Intraductal Papillary Mucinous Neoplasm Surveillance Leads to Early Diagnosis and Better Outcomes of Concomitant Cancer.

OBJECTIVE: To examine whether long-term surveillance of intraductal papillary mucinous neoplasms (IPMNs) leads to early diagnosis and better clinical outcomes of pancreatic ductal adenocarcinomas (PDACs) developing concomitantly with IPMNs. SUMMARY BACKGROUND DATA: Long-term image-based surveillance is recommended for patients with low-risk IPMNs. However, it is unknown whether the surveillance can improve surgical and survival outcomes of patients with concomitant PDACs. METHODS: Using a prospective single-institutional cohort of 4,620 patients with pancreatic cysts including 3,638 IPMN patients, we identified 63 patients who developed concomitant PDAC during long-term surveillance. We compared overall survival (OS) of 46 cases with concomitant PDAC to that of 460 matched cases diagnosed with non-IPMN-associated PDAC at the same institution. Multivariable hazard ratios and 95% confidence intervals (CIs) for overall mortality were computed using the Cox regression model with adjustment for potential confounders. RESULTS: Concomitant PDACs were identified at an earlier cancer stage compared to non-IPMN-associated PDACs with 67% and 38% cases identified at stage 2 or earlier, respectively (P<0.001) and 57% and 21% cases with R0 resection, respectively (P<0.001). Compared to non-IPMN-associated PDACs, concomitant PDACs were associated with longer OS (P=0.034) with a multivariable hazard ratio of 0.61 (95% CI, 0.39-0.96). The 5-year survival rate of patients with concomitant PDAC was higher compared to patients with non-IPMN-associated PDAC (34% vs. 18%, respectively; P=0.018). CONCLUSIONS: The surveillance for patients with IPMNs was associated with early identification of concomitant PDACs and longer survival of patients diagnosed with this malignancy.

The Revised Kyoto Criteria and Risk of Malignancy Among Patients With Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: The revised Kyoto guidelines have a new catalog of high-risk stigmata and worrisome features for the risk stratification of intraductal papillary mucinous neoplasms (IPMNs). We aimed to validate the stratification system in terms of short- and long-term risks of pancreatic carcinoma. METHODS: We included 3336 patients diagnosed with IPMNs in 2000-2021 and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma diagnosis. We used the multivariable competing-risks proportional hazards regression model to calculate subdistribution hazard ratios for long-term incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In short-term analyses, pancreatic carcinomas were prevalent predominantly in IPMNs with high-risk stigmata (49% vs 1.3% and 0.05% in IPMNs with worrisome features and no risk factors, respectively). In long-term analyses of worrisome features, the main pancreatic duct diameter of 5-9.9 mm, acute pancreatitis, and IPMN growth rate of 2.5 mm/y were associated with a high incidence with multivariable subdistribution hazard ratios of 3.46 (95% confidence interval [CI], 2.04-5.89), 5.65 (95% CI, 1.86-17.2), and 3.83 (95% CI, 2.14-6.86), respectively. An increasing number of worrisome features at baseline was associated with a higher prevalence and incidence of pancreatic carcinoma (Ptrend < .001). Patients with 1, 2, and 3-4 worrisome features had multivariable subdistribution hazard ratios for pancreatic cancer incidence of 1.43 (95% CI, 0.93-2.19), 2.17 (95% CI, 1.17-4.05), and 10.1 (95% CI, 4.20-24.5), respectively (vs no positive feature). CONCLUSIONS: The revised Kyoto criteria stratify IPMN patients well in terms of the short- and long-term risks of pancreatic carcinoma diagnosis, potentially informing personalized patient management.

Older Age as a Worrisome Feature in Patients With Intraductal Papillary Mucinous Neoplasms: A Long-Term Surveillance Study.

INTRODUCTION: Aging has been implicated in the development of various cancer types. No study has specifically investigated age at intraductal papillary mucinous neoplasm (IPMN) diagnosis in relation to the long-term risk of pancreatic carcinogenesis. METHODS: Within a prospective cohort of 4,104 patients diagnosed with pancreatic cysts, we identified 3,142 patients with IPMNs and examined an association of age at IPMN diagnosis with the incidence of pancreatic carcinoma. Using the multivariable competing-risks proportional hazards regression model, we estimated subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs) for pancreatic carcinoma incidence according to age at IPMN diagnosis. RESULTS: During 22,187 person-years of follow-up, we documented 130 patients diagnosed with pancreatic carcinoma (64 with IPMN-derived carcinoma and 66 with concomitant ductal adenocarcinoma). Older age at IPMN diagnosis was associated with a higher risk of pancreatic cancer incidence ( Ptrend = 0.002). Compared with patients younger than 55 years, patients aged 55-64, 65-74, and ≥ 75 years had adjusted SHRs of 1.80 (95% CI, 0.75-4.32), 2.56 (95% CI, 1.10-5.98), and 3.31 (95% CI, 1.40-7.83), respectively. Patients aged 70 years and older had a numerically similar adjusted SHR compared with patients younger than 70 years with worrisome features defined by the international consensus guidelines (1.73 [95% CI, 1.01-2.97] and 1.66 [95% CI, 0.89-3.10], respectively). DISCUSSION: Older patients with IPMNs were at a higher risk of developing pancreatic carcinoma during surveillance. Surgically fit elderly patients may be good candidates for periodic surveillance aimed at a reduction of pancreatic cancer-related deaths.

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.

Balloon endoscopy-assisted endoscopic retrograde cholangiopancreatography for hepatolithiasis in patients with hepaticojejunostomy.

BACKGROUND AND AIM: Balloon endoscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) is an emerging procedure for pancreatobiliary diseases in patients with surgically altered anatomy. However, data on BE-ERCP for hepatolithiasis after hepaticojejunostomy (HJS) are still limited. METHODS: Stone removal success, adverse events and recurrence were retrospectively studied in consecutive patients who underwent BE-ERCP for hepatolithiasis after HJS between January 2011 and October 2022. Subgroup analysis was performed to compare clinical outcomes between patients who had undergone HJS over 10 years before (past HJS group) and within 10 years (recent HJS group). RESULTS: A total of 131 patients were included; 39% had undergone HJS for malignancy and 32% for congenital biliary dilation. Scope insertion and complete stone removal were successful in 89% and 73%, respectively. Early adverse events were observed in 9.9%. Four patients (3.1%) developed gastrointestinal perforation but could be managed conservatively. Hepatolithiasis recurrence rate was 17%, 20% and 31% in 1-year, 3-year, and 5-year after complete stone removal. The past HJS group was the only risk factor for failed stone removal (odds ratio 10.4, 95% confidence interval 2.99-36.5) in the multivariable analysis. Failed scope insertion (20%) and failed guidewire or device insertion to the bile duct (22%) were two major reasons for failed stone removal in the past HJS group. CONCLUSIONS: BE-ERCP for hepatolithiasis was effective and safe in cases with HJS but the complete stone removal rate was low in the past HJS group. Recurrent hepatolithiasis was common and careful follow up study is needed even after complete stone removal.

A retrospective comparative study of biliary drainage using balloon endoscopy and endoscopic ultrasound for malignant obstruction in patients with surgically altered anatomy.

BACKGROUND AND AIMS: Endoscopic biliary drainage for malignant biliary obstruction (MBO) in patients with surgically altered anatomy is challenging, and technical difficulty could differ by the anatomy. Balloon endoscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) and endoscopic ultrasonography-guided biliary drainage (EUS-BD) are both emerging procedures, and we conducted the single-center, retrospective study to compare clinical outcomes of BE-ERCP and EUS-BD for MBO. METHODS: Consecutive patients with surgically altered anatomy who underwent BE-ERCP or EUS-BD for MBO were retrospectively studies. Technical and clinical success rates, adverse events (AEs), and time to recurrent biliary obstruction (TRBO) were compared. RESULTS: Patient characteristics were comparable between BE-ERCP (n = 118) and EUS-BD (n = 32), other than more patients with hepaticojejunostomy in the BE-ERCP group (66% vs. 44%, P = 0.03). Technical success rate was significantly higher in the EUS-BD group (70% vs. 94%, P = 0.005), but clinical success rates (84% vs. 90%, P = 0.55), early AE (14% vs. 22%, P = 0.29) and late AE rates (42% vs. 38%, P = 0.84), and RBO rates (31% vs. 34%, P = 0.67) were comparable between the groups. TRBO was 170 and 206 days in the BE-ERCP and EUS-BD group (P = 0.37). In the subgroup analysis of patients with the intact papilla, the technical success rate of BE-ERCP was as low as 55%, compared to 94% in EUS-BD (P = 0.003). CONCLUSION: EUS-BD was associated with higher technical success rate than BE-ERCP for MBO in patients with surgically altered anatomy.

Skeletal muscle status and survival among patients with advanced biliary tract cancer.

BACKGROUND: Studies have demonstrated a prognostic role of sarcopenia (i.e., loss of skeletal muscle volume and functionality) in patients with various cancer types. In patients with biliary tract cancer, the quantity and quality of skeletal muscles and their serial changes have not been fully investigated in relation to survival outcomes. METHODS: We identified 386 patients with unresectable or recurrent biliary tract cancer and calculated skeletal muscle index (SMI) and skeletal muscle density (SMD) to estimate muscular quantity and quality, respectively, based on computed tomography images. Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) according to skeletal muscle status and its serial change. RESULTS: Compared to patients without sarcopenia, patients with sarcopenia were associated with shorter PFS (multivariable HR, 1.60; 95% CI, 1.15-2.22; P = 0.005), but not with OS (P = 0.027) at the adjusted α level of 0.013. SMD at baseline was associated with OS (multivariable HR comparing the extreme quartiles, 1.52; 95% CI, 1.07-2.14; Ptrend = 0.012), but not with PFS (Ptrend = 0.13). A reduction in SMI rather than that in SMD was associated with OS. Progressive disease was a risk factor for reductions in SMI and SMD. CONCLUSIONS: Skeletal muscle quantity and quality and their serial changes were associated with survival outcomes in patients with advanced biliary tract cancer. Our data highlight the importance of designing nutritional and physical interventions for improvements in skeletal muscle status.

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.

Early skeletal muscle mass decline is a prognostic factor in patients receiving gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer: a retrospective observational study.

PURPOSE: Patients with pancreatic cancer often have cancer cachexia at diagnosis. Recent studies suggested that loss of skeletal muscle mass was related to cancer cachexia, which hindered continuance of chemotherapy and could be one of prognostic factors in pancreatic cancer, however the association remains unclear in patients receiving gemcitabine and nab-paclitaxel (GnP). METHODS: We retrospectively studied 138 patients with unresectable pancreatic cancer receiving first-line GnP at the University of Tokyo from January 2015 to September 2020. We calculated body composition in CT images before chemotherapy and at initial evaluation, and evaluated the association of both body composition before chemotherapy and its changes at initial evaluation. RESULTS: Compared by skeletal muscle mass index (SMI) change rate between pre-chemotherapy and initial evaluation, there were statistically significantly differences in the median OS: 16.3 months (95%CI 12.3-22.7) and 10.3 months (95%CI 8.3-18.1) between SMI change rate ≥ -3.5% and < -3.5% groups (P = 0.01). By multivariate analysis for OS, CA19-9 (HR 3.34, 95%CI 2.00-5.57, P < 0.01), PLR (HR 1.68, 95%CI 1.01-2.78, P = 0.04), mGPS (HR 2.32, 95%CI 1.47-3.65, P < 0.01) and relative dose intensity (HR 2.21, 95%CI 1.42-3.46, P < 0.01) were significantly poor prognostic factors. SMI change rate (HR 1.47, 95%CI 0.95-2.28, P = 0.08) showed a trend to poor prognosis. Sarcopenia before chemotherapy was not significantly associated with PFS or OS. CONCLUSION: Early skeletal muscle mass decline was associated with poor OS. Further investigation is warranted whether the maintenance of skeletal muscle mass by nutritional support would improve prognosis.

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 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 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.

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.

The impact of age and comorbidity in advanced or recurrent biliary tract cancer receiving palliative chemotherapy.

BACKGROUND AND AIM: Limited data are available on age and comorbidity assessment in patients with biliary tract cancer (BTC). This study aimed to evaluate the association of age and comorbidity burden with clinical outcomes of chemotherapy for BTC. METHODS: Consecutive 197 BTC patients undergoing first-line chemotherapy between 2007 and 2017 were retrospectively studied. Patients were classified to three groups according to the age-adjusted Charlson comorbidity index (ACCI) excluding the score about BTC and progression-free survival, overall survival (OS), and safety were compared. RESULTS: Fifty-one patients (26%) were elderly (≥ 75 years), and ACCI was 0-2 in 73 patients (37%), 3-4 in 98 (50%), and ≥ 5 in 26 (13%). ACCI was associated with the administration of first-line combination chemotherapy (89% in 0-2, 80% in 3-4, and 64% in ≥ 5, P < 0.01) and second-line chemotherapy (67% in 0-2, 51% in 3-4, and 35% in ≥ 5, P = 0.01). ACCI was prognostic for OS in addition to performance status, disease status, and CA19-9: The hazard ratios in ACCI of 3-4 and ≥ 5 were 1.39 and 1.79, compared with ACCI of 0-2 (P = 0.04). While overall safety profile did not differ by ACCI, higher ACCI score group developed Grade 3-4 neutropenia more frequently (26% in 0-2, 42% in 3-4, and 46% in ≥ 5, P = 0.04). CONCLUSION: Age and comorbidity burden did affect OS and safety profile in BTC patients undergoing first-line palliative chemotherapy. ACCI can be a simple and useful tool to evaluate the age and comorbidity burden in these patients.

Second-line chemotherapy in patients with advanced or recurrent biliary tract cancer: a single center, retrospective analysis of 294 cases.

Purpose The survival benefit of first-line chemotherapy (CT1) for biliary tract cancer (BTC) is now established but the role of second-line chemotherapy (CT2) has not been fully elucidated yet. Methods Consecutive advanced BTC patients receiving CT1 between 2000 and 2016 were retrospectively studied. We investigated the safety and efficacy of CT2, prognostic factors for residual survival after CT1, and explored subgroups who would benefit from CT2. Results Among 294 patients receiving CT1 for advanced BTC, CT2 was given in 139 patients (47%). CT2 provided a response rate of 4%, a disease control rate of 52%, a median progression-free survival of 2.8 and overall survival of 7.7 months, respectively. CT2 was associated with longer residual survival after CT1 (hazard ratio [HR] 0.61, p < 0.01), as well as PS of 0-1 (HR 0.53, p < 0.01), best response to CT1 of PD (HR 1.46, p = 0.01), and CEA ≥5.0 ng/mL (HR 1.69, p < 0.01). The effects of CT2 were homogeneous across almost all subgroups but were more prominent in patients with age ≥ 70 years (HR 0.32, p for interaction =0.02), CA19-9 ≥ 200 IU/mL (HR 0.41, p for interaction = 0.08) and CEA ≥5.0 ng/mL (HR 0.41, p for interaction = 0.06). Conclusions The introduction rate of CT2 was 47%. Although the efficacy of CT2 was modest in terms of tumor response, it was associated with better survival. Further investigations are necessary both to develop more effective regimens and to select patients who will benefit from CT2.