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Background Lack of forward-viewing endoscopy experience impairs training in endoscopic retrograde cholangiopancreatography (ERCP). We evaluated the effect of ERCP mechanical simulator (EMS) practice on ERCP performance by surgical trainees. Patients and methods 12 surgical trainees without endoscopy experience were randomly allocated to non-EMS (n = 6) programs or to EMS (n = 6) programs with coaching and 20 hours of supervised EMS practice. All trainees then received supervised hands-on clinical ERCP training. Trainers provided verbal instructions and hands-on assistance, and took over if cannulation was not achieved by 20 minutes. Blinded trainers rated clinical performance. Results Each group performed 150 clinical ERCPs. Biliary cannulation success was significantly higher in the EMS vs. the non-EMS group (P = 0.006), with shorter mean times (in minutes) for intubation, cannulation, and completion (all P Conclusions EMS practice shortens the ERCP early learning curve of inexperienced surgical trainees, improves clinical success in selective biliary cannulation, and may reduce complications.

BACKGROUND Different types of periampullary diverticulum (PAD) may differentially affect the success of endoscopic retrograde cholangiopancreatography (ERCP) cannulation, but the clinical significance of the two current PAD classifications for cannulation is limited. AIM To verify the clinical value of our newly proposed PAD classification. METHODS A new PAD classification (Li-Tanaka classification) was proposed at our center. All PAD patients with native papillae who underwent ERCP from January 2012 to December 2017 were classified according to three classification systems, and the effects of various types of PAD on ERCP cannulation were compared. RESULTS A total of 3564 patients with native papillae were enrolled, including 967 (27.13%) PAD patients and 2597 (72.87%) non-PAD patients. In the Li-Tanaka classification, type I PAD patients exhibited the highest difficult cannulation rate (23.1%, P = 0.01), and type II and IV patients had the highest cannulation success rates (99.4% in type II and 99.3% in type IV, P < 0.001). In a multivariable-adjusted logistic model, the overall successful cannulation rate in PAD patients was higher than that in non-PAD patients [odds ratio (OR) = 1.87, 95% confidence interval (CI): 1.04-3037, P = 0.037]. In addition, compared to the non-PAD group, the difficulty of cannulation in the type I PAD group according to the Li-Tanaka classification was greater (OR = 2.04, 95%CI: 1.13-3.68, P = 0.004), and the successful cannulation rate was lower (OR = 0.27, 95%CI: 0.11-0.66, P < 0.001), while it was higher in the type II PAD group (OR = 4.44, 95%CI: 1.61-12.29, P < 0.01). CONCLUSION Among the three PAD classifications, the Li-Tanaka classification has an obvious clinical advantage for ERCP cannulation, and it is helpful for evaluating potentially difficult and successful cannulation cases among different types of PAD patients.

Hepatocellular carcinoma (HCC) is a highly aggressive and heterogeneous disease. Cell lines are commonly employed as in vitro models for cell type studies. However, the success rate of HCC primary culture establishment is low. In this study, we successfully established a liver cancer cell line, Hep-X1. Primary culture and passage of surgically removed tissues were used to establish hepatoma cell lines. Morphological examination, short tandem repeat (STR) analysis, immunohistochemical staining, doubling time, karyotype analysis, plate tumor formation experiments, organoid culture, and in vivo tumor formation investigations in animals were used to identify the cell lines. A novel liver cancer cell line, Hep-X1, was established based on morphology, immunophenotype, cytogenetics, and STR analysis. The novel cell line can be a valuable model for studying primary liver cancer.

Endoscopic retrograde cholangiopancreatography (ERCP) is an established treatment for common bile duct (CBD) stones. Post- ERCP cholecystitis (PEC) is a known complication of such procedure and there are no effective models and clinical applicable tools for PEC prediction.A random forest (RF) machine learning model was developed to predict PEC. Eligible patients at The First Hospital of Lanzhou University in China with common bile duct (CBD) stones and gallbladders in-situ were enrolled from 2010 to 2019. Logistic regression analysis was used to compare the predictive discrimination and accuracy values based on receiver operation characteristics (ROC) curve and decision and clinical impact curve. The RF model was further validated by another 117 patients. This study was registered with ClinicalTrials.gov, NCT04234126.A total of 1117 patients were enrolled (90 PEC, 8.06%) to build the predictive model for PEC. The RF method identified white blood cell (WBC) count, endoscopic papillary balloon dilatation (EPBD), increase in WBC, residual CBD stones after ERCP, serum amylase levels, and mechanical lithotripsy as the top six predictive factors and has a sensitivity of 0.822, specificity of 0.853 and accuracy of 0.855, with the area under curve (AUC) value of 0.890. A separate logistic regression prediction model was built with sensitivity, specificity, and AUC of 0.811, 0.791, and 0.864, respectively. An additional 117 patients (11 PEC, 9.40%) were used to validate the RF model, with an AUC of 0.889 compared to an AUC of 0.884 with the logistic regression model.The results suggest that the proposed RF model based on the top six PEC risk factors could be a promising tool to predict the occurrence of PEC.

Background and study aims Preoperative biliary drainage of hilar cholangiocarcinoma (HC) is controversial. The goal of this study was to compare the clinical outcome and associated complications for types II, III, and IV HC managed by percutaneous transhepatic biliary drainage (PTBD) and endoscopic retrograde cholangiopancreatography (ERCP). Patients and methods Between January 2011 and June 2017, a total of 180 patients with II, III, and IV HC were enrolled in this retrospective cohort study. According to the drainage method, patients were divided into two groups: PTBD (n = 81) and ERCP (n = 99). This study was registered with ClinicalTrials.gov, NCT03104582, and was completed. Results Compared with the PTBD group, the ERCP group had a higher incidence of post-procedural cholangitis (37 [37.37 %] vs. 18 [22.22 %], P = 0.028) and pancreatitis (17 [17.17 %] vs. 2 [2.47 %], P = 0.001); required more salvaged biliary drainage (18 [18.18 %] vs. 5 [6.17 %], P = 0.029), and incurred a higher cost (P Conclusion Compared to ERCP, PTBD reduced the rate of cholangitis, pancreatitis, salvage biliary drainage, and decreased hospitalization costs in patients with types II, III, and IV HC. Risk of cholangitis for patients with types III and IV was significantly lower in the PTBD group.

Endoscopic sphincterotomy is the established treatment for common bile duct stones. Balloon dilation offers an alternative. Prolonged dilation (300 s) with a 10 mm diameter balloon decreases the occurrence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). We aimed to determine the optimal duration of dilation for combined endoscopic sphincterotomy and balloon dilation for the removal of common bile duct stones.We did a multicentre, single-blinded, randomised controlled trial at 15 tertiary surgical centres in China. Eligible patients (≥18 years) with native papilla and common bile duct stones (≤1·5 cm in size and2 cm in diameter) undergoing ERCP were randomly assigned (1:1:1:1:1) to receive balloon dilation for 0, 30, 60, 180, or 300 s after deep bile duct cannulation. Randomisation was done by an independent statistician using a computer-generated randomisation list with a block size of ten, stratified by centre. Patients and outcome assessors, but not endoscopists and investigators, were masked to treatment allocation. Balloon dilation was done with controlled radial expansion balloons according to common bile duct stone size. Stones were removed using stone retrieval balloons or baskets. The primary endpoint was overall frequency of post-ERCP pancreatitis. The primary efficacy analysis and safety analyses were done in the modified intention-to-treat population, which included all randomly assigned patients with successful cannulation, but excluded those who withdrew consent after randomisation. This study was registered with ClinicalTrials.gov, number NCT02510495, and is complete.Between July 29, 2015, and Dec 1, 2017, 3721 consecutive patients with common bile duct stones were recruited, 1718 of whom were excluded. The remaining 2003 patients underwent a small (3-5 mm) endoscopic sphincterotomy. 83 patients withdrew consent after the ERCP procedure, thus 1920 patients were included in the modified intention-to-treat analysis (0 s [n=371], 30 s [n=384], 60 s [n=388], 180 s [n=390], and 300 s [n=387]). Overall, post-ERCP pancreatitis occurred in 199 (10%) of 1920 patients (44 [12%] patients in the 0 s group, 28 [7%] in the 30 s group, 32 [8%] in the 60 s group, 36 [9%] in the 180 s group, and 59 [15%] in the 300 s group). Prolonged dilation (300 s) significantly increased the occurrence of post-ERCP pancreatitis compared with shorter balloon dilation (p=0·002). The frequency of post-ERCP pancreatitis was significantly lower in the 30, 60, and 180 s groups than in the 300 s group (relative risk [RR] 0·48, 95% CI 0·31-0·73; p=0·0005 vs the 30 s group; 0·54, 0·36-0·81; p=0·003 vs the 60 s group; 0·61, 0·41-0·89; p=0·01 vs the 180 s group). The frequency of post-ERCP pancreatitis was significantly higher in the 0 s group than the 30 s group (RR 1·62, 1·04-2·56; p=0·03). No difference in stone extraction (all ≥90%) was observed between groups. Following ERCP, 90 (5%) of 1920 patients had acute cholangitis, 14 (1%) had acute cholecystitis, and five (1%) had gastrointestinal bleeding, with no significant differences between groups. One (1%) patient had Stapfer II perforation, which resolved spontaneously with conservative treatment.A balloon dilation time of 30 s for combined endoscopic sphincterotomy and balloon dilation reduced the frequency of post-ERCP pancreatitis and was determined to be the optimum dilation time for the removal of common bile duct stones.National Natural Science Foundation of China, Gansu Competitive Foundation Projects for Technology Development and Innovation.

BACKGROUND Early gastric cancer (EGC), compared with advanced gastric cancer (AGC), has a higher 5-year survival rate. However, due to the lack of typical symptoms and the difficulty in diagnosing EGC, no effective biomarkers exist for the detection of EGC, and gastroscopy is the only detection method. AIM To provide new biomarkers with high specificity and sensitivity through analyzed the differentially expressed microRNAs (miRNAs) in EGC and AGC and compared them with those in benign gastritis (BG). METHODS We examined the differentially expressed miRNAs in the plasma of 30 patients with EGC, AGC, and BG by miRNA chip analysis. Then, we analyzed and selected the significantly different miRNAs using bioinformatics. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) confirmed the relative transcription level of these miRNAs in another 122 patients, including patients with EGC, AGC, Helicobacter pylori (H. pylori)-negative gastritis (Control-1), and H. pylori-positive atrophic gastritis (Control-2). To establish a diagnostic model for the detection of plasma miRNA in EGC, we chose miRNAs that can be used to determine EGC and AGC from Control-1 and Control-2 and miRNAs in EGC from all other groups. RESULTS Among the expression profiles of the miRNA chips in the three groups in the discovery set, of 117 aberrantly expressed miRNAs, 30 confirmed target prediction, whereas 14 were included as potential miRNAs. The RT-qPCR results showed that 14 potential miRNAs expression profiles in the two groups exhibited no differences in terms of H. pylori-negative gastritis (Control-1) and H. pylori-positive atrophic gastritis (Control-2). Hence, these two groups were incorporated into the Control group. A combination of four types of miRNAs, miR-7641, miR-425-5p, miR-1180-3p and miR-122-5p, were used to effectively distinguish the Cancer group (EGC + AGC) from the Control group [area under the curve (AUC) = 0.799, 95% confidence interval (CI): 0.691-0.908, P < 0.001]. Additionally, miR-425-5p, miR-24-3p, miR-1180-3p and miR-122-5p were utilized to distinguish EGC from the Control group (AUC = 0.829, 95%CI: 0.657-1.000, P = 0.001). Moreover, the miR-24-3p expression level in EGC was lower than that in the AGC (AUC = 0.782, 95%CI: 0.571-0.993, P = 0.029), and the miR-4632-5p expression level in EGC was significantly higher than that in AGC (AUC = 0.791, 95%CI: 0.574-1.000, P = 0.024). CONCLUSION The differentially expressed circulatory plasma miR-425-5p, miR-1180-3p, miR-122-5p, miR-24-3p and miR-4632-5p can be regarded as a new potential biomarker panel for the diagnosis of EGC. The prediction and early diagnosis of EGC can be considerably facilitated by combining gastroscopy with the use of these miRNA biomarkers, thereby optimizing the strategy for effective detection of EGC. Nevertheless, larger-scale human experiments are still required to confirm our findings.

Background Although Helicobacter pylori (Hp) as high risk factor for gastric cancer have been investigated from human trial, present data is inadequate to explain the effect of Hp on the changes of metabolic phenotype of gastric cancer in different stages. Purpose Herein, plasma of human superficial gastritis (Hp negative and positive), early gastric cancer and advanced gastric cancer analyzed by UPLC-HDMS metabolomics can not only reveal metabolic phenotype changes in patients with gastric cancer of different degrees (30 Hp negative, 30 Hp positive, 20 early gastric cancer patients, and 10 advanced gastric cancer patients), but also auxiliarily diagnose gastric cancer. Results Combined with multivariate statistical analysis, the results represented biomarkers different from Hp negative, Hp positive, and the alterations of metabolic phenotype of gastric cancer patients. Forty-three metabolites are involved in amino acid metabolism, and lipid and fatty acid metabolism pathways in the process of cancer occurrence, especially 2 biomarkers glycerophosphocholine and neopterin, were screened in this study. Neopterin was consistently increased with gastric cancer progression and glycerophosphocholine tended to consistently decrease from Hp negative to advanced gastric cancer. Conclusion This method could be used for the development of rapid targeted methods for biomarker identification and a potential diagnosis of gastric cancer.

Background: There search of PARP inhibitors has made great breakthroughs and progress. Become a new type of medicine for cancer treatment,bringing hope to more advanced cancer patients.The purpose of this systematic review is to evaluate the clinical efficacy and adverse effects of PARP inhibitorscombined with chemotherapy and chemotherapy alone in the treatment of cancer patients. Methods: We searched the following 4 databases, including: PubMed, EMBASE, Web of Science, and Cochrane Library. The search will also be conducted at the clinical trial centers: ClinicalTrials.gov, ISRCTN Registry, WHO International Clinical Trials Registration Platform. The search date is as of September 22, 2020. There is no language restriction during this search, and the latest documents are kept updated through settings. The subject search terms were identified as “PARP Inhibitor”, “Neoplasms” and “Dug therapy”. The Phase 2 and Phase 3 clinical trials comparing PARP inhibitor combined with chemotherapy and chemotherapy alone were included. The results include overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse events. Two researchers separately completed the article inclusion, data extraction and quality evaluation of this study. The assessment of the risk of bias and data will be conducted using Review Manager. Ethics and dissemination: All articles are published and do not require the approval of the ethics committee and the signed informed consent form. The results of this systematic review will be published through peer-reviewed publications. Registered: Registered on INPLASY and the registration number is INPLASY202090087.

Neuropilin-1 (NRP1) is a type I transmembrane glycoprotein that was originally found playing a role in neuronal axon guidance and embryonic angiogenesis. NRP1 can promote various aspects of tumorigenesis, such as angiogenesis, cell survival, migration, invasion and chemo-resistance, but little is known about the nanomechanica signature of NRP1 inregulating hepatocellular carcinoma(HCC) cells. Our study found that NRP1 was overexpressed in HCC and high expression of NRP1 was associated with poor prognosis in HCC patients.but there are no correlation between NRP1 and liver cirrhosis. In vivo and vitro experiments knockdown of NRP1 reduced proliferation and invasion of HCC. We quantified the Young's modulus, RMS residuals of HCC cell lines and normal liver cell line L02 using Atomic force microscopy (AFM). AFM data indicated that Young's modulus decreased in highly metastatic HCC cells, which is consistent with the verification results of NRP1 knockdown. Our analyses revealed that down regulation of NRP1 negatively correlated with increased Young's modulus in cells exhibiting differing degrees of invasiveness. Our molecular data showed that NRP1 activated AKT, ERK1/2, and epithelial-mesenchymal transition (EMT)-related signals in HCC cells and promoted tumor apoptosis and invasion. As an important biophysical property of cells, the membrane stiffness of HCC cells was further quantified by AFM force measurements, which indicated that these cells became much stiffer after NRP1 knockdown. These results collectively illuminated that Neuropilin-1 alterrated namomechanica signature in hepatocellular carcinoma cells and can be a potential therapeutic agent for HCC. Funding Statement: The present study was supported by the National Natural Science Fund of China (grant nos. 31570509 and 81702326), Science and Technology Major Project of Gansu province(1602FKDA001), the Talent innovation and Entrepreneurship Program of Lanzhou City (grant no. 2016-RC57) and the science and technology project of Chenguan District (2017SHFZ0014); Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The study was approved by the Zhongshan Hospital Ethics Committee and informed consent was obtained from each patient under Institutional Reviewer Board protocols. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the institution's human research committee.

Background and Objective: Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1), a protein involved in the DNA repair mechanism, plays an important role in carcinogenesis. In this study, we investigated whether single nucleotide polymorphisms of PARP1 contribute to gastric cancer (GC) and its precursor lesions (gastric precancerous lesions; GPL) in a case-control study conducted in the Hexi area of China, a high-risk area for GC. Methods: PARP1 162C>G (Phe54Leu) and 2819A>G (Lys940Arg) polymorphisms were genotyped by realtime PCR using a TaqMan assay in 140 GC cases, 110 GPL cases, and 120 controls. Data were statistically analyzed using the chi-squared test and a logistic regression model. Results: The presence of the PARP1 2819G allele was associated with an increased risk of GC (odds ratio [OR] 2.354; 95% CI 1.140, 4.861; p = 0.018), especially for cardia GC and diffuse-type GC (ORs 2.988 and 3.784, respectively). We also observed an interaction between Helicobacter pylori infection, GC family history, and the presence of the PARP1 2819G allele. In contrast, the PARP1 162C>G polymorphism wasnot significantly associated with GPL or GC. Conclusion: The study suggests that the PARP1 2819G allele is associated with an increased risk of GC. In addition, H. pylori-positive status and family history jointly contribute to a higher risk of GC.

Postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) is one of the most common and serious complications after endoscopic retrograde cholangiopancreatography (ERCP). This study aims to test the hypothesis that the incidence of PEP declined over time due to improved patient selection and/or endoscopic equipment and endoscopic techniques. Therefore, we compared the incidence and risk factors of PEP between four arbitrary chronologically stratified groups.A total of 7,168 cases of ERCP procedures were retrospectively analyzed. According to the different developmental stages of ERCP equipment and techniques, cases were divided into four groups. The incidence rates and major risk factors for acute PEP were compared between groups.Among the 7,168 cases, the overall incidence of PEP was 3.70% (265/7,168). When analyzed against each stage of ERCP development, the incidence of PEP was 4.09% (77/1,884) in stage I, 5.79% (86/1,489) in stage II, 3.95% (62/1,568) in stage III and 1.80% (40/2,227) in stage IV. By univariate analysis, pancreatic stent placement (OR: 0.300) and use of propofol-balanced anesthesia (OR: 0.632) seem to be protective factors for acute PEP. By multivariate analysis, the following risk factors for PEP could be identified: repeated cannulation (OR: 3.462), pancreatic duct injection (OR: 3.218), balloon dilation of biliary sphincter (OR: 2.847), papillae precut (OR: 2.493), nonselective high-pressure injection (OR: 1.428), excessive electrocoagulation incision (OR: 1.263), history of pancreatitis (OR: 3.843) and suspected sphincter of Oddi dysfunction (OR: 1.782).Improved technical procedures were associated with a significant reduction in the incidence of PEP. Risks for developing PEP may be minimized by constant improvement in ERCP techniques, such as routine use of a guidewire, highly selective cannulation, pancreatic stent placement and cautious incision.

[Meng, Wenbo] Lanzhou Univ, Special Minimally Invas Surg, Hosp 1, Lanzhou, Gansu, Peoples R China

5-Azacytidine has been shown to be an effective anti-pancreatic cancer drug, but the mechanism remains unknown. In the current study, we explored the effect of 5-azacytidine on abnormal activation of the Wnt-β-catenin signaling pathway in pancreatic cancer cells. The human pancreatic cancer cell line Bxpc-3 was treated with different concentrations of 5-azacytidine for various times. The proliferation and early apoptosis of the cells were evaluated using the CCK8 method and flow cytometry, respectively. mRNA and protein expression of β-catenin, c-myc, and cyclinD1 were detected using real-time fluorescent quantitative polymerase chain reaction and Western blot analysis, respectively. The proliferation of Bxpc-3 cells was suppressed by 5-azacytidine. The early apoptosis of the cells was significantly enhanced over time and with increasing drug concentrations. The expression of β-catenin, c-myc, and cyclinD1 were down-regulated, showing significant differences between different concentrations and treatment times (P < 0.05). 5-Azacytidine suppressed the proliferation of pancreatic cancer cells by inhibiting the Wnt/β-catenin signaling pathway, particularly the expression of β-catenin, c-myc, and cyclinD1. This study may provide a new potential strategy for diagnosing and treating pancreatic cancer.

Alpha-fetoprotein not only serves as a diagnostic marker for liver cancer, but also posses a variety of biological functions. However, the role of Alpha-fetoprotein on tumor angiogenesis and cell invasion remains incompletely understood. In this study, we aimed to evaluate if Alpha-fetoprotein can regulate the major angiogenic factors and matrix metalloproteinases in human liver cancer cells. Alpha-fetoprotein silencing was achieved by Stealth RNAi. Expression of Alpha-fetoprotein was examined by a full-automatic electrochemistry luminescence immunity analyzer. Expression of VEGF, VEGFR-2, MMP-9, and MMP-2 was examined by Western blot and immunocytochemistry. Apoptosis was detected by TUNEL assay. Angiogenesis was detected by in vitro angiogenesis assay kit. Silencing of Alpha-fetoprotein led to an increased apoptosis, which was associated with a decreased expression of vascular endothelial growth factor, vascular endothelial growth factor receptor 2, matrix metalloproteinases-2/9. These results suggest that Alpha-fetoprotein may play a regulatory role on angiogenesis and cell invasion during liver cancer development.

The aim of this study was to examine the relation between periampullary diverticula (PAD) and biliary tract stones. A total of 732 cases of patients with PAD identified from among 6,221 patients who underwent endoscopic retrograde cholangiopancreatography were compared to 750 controls (without PAD) in terms of biliary stone formation, incidence of sphincter of Oddi dysfunction (SOD), and choledocholithiasis. The biliary tract diseases were diagnosed based on medical history, clinical symptoms and signs, and imaging findings using ultrasonography, computed tomography, or magnetic resonance cholangiopancreatography. The PAD group contained a significantly larger number of patients with biliary stones including stones in the primary common bile duct, SOD with bile duct stones (p