Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

LRH-1 agonist DLPC through STAT6 promotes macrophage polarization and prevents parenteral nutrition-associated cholestasis in mice.

BACKGROUND AND AIMS: Parenteral nutrition-associated cholestasis (PNAC) is an important complication in patients with intestinal failure with reduced LRH-1 expression. Here, we hypothesized that LRH-1 activation by its agonist, dilauroylphosphatidylcholine (DLPC), would trigger signal transducer and activator of transcription 6 (STAT6) signaling and hepatic macrophage polarization that would mediate hepatic protection in PNAC. APPROACH AND RESULTS: PNAC mouse model (oral DSSx4d followed by PNx14d; DSS-PN) was treated with LRH-1 agonist DLPC (30 mg/kg/day) intravenously. DLPC treatment prevented liver injury and cholestasis while inducing hepatic mRNA expression of Nr5a2 (nuclear receptor subfamily 5 group A member 2), Abcb11 (ATP binding cassette subfamily B member 11), Abcg5 (ATP-binding cassette [ABC] transporters subfamily G member 5), Abcg8 (ATP-binding cassette [ABC] transporters subfamily G member 8), nuclear receptor subfamily 0, and ATP-binding cassette subfamily C member 2 ( Abcc2) mRNA, all of which were reduced in PNAC mice. To determine the mechanism of the DLPC effect, we performed RNA-sequencing analysis of the liver from Chow, DSS-PN, and DSS-PN/DLPC mice, which revealed DLPC upregulation of the anti-inflammatory STAT6 pathway. In intrahepatic mononuclear cells or bone-marrow derived macrophages (BMDM) from PNAC mice, DLPC treatment prevented upregulation of pro-inflammatory (M1) genes, suppressed activation of NFκB and induced phosphorylation of STAT6 and its target genes, indicating M2 macrophage polarization. In vitro, incubation of DLPC with cultured macrophages showed that the increased Il-1b and Tnf induced by exposure to lipopolysaccharides or phytosterols was reduced significantly, which was associated with increased STAT6 binding to promoters of its target genes. Suppression of STAT6 expression by siRNA in THP-1 cells exposed to lipopolysaccharides, phytosterols, or both resulted in enhanced elevation of IL-1B mRNA expression. Furthermore, the protective effect of DLPC in THP-1 cells was abrogated by STAT6 siRNA. CONCLUSIONS: These results indicate that activation of LRH-1 by DLPC may protect from PNAC liver injury through STAT6-mediated macrophage polarization.

EUS-Guided Choledocho-duodenostomy Using Lumen Apposing Stent Versus ERCP With Covered Metallic Stents in Patients With Unresectable Malignant Distal Biliary Obstruction: A Multicenter Randomized Controlled Trial (DRA-MBO Trial).

BACKGROUND & AIMS: Several studies have compared primary endoscopic ultrasound (EUS)-guided biliary drainage to endoscopic retrograde cholangiopancreatography (ERCP) with insertion of metal stents in unresectable malignant distal biliary obstruction (MDBO) and the results were conflicting. The aim of the current study was to compare the outcomes of the procedures in a large-scale study. METHODS: This was a multicenter international randomized controlled study. Consecutive patients admitted for obstructive jaundice due to unresectable MDBO were recruited. Patients were randomly allocated to receive EUS-guided choledocho-duodenostomy (ECDS) or ERCP for drainage. The primary outcome was the 1-year stent patency rate. Other outcomes included technical success, clinical success, adverse events, time to stent dysfunction, reintervention rates, and overall survival. RESULTS: Between January 2017 and February 2021, 155 patients were recruited (ECDS 79, ERCP 76). There were no significant differences in 1-year stent patency rates (ECDS 91.1% vs ERCP 88.1%, P = .52). The ECDS group had significantly higher technical success (ECDS 96.2% vs ERCP 76.3%, P < .001), whereas clinical success was similar (ECDS 93.7% vs ERCP 90.8%, P = .559). The median (interquartile range) procedural time was significantly shorter in the ECDS group (ECDS 10 [5.75-18] vs ERCP 25 [14-40] minutes, P < .001). The rate of 30-day adverse events (P = 1) and 30-day mortality (P = .53) were similar. CONCLUSION: Both procedures could be options for primary biliary drainage in unresectable MDBO. ECDS was associated with higher technical success and shorter procedural time then ERCP. Primary ECDS may be preferred when difficult ERCPs are anticipated. This study was registered to Clinicaltrials.gov NCT03000855.

Effects of Clip Anchoring on Preventing Migration of Fully Covered Self-Expandable Metal Stent in Patients Undergoing Endoscopic Retrograde Cholangiopancreatography: A Multicenter, Randomized Controlled Study.

INTRODUCTION: Fully covered self-expandable metal stents (FCSEMSs) are commonly placed in patients with biliary stricture during endoscopic retrograde cholangiopancreatography (ERCP). However, up to 40% of migration has been reported, resulting in treatment failure or the requirement for further intervention. Here, we aimed to investigate the effects of metal clip anchoring on preventing the migration of FCSEMS. METHODS: Consecutive patients requiring placement of FCSEMS were included in this multicenter randomized trial. The enrolled patients were randomly assigned in a 1:1 ratio to receive clip anchoring (clip group) or not (control group). The primary outcome was the migration rate at 6 months after stent insertion. The secondary outcomes were the rates of proximal and distal migration and stent-related adverse events. The analysis followed the intention-to-treat principle. RESULTS: From February 2020 to November 2022, 180 patients with biliary stricture were enrolled, with 90 in each group. The baseline characteristics were comparable between the 2 groups. The overall rate of stent migration at 6 months was significantly lower in the clip group compared with the control group (16.7% vs 30.0%, P = 0.030). The proximal and distal migration rates were similar in the 2 groups (2.2% vs 5.6%, P = 0.205; 14.4% vs 22.2%, P = 0.070). Notably, none of the patients (0/8) who received 2 or more clips experienced stent migration. There were no significant differences in stent-related adverse events between the 2 groups. DISCUSSION: Our data suggest that clip-assisted anchoring is an effective and safe method for preventing migration of FCSEMS without increasing the adverse events.

Diagnostic Efficacy of a Novel Rotating Brush for Endoscopic Sampling of Malignant Biliary Strictures: A Multicenter Prospective Study.

INTRODUCTION: Although cytologic examination of biliary stricture brushings obtained by endoscopic retrograde cholangiopancreatography is commonly used for diagnosing malignant biliary strictures (MBSs), it has low sensitivity. Several new brushes have capabilities that are still being debated. We have developed a novel brush working from conventional back-and-forth movement to rotation in situ (RIS) that may be more efficient for MBS sampling. We aimed to compare the MBS detection sensitivity of our RIS brush with that of the conventional brush. METHODS: In this multicenter prospective study, we enrolled patients who underwent endoscopic retrograde cholangiopancreatography for suspected MBSs involving biliary stricture brushings obtained using our RIS brush. The historical control group consisted of the 30-brushing arm of our previous randomized trial (patient inclusion, 2018-2020) that used the study design in the same centers and with the same endoscopists as were used in this study. The primary outcome was to compare the sensitivity and specificity of detecting MBSs by cytologic evaluation of biliary stricture brushings between the 2 groups. RESULTS: We enrolled 155 patients in the intent-to-treat analysis. Using the same number of brushing cycles, the RIS brush showed a higher sensitivity than the conventional brush (0.73 vs 0.56, P = 0.003). In per-protocol population, the sensitivity was also higher in the RIS brush group than in the conventional brush group (0.75 vs 0.57, P = 0.002). Multivariate analysis revealed that the RIS brush was the only predictive factor for MBS detection. No significant differences were observed in procedure-related complications between the 2 groups. DISCUSSION: The RIS brush was a promising tool for effective and safe MBS sampling and diagnosis. Further randomized studies are warranted to confirm our results (Chictr.org.cn, identifier: ChiCTR2100047270).

Endoscopic Ultrasound-Guided vs Endoscopic Retrograde Cholangiopancreatography-Guided Biliary Drainage as Primary Approach to Malignant Distal Biliary Obstruction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Endoscopic ultrasound-guided biliary drainage (EUS-BD) is an alternative to endoscopic retrograde cholangiopancreatography (ERCP)-guided transpapillary drainage in malignant distal biliary obstruction (MDBO). This meta-analysis of randomized controlled trials (RCTs) aims to compare the outcomes of these 2 approaches. METHODS: Electronic databases from January 2005 through December 2023 were searched for RCTs comparing outcomes of EUS-BD and ERCP for treating MDBO. Pooled proportions, risk ratio (RR), and odds ratio were calculated using random-effects models. RESULTS: Five RCTs comprising 519 patients were included in the final analysis. The pooled RR for overall technical success with EUS-BD compared with ERCP was 1.05 (95% confidence interval [CI] = 0.96-1.16, P = 0.246, I2 = 61%) and for clinical success was 0.99 (95% CI = 0.95-1.04, P = 0.850, I2 = 0%). The pooled rate of procedure-related pancreatitis was 7.20% (95% CI = 3.60-13.80, I2 = 34%) in the ERCP group compared with zero in the EUS-BD group. The pooled RR for stent dysfunction with EUS-BD compared with ERCP was 0.48 (95% CI = 0.28-0.83, P = 0.008, I2 = 7%). The weighted mean procedure time was 13.43 (SD = 10.12) minutes for EUS-BD compared with 21.06 (SD = 6.64) minutes for ERCP. The mean stent patency was 194.11 (SD = 52.12) days in the EUS-BD group and 187 (SD = 60.70) days in the ERCP group. DISCUSSION: EUS-BD is an efficient and safe alternative to ERCP in MDBO. An almost nonexistent risk of procedure-related pancreatitis, lower procedure time, and ease of use make this an attractive primary approach to biliary decompression in centers with expertise.

Runt-related transcription factor-1 ameliorates bile acid-induced hepatic inflammation in cholestasis through JAK/STAT3 signaling.

BACKGROUND AND AIMS: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. APPROACH AND RESULTS: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5- ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1 -P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2 , and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid-induced CCL2 and CXCL2 in hepatocytes. CONCLUSIONS: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

Comparison Between Plastic and Metallic Biliary Stent Placement for Preoperative Patients with Pancreatic Head Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Optimal preoperative biliary drainage for patients with pancreatic cancer before pancreatoduodenectomy remains unclear. This study aimed to investigate the comparison of efficacy and safety between a metallic stent (MS) and a plastic stent (PS). METHODS: Comparative studies on the use of MS and PS for pancreatic cancer before pancreatoduodenectomy were systematically searched using the MEDLINE and Web of Science databases. Pre- and postoperative data also were extracted. Random-effects meta-analyses were performed to compare post-endoscopic retrograde cholangiopancreatography (ERCP) complications as well as intra- and postoperative outcomes between the two arms of the study, and pooled odds ratios (ORs) or mean differences (MDs) were calculated with 95 percent confidence intervals (CIs). RESULTS: The study analyzed 12 studies involving 683 patients. Insertion of MS was associated with a lower incidence of re-intervention (OR, 0.06; 95% CI 0.03-0.15; P < 0.001), increased post-ERCP adverse events (OR, 2.22; 95% CI 1.13-4.36; P = 0.02), and similar operation time (MD, 18.0 min; 95% CI -29.1 to 65.6 min; P = 0.46), amount of blood loss (MD, 43.0 ml; 95% CI -207.1 to 288.2 ml; P = 0.73), and surgical complication rate (OR, 0.78; 95% CI 0.53-1.15; P = 0.21). The cumulative stent patency rate after 3 months was higher in the MS group than in the PS group (70-100 % vs 30.0-45.0 %). CONCLUSION: For biliary drainage in patients with pancreatic cancer during this era of multidisciplinary treatment, MS use might be the first choice because MS provides a more durable biliary drainage and a similar risk of postoperative outcomes compared with PS.

Laparoscopic Right Hemi-hepatectomy of the Bile Duct-Obstructed Area Guided by Real-Time Fluorescence Imaging.

BACKGROUND: The regions of the liver with cholestasis caused by biliary tumors or thrombosis can be distinctly identified using indocyanine green (ICG) fluorescence imaging.1 The authors' team reported the application of bile-duct obstructed area imaging (BOAI) to assist open hepatectomy for intrahepatic cholangiocarcinoma (ICC) combined with intrahepatic bile duct obstruction previously.2 This video is the first report of real-time BOAI-guided three-dimensional (3D) laparoscopic hepatectomy using a 3D-4K fluorescence imaging system. METHODS: A 65-year-old man was admitted to the authors' institution with clonorchiasis. Preoperative computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) showed an obstruction and diffuse dilation of the right hepatic duct. A 15-min retention of ICG (ICG R15) was performed 5 days before the operation, with a 3.3% result. Preoperative planning involved performing laparoscopic right hemi-hepatectomy with regional lymph node dissection assisted by visualization technology.3 During the procedure, significant fluorescence accumulation in the right liver was shown by fluorescence imaging. With the guidance of real-time BOAI (Fig. 1), the regions of biliary obstruction were precisely resected, and the middle hepatic vein (MHV) was passively and adequately exposed on the cutting plane. Fig. 1 Administration steps for real-time bile duct-obstructed area imaging. A ICG is injected intravenously 3-5 days before operation at a dose of 0.5 mg/kg. B ICG is accumulated in the whole liver within a few minutes after injection. C ICG is selectively absorbed by the liver and excreted into the intestines, whereby it is retained in areas of biliary obstruction RESULTS: The histopathologic diagnosis indicated high-grade intraepithelial neoplasia of the right bile duct tumor without lymph node metastases and clonorchiasis. The duration of the operation was 300 min, with an intraoperative blood loss of 50 ml. No postoperative complications occurred, and the patient was discharged after 7 days. CONCLUSION: Laparoscopic right hemi-hepatectomy for the bile-duct obstructed area with the guidance of real-time BOAI is feasible and effective.

Fully covered versus partially covered self-expandable metal stents for palliation of distal malignant biliary obstruction: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Self-expandable metal stents (SEMSs) are standardly used for distal malignant biliary obstruction (dMBO). Although data suggest that covered versus uncovered SEMSs increase the time to recurrent biliary obstruction (TRBO), no data are available for fully covered (FC) versus partially covered (PC) designs. METHODS: PubMed, Scopus, and Cochrane databases were screened up to January 2023 for studies concerning dMBO treated by an FC- or PC-SEMS and describing adverse events (AEs), recurrences, or TRBO for specific design subpopulations. Pooled proportions or means were calculated using a random-effects model. Several subanalyses were preplanned, including a subanalysis restricted to prospective studies and unresectable diseases. Heterogeneity and publication bias were explored. Standardized differences (d-values) were calculated between groups. RESULTS: From 1290 records, 62 studies (3327 using FC-SEMSs and 2322 using PC-SEMSs) were included. FC- versus PC-SEMSs showed negligible differences in the rate of total AEs (12% vs 9.9%) and all specific AEs, including cholecystitis (2.5% vs 2.6%). In a subanalysis restricted to prospective studies and unresectable diseases, the rate of RBO was comparable between FC-SEMSs (27.3% [95% confidence interval {CI}, 23.7-31.2], I2 = 35.34%) and PC-SEMSs (25.3% [95% CI, 20.2-30.7], I2 = 85.09%), despite small differences (d-values between .186 and .216) in the rate of ingrowth (.5% vs 2.9%) favoring FC-SEMSs and migration (9.8% vs 4.3%) favoring PC-SEMSs. TRBO was shorter for FC-SEMSs (238 days [95% CI, 191-286], I2 = 63.1%) versus PC-SEMSs (369 days [95% CI, 290-449], I2 = 71.9%; d-value = .116). CONCLUSIONS: Despite considerable heterogeneity and small standardized differences, PC-SEMSs consistently exhibited longer TRBO than FC-SEMSs across analyses, without any other differences in AE rates, potentially proposing PC-SEMSs as the standard comparator and TRBO as the primary outcome for future randomized studies on dMBO. (Clinical trial registration number: CRD42023393965.).

Anchoring fins of fully covered self-expandable metal stents affect pull-out force and stent migration.

BACKGROUND AND AIMS: Stent migration and subsequent adverse events are frequently observed in the use of fully covered self-expandable metal stents (FCSEMSs) for distal biliary stenosis. In this study, we identified predictors for stent migration based on biomechanical stent characteristics and associated these findings with clinical outcomes. METHODS: The migration resistance of FCSEMSs was quantified by measuring the pull-out force. We analyzed a single-center retrospective cohort of 178 FCSEMSs for treatment success and adverse events occurring during 180 days of follow-up. RESULTS: Biomechanical measurements revealed a 4-fold higher migration resistance of FCSEMSs with anchoring fins (AF-FCSEMSs; Fmax = 14.2 ± .1 N) compared with FCSEMSs with flared ends (FE-FCSEMSs; Fmax = 3.8 ± 1.0 N; P < .0001). Clinically, AF-FCSEMSs showed lower rates of migration compared with FE-FCSEMSs (5% vs 34%, P < .0001). Unscheduled ERCP procedures because of stent dysfunction were less frequent in the AF group compared with the FE group (15% vs 29%, P = .046). Cholangitis because of stent dysfunction was observed in 5% of the AF group compared with 19% in the FE group (P = .02). Stent patency rates at 1, 3, and 6 months were higher in the AF group (96%, 90%, and 80%, respectively) compared with the FE group (90%, 74%, and 66%; log-rank test: P = .03). CONCLUSIONS: The pull-out force as a biomechanical stent property predicts the migration resistance of FCSEMSs in distal biliary stenosis and may thus be used to classify stents for this application. AF-FCSEMSs showed a significantly lower rate of migration and adverse events compared with FE-FCSEMSs.

Aspirin exposure and its association with metal stent patency in malignant distal biliary obstruction: a large international multicenter propensity score-matched study.

BACKGROUND AND AIMS: Stent dysfunction is common after ERCP with self-expandable metal stent (SEMS) insertion for malignant distal biliary obstruction (MDBO). Chronic aspirin (acetylsalicylic acid; ASA) exposure has been previously shown to potentially decrease this risk. We aim to further ascertain the protective effect of ASA and to identify other predictors of stent dysfunction. METHODS: This multicenter retrospective cohort study was conducted at 9 sites in Canada and 1 in the United States. Patients with MDBO who underwent ERCP with SEMS placement between January 2014 and December 2019 were included and divided into 2 cohorts: ASA exposed (ASA-E) and ASA unexposed (ASA-U). Propensity-score matching (PSM) was performed to limit selection bias. Matched variables were age, sex, tumor stage, and type of metal stent. The primary outcome was the hazard rate of stent dysfunction. A multivariable Cox proportional hazards model was used to identify independent predictors of stent dysfunction. RESULTS: Of 1396 patients assessed, after PSM 496 patients were analyzed (248 ASA-E and 248 ASA-U). ERCP with SEMS placement was associated with a high clinical success of 82.2% in ASA-E and 81.2% in ASA-U cohorts (P = .80). One hundred eighty-four patients had stent dysfunction with a mean stent patency time of 229.9 ± 306.2 days and 245.4 ± 241.4 days in ASA-E and ASA-U groups, respectively (P = .52). On multivariable analysis, ASA exposure did not protect against stent dysfunction (hazard ratio [HR], 1.25; 95% confidence interval [CI], .96-1.63). An etiology of pancreatic cancer (HR, 1.36; 95% CI, 1.15-1.61) predicted stent dysfunction, whereas cancer therapy was protective (HR, .73; 95% CI, .55-.96). Chronic ASA use was not associated with an increased risk for adverse events including bleeding, post-ERCP pancreatitis, and perforation. CONCLUSIONS: In this large, multicenter study using PSM, chronic exposure to ASA did not protect against stent dysfunction in MDBO. Instead, the analysis revealed that the etiology of pancreatic cancer was an independent predictor of stent dysfunction and cancer therapy was protective.

EUS-guided hepaticogastrostomy versus EUS-guided hepaticogastrostomy with antegrade stent placement in patients with unresectable malignant distal biliary obstruction: a propensity score-matched case-control study.

BACKGROUND AND AIMS: EUS-guided hepaticogastrostomy (EUS-HGS) is a rescue procedure when ERCP fails. Peritonitis and recurrent biliary obstruction (RBO) are adverse events (AEs) associated with EUS-HGS. Antegrade stent placement across a malignant distal biliary obstruction (DBO) followed by EUS-HGS (EUS-HGAS) creates 2 biliary drainage routes, potentially reducing peritonitis and prolonging time to RBO (TRBO). We compared the outcomes of the 2 techniques. METHODS: Data of consecutive patients with malignant DBO who underwent attempted EUS-HGS or EUS-HGAS across 5 institutions from January 2014 to December 2020 were retrospectively analyzed. A matched cohort of patients was obtained using 1-to-1 propensity score matching. The primary outcome was TRBO, and secondary outcomes were AEs except for RBO and overall survival. RESULTS: Among 360 patients, 283 (176 and 107 in the HGS and HGAS groups, respectively) were eligible. The matched cohorts included 81 patients in each group. AEs developed in 10 (12.3%) and 15 (18.5%) patients (P = .38) in the HGS and HGAS groups, respectively. RBO occurred in 18 and 2 patients in the HGS and HGAS groups, respectively (P < .001). TRBO was significantly longer in the HGAS group (median, 194 days vs 716 days; hazard ratio, .050; 95% confidence interval, .0066-.37; P < .01). However, no significant differences occurred in overall survival between the groups (median, 97 days vs 112 days; hazard ratio, .97; 95% confidence interval, .66-1.4; P = .88). CONCLUSIONS: EUS-HGAS extended TRBO compared with EUS-HGS, whereas AEs, except for RBO and overall survival, did not differ. The longer TRBO of EUS-HGAS could benefit patients with longer life expectancy.

Novel self-expandable stent-based endobiliary radiofrequency ablation for unresectable malignant biliary obstruction.

BACKGROUND AND AIMS: Endobiliary radiofrequency ablation (RFA) is an emerging endoscopic palliative adjunctive therapy used for the local treatment of unresectable malignant biliary obstruction (MBO). However, irregular ablation ranges caused by insufficient electrode-to-bile duct contact pose a significant obstacle. We investigated the feasibility of a self-expandable stent (SES)-based electrode with a customized RFA generator in the porcine liver and common bile duct (CBD). METHODS: An SES-RFA system with polarity switching was developed to perform endobiliary RFA. The ablation ranges of 20 ablation protocols were evaluated to validate the feasibility of the newly developed RFA system in the porcine liver. Nine of 20 ablation protocols were selected for evaluation in the porcine CBD with cholangiography, endoscopy, and histologic and immunohistochemical analysis. RESULTS: The SES-RFA system with polarity switching was successfully constructed and demonstrated high accuracy and reproducibility. The ablation area was clearly identified between the 2 SESs. The ablation ranges and degree of mucosal damage, including terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling-positive and heat shock protein 70-positive depositions, increased proportionally with ablation protocols in the porcine liver and CBD (all P < .05). Ablation length and depth linearly increased with ablation protocols from 8.74 ± .25 to 31.25 ± .67 mm and 1.61 ± .09 to 11.94 ± .44 mm, respectively. CONCLUSIONS: The SES-RFA system with polarity switching between electrodes provided an even circumferential area of ablation and enhanced ablation depth between the electrodes. This novel endobiliary RFA system is a promising modality for local ablation in patients with unresectable MBO.

Preoperative endoscopic biliary drainage by metal versus plastic stents for resectable perihilar cholangiocarcinoma.

BACKGROUND AND AIMS: Adequate preoperative biliary drainage (PBD) is recommended in most patients with resectable perihilar cholangiocarcinoma (pCCA). Most expert centers use endoscopic plastic stents rather than self-expandable metal stents (SEMSs). In the palliative setting, however, use of SEMSs has shown longer patency and superior survival. The aim of this retrospective study was to compare stent dysfunction of SEMSs versus plastic stents for PBD in resectable pCCA patients. METHODS: In this multicenter international retrospective cohort study, patients with potentially resectable pCCAs who underwent initial endoscopic PBD from 2010 to 2020 were included. Stent failure was a composite end point of cholangitis or reintervention due to adverse events or insufficient PBD. Other adverse events, surgical outcomes, and survival were recorded. Propensity score matching (PSM) was performed on several baseline characteristics. RESULTS: A total of 474 patients had successful stent placement, of whom 61 received SEMSs and 413 plastic stents. PSM (1:1) resulted in 2 groups of 59 patients each. Stent failure occurred significantly less in the SEMSs group (31% vs 64%; P < .001). Besides less cholangitis after SEMSs placement (15% vs 31%; P = .012), other PBD-related adverse events did not differ. The number of patients undergoing surgical resection was not significantly different (46% vs 49%; P = .71). Complete intraoperative SEMSs removal was successful and without adverse events in all patients. CONCLUSIONS: Stent failure was lower in patients with SEMSs as PBD compared with plastic stents in patients with resectable pCCA. Removal during surgery was quite feasible. Surgical outcomes were similar.

EUS- versus ERCP-guided biliary drainage for malignant biliary obstruction: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Increasing evidence supports EUS-guided biliary drainage (EUS-BD) as a potential alternative to ERCP-guided biliary drainage (ERCP-BD) in the primary treatment of malignant biliary obstruction (MBO). This systematic review and meta-analysis aimed to compare the efficacy and safety of both techniques as the initial approach for MBO. METHODS: We systematically searched in MEDLINE, Embase, and Cochrane databases for randomized controlled trials comparing both techniques and reporting at least one of the outcomes of interest. The pooled estimates were calculated using the random-effects model, and I2 statistics were used to evaluate heterogeneity. RESULTS: We included 6 randomized controlled trials (577 patients). There were no significant differences between both groups in terms of stent patency (mean difference [MD], 8.18 days; 95% confidence interval [CI], -22.55 to 38.91), procedure time (MD, -6.31 minutes; 95% CI, -12.68 to 0.06), and survival (MD, 4.59 days; 95% CI, -34.23 to 43.40). Technical success (risk ratio [RR], 1.04; 95% CI, 0.96-1.13), clinical success (RR, 1.02; 95% CI, 0.96-1.08), overall adverse events (RR, 0.58; 95% CI, 0.24-1.43), and cholangitis (RR, 1.19; 95% CI, 0.39-3.61) were also similar between groups. However, the hospital stay was significantly shorter (MD, -1.03 days; 95% CI, -1.53 to -0.53), and the risk of reintervention (RR, 0.57; 95% CI, 0.37-0.88), postprocedure pancreatitis (RR, 0.15; 95% CI, 0.03-0.66), and tumor ingrowth/overgrowth (RR, 0.28; 95% CI, 0.11-0.70) were significantly lower with EUS-BD. CONCLUSIONS: EUS-BD and ERCP-BD had similar efficacy and safety as the initial approach for MBO. However, EUS-BD had a significantly lower risk of reintervention, postprocedure pancreatitis, tumor ingrowth/overgrowth, and reduced hospital stay.

Impact of the suprapapillary method on patency in distal malignant biliary obstruction: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Placement of a self-expandable metal stent (SEMS) across the duodenal major papilla carries a risk of duodenobiliary reflux (DBR). The suprapapillary method of stent placement may reduce DBR and improve stent patency compared with the transpapillary method. This study compared the clinical outcomes between the suprapapillary and transpapillary methods for distal malignant biliary obstruction (DMBO). METHODS: Between January 2021 and January 2023, consecutive patients with DMBO from 6 centers in South Korea were randomly assigned to either the suprapapillary arm or transpapillary method arm in a 1:1 ratio. The primary outcome was the duration of stent patency, and secondary outcomes were the cause of stent dysfunction, adverse events, and overall survival rate. RESULTS: Eighty-four patients were equally assigned to each group. The most common cause of DMBO was pancreatic cancer (50, 59.5%), followed by bile duct (20, 23.8%), gallbladder (11, 13.1%), and other cancers (3, 3.6%). Stent patency was significantly longer in the suprapapillary group (median, 369 days [interquartile range, 289-497] vs 154 days [interquartile range, 78-361]; P < .01). Development of DBR was significantly lower in the suprapapillary group (9.4% vs 40.8%, P < .01). Adverse events and overall survival rate were not significantly different between the 2 groups. CONCLUSIONS: The placement of SEMSs using the suprapapillary method resulted in a significantly longer duration of stent patency. It is advisable to place the SEMS using the suprapapillary method in DMBO. Further studies with a larger number of patients are required to validate the benefits of the suprapapillary method. (Clinical trial registration number: KCT0005572.).

Adverse events of self-expandable metal stent placement for malignant distal biliary obstruction: a large multicenter study.

BACKGROUND AND AIMS: Endoscopic placement of self-expandable metal stents (SEMSs) for malignant distal biliary obstruction (MDBO) may be accompanied by several types of adverse events. The present study analyzed the adverse events occurring after SEMS placement for MDBO. METHODS: The present study retrospectively investigated the incidence and types of adverse events in patients who underwent SEMS placement for MDBO between April 2018 and March 2021 at 26 hospitals. Risk factors for acute pancreatitis, cholecystitis, and recurrent biliary obstruction (RBO) were evaluated by univariate and multivariate analyses. RESULTS: Of the 1425 patients implanted with SEMSs for MDBO, 228 (16.0%) and 393 (27.6%) experienced early adverse events and RBO, respectively. Pancreatic duct without tumor involvement (P = .023), intact papilla (P = .025), and SEMS placement across the papilla (P = .037) were independent risk factors for acute pancreatitis. Tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis (P < .001). Use of fully and partially covered SEMSs was an independent risk factor for food impaction and/or sludge. Use of fully covered SEMSs was an independent risk factor for stent migration. Use of uncovered SEMSs and laser-cut SEMSs was an independent risk factor for tumor ingrowth. CONCLUSIONS: Pancreatic duct without tumor involvement, intact papilla, and SEMS placement across the papilla were independent risk factors for acute pancreatitis, and tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis. The risk factors for food impaction and/or sludge, stent migration, and tumor ingrowth differed among types of SEMSs.

Risk factors and treatment strategies for cholecystitis after metallic stent placement for malignant biliary obstruction: a multicenter retrospective study.

BACKGROUND AND AIMS: Cholecystitis can occur after self-expandable metallic stent (SEMS) placement for malignant biliary obstruction (MBO), but the best treatment option for cholecystitis has not been determined. Here, we aimed to identify the risk factors of cholecystitis after SEMS placement and determine the best treatment option. METHODS: Incidence, treatments, and predictive factors of cholecystitis were retrospectively evaluated in 1084 patients with distal MBO (DMBO) and 353 patients with hilar MBO (HMBO) who underwent SEMS placement at 12 institutions from January 2012 to March 2021. RESULTS: Cholecystitis occurred in 7.5% of patients with DMBO and 5.9% of patients with HMBO. The recurrence rate was significantly lower (P = .043) and the recurrence-free period significantly longer (P = .039) in endoscopic procedures than in percutaneous procedures for cholecystitis treatment. EUS-guided gallbladder drainage (EUS-GBD) was better in terms of technical success, procedure time, and recurrence-free period than endoscopic transpapillary gallbladder drainage. Obstruction across the cystic duct orifice by tumor (P = .015) and by stent (P = .037) were independent risk factors for cholecystitis in DMBO. Cases with multiple SEMS placements (odds ratio [OR], 11; 95% confidence interval [CI], 0.68-190; P = .091) and with gallbladder stones (OR, 2.3; 95% CI ,0.92-5.6; P = .075) had a higher risk for cholecystitis in HMBO. CONCLUSIONS: The incidences of cholecystitis after SEMS placement for DMBO and HMBO were similar. EUS-GBD is the optimal treatment option for patients with cholecystitis after SEMS placement for MBO.

The addition of endoscopic sphincterotomy to biliary stent placement and its impact on the risk of adverse events: an updated meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Endoscopic sphincterotomy (ES) is not mandatory before biliary stenting. The impact of ES before biliary stent placement remains uncertain. Previous studies have reported that ES can increase adverse event rates by up to 4.5 times compared with no ES. We aimed to assess the occurrence of post-ERCP adverse events following biliary stent placement with and without ES. METHODS: PubMed, Embase, and Cochrane databases were systematically searched for randomized controlled trials. The primary outcome was post-ERCP pancreatitis (PEP). Subgroup analyses were performed with patients undergoing biliary drainage due to obstruction, using metal stents, and using plastic stents. Secondary outcomes were postprocedural bleeding, perforation, stent/catheter occlusion, stent/catheter migration, and cholangitis. Heterogeneity was examined with I2 statistics, and a random-effects model was used. Review Manager 5.4 was used for statistical analyses. RESULTS: Seven RCTs with 1022 patients were included. There was no significant difference between the ES and non-ES groups (odds ratio [OR], .46; 95% CI, .19-1.09; P = .08; I2 = 59%) regarding PEP; however, a significant difference in bleeding rates was found between groups, favoring non-ES (OR, 7.01; 95% CI, 2.24-21.99; P = .0008; I2 = 0%). The analysis of the occurrence of cholangitis (OR, 1.25; 95% CI, .58-2.69; P = .56; I2 = 67%), perforation (OR, 1.95; 95% CI, .07-55.73; P = .70; I2 = 58%), stent/catheter migration (OR, 2.15; 95% CI, .61-7.57; P = 0.23; I2 = 6%), and stent/catheter occlusion (OR, .91; 95% CI, .37-2.25; P = .84; I2 = 0%) did not favor either group. CONCLUSIONS: Performing ES before biliary drainage does not affect the PEP rate but is associated with an increased postprocedural bleeding rate.