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Malignant hilar biliary obstruction (MHBO) can cause obstructive jaundice and/or cholangitis necessitating appropriate biliary drainage. Endoscopic biliary stenting is the first-choice treatment, especially in unresectable cases, owing to its minimally invasive nature and utility. However, the hilar region is complex because of the branching and curving of bile ducts, making strictures in this area more complicated. Therefore, MHBO stenting is challenging, and treatment strategies have yet to be established. Furthermore, recent advances in antitumor therapies have altered the background surrounding the development of stenting strategies. Therefore, it is necessary to understand and grasp the current evidence well and to accumulate additional evidence reflecting the current situation. This study reviews the current status, issues, and prospects of endoscopic stenting for MHBO, especially in unresectable cases.

Competing Interests: None declared.

The consensus-based TOKYO criteria were proposed as a standardized reporting system for endoscopic transpapillary biliary drainage. The primary objective was to address issues arising from the inconsistent reporting of stent outcomes across studies, which has complicated the comparability and interpretation of study results. However, the original TOKYO criteria were not readily applicable to recent modalities of endoscopic biliary drainage such as biliary drainage based on endoscopic ultrasound or device-assisted endoscopy. There are increasing opportunities for managing hilar biliary obstruction and benign biliary strictures through endoscopic drainage. Biliary ablation has been introduced to manage benign and malignant biliary strictures. In addition, the prolonged survival times of cancer patients have increased the importance of evaluating overall outcomes during the period requiring endoscopic biliary drainage rather than solely focusing on the patency of the initial stent. Recognizing these unmet needs, a committee has been established within the Japan Gastroenterological Endoscopy Society to revise the TOKYO criteria for current clinical practice. The revised criteria propose not only common reporting items for endoscopic biliary drainage overall, but also items specific to various conditions and interventions. The term "stent-demanding time" has been defined to encompass the entire duration of endoscopic biliary drainage, during which the overall stent-related outcomes are evaluated. The revised TOKYO criteria 2024 are expected to facilitate the design and reporting of clinical studies, providing a goal-oriented approach to the evaluation of endoscopic biliary drainage., (© 2024 The Author(s). Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background/objectives: The association between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) remains controversial. This study aimed to clarify the long-term prognosis and risk of malignancies in AIP patients in Japan., Methods: We conducted a multicenter retrospective cohort study on 1364 patients with type 1 AIP from 20 institutions in Japan. We calculated the standardized incidence ratio (SIR) for malignancies compared to that in the general population. We analyzed factors associated with overall survival, pancreatic exocrine insufficiency, diabetes mellitus, and osteoporosis., Results: The SIR for all malignancies was increased (1.21 [95 % confidence interval: 1.05-1.41]) in patients with AIP. Among all malignancies, the SIR was highest for PC (3.22 [1.99-5.13]) and increased within 2 years and after 5 years of AIP diagnosis. Steroid use for ≥6 months and ≥50 months increased the risk of subsequent development of diabetes mellitus and osteoporosis, respectively. Age ≥65 years at AIP diagnosis (hazard ratio [HR] = 3.73) and the development of malignancies (HR = 2.63), including PC (HR = 7.81), were associated with a poor prognosis, whereas maintenance steroid therapy was associated with a better prognosis (HR = 0.35) in the multivariate analysis. Maintenance steroid therapy was associated with a better prognosis even after propensity score matching for age and sex., Conclusions: Patients with AIP are at increased risk of developing malignancy, especially PC. PC is a critical prognostic factor for patients with AIP. Although maintenance steroid therapy negatively impacts diabetes mellitus and osteoporosis, it is associated with decreased cancer risk and improved overall survival., Competing Interests: Declaration of competing interest None., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICIs) are being increasingly used to treat advanced malignancies. ICI-induced pancreatic injury (ICI-PI), which is an immune-related adverse event that may be a risk factor of ICI-associated pancreatitis, is not well documented in the literature., Methods: Consecutive patients who received ICIs for advanced malignancies from August 2015 through October 2022 were analyzed for the incidence of ICI-PI based on the Common Terminology Criteria for Adverse Events and ICI-associated pancreatitis. The imaging, clinical, and pathological findings of ICI-associated pancreatitis were also assessed., Results: This study enrolled 843 patients. In multivariable analyses, dual or simultaneous immunotherapy and ≥10 cycles of ICI administration were significant predictive factors for all grades of pancreatic injury, including grade ≥3. Notably, patients who received simultaneous immunotherapy exhibited a higher incidence of grade ≥3 pancreatic injuries compared with those receiving asynchronous immunotherapy in univariable analysis ( P = 0.032). One-fifth of the patients (16/70) with grade ≥3 pancreatic injuries had imaging evidence of pancreatitis similar to mild acute pancreatitis. ICI-associated pancreatitis was observed in 5.7% (48/843) of patients, including 1.8% (15/843) with moderate-to-severe pancreatitis (grade ≥2). Symptomatic cases (0.36%, 3/843) were treated with steroids with favorable outcomes. Immunohistochemistry for CD4 and CD8 revealed greater infiltration of CD8 + than CD4 + lymphocytes., Discussion: Simultaneous immunotherapy and dual immunotherapy are risk factors of ICI-PI. Although most patients diagnosed with ICI-PI and ICI-associated pancreatitis were asymptomatic and had a low mortality likelihood, long-term outcomes, including endocrine and exocrine function, should be carefully monitored., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest.

Background and Aims: Although long-term stent placement using endoscopic transpapillary gallbladder drainage (ETGBD) and EUS-guided gallbladder drainage (EUS-GBD) reportedly reduces cholecystitis recurrence, comparative evidence of their safety and efficacy is scarce. This study aimed to examine and compare the long-term utility of EUS-GBD versus that of ETGBD in poor surgical candidates., Methods: A total of 379 high-risk surgical patients with acute calculous cholecystitis met the eligibility criteria for enrollment in this study. The technical success and adverse events (AEs) were compared between the EUS-GBD and ETGBD groups, and propensity score matching was performed to adjust for differences between the groups. Both groups underwent plastic stent placement, and scheduled stent exchange and removal were not performed in either group., Results: The technical success rate of EUS-GBD was significantly higher than that of ETGBD (96.7% vs 78.9%, P < .001), whereas the early AE rate did not differ significantly between the 2 methods (7.8% vs 8.9%, P = 1.000). The rate of recurrent cholecystitis did not differ significantly (3.8% vs 3.0%, P = 1.000), but the rate of symptomatic late AEs, in addition to cholecystitis, was significantly lower with EUS-GBD than with ETGBD (1.3% vs 13.4%, P = .006). Consequently, the overall late AE rate was significantly lower with EUS-GBD (5.0% vs 16.4%, P = .029). Multivariate analysis revealed that EUS-GBD was associated with a significantly longer time to late AE (hazard ratio, .26; 95% confidence interval, .10-.67; P = .005)., Conclusions: Long-term stent placement via EUS-GBD is a promising potential option for limiting late AEs, including recurrence, in poor surgical candidates with calculous cholecystitis., Competing Interests: Disclosure The authors declare no conflicts of interest for this study., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: We attempted to determine the indications and limitations of steroid therapy as the first-line therapy in patients with autoimmune pancreatitis (AIP) with cyst formation (ACF)., Methods: This Japanese multicenter survey was conducted to examine the merits/demerits of steroid treatment as the initial therapy for ACF., Results: Data of a total of 115 patients with ACF were analyzed. Complete remission was achieved in 86% (86/100) of patients who had received steroid treatment, but only 33.3% (5/15) of patients who had not received steroids. Relapse after the remission (n = 86) occurred in 7.6% (6/86) of patients who had received steroid therapy, but 40% (2/5) of patients who had not received steroid therapy. Multivariate analysis identified adoption of the wait and watch approach without steroid treatment (odds ratio = 0.126, P < .001) as a significant and independent negative predictor of remission of ACF. As for predictors of relapse, the presence of varix (odds ratio = 5.83, P = .036) was identified as an independent risk factor., Conclusion: Steroid therapy plays an important role as first-line therapy in AIP patients with pancreatic cyst formation, however, varix formation, besides the diameter of the cyst(s), is a risk factor for refractoriness to steroid therapy., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk., Design: We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated., Results: Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8 years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients., Conclusion: Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Although long-term stent placement using endoscopic gallbladder stenting (EGBS) reportedly reduces cholecystitis recurrence in patients unfit to undergo cholecystectomy, its efficacy and safety remain uncertain., Aims: This study aimed to examine the long-term effect of EGBS in poor surgical candidates of cholecystectomy., Methods: A total of 528 high-risk surgical patients with acute calculous cholecystitis met this study's eligibility criteria. The technical success and adverse events (AE) were compared between patients who underwent EGBS and those who underwent percutaneous transhepatic gallbladder drainage (PTGBD). Elective stent exchange and removal were not performed after EGBS. The external tube was removed after improvement of cholecystitis following PTGBD., Results: The technical success rate was significantly lower with EGBS compared to PTGBD (75.4% versus 98.7%, P < 0.001), while the early-AE rate did not differ significantly between the two methods (7.7% versus 4.3%, P = 0.146). The 1-, 3-, and 5-year cumulative incidence rates of cholecystitis were 3.8%, 7.2%, and 7.2% with EGBS, and 11.7%, 17.6%, and 30.2% with PTGBD, respectively (P = 0.001). Conversely, those of symptomatic late-AE (except cholecystitis) were 8.2%, 22.7%, and 31.4% with EGBS, and 7.5%, 10.9%, and 13.1% with PTGBD, respectively (P = 0.035). Thus, the 1-, 3-, and 5-year cumulative incidence of overall late-AE was 12.0%, 30.4%, and 40.4% with EGBS, and 19.2%, 28.3%, and 42.5% with PTGBD, respectively (P = 0.649)., Conclusions: Long-term stent placement via EGBS is useful for preventing the recurrence of cholecystitis, but the success rate is low and the frequency of other late-AE increases with the prolongation of the indwelling period., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endoscopic biliary drainage strategies for managing unresectable malignant hilar biliary obstruction differ in terms of stent type, drainage area, and deployment method. However, the optimal endoscopic drainage strategy remains unclear. Uncovered self-expandable metal stents (SEMS) are the preferred type because of their higher functional success rate, longer time to recurrent biliary obstruction (RBO), and fewer cases of reintervention than plastic stents (PS). Other PS subtypes and covered SEMS, which feature a longer time to RBO than PS, can be removed during reintervention for RBO. Bilateral SEMS placement is associated with a longer time to RBO and a longer survival time than unilateral SEMS placement. Unilateral drainage is acceptable if a drainage volume of greater than 50% of the total liver volume can be achieved. In terms of deployment method, no differences were observed in clinical outcomes between side-by-side (SBS) and stent-in-stent deployment. Simultaneous SBS boasts a shorter procedure time and higher technical success rate than sequential SBS. This review of previous studies aimed to clarify the optimal endoscopic biliary drainage strategy for unresectable malignant hilar biliary obstruction.

We herein report a 64-year-old man with concomitant pancreatic ductal adenocarcinoma (PDAC) and type 1 autoimmune pancreatitis (AIP). An endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from the pancreatic head mass revealed level 2 histology of AIP and atypical glands. We diagnosed definitive focal AIP using the clinical diagnostic criteria. Computed tomography revealed that the pancreatic mass had not been reduced by steroid therapy. Surgery was performed after a histological PDAC diagnosis was made via a transpapillary biliary biopsy. The resected specimen revealed PDAC associated with AIP. It is important to consider the cooccurrence of PDAC and AIP even if the histological diagnosis via an EUS-FNB is AIP.

Background: Endoscopic transpapillary gallbladder drainage (ETGBD) has been reported as an alternative procedure for acute cholecystitis but remains a challenging procedure., Aims: To elucidate the efficacy of a strategic approach for ETGBD that utilizes a four-step classification system and the optional use of 'Three-pillar' assistance with the following devices: cholangioscopy (SpyGlass DS, SG), a flex-type guidewire (Flex-GW), and a 3-Fr microcatheter (3-Fr Micro)., Methods: A total of 115 patients undergoing ETGBD were studied retrospectively. Characteristics and technical outcomes were compared between conventional ETGBD technique (Classical ETGBD, N = 50) and strategic ETGBD with optional Three-pillar assistance (Strategic ETGBD, N = 65)., Results: SG-assistance (15/65, 23.1%) was as an excellent troubleshooter in Category 1 (failure to identify the cystic duct [CD] orifice) and Category 2 (failure to advance the GW across the CD takeoff due to unfavorable angle). Flex-GW (19/65, 29.2%) worked for Category 3b (failure of GW access to the GB due to multiple tortuosities). 3-Fr Micro (11/65, 16.9%) was effective for Category 3a (failure of GW access to the GB due to CD obstruction) and Category 4 (failure of drainage stent insertion to the GB). The overall technical success rate was significantly higher for Strategic ETGBD (63/65, 96.9%) compared with Classical ETGBD (36/50, 72.0%) (p = 0.0001)., Conclusions: Strategic ETGBD, which includes the Three-pillar assistance options of SG in the initial steps, Flex-GW for tortuous CD, and 3-Fr Micro for stenotic CD, achieved a significantly higher success rate than for Classical ETGBD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yoshida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Sampling of bile juice during endoscopic retrograde cholangiopancreatography (ERCP) has potential benefit of being amenable to the identification of novel biomarkers in liquid biopsy. This study reports the results of a global investigation of exosomal microRNAs (miRNAs) in bile to identify potential biomarkers for biliary tract cancers (BTCs). Eighty-eight bile samples collected during ERCP (45 BTC and 43 noncancer control samples) were enrolled in this study. Eleven BTC samples and nine control samples were assigned as the discovery set. Exosomes in bile and serum samples were collected using a glass membrane column with size-controlled macroporous glass (MPG), and exosomal miRNA expression profiles were evaluated using comprehensive miRNA microarray analysis (3D-Gene). For validation, exosomal miRNA in the bile samples of 34 BTCs and 34 controls were comprehensively evaluated using 3D-Gene. In the discovery set, eight exosomal miRNAs in bile were identified as significant aberrant expression markers, while no miRNA with aberrant expression in serum was identified. In a comparison of the discovery and validation sets, miR-451a and miR-3619-3p were identified as reproducible upregulated markers, and the combination of the two bile miRNAs showed an excellent area under the curve (0.819) value for diagnosing BTCs. In addition, high miR-3619-3p expression in bile reflects poorer prognosis of BTCs (hazard ratio = 2.89). The MPG-extracted exosomal miRNAs in bile aspirated during ERCP provide a convenient new approach for diagnosing biliary diseases. Bile-derived miRNA analysis with miR-451a and miR-3619-3p represents a potentially valuable diagnostic strategy for identifying BTCs as well as a predictive indicator of BTC prognosis., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sahashi, Kato, Yoshida, Hayashi, Naitoh, Hori, Natsume, Jinno, Kachi, Asano, Toyohara, Kito, Ammanamanchi and Kataoka.)

Histological evidence is essential for diagnosing malignant biliary strictures. However, conventional brush cytology remains the primary method used worldwide, despite its low diagnostic sensitivity and accuracy, as it is technically easy, rapid, and cost-effective. The aim of this study was to evaluate the diagnostic performance of a recently introduced endoscopic scraper, the simplicity of which is comparable to that of a conventional brush, by comparing diagnostic yields and the number of collected cells. The sensitivity of the endoscopic scraper when using the cell block technique was significantly higher than when using brush cytology or a brush with the cell block technique (53.6% vs. 30.9%, p < 0.001; 53.6% vs. 31.6%, p = 0.024, respectively). Quantitative digital image analysis of cell block sections revealed that the median number of cells obtained with the endoscopic scraper was significantly higher than when using the brush (1917 vs. 1014 cells, p = 0.042). Furthermore, seven cases (8.3%; 7/84) were diagnosed by immunohistochemical analysis of the cell block section obtained from the endoscopic scraper. Given its simplicity and greater capacity for sample acquisition, use of the endoscopic scraper in conjunction with the cell block technique could replace brush cytology for the histological diagnosis of malignant biliary strictures.

The case of a 28-year-old man who had primary sclerosing cholangitis and autoimmune hepatitis overlapping syndrome (PSC-AIH OS) complicated by ulcerative colitis (UC) is reported. First, he was diagnosed with PSC complicated by UC and initially treated with ursodeoxycholic acid and mesalazine. Twenty-four months later, liver damage reappeared, and we performed a liver biopsy, which showed the features of AIH. We eventually diagnosed him with PSC-AIH OS complicated by UC. If liver damage worsens in PSC patients, PSC-AIH OS should be considered. The optimum management approach for PSC-AIH OS should be established.

Competing Interests: The authors declare that they have no conflict of interest.

Objective: The acceptable duration of steroid therapy for patients with IgG4-sclerosing cholangitis (SC) has been under debate. Our aim is to clarify the feasible duration of steroid treatment., Design: We retrospectively reviewed the data of patients with IgG4-SC and analyzed the following: biliary status during the steroid therapy, incidence of remission, relapse, relapse-free survival rate, and steroid-related complications (SRCs)., Results: Remission was achieved 99.5% (763/767) of patients who received steroid therapy, while remission rate dropped to 63.6% (78/129) of patients who didn't receive it. Relapse was noted in 19.7% (151/763) of the patients who received steroid. Besides, relapse rate went up 38.4% (30/78) of the counterpart. Normalization of the serum total bilirubin and serum alkaline phosphatase (ALP) levels were achieved at two weeks regardless of biliary drainage. Multivariate analysis identified younger onset, MST less than three years, immunosuppressant, and steroid cessation as independent risk factors for relapse. Steroid-free was achieved in the patients underwent MST only 3.4% over 54 months. SRCs were recorded in a total of 99 patients (12.9%) despite sufficient preemptive medications. Multivariate analysis identified history of malignancy and immunosuppressant as independent risk factors for SRCs., Conclusion: Steroid therapy should be continued for no less than three years to reduce the risk of relapse, with use of preemptive measures taken around five years. The biliary drainage might not be mandatory. Steroid as 1 st line therapy could serve as a bridge to further promising treatments., (This article is protected by copyright. All rights reserved.)

Objectives: Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III β-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response., Methods: We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration., Results: High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS., Conclusions: Class III β-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Endobiliary radiofrequency ablation (RFA) is a promising treatment modality for patients with extrahepatic cholangiocarcinoma (eCCA). However, no study has investigated the combined use of endobiliary RFA and gemcitabine plus cisplatin (GC) chemotherapy. This study aimed to examine the feasibility and efficacy of endobiliary RFA with GC therapy for patients with unresectable eCCA., Methods: The study outcomes included overall survival (OS), progression-free survival (PFS), time to recurrent biliary obstruction (RBO), and adverse events associated with the treatment. These parameters were retrospectively compared between 25 patients who underwent RFA with self-expandable metal stent (SEMS) placement followed by GC therapy (with-RFA group) and a control cohort of 25 patients who underwent SEMS placement alone and GC therapy (without-RFA group)., Results: The median time to RBO was significantly longer in the with-RFA group (10.7 versus 5.2 months, p = 0.048). The median OS was significantly higher in patients with locally advanced tumors in the with-RFA group (23.1 versus 16.6 months, p = 0.032), but did not differ significantly in patients with metastasis (11.4 versus 8.5 months, p = 0.180). Similarly, the median PFS was significantly higher in the with-RFA group in patients with locally advanced disease (10.1 versus 7.3 months, p = 0.015), while there was no significant difference in patients with metastasis (5.4 versus 4.4 months, p = 0.529). The rates of various toxicities did not differ significantly between the groups., Conclusions: Endobiliary RFA prolonged the patency period of uncovered SEMS combined with GC therapy in patients with eCCA. Although RFA also yielded survival benefits, its effect was restricted to locally advanced tumors.

With the development of newer devices and technical innovations, pancreaticobiliary endoscopy is expanding to assume more advanced therapeutic roles. As with other devices, slimmed-down "3-Fr microcatheters" are considered to be opening new windows toward entirely new therapeutic techniques for various purposes. Our practical experience with a total of 34 consecutive patients in whom 3-Fr microcatheters were applied during pancreaticobiliary endoscopic procedures clarified the potential roles of this instrument in pancreaticobiliary endoscopy. The major benefits of 3-Fr microcatheters involve their slimness and flexibility. Applications of 3-Fr microcatheters could be categorized into three groups according to the characteristics of usage: (1) utilization as a cannulation catheter for peroral digital cholangioscopy (n = 15); (2) selective advancement through deep flexures or severely stenotic ducts (n = 11); or (3) two-devices-in-one-channel technique (n = 8). The microcatheter worked successfully for cannulation of cholangioscopy in all but one case (14/15, 93.3%). For selective advancement, the microcatheter worked for troubleshooting in 9 of 11 cases (81.8%). With the two-devices-in-one-channel technique, the microcatheter proved satisfactory in all cases (8/8, 100%). In total, the microcatheter was successfully maneuvered in 31 of 34 cases (91.1%), following the failure of procedures using conventional endoscopic techniques. In terms of adverse events, cystic duct injury was only observed in two cases (5.8%), who recovered under conservative observation, because its slimness could minimize the damage. We believe that 3-Fr microcatheters offer effective and safe salvage troubleshooting during various endoscopic pancreaticobiliary procedures that face troublesome situations with conventional strategies., (© 2021 Japan Gastroenterological Endoscopy Society.)

The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss' к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare that they have no conflict of interest.

IgG4-related sclerosing cholangitis (IgG4-SC) can be classified into four types based on cholangiographic findings and regions of biliary stricture. This cholangiographic classification is useful to differentiate IgG4-SC from mimickers including cholangiocarcinoma, primary sclerosing cholangitis, and pancreatic cancer. Autoimmune pancreatitis (AIP) is a valuable clue for the diagnosis of IgG4-SC because the two are frequently found in association with each other. Two sets of diagnostic criteria for IgG4-SC have been proposed. In Japan, the clinical diagnostic criteria 2020 were recently developed. These clinical diagnostic criteria include narrowing of the intrahepatic and/or extrahepatic bile duct, thickening of the bile duct wall, serological findings, pathological findings, other organ involvement, and effectiveness of steroid therapy. When these criteria are applied, IgG4-SC is initially classified as associated or not associated with AIP, and cholangiographic classification is used for differential diagnosis. In most instances, IgG4-SC can be diagnosed on the basis of clinical diagnostic criteria. However, it is challenging to diagnose isolated IgG4-SC or IgG4-SC not associated with AIP. Here, we review the classification and diagnostic criteria for IgG4-SC, specifically focusing on the clinical diagnostic criteria 2020 and a large IgG4-SC case series from a nationwide survey in Japan.

We aimed to assess some of the potential genetic pathways for cancer development from non-malignant intraductal papillary mucinous neoplasm (IPMN) by evaluating genetic mutations and methylation. In total, 46 dissected regions in 33 IPMN cases were analyzed and compared between malignant-potential and benign cases, or between malignant-potential and benign tissue dissected regions including low-grade IPMN dissected regions accompanied by malignant-potential regions. Several gene mutations, gene methylations, and proteins were assessed by pyrosequencing and immunohistochemical analysis. RASSF1A methylation was more frequent in malignant-potential dissected regions (p = 0.0329). LINE-1 methylation was inversely correlated with GNAS mutation (r =  - 0.3739, p = 0.0105). In cases with malignant-potential dissected regions, GNAS mutation was associated with less frequent perivascular invasion (p = 0.0128), perineural invasion (p = 0.0377), and lymph node metastasis (p = 0.0377) but significantly longer overall survival, compared to malignant-potential cases without GNAS mutation (p = 0.0419). The presence of concordant KRAS and GNAS mutations in the malignant-potential and benign dissected regions were more frequent among branch-duct IPMN cases than among the other types (p = 0.0319). Methylation of RASSF1A, CDKN2A, and LINE-1 and GNAS mutation may be relevant to cancer development, IPMN subtypes, and cancer prognosis., (© 2022. The Author(s).)

Laparoscopic cholecystectomy is the standard and fundamental treatment of choice for acute cholecystitis; however, there are cases in which patients may be poor surgical candidates due to advanced age, comorbidities, and/or general condition. The rate of recurrent cholecystitis is high in patients who are not surgically treated; therefore, the prevention of recurrence in this patient population is an important subject of investigation in the management of cholecystitis. Although it has recently been reported that long-term stent placement by endoscopic gallbladder stenting or endoscopic ultrasound-guided gallbladder drainage may reduce the recurrence rate, its efficacy and safety remain controversial. Additionally, details surrounding the long-term stent management of these treatment methods should be further investigated. In this review, we summarize the updated evidence regarding the usefulness of long-term stent placement with endoscopic gallbladder stenting or endoscopic ultrasound-guided gallbladder drainage as a preventive measure for recurrence of cholecystitis and discuss issues that should be addressed in future studies.

Migration of duodenal covered self-expandable metal stents (C-SEMSs) is the main cause of stent dysfunction in patients with malignant gastric outlet obstruction (mGOO). Because endoscopic SEMS placement is frequently selected in patients with poor performance status, we concurrently focused on the safety of the treatment. This pilot study included 15 consecutive patients with mGOO who underwent duodenal partially covered SEMS (PC-SEMS) placement with fixation using an over-the-scope-clip (OTSC). Technical feasibility, clinical success for oral intake estimated by the Gastric Outlet Obstruction Scoring System (GOOSS) score, and adverse events including stent migration were retrospectively assessed. All procedures were successful, and clinical success was achieved in 86.7% (13/15). Mean GOOSS scores were improved from 0.07 to 2.53 after the procedure (P < 0.001). Median survival time was 84 days, and all patients were followed up until death. Stent migration occurred in one case (6.7%) at day 17, which was successfully treated by removal of the migrated PC-SEMS using an enteroscope. For fixation using an OTSC, additional time required for the procedure was 8.9 ± 4.1 min and we did not observe OTSC-associated adverse events. Poor performance status was associated with clinical success (P = 0.03), but we could provide the treatment safely and reduce mGOO symptoms even in patients with poor performance status. In conclusion, duodenal PC-SEMS fixation using an OTSC is feasible for preventing stent migration in patients with mGOO including those with poor performance status., (© 2021. The Author(s).)