Updates on Endoscopic Stenting for Unresectable Malignant Hilar Biliary Obstruction.

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.

TOKYO criteria 2024 for the assessment of clinical outcomes of endoscopic biliary drainage.

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.

Maintenance steroid therapy is associated with decreased risk of malignancy and better prognosis of patients with autoimmune pancreatitis: A multicenter cohort study in Japan.

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.

Simultaneous presentation and resection of esophageal cancer and metastasis to the pancreas: Α case report and literature review.

The frequency of metastasis to the pancreas is limited, and the frequency of metastasis of a squamous cell carcinoma of the esophagus is limited even further. The curative resection of this type of metastatic lesion has been reported for some patients; however, the survival benefit that can be attributed to these procedures has not yet been clearly determined. The patient examined in the present study was a 54-year-old man who was diagnosed with a lower thoracic esophageal cancer. Computed tomography revealed a 2-cm tumor at the tail of the pancreas. Since no other obvious distal metastases were observed, the patient underwent simultaneous surgical procedures, excising the esophageal squamous cell carcinoma and the pancreatic metastasis. A histopathological examination confirmed squamous cell carcinoma in both specimens. The patient has been free of disease for 9 months since the resection. A literature review of all relevant cases to date also demonstrated that the primary tumor site in all cases of patients with esophageal cancer presenting with metastasis to the pancreas was the lower thoracic esophagus. Complete simultaneous resections of esophageal squamous cell carcinoma and a solitary metastasis to the pancreas is beneficial and may produce favorable outcomes. However, due to the reduced number of corresponding reports, further studies are required for the confirmation of the benefits of surgery.

3-Fr microcatheter-assisted endoscopic ultrasound-guided rendezvous technique with a 22-gauge needle and a 0.018-inch guidewire for difficult biliary cannulation.

Endoscopic ultrasound-guided rendezvous with a 22-gauge needle and a 0.018-inch guidewire, assisted by a 3-Fr microcatheter, effectively addresses challenges in biliary cannulation, improving guidewire manipulation and reducing risks of injury and leakage. Natsume and colleagues describe the successful extraction of common bile duct stones to demonstrate the efficacy of this technique.

Incidence of pancreatic injury and pancreatitis in patients treated with immune checkpoint inhibitors.

OBJECTIVES: 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 for 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 with regard to 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 to 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. CONCLUSION: Simultaneous immunotherapy and dual immunotherapy are risk factors for 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.

Dual role of autotaxin as novel biomarker and therapeutic target in pancreatic neuroendocrine neoplasms.

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.

Comparison of the long-term outcomes of EUS-guided gallbladder drainage and endoscopic transpapillary gallbladder drainage for calculous cholecystitis in poor surgical candidates: a multicenter propensity score-matched analysis.

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.

Theoretical step approach with 'Three-pillar' device assistance for successful endoscopic transpapillary gallbladder drainage.

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.

Optimal endoscopic drainage strategy for unresectable malignant hilar biliary obstruction.

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.

Reducing relapse through maintenance steroid treatment can decrease the cancer risk in patients with IgG4-sclerosing cholangitis: Based on a Japanese nationwide study.

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.

Steroid therapy has an acceptable role as the initial treatment in autoimmune pancreatitis patients with pancreatic cyst formation: Based on a Japanese nationwide study.

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.

Concomitant Pancreatic Ductal Adenocarcinoma and Type 1 Autoimmune Pancreatitis: A Potential Issue in the Diagnosis of Carcinoma by Endoscopic Ultrasound-guided Fine-needle Biopsy.

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.