Programmed cell death-1 (PD-1) inhibitor has been indicated for many types of malignancies. However, these inhibitors also cause immune-related adverse events. Hepatobiliary disorder is a phenotype of immune-related adverse event affecting 0%-4.5% of patients treated with PD-1 inhibitors. Recent studies have reported PD-1 inhibitor-related sclerosing cholangitis (SC); however, the associated clinical and pathological features are unclear. To evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the literature. The review, conducted using electronic databases in PubMed, was restricted to the period from January 2014 to September 2019 and focused on case reports/series on PD-1 inhibitor-related SC published in English. We scanned the references of the selected literature to identify any further relevant studies. Six cases previously studied by us, including three that have not yet been published, were included in this review. Thirty-one PD-1 inhibitor-related SC cases were evaluated. Median age of patients was 67 years (range, 43-89), with a male to female ratio of 21:10. The main disease requiring PD-1 inhibitor treatment was non-small cell lung cancer. Agents that caused PD-1 inhibitor-related SC were nivolumab (19 cases), pembrolizumab (10 cases), avelumab (1 case), and durvalumab (1 case). The median number of cycles until PD-1 inhibitor-related SC onset was 5.5 (range, 1-27). Abdominal pain or discomfort (35.5%, 11/31) was the most frequent symptom. Blood serum tests identified liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes, and a normal level of serum immunoglobulin G4. Biliary dilation without obstruction (76.9%, 20/26), diffuse hypertrophy of the extrahepatic biliary tract (90.5%, 19/21), and multiple strictures of the intrahepatic biliary tract (30.4%, 7/23) were noted. In 11/23 (47.8%) cases, pathological examination indicated that CD8+ T cells were the dominant inflammatory cells in the bile duct or peribiliary tract. Although corticosteroids were mainly used for PD inhibitor-related SC treatment, the response rate was 11.5% (3/26). Some clinical and pathological features of PD-1 inhibitor-related SC were revealed. To establish diagnostic criteria for PD-1 inhibitor-related SC, more cases need to be evaluated.

Objectives: The reported incidence of adverse events (AEs) in endoscopic retrograde cholangiopancreatography (ERCP) varies between 2.5% and 14%. The aim of this study was to evaluate the incidence and severity of AEs in biliary ERCP and to specify the risk factors and preventive measures for post‐ERCP pancreatitis (PEP).Methods: Patients with biliary disease with intact papilla were prospectively enrolled at 36 hospitals between April 2017 and March 2018. The primary outcomes were the incidence and severity of AEs.Results: A total of 16,032 ERCP procedures were performed at the 36 hospitals during the study period and 3739 patients were enrolled. The overall incidence of AEs was 10.1% and ERCP‐related mortality was 0.08%. PEP developed in 258 cases (6.9%), bleeding in 33 (0.9%), instrumental AEs in 17 (0.5%), infections in 37 (1.0%), cardiovascular AEs in eight (0.2%), pulmonary AEs in eight (0.2%), drug reaction AE in one (0.03%), pain in 15 (0.4%), and other AEs in 15 (0.4%). Multivariable analysis showed significant risk factors for PEP were: female of younger age, pancreatic guidewire‐assisted biliary cannulation, temporary guidewire insertion into the pancreatic duct, total procedure time >60 min, and post‐ERCP administration of non‐steroidal anti‐inflammatory drugs. Effective preventive measures were prophylactic pancreatic stenting (PPS) and epinephrine spraying onto the papilla.Conclusions: In patients with intact papilla who underwent biliary ERCP, the incidence of AEs was 10.1% and the mortality was 0.08%. PPS and epinephrine spraying may prevent PEP.Registration: This study was registered in the University Hospital Medical Information Network (UMIN000024820).

Few studies have compared the diagnostic utility of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) and endoscopic retrograde cholangiopancreatography (ERCP) tissue sampling for extrahepatic cholangiocarcinoma (ECC). We evaluated the efficacy and safety of EUS-FNA for diagnosing ECC compared with ERCP tissue sampling. Patients who underwent EUS-FNA or ERCP tissue sampling to differentiate ECC from benign biliary disease were enrolled retrospectively between October 2011 and March 2017. We evaluated diagnostic performances of EUS-FNA and ERCP tissue sampling based on pathological evaluation. We compared adverse events in EUS-FNA and ERCP tissue sampling. We enrolled 73 patients with biliary disease and performed EUS-FNA and ERCP in 19 and 54 patients, respectively. Sensitivity, specificity, and accuracy of ERCP tissue sampling were 76.0%, 100%, and 88.9%, respectively, and for EUS-FNA these were 81.8%, 87.5%, and 84.2%, respectively. Statistical values of ERCP tissue sampling and EUS-FNA were not significantly different. The adverse event frequency of EUS-FNA was significantly lower than that of ERCP tissue sampling (0% vs. 25.9%, p = 0.033). The diagnostic ability of EUS-FNA for ECC is similar to that of ERCP tissue sampling. EUS-FNA is a safer tissue sampling modality than ERCP for evaluating biliary disease.

Non-alcoholic steatohepatitis is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The dipeptidyl peptidase‑IV enzyme is important in glucose metabolism, as well as lipid accumulation, extracellular matrix metabolism and immune stimulation. Furthermore, the enzyme activity of dipeptidyl peptidase‑IV is known to be increased in non‑alcoholic steatohepatitis. Therefore, dipeptidyl peptidase‑IV inhibitors are potential therapeutic agents for non‑alcoholic steatohepatitis. The present study assessed the therapeutic effects of sitagliptin, a dipeptidyl peptidase‑IV inhibitor, on non‑alcoholic steatohepatitis using fatty liver Shionogi‑ob/ob male mice. Sitagliptin (2 mg/kg/day; n=10) or placebo (control; n=10) was orally administered to fatty liver Shionogi‑ob/ob mice for 12 weeks, and hepatic steatosis, fibrosis, inflammation and oxidative stress were assessed in comparison with the controls. Sitagliptin administration reduced body weight and blood glucose levels, and improved hepatic fibrosis. It also inhibited the gene expression levels of fatty acid synthase, transforming growth factor‑β1, tissue inhibitor of metalloproteinases‑1, procollagen‑type 1, tumor necrosis factor‑α, monocyte chemoattractant protein‑1 and enhanced peroxisome proliferator activated receptor‑α. Furthermore, a marked attenuation of hepatic stellate cell activation and Kupffer cells was observed in the sitagliptin group. A decrease in oxidative stress and apoptosis was also observed. Sitagliptin attenuated the progression of hepatic fibrosis by improving lipid metabolism, inflammation and oxidative stress in non-alcoholic steatohepatitis.

Programmed cell death-1 (PD-1) inhibitor therapy is indicated for many types of malignancies, but can lead to immune-related adverse events [1] [2]. Recently, PD-1 inhibitor-related cholangitis and its clinical features, including peroral cholangioscopy, were reported [3] [4] [5]. However, the diagnostic criteria of PD-1 inhibitor-related cholangitis are unclear. We herein report peroral cholangiography for three patients with suspected pembrolizumab-related sclerosing chol-angitis. Case #1 was a 61-year-old man with bladder cancer who had been treated with pembrolizumab as third-line chemotherapy. After his fifth course of pembrolizumab, he was admitted to our hospital complaining of pyrexia. Case #2 was an 89-year-old man with bladder cancer. After his fourth course of pembrolizumab as second-line chemotherapy, he was admitted to our hospital for examination of liver dysfunction. Case #3 was a 63-year-old man with lung cancer. After his seventh course of pembrolizumab as first-line chemotherapy, he was admitted to our hospital because of liver dysfunction. Laboratory data from all three patients revealed increased liver and biliary enzymes. Computed tomography and endoscopic ultrasonography consistently showed diffuse symmetric wall thickening of extrahepatic bile ducts without any obstruction ([Fig. 1 a, b]). Endoscopic retrograde cholangiopancreatography revealed an irregular bile duct wall in all three patients ([Fig. 1 c]). Peroral cholangioscopy revealed band-like narrowing of the wall of the biliary tract in all three patients and diverticulum-like outpouching in patients #1 and #3 ([Fig. 1 d]; [Video 1]). Video 1 Peroral cholangioscopy showing multiple areas of band-like narrowing of the wall of the biliary tract, which was present in all patients, and a diverticulum-like outpouching, which was present in patients #1 and #3. A biopsy of the lesions of the extrahepatic bile duct showed inflammatory cells in the bile duct epithelium ([Fig. 2]). All patients received internal treatment with ursodeoxycholic acid. Patient #1 was also treated with oral prednisolone. Liver and biliary enzymes improved gradually in all three patients, although normalization of enzyme activities was not achieved. Endoscopy_UCTN_Code_CCL_1AZ_2AJ

Background: Peroral cholangioscopy (POCS)-guided forceps biopsy is a method for diagnosing indeterminate biliary strictures and for the preoperative identification of the exact perihilar and distal margins of biliary tract cancer (BTC). However, POCS-guided forceps biopsy may result in an insufficient amount of specimen at times. Therefore, we evaluated the adequate tissue acquisition rate and the factors affecting the adequate tissue acquisition of POCS-guided forceps biopsy for the biliary tract. Methods: Patients who underwent POCS-guided forceps biopsy for biliary disease between September 2016 and October 2018 at our hospital were enrolled retrospectively. We evaluated the adequate tissue acquisition rate of POCS-guided forceps biopsy for the biliary lesion and that for non-stenotic bile duct. In addition, the factors affecting the adequate tissue acquisition rate of POCS-guided forceps biopsy were evaluated. Results: We enrolled 47 patients with biliary disease and performed POCS-guided forceps biopsy for biliary lesion and POCS-guided forceps mapping biopsy for non-stenotic bile duct in 40 and 36 patients, respectively. The adequate tissue acquisition rates of POCS-guided forceps biopsy for biliary lesions and that for non-stenotic bile duct were 86.4%, and 68.9%, respectively. In the multivariate logistic regression analyses, age, and previous biliary stenting before POCS were factors affecting the adequate tissue acquisition rate of POCS-guided forceps biopsy for the biliary lesion. For non-stenotic bile duct, the location of the biliary lesion, endoscopic sphincterotomy (EST), and procedure time of POCS were factors affecting the adequate tissue acquisition rate of POCS-guided forceps mapping biopsy. Conclusions: Previous biliary stenting was a factor affecting a low tissue acquisition rate of POCS-guided forceps biopsy for the biliary lesion. In the POCS-guided forceps mapping biopsy, the location of the biliary lesion, EST, and procedure time were factors affecting tissue acquisition rates.