Switching from combination therapy with entecavir hydrate plus tenofovir alafenamide fumarate to tenofovir alafenamide fumarate monotherapy in patients with chronic hepatitis B based on nucleotide sequences of hepatitis B virus pregenome RNA.

AIM: Patients with chronic hepatitis B virus (HBV) infection experiencing viral breakthrough (BTH) or partial response (PR) during lamivudine (LAM) or entecavir hydrate (ETV) administration often took ETV plus tenofovir alafenamide fumarate (TAF) due to the emergence of a drug-resistance mutation. However, in patients lacking drug-resistance mutation against TAF, sufficient antiviral effects may be achievable with TAF monotherapy. We assessed the drug-resistance profile through nucleotide sequences of HBV pregenome RNA, and subsequently changed to TAF monotherapy from ETV plus TAF. METHODS: This prospective study included 25 patients with serum HBV-DNA below 20 IU/mL under ETV plus TAF administration. Pregenome RNA nucleotide sequences of HBV in the sera were analyzed using direct sequencing and deep sequencing. ETV was discontinued in patients without rtA194T and rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutations in direct sequencing. RESULTS: LAM-PR, LAM-BTH, ETV-PR, and ETV-BTH were observed in 1, 16, 7, and 1 patient(s), respectively. Pregenome RNA nucleotide sequences were analyzable in 20 patients. Among the 12 patients classified as LAM-BTH, six patients showed rtL180M + rtM204V/I in direct sequencing, and one patient showed minor clones containing rtL180M + rtM204V + A194T in deep sequencing at a frequency of 0.3%. In the six patients classified as ETV-PR, one patient harbored rtM204I. No clones showing rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutation were detected in deep sequencing. Subsequently, ETV was discontinued, and serum HBV-DNA remained undetectable up to 48 weeks in all patients. CONCLUSION: Patients receiving ETV plus TAF due to partial response or BTH during initial LAM or ETV administration were able to safely transition to TAF monotherapy based on nucleotide sequences of HBV pregenome RNA in the sera.

Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

Retrospective comparative study of new slim-delivery and conventional large-cell stents for stent-in-stent methods for hilar malignant biliary obstruction.

OBJECTIVES: Endoscopic management of unresectable hilar malignant biliary obstruction (HMBO) is technically challenging, and effectiveness of stent-in-stent using large-cell, metal stents was reported. A new, large-cell stent with a 6F tapered delivery system was recently developed. The aim of this study was to compare clinical outcomes of slim-delivery and conventional large-cell stents. METHODS: This was a multicenter retrospective comparative study of stent-in-stent methods using slim-delivery stents (Niti-S Large Cell SR Slim Delivery [LC slim-delivery]) and conventional stents (Niti-S large-cell D-type; LCD) for unresectable HMBO. RESULTS: Eighty-three patients with HMBO were included; 31 LC slim-delivery and 52 LCD. Overall technical and clinical success rates were 100% and 90% in LC slim-delivery group and 98% and 88% in LCD group. Use of the LC slim-delivery was associated with shorter stent placement time in the multiple regression analysis, with a stent placement time of 18 and 23 min in LC slim-delivery and LCD groups, respectively. The early adverse event (AE) rate of LC slim-delivery was 10%, with no cholangitis or cholecystitis as compared to 23% in the LCD group. Recurrent biliary obstruction (RBO) rates and time to RBO were comparable between the two groups: 35% and 44%, and 8.5 and 8.0 months in LC slim-delivery and LCD groups, respectively. The major cause of RBO was tumor ingrowth (82%) in the LC slim-delivery group and sludge (43%) and ingrowth (48%) in LCD group. CONCLUSION: Stent-in-stent methods using LC slim-delivery shortened stent placement time with low early AE rates and comparable time to RBO in patients with HMBO.

Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct.

BACKGROUND & AIMS: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation. METHODS: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively. CONCLUSIONS: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation.

MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages.

BACKGROUND & AIMS: Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers. METHODS: We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference. RESULTS: Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared with PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions compared with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes, including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv. CONCLUSIONS: Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.

Development and external validation of a nomogram for prediction of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is widely performed for management of pancreatobiliary diseases; however, post-ERCP pancreatitis (PEP) remains as an unsolved problem. Although various risk factors for PEP have been reported, the prediction of PEP remains controversial. This study aimed to develop a predictive model for PEP. METHODS: Consecutive patients undergoing ERCP for biliary indications at two centers were retrospectively studied. Using data from a training cohort, we utilized a multivariable model to select five variables to construct a nomogram. The predictive model was internally and externally validated. Based on the nomogram, the patients were categorized into low-, moderate-, and high-risk groups. RESULTS: Using the data of 2224 patients in the training cohort, five variables were selected to generate a nomogram: 1) sex, 2) indication for ERCP, 3) difficult cannulation, 4) guidewire insertion into the pancreatic duct, and 5) endoscopic sphincterotomy or sphincteroplasty. The most significant risk factor was endoscopic papillary balloon dilation such as endoscopic sphincterotomy or sphincteroplasty. The bias-corrected concordance index was 0.72 in the training cohort and 0.72 in the validation cohort. Calibration curves for both cohorts demonstrated good agreement between the predicted and observed frequencies of the actual outcome. In the validation cohort, PEP developed in 5.0% and 14% of patients in the moderate- and high-risk groups, respectively. CONCLUSIONS: We successfully developed a good predictive model for PEP. The prevention of PEP in high risk patients should be investigated further.

Significance of portal venous blood flow as a factor to determine liver function in patients with decompensated cirrhosis due to hepatitis C virus infection following achievement of sustained viral response by sofosbuvir plus velpatasvir.

AIM: To determine the outcomes concerning portal venous blood flow and portosystemic shunts in patients with decompensated cirrhosis due to hepatitis C virus (HCV) infection who achieved sustained viral response (SVR) following antiviral therapy. METHODS: Portal hypertension-related events and liver function were evaluated in 24 patients achieving SVR following sofosbuvir plus velpatasvir therapy. RESULTS: Serum albumin level (median; g/dL) increased from 2.9 at baseline to 3.5 at 12 weeks after the end of treatment (EOT) (p = 0.005), while liver volumes (cm3 ) decreased from 1260 to 1150 (p = 0.0002). Portal hypertension-related events developed in 10 patients (41.7%), and the cumulative occurrence rates after the EOT were 29.2%, 33.3%, and 46.1% at 24, 48, and 96 weeks, respectively. Multivariate logistic regression analysis revealed that the maximal diameter of the shunts (p = 0.0235) was associated with the development of the events, with a cut-off value of 8.3 mm (p = 0.0105). Meanwhile, multiple linear regression analysis revealed that portal venous blood flow, liver volume, serum albumin, and bilirubin levels at baseline were associated with serum albumin levels at 12 weeks after EOT (p = 0.0019, p = 0.0154, p = 0.0010, and p = 0.0350, respectively). CONCLUSION: In patients with decompensated cirrhosis due to HCV infection, the baseline portal venous blood flow and liver volume and function were predictive of liver function following SVR, while the maximal diameter of portosystemic shunts predicted the occurrence of portal hypertension-related events.

Comparison of novel large-bore and conventional-bore covered self-expandable metal stents for malignant gastric outlet obstruction: Multicenter, retrospective study.

OBJECTIVES: Covered self-expandable metal stent (cSEMS) for gastric outlet obstruction (GOO) has been developed to overcome tumor ingrowth but is prone to be associated with an increased risk of migration. Clinical impact of the novel large-bore cSEMS for malignant GOO remains unclear. METHODS: A total of 117 patients undergoing endoscopic cSEMS placement for malignant GOO were enrolled in this multicenter retrospective study. Technical and clinical success, adverse events, recurrent GOO, and survival after stent placement were compared between 24 mm-cSEMS (n = 49) and 20 mm-cSEMS (n = 68). RESULTS: Patient characteristics were well-balanced and thus similar survival was observed between the two groups (136 days vs. 89 days, P = 0.60). Technical success rate of 100% and clinical success rate of 96% were achieved both in 24 mm-cSEMS and 20 mm-cSEMS, respectively. The median cumulative time to recurrent GOO was significantly longer in 24 mm-cSEMS than in 20 mm-cSEMS (380 days vs. 138 days, P = 0.01). The incidence of adverse events and recurrent GOO was comparable: 12% vs. 15% (P = 0.91), and 16% vs. 31% (P = 0.11); however, no stent migration was observed in 24 mm-cSEMS. In a subgroup analysis, the superiority of 24 mm-cSEMS to 20 mm-cSEMS was demonstrated in extrinsic cancers (380 days vs. 121 days, P = 0.01) but not in intrinsic cancers (151 days vs. not reached, P = 0.47). CONCLUSIONS: The 24 mm-cSEMS may improve time to recurrent GOO with ensuring acceptable safety in patients with malignant GOO.

Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer. Cancer-associated thrombosis/thromboembolism (CAT), frequently observed in PDAC, is known as a poor prognostic factor. Here, we investigated the underlying mechanisms between PDAC and CAT, and performed a trial of therapeutic approach for PDAC using a genetically engineered mouse model, PKF (Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox ). DESIGN: Presence of CAT in PKF mice was detected by systemic autopsy. Plasma cytokines were screened by cytokine antibody array. Murine and human plasma atrial natriuretic peptide (ANP) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were determined by ELISA. Distribution of VCAM-1 in PKF mice and human autopsy samples was detected by immunohistochemistry. PKF mice were treated with anti-VCAM-1 antibody and the effects on survival, distribution of CAT and the tumour histology were analysed. RESULTS: We found spontaneous CAT with cardiomegaly in 68.4% PKF mice. Increase of plasma ANP and sVCAM-1 was observed in PKF mice and PDAC patients with CAT. VCAM-1 was detected in the activated endothelium and thrombi. Administration of anti-VCAM-1 antibody to PKF mice inhibited tumour growth, neutrophil/macrophage infiltration, tumour angiogenesis and progression of CAT; moreover, it dramatically extended survival (from 61 to 253 days, p<0.01). CONCLUSION: Blocking VCAM-1/sVCAM-1 might be a potent therapeutic approach for PDAC as well as CAT, which can contribute to the prognosis. Increase of plasma ANP and sVCAM-1 might be a diagnostic approach for CAT in PDAC.

Long-term Risk of Malignancy in Branch-Duct Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: Long-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years of surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]) over 20 years in a large population of patients. METHODS: We identified 1404 consecutive patients (52% women; mean age, 67.5 years) with a diagnosis of branch-duct IPMN, from 1994 through 2017, at the University of Tokyo in Japan. Using a competing risk analysis, we estimated cumulative incidence of pancreatic carcinoma, overall and by carcinoma type. We used competing risks proportional hazards models to estimate subdistribution hazard ratios (SHRs) for incidences of carcinomas. To differentiate IPMN-derived and concomitant carcinomas, we collected genomic DNA from available paired samples of IPMNs and carcinomas and detected mutations in GNAS and KRAS by polymerase chain reaction and pyrosequencing. RESULTS: During 9231 person-years of follow-up, we identified 68 patients with pancreatic carcinomas (38 patients with IPMN-derived carcinomas and 30 patients with concomitant PDACs); the overall incidence rates were 3.3%, 6.6%, and 15.0% at 5, 10, and 15 years, respectively. Among 804 patients followed more than 5 years, overall cumulative incidence rates of pancreatic carcinoma were 3.5% at 10 years and 12.0% at 15 years from the initial diagnosis. The size of the IPMN and the diameter of the main pancreatic duct associated with incidence of IPMN-derived carcinoma (SHR 1.85; 95% confidence interval 1.38-2.48 for a 10-mm increase in the IPMN size and SHR 1.56; 95% confidence interval 1.33-1.83 for a 1-mm increase in the main pancreatic duct diameter) but not with incidence of concomitant PDAC. CONCLUSIONS: In a large long-term study of patients with branch-duct IPMNs, we found the 5-year incidence rate of pancreatic malignancy to be 3.3%, reaching 15.0% at 15 years after IPMN diagnosis. We observed heterogeneous risk factor profiles between IPMN-derived and concomitant carcinomas.

A phase I study of intraperitoneal paclitaxel combined with gemcitabine plus nab-paclitaxel for pancreatic cancer with peritoneal metastasis.

PURPOSE: A phase I study of intraperitoneal paclitaxel (ip PTX) combined with gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) (GnP) was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in pancreatic cancer patients with peritoneal metastasis in first-line setting. METHODS: Based on the 3 + 3 dose-escalation model, ip PTX, GEM and nab-PTX were administered at doses of 20 or 30 mg/m2, 800 or 1000 mg/m2 and 100 or 125 mg/m2 (level 1, 2 and 3, respectively) on days 1, 8 and 15 in 4-week cycles. Dose-limiting toxicity (DLT) defined as severe adverse events was evaluated during the first cycle of the treatment. Safety and preliminary efficacy were also investigated. RESULTS: In total, 12 patients were enrolled. While 2 of the first 6 patients enrolled at level 1 experienced DLTs (grade 3 ip port dysfunction and grade 3 pneumonia), no DLT was observed in the next 6 patients enrolled at level 2 and 3. Therefore, we did not reach the MTD and the RD was determined to be level 3 (ip PTX of 30 mg/m2, GEM of 1000 mg/m2, and nab-PTX of 125 mg/m2). The major grade 3/4 adverse events included neutropenia (58%), anemia (33%), and ip port dysfunction (25%). The response rate was 25% and the median PFS was 5.4 (95% confidence interval; 2.4-16.0). The cytological status in peritoneal lavage turned negative in 8 patients (67%). CONCLUSIONS: Ip PTX combined with GnP was feasible and potentially effective in pancreatic cancer with peritoneal metastasis as a first-line treatment deserved further evaluations.

A retrospective comparative study of S-IROX and modified FOLFIRINOX for patients with advanced pancreatic cancer refractory to gemcitabine plus nab-paclitaxel.

PURPOSE: The aim of this study was to evaluate the efficacy and tolerability of S-IROX and modified FOLFIRINOX (mFFX) after gemcitabine plus nab-paclitaxel for advanced pancreatic cancer (PC) in the real world setting. METHODS: Consecutive patients receiving S-IROX or mFFX as a second-line chemotherapy for advanced PC refractory to gemcitabine plus nab-paclitaxel were retrospectively studied. Patients were treated every 2 weeks: S-1 40 mg/m2 was administered orally twice daily on days 1 to 7 in S-IROX and 5-fluorouracil 2400 mg/m2 was intravenously administered for 46 h without bolus infusion in mFFX, in addition to intravenous oxaliplatin 85 mg/m2 and irinotecan 150 mg/m2 on day 1 in both regimens. RESULTS: Fifty-four patients with advanced PC who received S-IROX (n = 19) or mFFX (n = 35) were retrospectively studied. The disease control rate and response rate were 73.7% and 10.5% in the S-IROX group and 62.2% and 2.7% in the mFFX group, respectively. The median progression free survival (PFS) was 7.8 and 5.7 months in the S-IROX and mFFX groups (p = 0.24). The median overall survival (OS) was 14.2 and 11.5 months in the S-IROX and mFFX groups (p = 0.34). There were no significant differences in the incidences of grade 3-4 adverse effects. The subgroup analyses suggested S-IROX demonstrated favorable OS in patients with PFS ≥6 months of first-line gemcitabine plus nab-paclitaxel (p for interaction = 0.02). CONCLUSIONS: S-IROX and mFFX were similarly tolerable and effective as a second-line chemotherapy in patients with PC refractory to gemcitabine plus nab-paclitaxel.

Long-term outcome of endotherapy for pancreatic stones by using a dedicated pancreatic basket catheter.

BACKGROUND AND AIM: Although endotherapy for pancreatic stones is less invasive compared with surgical interventions, its recurrence rate is high and residual pancreatic stones can be a cause of recurrence. We previously reported usefulness of a novel basket catheter with nitinol fine reticular structure for pancreatic stone retraction. In this retrospective study, we aimed to evaluate the long-term outcomes of endotherapy for pancreatic stones with and without the use of this dedicated basket catheter. METHODS: We retrospectively compared patients with symptomatic pancreatic stones who underwent the initial endotherapy between 2008 and 2019. The primary outcome was the symptomatic recurrence after complete stone clearance. Secondary outcomes were the rate of complete stone clearance, complications, risk factors for recurrences, and the treatment cost. RESULTS: A total of 101 patients who underwent endotherapy for pancreatic stones were analyzed: 41 patients by using the dedicated basket catheter and 60 patients by only the conventional devices. The complete stone clearance was achieved in 87.8% in the dedicated basket group and 88.3% in the conventional device group. Symptomatic recurrence was observed in 16.7% of the dedicated basket group and 47.2% of the conventional device group (P < 0.01). In the multivariate analysis, the use of the dedicated basket catheter was significantly associated with the reduced risk of symptomatic recurrence (hazard ratio, 0.40; 95% confidence interval, 0.15-0.92, P = 0.031). The complication rate and the cost were comparable between the two groups. CONCLUSION: The use of this dedicated pancreatic basket catheter significantly reduced symptomatic recurrence after complete pancreatic stone removal.

Double Guidewire Technique Using an Uneven Double Lumen Catheter for Endoscopic Ultrasound-Guided Interventions.

BACKGROUND: Endoscopic ultrasonography (EUS)-guided interventions are often performed using a single guidewire (SGW), but there are a few reports on the use of double guidewire (DGW) technique to facilitate multiple drainage placement during EUS-guided drainage of pancreatic fluid collections. This DGW technique may have advantages other than multiple drainage placement during EUS-guided interventions such as scope stabilization, support for stone extraction and device insertion. METHODS: Consecutive patients who underwent EUS-guided interventions between Feb 2012 and Apr 2019 were retrospectively reviewed. The rate and reasons of DGW technique, and clinical outcomes were evaluated. DGW technique was performed, using an uneven double lumen cannula (UDLC), which facilitates insertion of 0.025-in. and 0.035-in. guidewires. RESULTS: A total of 249 EUS-guided interventions were analyzed, and DGW technique was utilized primarily in 65 cases (25.7%) and as a salvage after failed SGW technique in 18 cases (7.1%). The reasons for DGW technique were 60 multiple drainage placement, 10 scope stabilization, 7 device insertion, 5 safety guidewire, and 4 antegrade stone removal. Insertion of UDLC and DGW was successful in 100%. Technical success rate of preplanned interventions was 92.7% (96.9% in primary DGW and 77.8% in salvage DGW technique). Adverse events were observed in 19.5% after DGW but were not related to DGW technique. CONCLUSIONS: DGW technique using UDLC during EUS-guided interventions was technically feasible and safe. In addition to multiple drainage insertion, it can potentially support complex EUS-guided interventions.

Endoscopic management of pancreatic diseases in patients with surgically altered anatomy: clinical outcomes of combination of double-balloon endoscopy- and endoscopic ultrasound-guided interventions.

OBJECTIVES: In patients with surgically altered anatomy, endoscopic treatment of pancreatic diseases is technically challenging. We aimed to evaluate the feasibility, effectiveness, and safety of an interchangeable combination of double-balloon endoscope-assisted ERP (DB-ERP) and endoscopic ultrasonography-guided pancreatic duct drainage (EUS-PD) in this clinical setting. METHODS: Consecutive patients with surgically altered anatomy undergoing endoscopic treatment (DB-ERP, EUS-PD, or both) for pancreatic diseases were studied. The primary outcome was technical success; secondary outcomes were clinical success and adverse events. RESULTS: Forty patients who underwent DB-ERP (38) and EUS-PD (2) as an initial intervention were retrospectively studied. Indications for intervention included 18 pancreaticojejunostomy anastomotic stricture (PJAS), four pancreatic duct stone (PDS), four pancreatic fistula (PF), 11 PJAS with PDS, and three PJAS with PF. Prior surgical reconstruction was 26 Billroth-II, 13 Roux-en-Y, and one Imanaga reconstruction. Along with salvage procedures including three DB-ERP and seven EUS-PD, the overall technical success rates of DB-ERP and EUS-PD were 70.7% (29/41) and 100% (9/9), respectively. Clinical success was achieved in 85.0% (34/40) by combination of DB-ERP and EUS-PD; successful drainage for PJAS, complete removal of PDS, and resolution of PF were achieved in 90.6%, 80.0%, and 71.4%, respectively. Adverse event rates were 12.2% (5/41; one perforation, and four pancreatitis) in DB-ERP and 55.6% (5/9; three pancreatic leakage, and two abdominal pain) in EUS-PD. CONCLUSIONS: A combination of DB-ERP and EUS-PD can achieve high technical and clinical success for pancreatic diseases in surgically altered anatomy patients. A prospective multicenter study to investigate an appropriate treatment algorithm is warranted.

Endoscopic treatment of hepaticojejunostomy anastomotic strictures using fully-covered metal stents.

OBJECTIVES: With the emergence of the double-balloon endoscope (DBE), hepaticojejunostomy anastomotic strictures (HJASs) are increasingly managed endoscopically. However, balloon dilation and/or plastic stent placement may be associated with low stricture resolution rates and long treatment duration. We utilized a fully-covered metal stent (FCSEMS), which was designed for temporary placement for benign biliary strictures, and assessed its feasibility for patients with HJASs. METHODS: We retrospectively studied 20 patients who underwent DBE-assisted FCSEMS placement for HJASs between June 2017 and March 2019. The FCSEMS was removed endoscopically at three months of stent placement. The outcomes investigated were the stricture resolution at the time of FCSEMS removal, the stricture recurrence, and adverse events. RESULTS: Among 20 patients treated, stricture resolution was achieved in 17 patients (85.0%) at three months of stent placement. The FCSEMS was removed endoscopically without any technical difficulties in all cases except for two with asymptomatic stent migration due to stricture resolution. During a median follow-up period of 11.9 months (interquartile range, 7.5-18.0 months), an HJAS recurred in one patient (5.9%). For two patients without stricture resolution and one patient with recurrent stricture, another FCSEMS placement for 77, 84, and 186 days resolved the stricture. The overall stricture resolution rate was 95.0%. In one patient with FCSEMS-induced de novo stricture, long-term plastic stent placement was required. Procedure-related adverse events included mild cholangitis in two patients and mild pancreatitis in one patient. CONCLUSIONS: Endoscopic treatment using a FCSEMS via DB-ERCP was a feasible and effective treatment option for a HJAS.

Long-term outcomes of a long, partially covered metal stent for EUS-guided hepaticogastrostomy in patients with malignant biliary obstruction (with video).

BACKGROUND AND AIMS: We previously reported safety and effectiveness of EUS-guided hepaticogastrostomy (EUS-HGS) using a long, partially covered metal stent (LP-CMS) for malignant biliary obstruction (MBO). In this study, we aimed to evaluate long-term outcomes of EUS-HGS in an expanded cohort. METHODS: One hundred ten patients undergoing EUS-HGS using an LP-CMS in 2 centers were retrospectively studied. Technical and functional success, adverse events, recurrent biliary obstruction (RBO), and reinterventions were evaluated. RESULTS: The cause of MBO was pancreatic cancer in 50%, and the location of MBO was distal in 68%. The stent length was 8 cm in 2%, 10 cm in 84%, and 12 cm in 15%, with a median intragastric stent length of 54 mm. Technical and functional success rates were 100% and 94%, respectively. The adverse event rate was 25% (mild 15%, moderate 7%, severe 3%), but about one-half of adverse events were mild transient fever and abdominal pain. RBO developed in 33%, with a median cumulative time to RBO of 6.3 months. The major cause of RBO was hyperplasia at an uncovered portion. The presence of prior biliary drainage and short intragastric stent length were significantly associated with RBO. Reintervention for RBO was successfully achieved through the EUS-HGS route in 92%. The remaining reintervention procedures were 1 EUS-HGS and 2 percutaneous transhepatic biliary drainage all in cases with hilar MBO. CONCLUSIONS: EUS-HGS using an LP-CMS for unresectable MBO was safe and effective. RBO was not uncommon, but reintervention through the EUS-HGS route was technically possible in most cases.

A prospective study of fully covered metal stents for different types of refractory benign biliary strictures.

BACKGROUND: While endoscopic management of benign biliary strictures (BBSs) is the standard of care, long-term treatment remains the issue in refractory cases, especially for anastomotic strictures after living-donor liver transplantation (LDLT) and hepaticojejunostomy anastomotic strictures (HJAS). The aim of this prospective study was to evaluate the safety and effectiveness of a fully covered self-expandable metal stent (FCSEMS) for patients with refractory BBSs. METHODS: Patients with BBSs that were unamenable to endoscopic plastic stent placement with a treatment period of more than 6 months were eligible. An FCSEMS was placed endoscopically and removed after 90 days. In patients with surgically altered anatomy, an FCSEMS was placed using a double-balloon endoscope. The primary outcome was stricture resolution at FCSEMS removal. The secondary outcomes included stricture recurrence and adverse events. RESULTS: A total of 30 patients were enrolled: the causes of their BBSs were anastomotic stricture after LDLT in 13, HJAS in 12, post-cholecystectomy in two, chronic pancreatitis in two, and post-hepatectomy in one. The technical success rate of FCSEMS placement was 100 % and all FCSEMSs were successfully removed. The rate of stricture resolution at FCSEMS removal was 96.6 % (91.7 % in the post-LDLT group and 100 % in the HJAS group). Stricture recurrence occurred in three HJAS patients (10.7 %) during a median follow-up period of 15.6 months. Adverse events were observed in 12.1 %: five cholangitis, one pancreatitis, and one perforation. CONCLUSION: Temporary placement of an FCSEMS was a feasible and effective treatment option for refractory BBSs, especially for post-LDLT strictures and HJAS.

Regular Statin Use and Incidence of Postendoscopic Retrograde Cholangiopancreatography Pancreatitis.

GOALS AND BACKGROUND: Endoscopic retrograde cholangiopancreatography is widely utilized to diagnose and treat various pancreaticobiliary diseases, but postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) can be a fatal adverse event. Evidence suggests that statins may exhibit suppressive effects on inflammation in the pancreas. We carried out an observational cohort study to examine the protective effect of statins on PEP. STUDY: We retrospectively identified consecutive patients who underwent endoscopic retrograde cholangiopancreatography at a tertiary care center in Japan between January 2010 and January 2019. The incidences of PEP were compared between regular and nonregular statin users. Using the multivariable logistic regression model, we examined the association of regular statin use with the incidence of PEP controlling for potential risk factors for PEP. RESULTS: We included 2664 patients (328 regular statin users and 2336 nonregular users). The incidence of PEP did not differ by statin use status (P=0.52): 8.8% in regular statin users and 7.9% in nonregular users. The multivariable-adjusted odds ratio for PEP comparing regular statin use with nonregular use was 1.08 (95% confidence interval, 0.67-1.72; P=0.76). When we examined specific statin types (hydrophilic and lipophilic statins), we consistently observed the null association: 6.8% of 132 hydrophilic statin users and 10% of 196 lipophilic statin users (P=0.74 and 0.27, respectively, compared with nonregular users). CONCLUSIONS: Regular statin use was not shown to be protective against PEP. A further investigation is warranted before this medication is tested in prospective randomized trials.

Endoscopic ultrasound-guided gallbladder drainage with a combined internal and external drainage tubes for acute cholecystitis.

BACKGROUND AND AIM: Lumen-apposing metal stent is widely used for endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) nowadays but not approved in many countries and might be unsuitable for elective laparoscopic cholecystectomy (LC) because of its large enterocholecysto fistula. A combination of double pigtail plastic stent (DPPS) and naso-cystic tube (NCT) could overcome these problems. The aim of this study was to estimate the efficacy and safety of this method in patients with acute cholecystitis unfit for urgent cholecystectomy both as bridge to surgery and palliation. METHODS: This was a prospective, single-center feasibility study. EUS-GBD was performed with a 7Fr DPPS followed by an NCT placement. NCT was removed after 1 week. LC was performed 2 or 3 months after EUS-GBD in eligible patients. In patients who did not underwent cholecystectomy, DPPS was left in place. RESULTS: Twenty-three patients were enrolled. Both technical and clinical success rates were 96% (22/23). Early adverse events rate was 13% (3/23), including one bile peritonitis, one intraperitoneal abscess, and one melena. LC was attempted in 12 patients, and conversion to open cholecystectomy was required in three (25%). Neither recurrence of cholecystitis nor late adverse event occurred during 6 months of follow up in 10 patients who did not undergo cholecystectomy. CONCLUSION: EUS-GBD with a combination of DPPS and NCT is considered an effective and safe technique both as bridge to surgery and palliation.