In the CP group, three of eight (37.5%) patients without stents developed pancreatitis compared with zero of 15 patients with stents (P = 0.032). Conclusions: The WP method is a useful technique used to insert a pancreatic stent after ESP, compared with CP. However, there was no significant difference in the post-procedure pancreatitis or complete resection rates between the two methods.

Background and aims Catheter-based endobiliary radiofrequency ablation (RFA) is an endoscopic local treatment for patients with malignant biliary stricture (MBS). However, excessive heating of the bile duct by the current RFA system can induce serious complications. Recently, a new RFA system with automatic temperature control was developed. In the present study, we examined the safety of the new RFA system in patients undergoing endobiliary RFA for extrahepatic MBS. Methods This prospective, multicenter study enrolled patients with unresectable or inoperable extrahepatic (> 2 cm from the hilum) MBS. Endobiliary RFA was performed using a newly developed RFA catheter (ELRA™, STARmed, Goyang, Korea) at a setting of 7 or 10 W for 120 s and with a target temperature of 80°C. A self-expandable metallic stent was inserted after endobiliary RFA. The rate of procedure-related adverse events was assessed. Results The 30 patients were enrolled in this study. Cholangiocarcinoma was diagnosed in 19 patients, pancreatic cancer was found in 9, and gallbladder cancers were recorded in 2. The mean stricture length was 22.1 ± 6.6 mm. Post-procedural adverse events occurred in three patients (10.0%; 2 mild pancreatitis and 1 cholangitis) without hemobilia and bile duct perforation. The pancreatitis and cholangitis resolved with conservative treatment. The cumulative duration of stent patency and survival were 236 and 383 days, respectively. Conclusions Automatic temperature-controlled endobiliary RFA using a newly developed catheter was safely applied in patents with extrahepatic MBS. Further prospective studies are needed to confirm the efficacy of endobiliary RFA for MBS.

Recent advances in cholangiopancreatoscopy technology permit image-enhanced endoscopy (IEE) for pancreatobiliary diseases. There are limitations in endoscopy performance and in the study of the clinical role of IEE in bile duct or pancreatic duct diseases. However, currently available IEEs during cholangiopancreatoscopy including traditional dye-aided chromoendoscopy, autofluorescence imaging, narrow-band imaging, and i-Scan have been evaluated and reported previously. Although the clinical role of IEE in pancreatobiliary diseases should be verified in future studies, IEE is a useful promising tool in the evaluation of bile duct or pancreatic duct mucosal lesions.

ratio of cholangiocarcinoma (intrahepatic or extrahepatic), gall bladder cancer, and ampulla of Vater cancer was 41 (63.1%):18 (27.7%):6 (9.25%). Half of the patients (33 patients, 50.8%) were treated with gemcitabine-based and 28 patients (43.1%) with 5-fluo- rouracil-based therapy. The response rate was 3.0% and disease control rate was 21.5% in intention-to-treat analysis. Median overall survival (OS) was 7.2 months (95% confidence interval (CI), 3.9 to 10.5 months) and median progression free survival (PFS) was 3.7 months (95% CI, 2.5 to 4.9 months). In multivariate analysis, patients with good performance status (PS) (P = 0.001) and chemo-sensi- tive tumor to 2nd line chemotherapy (P = 0.000) had longer PFS as compared to the others. In addition, patients with good PS (P = 0.003), chemo-sensitive tumor to 1st line (P = 0.046), and 2nd line chemotherapy (P = 0.004) were good prognostic factors for OS. Conclusion: The effect of 2nd line chemotherapy in advanced BTC was modest and maybe beneficial in select patients.

Newly introduced direct peroral cholangioscopy and the development of video choledochoscopes have enabled more defined observation of bile duct mucosal lesions with clearer images. Narrow-band imaging (NBI) is a unique endoscopic imaging technology that provides enhanced endoscopic images of surface mucosal structures and its superficial microvessels. Advanced cholangioscopy and NBI are expected to be useful for precise evaluation and correct diagnosis of biliary tract diseases. However, the diagnostic value of advanced bile duct imaging with cholangioscopy requires further evaluation.

Direct peroral cholangioscopy (POC) using an ultra-slim upper endoscope is one modality of POC for intraductal endoscopic evaluation and treatment of the bile duct. Choledochoduodenostomy (CDS) is one modality of biliary bypass surgery that provides a new route to the bile duct. We carried out direct POC using an ultra-slim upper endoscope without the use of accessories in 10 patients (four sump syndromes, three bile duct strictures and three intrahepatic duct stones) previously undergoing surgical CDS. Direct POC was successful in all patients. The use of an intraductal balloon catheter was required in one patient for advancement of the endoscope into the bile duct. Distal bile ducts with sump syndromes were cleared using baskets and water irrigation under direct POC. Cholangiocarcinoma was diagnosed in one patient with hilar bile duct stricture after cholangioscopic evaluation and a targeting forceps biopsy under direct POC. Intrahepatic duct stones were successfully extracted after intraductal fragmentation under direct POC. Oozing bleeding occurred during intraductal lithotripsy but stopped spontaneously. Direct POC using an ultra-slim upper endoscope without the assistance of accessories can easily be carried out in patients undergoing CDS.

Background and Aim Identifying a bile duct (BD) stone in patients with acute biliary pancreatitis (ABP) is important for the management and prevention of recurrent attack of pancreatitis. However, small BD stones may not be detected on endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to prospectively evaluate the usefulness of intraductal ultrasonography (IDUS) in patients suspected to have ABP but with no evidence of choledocholithiasis on ERCP. Methods A total 92 patients suspected with ABP without evidence of BD stones on imaging studies including ERCP were enrolled. Wire-guided IDUS was performed during ERCP in all patients. Stones or sludge detected by IDUS were confirmed after endoscopic sphincterotomy (EST) and extraction. If IDUS finding was negative, then we swept the BD with a balloon catheter and/or basket without EST. After endoscopic management, comparison between IDUS and endoscopic finding was carried out to determine the diagnostic accuracy of IDUS. Results Among the 92 patients, IDUS revealed BD stones in 33 (35.9%). All 33 patients' stones were confirmed by endoscopic visualization after EST and BD exploration. During the mean follow up of 24 months, recurrent pancreatitis did not occur in 90 of 92 patients (97.9%) with ABP after endoscopic treatment according to the IDUS findings. Conclusions IDUS improves diagnostic accuracy for the detection of clinically occult BD stones in patients suspicious ABP. IDUS-guided endoscopic management for patients with ABP can avoid unnecessary EST and help prevent recurrent pancreatitis.

Background/Aims Endoscopic papillary balloon dilation (EPBD) has been advocated as an alternative therapy to endoscopic sphincterotomy for the treatment of common bile duct (CBD) stones. However, there is no established consensus on the optimal balloon dilation duration (BDD). We prospectively evaluated the efficacy and post-endoscopic retrograde cholangiopancreatography (ERCP) complications between the 20- and 60-second EPBD groups. Methods A total of 228 patients with small CBD stones (≤12 mm) were randomly assigned to undergo EPBD with a 20- or 60-second duration at six institutions. We evaluated baseline patient characteristics, endoscopic data, clinical outcomes, and procedure-related complications. In addition, we analyzed risk factors for postprocedural pancreatitis. Results CBD stones were removed successfully in 107 of 109 patients (98.1%) in the 20-second group and in 112 of 119 patients (94.1%) in the 60-second group (p=0.146). Post-ERCP pancreatitis developed in seven patients (6.4%) in the 20-second group and nine patients (7.5%) in the 60-second group (p=0.408). In multivariate analysis, contrast dye injection into the pancreatic duct is a significant risk factor for post-EPBD pancreatitis. Conclusions Based on the data showing that there were no significant differences in safety and efficacy between the two BDD groups, 20 seconds of BDD may be adequate for treatment of small CBD stones with EPBD.

Background and study aims I-SCAN is a computed virtual chromoendoscopy (CVC) system designed to enhance surface and vascular patterns. In this study, we evaluated the usefulness of direct peroral cholangioscopy (POC) using I-SCAN compared with a conventional white-light image (WLI) to diagnose bile duct lesions. Patients and methods Patients with mucosal lesions in the bile duct detected during direct POC were enrolled prospectively. The quality of endoscopic visualization and the visual diagnosis were assessed using I-SCAN and WLI modes, respectively, during direct POC. Results A total of 20 patients (9 malignant and 11 benign lesions) underwent I-SCAN to evaluate lesions in the bile duct using direct POC. The quality of endoscopic visualization using direct POC with I-SCAN was significantly higher than that of WLI for surface structure (P = 0.04), surface microvascular architecture (P = 0.01), and margins (P = 0.02). Overall diagnostic accuracy of the visual diagnosis was not different between I-SCAN and WLI (90.0 % vs. 75.0 %; P = 0.20). Conclusion Direct POC using CVC by I-SCAN seems to be helpful for evaluating mucosal lesions of the bile duct, without the interference from bile.Clinical trial registration: UMIN000021009

Detection of tumors of the ampulla of Vater, including ampullary adenoma, has been improved by routine screening endoscopic procedures and imaging modalities. Endoscopic resection by endoscopic papillectomy is rapidly replacing classic surgical resection and is a less invasive procedure. Endoscopic resection can have a role not only in the final histopathologic diagnosis but also as a definite therapeutic option. However, the indications for endoscopic resection are not fully established, and endoscopic procedures are not standardized. Significant complications, including severe pancreatitis, intractable bleeding and duodenal perforation, are rare but can occur, especially in less experienced hands. Severe pancreatitis is the most feared complication, but it can be prevented by pancreatic duct stent insertion in most cases. However, in some cases, pancreatic stenting can be challenging after resection. Incomplete resections are sometimes performed to avoid complications. Endoscopic surveillance is also important for identifying and managing remnant adenomatous tissue or recurrent lesions. Further technical development is needed to expand the indications for this procedure, minimize complications and ensure a high success rate.

Background/Aims It is sometimes difficult to incise the distal papillary roof (PR) completely in patients with choledocholiths and choledochoduodenal fistula (CDF). The Iso-Tome® (MTW-Endoskopie W. Haag KG), which is helpful in preventing electrical leakage, has good orientation capabilities and can be easily placed at the orifice of the CDF or ampulla of Vater (AV). We aimed to evaluate the efficacy of endoscopic sphincterotomy (ES) with the Iso-Tome® for cutting the distal PR. Methods Between May 2003 and July 2012, 35 patients were analyzed retrospectively. The distal PR was cut downward and/or upward using the Iso-tome® until the pink intrapapillary mucosa was fully exposed. Downward incisions were performed from the opening of the CDF to the orifice of the AV; upward incisions were performed in reverse. Results Spontaneous or artificial CDF occurred in four and 31 patients, respectively. The technical and therapeutic success rates were 94.3% (33/35) and 94.3% (33/35), respectively. There was no case of electrical damage to the pink intrapapillary mucosa. Adverse events occurred in 2.9% (1/35; 1, mild bleeding) of patients. Conclusions The new technique of ES with the Iso-tome® is feasible and useful for effectively incising the distal PR in patients with CDF and choledocholiths.

New technological developments in endoscopic retrograde cholangiopancreatography (ERCP) for diagnosis and treatment have been slow to progress. However, several informative study results were presented during the 2014 Digestive Disease Week (DDW; 3 - 6 May; Chicago, Illinois, USA) in specific ERCP areas, such as prevention of post-ERCP pancreatitis using nonsteroidal anti-inflammatory drugs and pancreatic duct stenting. Novel and interesting study results regarding preoperative stent selection for periampullary tumors, metal stents for hilar stricture or for prevention of duodenal reflux, and intraductal biliary tumor ablation using photodynamic therapy or radiofrequency ablation were discussed. Study results presented at the meeting regarding single-operator cholangioscopy using the SpyGlass system or direct peroral cholangioscopy have indicated the possibility of future development. Results using peroral pancreatoscopy and confocal laser endomicroscopy for biliary lesions, including strictures, were also presented.

Background A lumen-apposing stent can be used effectively under endosonographic guidance. Objective To evaluate a newly designed, fully covered self-expandable metal stent with folding anchoring flanges for lumen apposition assembled on a conventional delivery system. Design Retrospective case series and animal study. Setting Tertiary care academic medical centers. Subjects Six pigs for animal study and 7 patients, 3 of whom underwent endoscopic drainage for acute cholecystitis (AC) and 4 for pancreatic fluid collection (PFC). Intervention Stent deployment under EUS guidance after puncturing, passage of an endoscope through the stent into the gallbladder (GB), or PFC with conventional endoscopic procedures. Main Outcome Measurements Technical and clinical success, adverse events, and removability. Results In the animal study, the stent was successfully inserted and deployed in the GB via a transgastric approach under EUS guidance without adverse events in all 6 pigs. Contrast injection demonstrated the absence of leakage. Cholecystoscopy with enhanced endoscopy was performed successfully in all animals after stent placement. All stents were intact and were removed successfully at 4 weeks. GB firmly adhered to the stomach with an intact cholecystogastric tract on necropsy and histopathology. The stents were successfully deployed without adverse effects in 7 patients. AC or PFC was resolved after stent placement in all patients. Endoscopic procedures were possible through the stent. Stent migration was not observed. The stent was successfully removed from the 4 patients with PFC after complete resolution. Limitations Small sample size, retrospective study. Conclusions Transenteric drainage and endoscopic intervention by using a novel fully covered self-expandable metal stent for lumen apposition under EUS guidance is feasible for the management of AC and PFC. Further study is warranted.

Endoscopic papillary large balloon dilation (EPLBD) after an endoscopic sphincterotomy (EST) is an option for endoscopic removal of large common bile duct (CBD) stones. However, risks or fear of severe adverse events remain. Our aim was to compare the safety and efficacy of delayed EPLBD after EST with concurrent EST and EPLBD in patients with acute cholangitis by large CBD stones. A total of sixty-eight patients with acute cholangitis from large CBD stones were enrolled in this prospective observational study. Thirty-five patients underwent concurrent EST and EPLBD at the same session (group A). Thirty-three patients underwent only EST at the first session, and EPLBD with stone removal was performed during a second session (group B). The complete stone removal rate and adverse events rate were analyzed. Both groups resulted in similar outcomes in terms of overall successful stone removal (100 % in both groups) and the use of additional lithotripsy (22.9 % in group A and 24.2 % in group B). Six patients (17.1 %) in group A had procedural-related adverse events including one patient with death by perforation, one with significant bleeding, and four with pancreatitis, including one moderate grade. However, there was no procedure-related complication in group B (p

Endoscopic biliary sphincterotomy (EBS) results in permanent loss of sphincter function and its long-term complications are unknown. Endoscopic papillary balloon dilation (EPBD) is an alternative procedure that preserves sphincter function, although it is associated with a higher risk of pancreatitis than is EBS. The aim of this study was to evaluate the safety and outcomes of EPBD with limited indications for removal of common bile duct (CBD) stones combined with gallstones in patients younger than 40 years. Young (age

Objectives The mechanism of pancreatitis development following endoscopic papillary balloon dilation (EPBD) remains unknown. Antegrade dilation with percutaneous transhepatic papillary balloon dilation (PTPBD) allows the removal of bile duct stones or fragments during percutaneous choledochoscopic lithotomy, with less mechanical trauma to the papilla than with EPBD-mediated stone removal. Methods A total of 56 patients with bile duct stones underwent antegrade dilation with PTPBD from March 2006 to February 2011. A total of 208 patients with common bile duct stones underwent retrograde dilation with EPBD during the same period. The conditions of papillary balloon dilation were identical in both groups. The frequencies of pancreatitis and hyperamylasemia were compared in both groups. Results Pancreatitis occurred in 14 (6.7%) of 208 patients in the EPBD group (mild, nine; moderate, four; severe, one). There was no case of pancreatitis among 56 patients in the PTPBD group (P

Background Endoscopic management of recurrent bile duct stones after endoscopic sphincterotomy (EST) is effective and safe. However, repeat EST for extension of a previous EST for recurrent bile duct stones may involve substantial risk. The aim of the present study was to evaluate the safety and efficacy of endoscopic papillary large balloon dilation (EPLBD) without repeat EST for recurrent difficult bile duct stones after previous EST. Patients and Methods From January 2006 to October 2010, a total of 52 patients were enrolled; all had undergone EPLBD (balloon diameter: 12–20 mm) to remove recurrent difficult bile duct stones after previous EST. In all patients, stone removal had failed with conventional methods using a basket and/or balloon. The size of the balloon for EPLBD was selected to fit the diameter of the common bile duct or the largest stone. Results The median interval between initial EST and stone recurrence was 2.2 years (range 1–10). Median diameters of thelargest stone and balloon were 20.1 mm (range 12–40) and 14.7 mm (range 12–20), respectively. Complete stone removal was achieved in all patients (100%). The median number of endoscopic retrograde cholangiopancreatography sessions needed for complete stone removal was 1.6 (range 1–3). Additional lithotripsy was required in 16 patients (30.7%). No procedure-related complications were documented, with the exception of four cases of asymptomatic hyperamylasemia. The recurrence rate of CBD stones after bile duct clearance was 17.3% (9/52) during the follow-up period (mean 27.0 ± 14.1 months). Conclusions EPLBD without repeat EST is effective and relatively safe for the extraction of recurrent difficult bile duct stones after previous EST.

Background and Aim Endoscopic biliary drainage (BD) is an effective palliative treatment for acute cholangitis. Transnasal endoscopy (TNE) using an ultraslim endoscope can be less stressful and has limited hemodynamic effects compared with endoscopic retrograde cholangiography using a conventional duodenoscope. Here, we evaluate the clinical usefulness of direct BD by TNE in critically ill patients with acute cholangitis who had undergone endoscopic sphincterotomy (ES) previously. Methods Twenty-three patients with severe-to-moderate acute cholangitis who had undergone ES previously were enrolled prospectively. BD was achieved by TNE, using an ultraslim upper endoscope with a 5-Fr nasobiliary drainage catheter and/or a plastic stent. The technical and clinical success, as well as the safety, of the procedure were investigated. Results A total of 23 patients were enrolled, including 17 with bile duct stones. The severity of the cholangitis was severe in nine (39.1%) and moderate in 14 patients (60.9%). The technical success rate was 95.7% (22/23). Nasobiliary drainage was performed in 15 patients, a plastic stent was placed in three, and both treatments were used in four patients. In three patients, direct BD by TNE was achieved in the intensive care unit without fluoroscopy. Direct cholangioscopy for distal common bile duct was performed in nine patients (40.9%), and three patients underwent immediate stone extraction under endoscopic visualization. Clinical improvement was achieved in 20/23 (87.0%) of patients. No significant procedure-related complications occurred. Conclusion Direct BD by TNE may be useful in critically ill patients with severe-to-moderate acute cholangitis who had undergone ES previously.

Background Post-ERCP pancreatitis (PEP) is the most common and serious complication of ERCP. Difficult biliary cannulation can be a procedure-related risk factor for PEP. Recent studies reported that a prophylactic pancreatic stent (PS) can reduce the frequency and severity of PEP. Objective To evaluate the efficacy and usefulness of a temporary 3F PS to prevent PEP in patients with difficult biliary cannulations. Design A multicenter, prospective, randomized study. Setting Two tertiary-care academic medical centers. Patients In total, 101 patients with a difficult biliary cannulation were randomly divided into the 3F PS placement group (PS group, n=50) or the nonstent (NS) group (NS group, n=51). Interventions Endoscopic placement of a 3F unflanged PS. Main Outcome Measurements The incidence and severity of PEP in the 2 groups, spontaneous dislodgment of stents, and procedure-related complications. Results The technical success rate of 3F PS placement was 96% (48/50). The lengths of the stents were 4 cm (n = 21), 6 cm (n = 15), and 8 cm (n = 12). Spontaneous stent dislodgment within 7 days occurred in 94% of patients (45/48). The mean duration until spontaneous dislodgment was 3.5 days. The incidence rate of PEP was 12% (6/50: mild, 5; moderate, 1) in the PS group and 29.4% (15/51: mild, 12; moderate, 2; severe, 1) in the NS group. Severe pancreatitis occurred in only 1 patient in the NS group. In a multivariate analysis, prophylactic placement of PS was the only prophylactic factor for PEP (odds ratio, 0.126; 95% CI, 0.025-0.632, P = .012). Limitations No comparative results for stent size and diameter and a low-risk cohort group. Conclusions Prophylactic temporary 3F PS placement in patients with a difficult biliary cannulation during ERCP seems to be a safe and effective method for reducing PEP and results in a high rate of spontaneous passage of stents without complications.

BACKGROUND/AIMS Endoscopic sphincterotomy may be limited in Billroth II gastrectomy because of difficulty in orientating the duodenoscope and sphincterotome as a result of altered anatomy. This study was planned to investigate the efficacy and safety of endoscopic transpapillary large balloon dilation (EPBD) without preceding sphincterotomy for removal of large CBD stones in Billroth II gastrectomy. METHODS Between March 2010 and February 2011, one-step EPBD under cap-fitted forward-viewing endoscopy was performed in patients who had undergone Billroth II gastrectomy at two tertiary referral centers. Main outcome measurements were successful duct clearance and EPBD-related complications. RESULTS Successful access to major duodenal papilla was performed in 13 patients, but successful selective CBD cannulation was achieved in 12 patients (92.3%). Median maximum transverse stone size was 11.5 mm (10 to 14 mm). The mean number of stones was 2 (1-5). The median CBD diameter was 15 mm (12 to 19 mm). Mean procedure time from successful biliary access to complete stone removal was 17.8 min. Complete duct clearance was achieved in all patients. Four patients (33.3%) needed one more session of ERCP for removal of remnant stones. Asymptomatic hyperamylasemia in two patients and minor bleeding in another occurred. CONCLUSIONS Without preceding sphincterotomy, one-step EPBD (≥10 mm) under cap-fitted forward-viewing endoscopy may be safe and effective for the removal of large stones (≥10 mm) with CBD dilatation in Billroth II gastrectomy.

Peroral cholangioscopy (POC) provides direct visualization of the bile duct and facilitates diagnostic or therapeutic intervention. The currently available single-operator POC systems are “Mother-baby” scope system, SpyGlass direct visualization system, and direct POC using a regular ultra-slim upper endoscope. Direct POC using an ultra-slim upper endoscope having a larger 2-mm working channel can provide a valuable and economic solution for evaluating bile-duct lesions. Main diagnostic procedures under direct POC are visual characterization and optically guided target biopsy for the indeterminate bile duct lesion. Image-enhanced endoscopy such as narrow-band imaging has shown promise for more detailed evaluation of mucosal abnormality and can be performed under direct POC. Intracorporeal lithotripsy such as electrohydraulic lithotripsy or laser lithotripsy is a main therapeutic intervention of direct POC for patients with bile duct stones that are resistant to conventional endoscopic stone-removal procedures. Besides, tumor ablation therapy, such as photodynamic therapy and argon plasma coagulation may be also performed using direct POC. Further developments of the endoscope and specialized accessories or devices are expected to facilitate diagnostic and therapeutic role of this cholangioscopic procedure.

With the increasing use of pancreatic duct (PD) stents after endoscopic papillectomy (EP), complications such as proximal migration of the stent have become increasingly prevalent. A PD stent that migrates within a nondilated PD may be difficult to remove endoscopically. We performed endoscopic retrieval of proximally migrated PD stents after EP in 5 patients. Endoscopic retrieval was performed immediately after EP in one patient, the next day in 3 patients, and 2 weeks later in one patient. Wire-guided endoscopic retrieval was attempted in 4 patients, and the migrated stents were removed successfully in these 4 patients. No significant procedure-related complications occurred, other than mild pancreatitis in a single patient. In one patient, endoscopic retrieval performed immediately after EP failed when using the conventional method, and the migrated stent was removed using a minisnare without a guidewire the next day; this patient developed severe pancreatitis. Wire-guided endoscopic snare retrieval seems to be a safe and effective method for removing proximally migrated PD stents after EP.

The cause of pancreatitis is unknown in as many as 30% of cases of recurrent acute pancreatitis, even after ERCP.To investigate the role of intraductal US (IDUS) for managing idiopathic recurrent pancreatitis (IRP).Prospective study.Tertiary referral hospital.Thirty-one patients with suspicious IRP with negative findings on ERCP.IDUS during ERCP.IDUS findings showing any possible cause of pancreatitis.IDUS revealed small bile duct stones (≤3 mm) in 5 patients (16.1%) and sludge in 3 patients (9.7%). The detection rate for a bile duct stone and sludge was significantly higher in patients with a dilated CBD than a nondilated CBD on ERCP (71.4 vs 12.5%; P.05). Recurrent pancreatitis did not develop in 7 of 8 patients with biliary stones or sludge after an endoscopic sphincterotomy (EST). Two patients (6.5%) demonstrated a small polypoid lesion on the distal end of the pancreatic duct. One patient underwent surgery for intra-ampullary cancer, and another one underwent EST without another attack of pancreatitis. Three patients (9.7%) showed evidence of chronic pancreatitis with small pancreatic stones and/or calcifications on IDUS.Small number of patients. IDUS results were not compared with those of conventional EUS. There was no reference standard for chronic pancreatitis as diagnosed by IDUS.IDUS identified a possible cause of idiopathic recurrent pancreatitis in 42% of patients with negative findings on ERCP. The IDUS-guided approach combined with ERCP and EST may be useful for decreasing recurring attacks of pancreatitis.

Endoscopic sphincterotomy (EST) for endoscopic removal of bile duct stones is difficult in patients with a Billroth II gastrectomy. We retrospectively evaluated the usefulness of an endoscopic scissors papillotome by performing EST with subsequent endoscopic papillary balloon dilation (EPBD) for the removal of bile duct stones in 12 patients with a previous Billroth II gastrectomy. EST using the scissors papillotome was performed successfully in all patients. Endoscopic stone removal was successful in 11 patients, and lithotripsy was required in three patients. No significant procedure-related complications occurred. Preceding sphincterotomy using a scissors papillotome followed by papillary balloon dilation seems to be feasible and effective for the endoscopic removal of bile duct stones in patients with a Billroth II gastrectomy.

Background Peroral cholangioscopy (POC) provides direct visualization of the bile duct and facilitates diagnostic procedures and therapeutic intervention. The currently available mother−baby endoscope system is not widely used because of several limitations. Although direct cholangioscopy with an ultraslim upper endoscope with a guidewire has been reported, success is not always guaranteed. Objective To evaluate the feasibility and success rate of direct POC using an ultraslim endoscope with an intraductal balloon to maintain access compared with the guidewire method. Design Prospective, observational clinical feasibility study. Setting Tertiary referral center. Main Outcome Measurements We compared overall procedure success rates and complications. A successful procedure was defined as one in which the endoscope was advanced into the bifurcation or stenotic segment of the biliary system. Patients and Methods Twenty-nine patients with biliary disease underwent direct POC. All patients had previously undergone an endoscopic sphincterotomy or papillary balloon dilation with a large balloon. Eleven patients underwent wire-guided direct POC. Intraductal balloon-guided direct POC was performed in 21 patients. The balloon catheter was used to maintain access while an ultraslim upper endoscope was advanced over the balloon catheter, through the ampulla of Vater, and directly into the bile duct. Results Wire-guided direct POC was successful in 5 of 11 (45.5%) patients. In contrast, the success rate of intraductal balloon-guided direct POC was 95.2% (20/21 patients, P Limitations A small number of patients and no comparison with conventional cholangioscopy. Conclusions Intraductal balloon-guided direct POC with an ultraslim upper endoscope allows the direct visual examination and therapeutic intervention of bile ducts in patients with biliary disease. Further development of the endoscopic apparatus and specialized accessories are expected to facilitate this procedure.

Background Selective cannulation in patients with a Billroth II gastrectomy is still challenging. Objective To evaluate the usefulness of a multibending, forward-viewing endoscope (M-scope) for selective cannulation during diagnostic or therapeutic ERCP in patients with a Billroth II gastrectomy. Design Case series. Setting Tertiary center. Patients Fourteen patients having biliary disease with a Billroth II gastrectomy in whom selective cannulation failed when using a conventional forward-viewing endoscope. Interventions In all cases, we attempted selective biliary cannulation for ERCP with a single-bending, forward-viewing endoscope for 10 minutes. After failure with the conventional endoscope, we retried selective cannulation with the M-scope for 10 minutes. After cannulation, the diagnostic or therapeutic endoscopic procedures were performed. Main Outcome Measurements We assessed the success rate of selective cannulation, the possibility of therapeutic approaches, and procedure-related complications. Results In all cases, we successfully reached the ampulla of Vater with the M-scope. The overall success rate of selective cannulation with the M-scope was 92.9% (13/14). One patient developed mild pancreatitis. Therapeutic procedures such as sphincterotomy, balloon dilatation, stone removal, and biliary drainage were all possible. Limitations Small number of patients; uncontrolled, single-center study. Conclusions The M-scope seems to be helpful for selective cannulation during ERCP in patients with a Billroth II gastrectomy. All diagnostic and therapeutic procedures were possible through the M-scope.

Cases of pancreatic ductal adenocarcinoma with multiple masses accompanying underlying pancreatic diseases, such as intraductal papillary mucinous neoplasm, have been reported. However, synchronous invasion without underlying pancreatic disease is very rare. A 61-year-old female with abdominal discomfort and jaundice was admitted to our hospital. Abdominal computed tomography (CT) revealed cancer of the pancreatic head with direct invasion of the duodenal loop and common bile duct. However, positron emission tomography-CT showed an increased standardized uptake value (SUV) in the pancreatic head and tail. We performed endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for the histopathologic diagnosis of the pancreatic head and the evaluation of the increased SUV in the tail portion of the pancreas, as the characteristics of these lesions could affect the extent of surgery. As a result, pancreatic ductal adenocarcinomas were confirmed by both cytologic and histologic analyses. In addition, immunohistochemical analysis of the biopsy specimens was positive for carcinoembryonic antigen and p53 in both masses. The two masses were ultimately diagnosed as pancreatic ductal adenocarcinoma, stage IIB, based on EUS-FNB and imaging studies. In conclusion, the entire pancreas must be evaluated in a patient with a pancreatic mass to detect the rare but possible presence of synchronous pancreatic ductal adenocarcinoma. Additionally, EUS-FNB can provide pathologic confirmation in a single procedure.

Background/Aims: Various anatomical features of the biliary tree affect ability to remove difficult common bile duct (CBD) stones. In this study, we evaluated the clinical characteris- tics and outcomes of the endoscopic treatment of stones in stemware-shaped CBDs. Methods: Thirty-four patients with a stone and a stemware-shaped CBD who were treated at dif- ferent tertiary referral centers from January 2008 to Decem- ber 2012 were studied retrospectively. When stone removal failed, percutaneous or direct peroral cholangioscopic litho- tripsy, endoscopic retrograde biliary drainage, or surgery was performed as a second-line procedure. Results: The overall success rate of the first-line procedure was 41.2%. Five of the 34 patients (14.7%) experienced procedure-related com- plications. No procedure-related mortality occurred. Mechan- ical lithotripsy was required to completely remove stones in 13 patients (38.2%). Conversion to a second-line procedure was required in 20 patients (58.8%). Mechanical lithotripsy was needed in 75% and 66.7% of those with a stone size of

Evaluation of: Coté GA, Singh S, Bucksot LG et al. Association between volume of endoscopic retrograde cholangiopancreatography at an academic medical center and use of pancreatobiliarytherapy. Clin. Gastroenterol. Hepatol. 10(8), 920-924 (2012). Many patients have pancreatobiliary diseases involving complications and comorbidities. This study shows the trends in the use of endoscopic retrograde cholangiopancreatography (ERCP) at an academic medical center from 1994 to 2009. During that time, the use of ERCPs for the treatment of bile duct stones reached a plateau and those for the treatment of pancreas divisum showed a decline. However, endoscopic therapy for benign biliary stricture and management for obstructive chronic pancreatitis increased during this period. There was a trend toward greater use of therapeutic ERCP for bile duct stenting involving metal stents and for pancreatic therapeutics. In that same period, there was an increase in the proportion of patients who had undergone unsuccessful ERCP at various other centers. Consequently, at academic medical centers, ERCP has become an increasingly complex intervention. Increasing numbers of patients with comorbidities, complications and history of failed ERCPs are being referred to academic centers to receive endotherapy.

Cholangioscopy not only enables the direct visualization of the biliary tree, but also allows for forceps biopsy to diagnosis early cholangiocarcinoma. Recently, some reports have suggested the clinical usefulness of direct peroral cholangioscopy (POC) using an ultra-slim endoscope with a standard endoscopic unit by a single operator. Enhanced endoscopy, such as narrow band imaging (NBI), can be helpful for detecting early neoplasia in the gastrointestinal tract and is easily applicable during direct POC. A 63-year-old woman with acute cholangitis had persistent bile duct dilation on the left hepatic duct after common bile duct stone removal and clinical improvement. We performed direct POC with NBI using an ultra-slim upper endoscope to examine the strictured segment. NBI examination showed an irregular surface and polypoid structure with tumor vessels. Target biopsy under direct endoscopic visualization was performed, and adenocarcinoma was documented. The patient underwent an extended left hepatectomy, and the resected specimen showed early bile duct cancer confined to the ductal mucosa. (Gut Liver 2011;5:377-379)

Background and Aims Direct peroral cholangioscopy (POC) by using an ultraslim upper endoscope has been increasingly applied for diagnosis and treatment of diverse biliary diseases. Recently, an intraductal balloon catheter has been used commonly to guide the flexible ultraslim endoscope. However, accessibility into the bile duct remains a limitation of the procedure. The aim of this study was to evaluate the feasibility and success rate of an intraductal balloon-guided direct POC by using an ultraslim endoscope with a newly modified 5F balloon catheter. Methods In total, 36 patients with biliary obstruction were included prospectively for a direct POC by using an ultraslim endoscope with a newly modified intraductal 5F balloon catheter. The main outcome measure was technical success, defined as successful advancement of the ultraslim endoscope into the obstructed segment of the biliary tree or the bifurcation. Secondary outcomes were mean time for the total procedure, intubation into the common bile duct and advancement up to the target site after intubation of the ultraslim endoscope, technical success rates of diagnostic and therapeutic interventions, and adverse events. Results The intraductal balloon-guided direct POC using a newly modified 5F balloon catheter was completed successfully in 35 of 36 patients (97.2%). The mean times for total procedure, intubation into the distal common bile duct, and advancement up to the obstructed bile duct segment were 27.3 ± 7.2, 2.2 ± 0.5, and 0.8 ± 0.4 minutes, respectively. In total, 49 interventions were performed in 35 patients, excluding 1 patient in whom we failed to perform direct POC. Technical success of the interventions was achieved with 44 of 49 procedures (89.8%). No adverse events, including cholangitis, were observed. Conclusions A newly modified 5F balloon catheter seemed to facilitate performing intraductal balloon-guided direct POC for direct visual examination of the bile duct in patients with biliary obstruction. Continued development of endoscopes and accessories are expected to further improve the performance of direct POC.

Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) has been becoming the standard tool for acquiring pancreatic lesion tissue. However, a single cytologic or histologic evaluation is not satisfactory for diagnosis. In this study, we evaluated the diagnostic yield of EUS–FNA for pancreatic solid masses and intra-abdominal lymph nodes using a triple approach. This study included patients undergoing evaluation for a solid pancreatic mass (n = 59) or intra-abdominal lymph nodes (n = 16) using EUS–FNA with a 22- or 25-gauge (G) needle, respectively. The specimens from each pass were analyzed by on-site cytology using Diff-Quick stain, cytology using Papanicolaou stain, and histology with immunohistochemical (IHC) staining. A total of 75 patients (49 males; mean age; 63.7 years) were included. The median number of needle pass for diagnosis of malignancy was 2.0, and there was no technical failure. The diagnostic accuracies with on-site cytology, cytology using Papanicolaou staining, and histology were 70.7, 80.0, and 80.0 %, respectively. The diagnostic accuracy using a triple approach was significantly greater than cytology using Papanicolaou staining alone (94.7 vs. 80.0 %; p = 0.007). In patients with malignant lesions, cytology identified 12 of 71 (16.9 %) malignant lesions that were not diagnosed by histology using IHC, and histology identified six (8.5 %) malignant lesions that were not diagnosed by cytology. On-site cytopathologic evaluation combined with cytologic and histologic analysis with IHC stain for one-pass specimen is considered to be able to increase the overall accuracy of EUS–FNA in pancreatic solid masses and lymph nodes.

Choledocholithiasis is one of the causes of jaundice and may require urgent treatment. Endoscopic retrograde cholangiopancreatography (ERCP) has been the primary management strategy for choledocholithiasis. However, small stones can be overlooked during ERCP. The aim of this study was to evaluate the accuracy of intraductal ultrasonography (IDUS) for detecting choledocholithiasis in icteric patients with highly suspected common bile duct (CBD) stones without definite stone diagnosis on ERCP. Ninety-five icteric (bilirubin ≥3 mg/dL) patients who underwent ERCP for highly suspected choledocholithiasis without definite filling defects on cholangiography were prospectively enrolled in the present study. We evaluated the bile duct using IDUS for the presence of stones or sludge. Reference standard for choledocholithiasis was endoscopic extraction of stone or sludge. Bile duct stones were detected with IDUS in 31 of 95 patients (32.6 %). IDUS findings were confirmed by endoscopic stone extraction in all patients. The mean diameter of CBD stones detected by IDUS was 2.9 mm (range 1–7 mm). IDUS revealed biliary sludge in 24 patients (25.2 %) which was confirmed by sludge extraction in 21 patients (87.5 %). In dilated CBD, detection rate of bile duct stone/sludge based on IDUS was significantly higher than in non-dilated CBD (p = 0.004). IDUS is useful for the detection of occult CBD stone on ERCP in icteric patients with highly suspected CBD stones.

Limy bile is a relatively rare condition in which a radiopaque material is visible in the gallbladder, extending rarely into the bile duct, on plain radiography. Acute cholangitis or cholecystitis caused by limy bile is a very rare condition. There are no definite treatment guidelines for limy bile, but in most cases with cholangitis or cholecystitis, laparoscopic cholecystectomy has been the preferred treatment. We report a case of limy bile with biliary symptoms that was treated only with an endoscopic procedure.

Background/Aims Endoscopic ultrasound elastography (EUS-EG) has been widely used for the evaluation of pancreatic cancer in the Western world. To date, there is very little experience with EUS-EG in Korea. We described the results of comparison between normal pancreas and pancreatic cancer in Korea. Methods The present study was performed at a tertiary hospital on 35 subjects comprising 20 with normal pancreas (control group) and 15 with pancreatic cancer (disease group). We compared the EUS-EG performance of the two groups. Results The pancreas in the control group showed a mean elasticity value of 0.53% (95% confidence interval [CI], 0.45 to 0.61). The elasticity value was higher than that previously reported from Western country (0.47%; 95% CI, 0.38 to 0.57). In the disease group, the mean elasticity value of pancreatic lesions was 0.02% (95% CI, 0.01 to 0.02). The mean elasticity value of the disease group was significantly lower than that of the control group (p

Background Endoscopic placement of fully covered self-expandable metal stents (FCSEMS) has been attempted to manage benign biliary strictures, but currently available FCSEMSs may be associated with unintended complications, including de novo strictures, in patients with normal life expectancy. Objective To evaluate the feasibility of an intraductally placed modified FCSEMS to minimize stent-induced bile duct injury in patients with benign biliary strictures. Design Prospective observational clinical feasibility study. Setting Tertiary-care academic center. Patients This study involved 21 patients with symptomatic benign biliary strictures in whom conventional endoscopic management failed. Intervention Strictured segments were 15 mm above the ampulla of Vater. The modified FCSEMS has convex margins, a lasso, and an anti-migrating waist on the central portion. Stents were placed entirely above the papilla and removed after 3 to 5 months. Main Outcome Measurements Success, complications, removability, midterm outcome. Results FCSEMSs were successfully placed inside the bile duct in all patients. No episodes of pancreatitis, cholangitis, or sepsis were noted during the stenting period. Stent migration occurred in 4 patients (19.0%), but 3 were asymptomatic during follow-up. All stents were removed successfully with rat-tooth forceps without complications. Post-stenting cholangiograms showed improvement of strictures in 20 of 21 patients, without de novo focal stricture. The clinical success rate was 95.2%, with one recurrent stricture. Limitations The small number and lack of comparison with other types of FCSEMSs. Conclusion Temporary intraductal placement of a newly modified FCSEMS effectively improved strictures and prevented potential stent-induced complications in patients with benign biliary strictures. Controlled large-scale trials are needed to confirm the long-term efficacy.