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.

Clinical impact of bile-derived exosomal microRNAs as novel diagnostic and prognostic biomarkers for biliary tract cancers.

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.

Various innovative roles for 3-Fr microcatheters in pancreaticobiliary endoscopy.

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.

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.

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.

Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma.

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.

Use of Endoscopic Scraper and Cell Block Technique as a Replacement for Conventional Brush for Diagnosing Malignant Biliary Strictures.

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.

IgG4-related Sclerosing Cholangitis Complicated with Cholangiocarcinoma and Detected by Forkhead Box P3 Immunohistochemical Staining.

An 80-year-old man was admitted due to biliary stricture with autoimmune pancreatitis. Although radiographical examinations suggested Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC), punched biopsies from the bile duct revealed adenocarcinoma. In the resected specimen, abundant N-terminus of Forkhead box P3 (Foxp3)-positive cells were localized in cholangiocarcinoma (CCA) tissue, while IgG4-positive cells were spread around the entire bile duct. Therefore, the case was diagnosed with IgG4-SC accompanied by CCA, not sporadic CCA. We herein report an informative case wherein IgG4-positive cells were abundant in CCA tissue and Foxp3 immunohistochemical staining allowed us to determine that this case had two entities.

Perivascular Epithelial Cell Tumor of the Pancreas Diagnosed Preoperatively by Endoscopic Ultrasound-guided Fine-needle Aspiration.

We herein report a 49-year-old woman with a perivascular epithelial cell tumor (PEComa) of the pancreas. Imaging studies demonstrated a relatively well-demarcated mass, measuring approximately 40 mm in diameter, located in the pancreatic tail. It was heterogeneously enhanced almost to the same degree as the surrounding pancreatic tissue in both the arterial and portal venous phases. We performed endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) using the Acquire® 22-gauge needle and preoperatively obtained a definitive diagnosis with a sufficient sample. Clinicians should consider pancreatic PEComa in their differential diagnosis of patients with a pancreatic mass.

Acute Acalculous Cholecystitis Caused by Giardia lamblia.

We report a case of a 70-year-old man with acute acalculous cholecystitis caused by Giardia lamblia. Contrast-enhanced computed tomography (CT) showed distention of the gallbladder due to a pericholecystic abscess without gallstones. Magnetic resonance cholangiopancreatography and drip infusion cholecystocholangiography-CT demonstrated a stricture of the hilar bile duct and cystic duct obstruction. We conducted transpapillary bile duct brush cytology and a biopsy of the hilar bile duct stricture; numerous active trophozoites of Giardia lamblia were observed without malignant findings. We considered this bile duct lesion to be biliary giardiasis. Biliary giardiasis should be taken into consideration when diagnosing acute acalculous cholecystitis.