Endoscopic Papillary Large Balloon Dilation Reduces Further Recurrence in Patients With Recurrent Common Bile Duct Stones: A Randomized Controlled Trial.

INTRODUCTION: Up to 60% of patients with common bile duct stone (CBDS) recurrence suffer from further recurrence after endoscopic retrograde cholangiopancreatography (ERCP). There are no effective methods to prevent recurrence in most patients. In this study, we aimed to assess the short-term and long-term efficacies of endoscopic papillary large balloon dilation (EPLBD) for the management of recurrent CBDS in a randomized controlled trial. METHODS: Consecutive patients with recurrent CBDS were eligible and randomly assigned in a 1:1 ratio to the EPLBD group or the control group. The primary outcome was the CBDS recurrence rate within 2 years after ERCP. The analysis followed the intention-to-treat principle. RESULTS: From 2014 to 2021, 180 patients with recurrent CBDS were included, with 90 in each group. All patients underwent complete CBDS clearance by 1 or several sessions of ERCP. The rate of complete clearance in 1 session was significantly higher with EPLBD treatment (95.6% vs 85.6%, P = 0.017). During the follow-up, the CBDS recurrence rate within 2 years was significantly lower in the EPLBD group than in the control group (21.1% [19/90] vs 36.7% [33/90], relative risk 0.58, 95% confidence interval 0.36-0.93, P = 0.021). At a median follow-up of approximately 56 months, CBDS recurrence was found in 34.4% of the patients (31/90) in the EPLBD group and 51.1% (46/90) in the control group (hazard ratio 0.57, 95% confidence interval 0.36-0.89, P = 0.012). Multiple recurrences (≥2) were also decreased in the EPLBD group (4.4% vs 18.9%, P = 0.020). DISCUSSION: During the long-term follow-up, nearly half of the patients with recurrent CBDS experienced stone recurrence after traditional ERCP. Our study was the first to show that EPLBD effectively reduced the recurrence of CBDS.

Water exchange-assisted versus carbon dioxide-insufflated single-balloon enteroscopy: a randomized controlled trial.

BACKGROUND: Single-balloon enteroscopy (SBE) is a valuable but difficult modality for the diagnosis and treatment of small-bowel disease. The water exchange method has the advantage of facilitating intubation during colonoscopy. Here, we evaluated the effects of water exchange on procedure-related variables related to SBE. METHODS: This randomized controlled trial was conducted in a tertiary-care referral center in China. Patients due for attempted total enteroscopy were randomly allocated to undergo water exchange-assisted (water exchange group) or carbon dioxide-insufflated enteroscopy (CO2 group). All patients were planned to undergo both anterograde and retrograde procedures. The primary outcome was the total enteroscopy rate. Secondary outcomes included the maximal insertion depth, positive findings, procedural time, and adverse events. RESULTS: In total, 110 patients were enrolled, with 55 in each group. Baseline characteristics between the two groups were comparable. Total enteroscopy was achieved in 58.2 % (32/55) of the water exchange group and 36.4 % (20/55) of the control group (P = 0.02). The mean (standard deviation) estimated intubation depth was 521.2 (101.4) cm in the water exchange group and 481.6 (95.2) cm in the CO2 group (P = 0.04). The insertion time was prolonged in the water exchange group compared with the CO2 group (178.9 [45.1] minutes vs. 154.2 [27.6] minutes; P < 0.001). Endoscopic findings and adverse events were comparable between the two groups. CONCLUSIONS: The water exchange method improved the total enteroscopy rate and increased the intubation depth during SBE. The use of water exchange did not increase the complications of enteroscopy.

Relationship between papilla-related variables and post endoscopic retrograde cholangiopancreatography pancreatitis: A multicenter, prospective study.

BACKGROUND AND AIM: Papilla with hooknose or long protruding shape may increase the difficulty of cannulation during endoscopic retrograde cholangiopancreatography (ERCP). However, the relationship between papilla anatomy and complications of ERCP has not been fully understood. We aimed to investigate the effect of major duodenal papilla morphology on post-ERCP pancreatitis (PEP) and the procedure of cannulation. METHODS: Patients with native papilla who underwent ERCP were recruited to this multicenter study. Papilla-related variables were collected, including the length of long axis (L), short axis (S) and opening width (OW), transverse fold, periampullary diverticulum (PAD), papilla location, orientation, swelling, and presence of duodenal stenosis. Demographic data and the procedure of cannulation were also prospectively evaluated. The primary outcome was PEP incidence. Multivariate analysis was used to identify high risk factors for PEP. RESULTS: Six hundred and fifty-eight patients were enrolled. Overall PEP incidence was 4.7% (31/658). The papilla of patients complicated with PEP had higher long to short axis (L/S) ratio (odds ratio [OR] 3.84, 95% confidence interval [CI]: 1.37-10.74, P = 0.010), higher long axis to opening width (L/OW) ratio (OR 1.35, 95%CI: 1.06-1.71, P = 0.014), more transverse folds (OR 2.53, 95%CI: 1.02-6.26, P = 0.044), and less periampullary diverticulum (OR 0.21, 95%CI: 0.06-0.70, P = 0.011). Multivariate analysis revealed that the indication of common bile duct stones, normal bilirubin, inadvertent pancreatic duct cannulation > 1, L/S ratio ≥ 1.5, and absence of PAD were independent risk factors for PEP. CONCLUSION: Besides patient-related and procedure-related factors, papilla-related variables, such as L/S ratio and PAD, can be considered as a third type of factors associated with PEP (Clinicaltrials.gov number: NCT03550768).

Learning curve of double-guidewire technique by trainees during hands-on endoscopic retrograde cholangiopancreatography training.

BACKGROUND AND AIMS: Double-guidewire technique (DWT) has been successfully performed by experts in difficult biliary cannulation as an advanced technique. This study aimed to define the learning curve and safety of DWT by trainees during hands-on endoscopic retrograde cholangiopancreatography (ERCP) training. METHODS: Patients were eligible for inclusion in the study if the biliary cannulation was difficult and the pancreatic duct was inadvertently cannulated. DWT was performed by two trainees randomly under trainers' guidance. The primary outcome was the success rate of DWT biliary cannulation of trainees. Cumulative sum analysis was used to generate visual learning curves. RESULTS: A total of 60 patients with difficult cannulation were enrolled. The main indications for ERCP were common bile duct stones (65%) and biliary stricture (31.7%). The learning curve analysis showed that to achieve a 70% rate of successful DWT, 12 procedures were needed for trainee A and 15 for trainee B. Higher targeted success rate of DWT could be achieved if the number of DWT procedures increased. Compared with the early stage of learning DWT (case 1 to 15 for each trainee), trainees had significantly higher DWT success rate in the late stage (36.7% [11/30] vs 80% [24/30], P = 0.001). The final success rate of cannulation was 98.3% (59/60). The overall rate of post-ERCP pancreatitis and adverse events was 6.7% (4/60) and 8.3% (5/60), respectively. CONCLUSIONS: Double-guidewire technique was safely performed by two novel trainees during hands-on ERCP training. Fifteen procedures may be enough for trainees to achieve the competency of performing DWT. (Clinicaltrials.gov number: NCT03707613).

Patient-related factors associated with successful cannulation by trainees during hands-on endoscopic retrograde cholangiopancreatography training.

BACKGROUND AND AIM: Hands-on endoscopic retrograde cholangiopancreatography (ERCP) training is essential for trainees to grasp the technique. Cannulation success rate (CSR) is considered one of the main indicators of competency of trainees. We aimed to investigate whether patient-related factors had an impact on the CSR of trainees. METHODS: A post hoc analysis of data from two multicenter studies (NCT02002650 and NCT03057769) was conducted. Patients aged 18-90 years with native papilla undergoing ERCP were eligible for this study. Only procedures involving trainees in centers strictly following "10-min criteria" for initial cannulation were enrolled. Primary outcome was CSR by trainees. RESULTS: From December 2013 to October 2017, 20 trainees in four centers were involved in initial cannulation in 1044 patients with native papilla. Primary CSR by trainees was 61.0% (436/715), 31.5% (70/222) and 44.9% (48/107) in patients with common bile duct stone (CBDS), biliary stricture (BS) and other indications, respectively (P < 0.001). In multivariate analysis, indication of BS (OR, 0.31; 95% CI, 0.22-0.44; P < 0.001) and presence of type A diverticulum (OR, 1.69; 95% CI, 1.23-2.33; P = 0.001) were both independently associated with cannulation success of trainees. Biliary infection was significantly higher in the BS than in the CBDS group (3.6% vs 0.7%, P = 0.004), whereas other post-ERCP complications were comparable between the two groups. CONCLUSIONS: Indication of BS and the presence of type A diverticulum were independently associated with the success of cannulation by trainees. These findings indicate that greater effort is needed for trainees to improve the ability of cannulation in BS.

Different pattern of risk factors for post-ERCP pancreatitis in patients with biliary stricture.

OBJECTIVE: To identify possible risk factors associated with post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in biliary stricture (BS), common bile duct stone (CBDS) and unselected patients. MATERIALS AND METHODS: Consecutive ERCP patients with native papilla from January 2010 to December 2014 in Xijing Hospital were eligible. Patient-related and procedure-related parameters were collected retrospectively. The primary outcome was PEP. Univariate and multivariate logistic regression were used for data analysis. RESULTS: Totally 3133 unselected patients were included. 695 (22.2%) had BS alone and 1893 (60.4%) had CBDS alone. PEP incidence was higher in BS group compared with CBDS group (6.8% vs. 3.8%, p = .001). Among patient-related factors, duodenal stenosis (OR, 2.74; 95%CI, 1.14-6.59) and hilar stricture (OR, 2.59; 95%CI, 1.41-4.77) were found to be independently associated with PEP in BS group. While female gender (OR, 2.11; 95%CI, 1.20-3.73) and normal total bilirubin (OR, 1.93; 95%CI, 1.13-3.32) were related to PEP in CBDS group. Among procedure-related factors, cannulation time ≥ 5 min (OR, 2.38; 95%CI, 1.06-5.33) and precut (OR, 3.20; 95%CI, 1.35-7.59) was respectively the only independent risk factor for PEP in BS and CBDS group. CONCLUSIONS: Patients with BS and CBDS had different patterns of patient-related and procedure-related risk factors for PEP. The prophylaxis of PEP may need to be individualized based on different indications.

Routine pre-procedural rectal indometacin versus selective post-procedural rectal indometacin to prevent pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatography: a multicentre, single-blinded, randomised controlled trial.

BACKGROUND: Rectal indometacin decreases the occurrence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, the population most at risk and the optimal timing of administration require further investigation. We aimed to assess whether pre-procedural administration of rectal indometacin in all patients is more effective than post-procedural use in only high-risk patients to prevent post-ERCP pancreatitis. METHODS: We did a multicentre, single-blinded, randomised controlled trial at six centres in China. Eligible patients with native papilla undergoing ERCP were randomly assigned in a 1:1 ratio (with a computer-generated list) to universal pre-procedural indometacin or post-procedural indometacin in only high-risk patients, with stratification by trial centres and block size of ten. In the universal indometacin group, all patients received a single dose (100 mg) of rectal indometacin within 30 min before ERCP. In the risk-stratified, post-procedural indometacin group, only patients at predicted high risk received rectal indometacin, immediately after ERCP. Investigators, but not patients, were masked to group allocation. The primary outcome was overall ocurrence of post-ERCP pancreatitis. The analysis followed the intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT02002650. FINDINGS: Between Dec 15, 2013, and Sept 21, 2015, 2600 patients were randomly assigned to universal, pre-procedural indometacin (n=1297) or risk-stratified, post-procedural indometacin (n=1303). Overall, post-ERCP pancreatitis occurred in 47 (4%) of 1297 patients assigned to universal indometacin and 100 (8%) of 1303 patients assigned to risk-stratified indometacin (relative risk 0·47; 95% CI 0·34-0·66; p<0·0001). Post-ERCP pancreatitis occurred in 18 (6%) of 305 high-risk patients in the universal group and 35 (12%) of 281 high-risk patients in the risk-stratified group (p=0·0057). Post-ERCP pancreatitis was also less frequent in average-risk patients in the universal group (3% [29/992]), in which they received indometacin, than in the risk-stratified group (6% [65/1022]), in which they did not receive the drug (p=0·0003). Other than pancreatitis, adverse events occurred in 41 (3%; two severe) patients in the universal indometacin group and 48 (4%; one severe) patients in the risk-stratified group. The most common adverse events were biliary infection (22 [2%] patients vs 33 [3%] patients) and gastrointestinal bleeding (13 [1%] vs ten [1%]). INTERPRETATION: Compared with a risk-stratified, post-procedural strategy, pre-procedural administration of rectal indometacin in unselected patients reduced the overall occurrence of post-ERCP pancreatitis without increasing risk of bleeding. Our results favour the routine use of rectal indometacin in patients without contraindications before ERCP. FUNDING: National Key Technology R&D Program, National Natural Science Foundation of China.

Mechanism study of peptide GMBP1 and its receptor GRP78 in modulating gastric cancer MDR by iTRAQ-based proteomic analysis.

BACKGROUND: Multidrug resistance (MDR) is a major obstacle to the treatment of gastric cancer (GC). Using a phage display approach, we previously obtained the peptide GMBP1, which specifically binds to the surface of MDR gastric cancer cells and is subsequently internalized. Furthermore, GMBP1 was shown to have the potential to reverse the MDR phenotype of gastric cancer cells, and GRP78 was identified as the receptor for this peptide. The present study aimed to investigate the mechanism of peptide GMBP1 and its receptor GRP78 in modulating gastric cancer MDR. METHODS: Fluorescence-activated cell sorting (FACS) and immunofluorescence staining were used to investigate the subcellular location and mechanism of GMBP1 internalization. iTRAQ was used to identify the MDR-associated downstream targets of GMBP1. Differentially expressed proteins were identified in GMBP1-treated compared to untreated SGC7901/ADR and SGC7901/VCR cells. GO and KEGG pathway analyses of the differentially expressed proteins revealed the interconnection of these proteins, the majority of which are involved in MDR. Two differentially expressed proteins were selected and validated by western blotting. RESULTS: GMBP1 and its receptor GRP78 were found to be localized in the cytoplasm of GC cells, and GRP78 can mediate the internalization of GMBP1 into MDR cells through the transferrin-related pathway. In total, 3,752 and 3,749 proteins were affected in GMBP1-treated SGC7901/ADR and SGC7901/VCR cells, respectively, involving 38 and 79 KEGG pathways. Two differentially expressed proteins, CTBP2 and EIF4E, were selected and validated by western blotting. CONCLUSION: This study explored the role and downstream mechanism of GMBP1 in GC MDR, providing insight into the role of endoplasmic reticulum stress protein GRP78 in the MDR of cancer cells.

[Influencing factors for the performance of trainees after hands-on training of endoscopic retrograde cholangiopancreatography].

OBJECTIVE: To evaluate the performance of trainees after finishing hands-on training of endoscopic retrograde cholangiopancreatography (ERCP) at our hospital. METHODS: Questionnaire was distributed to 46 trainees of ERCP training over the past 5 years. And the effects of training duration, case volume and hospital facilities on ERCP performance were examined. RESULTS: A total of 41 valid questionnaires (89.1%) were retrieved. And 34 trainees (82.9%) worked at tertiary medical centers. The mean training duration was 8.9 months. Compared with trainees with less annual ERCP volume (TL) (< 4 cases per month, n = 23), trainees with more volume (TM) (≥ 4 cases per month, n = 18) had a higher rate of successful cannulation and precut by a needle knife (both P < 0.05). More endoscopists could perform ERCP and more duodenoscopes were stocked at hospitals of TM compared with TL (both P < 0.05). The results of trainee self-evaluation showed that the major influencing factors of post-training ERCP performance were hospital supports, handling capacity and case volume. CONCLUSION: After hands-on training, the trainee performance of ERCP is influenced by such multiple factors as handling capacity and hospital supports, etc.

MGr1-Ag/37LRP induces cell adhesion-mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer.

It is well known that tumor microenvironment plays a vital role in drug resistance and cell adhesion-mediated drug resistance (CAM-DR), a form of de novo drug resistance. In our previous study, we reported that MGr1-Ag/37LRP ligation-induced adhesion participated in protecting gastric cancer cells from a number of apoptotic stimuli caused by chemotherapeutic drugs. Further study suggested that MGr1-Ag could prompt CAM-DR through interaction with laminin. However, the MGr1-Ag-initiated intracellular signal transduction pathway is still unknown. In this study, our experimental results showed that gastric cancer MDR cell lines mediated CAM-DR through upregulation of Bcl-2 by MGr1-Ag interaction with laminin. Further study found that, as a receptor of ECM components, MGr1-Ag/37LRP may activate the downstream signal pathway PI3K/AKT and MAPK/ERK through interaction with phosphorylated FAK. Moreover, the sensitivity to chemotherapeutic drugs could be significantly enhanced by inhibiting MGr1-Ag/37LRP expression through mAbs, siRNA, and antisense oligonucleotide. According to these results, we concluded that the FAK/PI3K and MAPK signal pathway plays an important role in MGr1-Ag-mediated CAM-DR in gastric cancer. MGr1-Ag/37LRP might be a potential effective reversal target to MDR in gastric cancer.

Increased expression of HSP27 inhibits invasion and metastasis in human esophageal squamous cell carcinoma.

Previous studies have indicated that heat shock protein 27 (HSP27) had high correlation with the development and progression in several tumors. However, the roles of HSP27 in esophageal squamous cell carcinoma (ESCC) were uncertain. The aim in this study is to investigate the potential roles of HSP27 in the metastasis of ESCC. The expression of HSP27 in ESCC tissues and four human esophageal cancer cell lines were examined by immunohistochemistry and Western blotting, respectively. Wound healing assays, transwell assays, and in vivo assays were used to identify the differences of metastasis potential between normal and HSP27 overexpressed cells. HSP27 expression was downregulated in cancer tissue compared to the matched normal tissue. And the positive staining was mainly located in the cytoplasm. Statistical analyses showed that the expression of HSP27 in ESCC was significantly correlated with the tumor differentiation (P = 0.023), the patient's TNM stage (P = 0.013), lymph metastasis (P = 0.020), and distant metastasis (P = 0.017). HSP27 expression was significantly lower in highly metastatic cells than the less ones. The metastatic potentials of EC9706-H and EC109-H cells were higher than EC9706-L and EC109-L cells. In vitro and in vivo assays showed that overexpression of HSP27 in highly metastatic cells dramatically decreased their metastatic capacity. This study indicated that the expression level of HSP27 may be inversely correlated with the metastasis behavior of ESCC, and HSP27 may play an important role in this progression. HSP27 may be a potential molecular target for the therapy and prognosis of patients with ESCC.

Increased expression of FOXQ1 is a prognostic marker for patients with gastric cancer.

Altered expression of forkhead box Q1 (FOXQ1) is observed in various types of human cancers. However, the clinical significance of FOXQ1 expression in gastric cancer (GC) remains largely unknown. The present study aims to explore the clinicopathological significance and prognostic value of FOXQ1 in GC. FOXQ1 messenger RNA (mRNA) and protein expression were determined by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blot in 20 pairs of fresh frozen GC tissues and corresponding noncancerous tissues. Additionally, FOXQ1 expression was analyzed by immunohistochemistry in 158 clinicopathologically characterized GC cases. The correlation of FOXQ1 expression with patients' survival rate was assessed by Kaplan-Meier and Cox regression. Our results showed that the expression levels of FOXQ1 mRNA and protein in GC tissues were both significantly higher than those in non-cancerous tissues. Our results showed that the high expression of FOXQ1 in GC was related to tumor size (P = 0.026), histological grade (P = 0.021), lymph node involvement (P = 0.002), and tumor-node-metastasis stage (P = 0.028). Kaplan-Meier survival analysis showed that a high expression level of FOXQ1 resulted in a significantly poor prognosis of GC patients. Furthermore, Cox multivariates analysis indicated that FOXQ1 expression level was an independent prognostic factor for the overall survival rate of GC patients. In conclusion, overexpression of FOXQ1 is closely related to progression of GC and might be regarded as an independent predictor of poor prognosis for GC.

Effect of CO2 cholangiography on post-ERCP cholangitis in patients with unresectable malignant hilar obstruction - a prospective, randomized controlled study.

BACKGROUND: Air cholangiogram has been used in patients with malignant hilar obstruction to reduce cholangitis after endoscopic retrograde cholangiopancreatography (ERCP). However, it still remains unclear whether CO2 could be used as an alternative for air cholangiography in such patients. OBJECTIVE: To investigate the effect of CO2 cholangiogram on post-ERCP complications. DESIGN: Prospective, randomized controlled study. SETTING: Tertiary care referral center. PATIENTS: 36 patients with Bismuth type II, III or IV were randomized into CO2 group or iodine contrast group (control group). INTERVENTION: Cholangiography was performed by injection of either CO2 or iodine contrast through a sphincterotome. One or two metal stents were placed. MAIN OUTCOME MEASURES: Post-ERCP complications, length of hospital stay after ERCP, 1-month and 1-year mortality. RESULT: There was no significant difference in age, gender, symptoms, liver function tests, type of tumor origin and Bismuth type between patients in CO2 and contrast groups (p > 0.05). Compared with one-stent placement, more volume of CO2 and longer operation time were observed when performing two-stent placement (both p < 0.05). The rate of cholangitis in CO2 group was significantly lower than that in control group (5.6% vs. 33.3%, p = 0.04). After ERCP, mean hospital stay time was shorter in CO2 group compared with control (p < 0.05). The difference of 1-month and 1-year mortality between two groups was not significant (both p > 0.05). CONCLUSION: CO2 cholangiogram could be a safe method to visualize intrahepatic bile duct with low incidence of post-ERCP cholangitis, which could be considered for the patients with malignant hilar obstruction.

MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor.

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis.

The human lung cancer drug resistance-related gene BC006151 regulates chemosensitivity in H446/CDDP cells.

This study aimed to investigate the mechanism by which the human lung cancer drug resistance-related gene BC006151 regulates chemosensitivity by down-regulating BC006151 expression via antisense gene transfer in H446/(C)DDP cells. A retroviral vector containing the antisense BC006151 sequence was constructed and transfected into H446/(C)DDP cells. Transfection of the empty vector served as a negative control. The two groups of transfected cells were treated with various chemotherapeutic agents, after which morphological changes in cell ultrastructure were compared by transmission electron microscopy, cell proliferation and chemosensitivity to particular chemotherapeutic agents were compared by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, the effects of chemotherapy on cell cycle and apoptosis were compared by flow cytometry, and Bcl-2 was evaluated by immunohistochemistry and Western blot analysis. Results showed that apoptotic body-like structures were identified by transmission electron microscopy in the antisense gene-transfected cells. MTT founded that these cells exhibited a significantly lower level of proliferation than the control cells (p<0.01), together with a markedly increased sensitivity to various chemotherapeutic agents (p<0.01). Flow cytometry analysis revealed that a G1 phase arrest accounted for the reduction in proliferation in the antisense gene-transfected cells; increased apoptosis was also detected (p<0.01). Both immunohistochemistry and western blot analysis confirmed that Bcl-2 expression was significantly down-regulated in the antisense gene-transfected cells compared to controls. In a word, down-regulation of BC006151 can significantly inhibit proliferation and increase apoptosis of H446/(C)DDP cells after chemotherapy, and this gene may play an important role in the development of multidrug resistance in lung cancer.

Risk Factors for Post-ERCP Pancreatitis in High-Risk Patients Receiving Post-procedure Rectal Indomethacin.

BACKGROUND: Post-ERCP pancreatitis (PEP) is the most common adverse event of ERCP. Rectal indomethacin has been widely administered to decrease the incidence of PEP in high-risk patients. However, it cannot completely prevent the occurrence of PEP. The purpose of the study was to evaluate the risk factors for PEP in high-risk patients receiving post-ERCP indomethacin. METHODS: From June 2012 to July 2015, patients undergoing ERCP and at high risk for PEP in three tertiary hospitals in China were enrolled. All patients received indomethacin after the procedure. Patient-related and procedure-related risk factors for PEP were collected. Logistic regression analysis was used to investigate the risk factors. RESULTS: Seven hundred ninety patients at high risk for PEP received post-ERCP indomethacin. The incidence of overall PEP and moderate-to-severe PEP was 8.0 and 1.5%, respectively. In multivariate analysis, suspected sphincter of Oddi dysfunction (SOD) (OR 2.73; 95%CI 1.38-5.43; p = 0.004), the presence of hilar obstruction (OR 4.53; 95%CI 1.60-12.81; p = 0.004), number of cannulation attempts ≥ 13 (OR 2.00; 95%CI 1.07-3.77; p = 0.030), inadvertent pancreatic duct (PD) cannulation ≥ 1 (OR 2.26; 95%CI 1.04-4.90; p = 0.040), and pancreatic contrast injections ≥ 1 (OR 2.30; 95%CI 1.02-5.23; p = 0.046) were high risk factors for overall PEP. For moderate-to-severe PEP, suspected SOD (OR 4.67; 1.19-18.35; p = 0.027), the presence of hilar obstruction (OR 7.95; 1.39-44.97; p = 0.010), and more cannulation attempts (OR 3.71; 1.09-12.65; p = 0.036) were three independent risk factors. CONCLUSIONS: A substantial number of high-risk patients had PEP even receiving post-ERCP rectal indomethacin. The independent risk factors included suspected SOD, hilar stricture, more cannulation attempts, inadvertent PD cannulation, and PD contrast injections. TRIAL REGISTRATION: NCT02709421.

In vivo molecular imaging of gastric cancer in human-murine xenograft models with confocal laser endomicroscopy using a tumor vascular homing peptide.

The early detection of premalignant lesions and cancers are very important for improving the survival of patients with gastric malignancies. Confocal laser endomicroscopy (CLE) is a novel imaging tool for achieving real-time microscopy during the ongoing endoscopy at subcellular resolution. In the present study, to evaluate the feasibility of real-time molecular imaging of GEBP11 by CLE in gastric cancer, CLE was performed on two types of tumor-bearing mice models, as well as surgical specimens of patients with gastric cancer, after the application of GEBP11. A whole-body fluorescent imaging device was first used to screen for the strongest specific fluorescent signal in xenograft models. Next, the tumor sites, as well as human tissues, were scanned with CLE. After this, targeted specimens were obtained for fluorescence microscopy and histology. We confirmed that GEBP11 could specifically bind to co-HUVECs by means of CLE in cell experiments. Thereafter, a specific signal was observed in both subcutaneous and orthotopic xenograft models in vivo after the injection of FITC-GEBP11 via tail vein, whereas the group injected with FITC-URP showed no fluorescent signals. In human tissues, a specific signal of GEBP11 was observed in 26/28 neoplastic specimens and in 8/28 samples of non-neoplastic specimens from the patients (p < 0.01). The findings from ex vivo immunofluorescence microscopy of cryostat sections correlated well with that obtained by CLE. These findings indicate that the peptide, GEBP11, might be a potential candidate for the molecular imaging of gastric cancer.

Gastric cancer cell adhesion to laminin enhances acquired chemotherapeutic drug resistance mediated by MGr1-Ag/37LRP.

Adhesion of cancer cells to the extracellular matrix (ECM) causes a novel acquired chemotherapeutic drug­resistant phenotype, referred to as cell adhesion-mediated drug resistance (CAM-DR). Our previous studies suggested that the adhesion molecule MGr1-Ag/37LRP may promote multidrug resistance in gastric cancer cells. Therefore, we investigated MGr1-Ag/37LRP binding-induced adhesion, and its role in CAM-DR. Initial studies revealed that, after adhesion to the ECM, the multidrug-resistant gastric cancer cell lines SGC7901/VCR and SGC7901/ADR showed significantly higher mean adhesive cell numbers than non­resistant SGC7901 cells. We then investigated expression of MGr1-Ag/37LRP in gastric cancer cells adhering to laminin. Western blotting, RT-PCR and dual-luciferase reporter assays showed that laminin induced MGr1-Ag/37LRP expression and activity. In vitro and in vivo assays revealed that small interfering RNA against MGr1-Ag/37LRP significantly reduced CAM-DR in SGC7901/VCR cells. In vivo and in vitro analyses revealed that binding of MGr1-Ag/37LRP decreased intracellular drug accumulation by increasing P-glycoprotein and multidrug-associated protein expression, and inhibited drug-induced apoptosis by regulating Bcl-2 and Bax expression. These results indicate that MGr1-Ag/37LRP contributes to laminin-mediated CAM-DR in gastric cancer cells, and is a potentially effective target for reversing this phenomenon in gastric cancer.