Laparoscopic common bile duct exploration with primary closure is preferred for selected elderly individuals with choledocholithiasis.

Background: Laparoscopic common bile duct exploration with primary closure (LCBDE-PC) exhibits more benefits than other surgeries for patients with choledocholithiasis. It remains unclear whether it is feasible for and beneficial to elderly individuals. This study aimed to clarify and stratify elderly patients who would benefit from LCBDE-PC. Methods: A retrospective study of 1240 patients with choledocholithiasis who underwent laparoscopic procedures between 2011 and 2019 was conducted. Patients were divided into the young group (<65 years old, n = 708) and the elderly group (≥65 years old, n = 532). Perioperative outcomes were compared between the two groups. Results: Laparoscopic common bile duct exploration with primary closure was successfully performed in 90.20% of the elderly and 94.20% of the young. No significant differences were observed between the two groups regarding reoperation, postoperative bile leakage, residual stones, drainage removal, and postoperative mortality. Compared with the young, the elderly had longer postoperative hospital stay (p = 0.035) and delayed postoperative eating time (p = 0.036) in the matched cohort. Independent risk factors for failed LCBDE-PC were preoperative pancreatitis (p = 0.018), year of the surgeon's experience (p = 0.008), preoperative C-reactive protein level (p = 0.034), preoperative total bilirubin (p = 0.021), impacted common bile duct (CBD) stones (p = 0.006), blood loss (p = 0.001), and edema of the CBD (p = 0.001). A novel nomogram for predicting failed LCBDE-PC in elderly individuals exhibited a sufficient discriminative ability according to the estimated area under the curve (AUC) of 0.869 (95% CI: 0.817-0.921, p < 0.01). Conclusion: Laparoscopic common bile duct exploration with primary closure is safe, feasible, and effective for elderly individuals with choledocholithiasis. Elderly patients with a high risk of failed LCBDE-PC should be cautious of undergoing LCBDE-PC.

Tumor Necrosis Factor Alpha Preconditioned Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Enhance the Inhibition of Necroptosis of Acinar cells in Severe Acute Pancreatitis.

Severe acute pancreatitis (SAP) is a common abdominal emergency with a high mortality rate and a lack of effective therapeutic options. Although mesenchymal stem cell (MSC) transplantation is a potential treatment for SAP, the mechanism remains unclear. It has been suggested that MSCs may act mainly through paracrine effects; therefore, we aimed to demonstrate the therapeutic efficacy of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (UCMSCs) for SAP. Na-taurocholate was used to induce a rat SAP model through retrograde injection into the common biliopancreatic duct. After 72 h of EVs transplantation, pancreatic pathological damage was alleviated, along with a decrease in serum amylase activity and pro-inflammatory cytokine levels. Interestingly, when UCMSCs were preconditioned with 10 ng/mL tumor necrosis factor alpha (TNF-α) for 48 h, the obtained EVs (named TNF-α-EVs) performed an enhanced efficacy. Furthermore, both animal and cellular experiments showed that TNF-α-EVs alleviated the necroptosis of acinar cells of SAP through RIPK3/MLKL axis. In conclusion, our study demonstrated that TNF-α-EVs were able to enhance the therapeutic effect on SAP by inhibiting necroptosis compared to normal EVs. This study heralds that TNF-α-EVs may be a promising therapeutic approach for SAP in the future.

Exosomes from TNF-α preconditioned human umbilical cord mesenchymal stromal cells inhibit the autophagy of acinar cells of severe acute pancreatitis via shuttling bioactive metabolites.

Severe acute pancreatitis (SAP) is a common critical disease of the digestive system, with high mortality and a lack of effective prevention and treatment measures. Despite mesenchymal stromal cell transplantation having the potential to treat SAP, its clinical application prospect is limited, and the mechanism is unclear. Here, we reveal the therapeutic role of exosomes from TNF-α-preconditioned human umbilical cord mesenchymal stromal cells (HUCMSCs) in attenuating SAP and show that it is partly dependent on exosomal metabolites. Bioactive metabolomics analysis showed that 48 metabolites be significantly differentially expressed between the two groups (Exo-Ctrl group versus Exo-TNF-α group). Then, the further functional experiments indicated that 3,4-dihydroxyphenylglycol could be a key molecule mediating the therapeutic effect of TNF-α-preconditioned HUCMSCs. The animal experiments showed that 3,4-dihydroxyphenylglycol reduced inflammation and oxidative stress in the pancreatic tissue and inhibited acinar cell autophagy in a rat model of SAP. Mechanistically, we revealed that 3,4-dihydroxyphenylglycol activated the mTOR pathway to inhibit acinar cell autophagy and alleviate SAP. In summary, our study demonstrated that exosomes from TNF-α-preconditioned HUMSCs inhibit the autophagy of acinar cells of SAP by shuttling 3,4-dihydroxyphenylglycol and inhibiting the mTOR pathway. This study revealed the vital role and therapeutic potential of metabolite-derived exosomes in SAP, providing a new promising method to prevent and therapy SAP.

Aspartate ß-hydroxylase (ASPH) Accelerates Intrahepatic Cholangiocarcinoma Metastasis via Upregulating SHH Signaling Pathway.

Background: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with a poor prognosis. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase involved in the post-translational hydroxylation of target proteins. ASPH has been demonstrated to be upregulated in ICC, yet its role remains to be elucidated. This study aimed to investigate the potential function of ASPH in ICC metastasis. Methods: Survival curves for the overall survival of pan-cancer data from The Cancer Genome Atlas (TCGA) database was depicted using the Kaplan-Meier method and compared using the log-rank test. The expression of ASPH, glycogen synthase kinase (GSK)-3ß, phosphorylation GSK-3ß (p-GSK-3ß), epithelial-mesenchymal transition (EMT) biomarkers, and sonic hedgehog (SHH) signaling elements in ICC cell lines was analyzed by western blot. Wound healing and transwell assays were conducted to examine the effects of ASPH knockdown and overexpression on cell migration and invasion. An immunofluorescence assay was conducted to evaluate the expression of glioma-associated oncogene 2 (GLI2), GSK-3ß and ASPH. The effect of ASPH on tumor in vivo was analyzed using a nude mouse xenograft model. Results: Pan-cancer data showed that expressed ASPH was significantly correlated with a poor prognosis in patients. ASPH knockdown inhibited the migration and invasion of human ICC cells lines QBC939 and RBE. ASPH overexpression contributed to an increase in the N-cadherin and Vimentin, resulting in the promotion of the EMT process. The p-GSK-3ß levels decreased in the presence of ASPH overexpression. The overexpression of ASPH led to an upregulation of the expression of SHH signaling elements GLI2 and SUFU. The results of in vivo experiments with a lung metastasis model in nude mice with ICC cell line RBE are consistent with these results. Conclusion: ASPH accelerated metastasis of ICC cells by facilitating EMT via a GSK-3ß/SHH/GLI2 axis-dependent manner, in which phosphorylation of GSK-3ß was downregulated and the SHH signaling pathway was activated.

The efficacy and safety of laparoscopic common bile duct exploration and cholecystectomy for the treatment of difficult common bile duct stones combined with gallstones: a multicenter retrospective study.

PURPOSE: To analyze the benefits of laparoscopic common bile duct exploration and laparoscopic cholecystectomy (LCBDE + LC) versus endoscopic retrograde cholangiopancreatography and/or endoscopic sphincterotomy following laparoscopic cholecystectomy (ERCP/EST + LC) for difficult common bile duct stones combined with gallstones. METHODS: A retrospective analysis of consecutive patients with difficult common bile duct stones combined with gallstones in three hospitals from January 2016 to January 2021 was performed. RESULTS: ERCP/EST + LC contributed to reducing postoperative drainage time. However, LCBDE + LC showed a higher rate of complete clearance, along with lower postoperative hospital stays, expenses and incidence of postoperative hyperamylasemia, pancreatitis, re-operation and recurrence. In addition, LCBDE + LC showed safe and feasible performance in the elderly and patients with previous upper abdominal surgery. CONCLUSION: It is an effective and safe method for LCBDE + LC for difficult common bile duct stones combined with gallstones.

Is T-tube drainage no longer needed for laparoscopic common bile duct exploration? A retrospective analysis and literature review.

Introduction: Primary closure (PC) following laparoscopic common bile duct exploration (LCBDE) is increasingly becoming a safe and effective option for choledocholithiasis. However, whether T-tube drainage (TTD) is no longer needed for LCBDE remains under debate. Aim: To evaluate the safety and efficacy of PC and TTD following LCBDE, and discuss their indications for selection of the procedure, combined with a literature review. Material and methods: 826 consecutive patients who underwent LCBDE with PC or TTD at Shanghai Tenth People's Hospital were reviewed. The clinical data of postoperative outcomes were compared and analyzed. Propensity score matching (PSM) was used to adjust for potential baseline confounding. Results: Of these patients, 796 underwent PC and 30 underwent TTD. Twenty-eight (3.52%) cases occurred in bile leakage in PC, and all of them were treated successfully with conservative therapy. Additionally, there was no evidence of bile duct stricture and death in all PC cases. TTD was mainly performed in patients with a higher rate of cholangitis (50.00%), large stones (26.67%), impacted stones (23.33%) and laser lithotripsy (26.67%). After PSM, 23 cases with PC and TTD were included. In the PC group, the operative time, postoperative stay, hospital expenses and recurrence rate were significantly shorter or less than in the TTD group. However, there were no significant differences between the two groups in postoperative drainage time, complications, reoperations and bile duct stricture rate. Conclusions: PC following LCBDE is safe and effective for choledocholithiasis. TTD is a safe alternative method for bile duct closure in certain special cases, such as acute cholangitis, large stones, impacted stones, and laser lithotripsy.

Long noncoding RNA CASC9 promotes pancreatic cancer progression by acting as a ceRNA of miR-497-5p to upregulate expression of CCND1.

BACKGROUND: Pancreatic cancer (PC) is an aggressive malignancy with poor prognosis. Accumulating studies have showed that long non-coding RNA (lncRNA) is a crucial regulator in various tumorigenesis and progression including PC. This research aims to explore the roles and molecular mechanism of lncRNA cancer susceptibility candidate 9 (CASC9) in PC. METHODS: The expression levels of lncRNA CASC9 and miR-497-5p were evaluated in PC tissues and paired adjacent healthy tissues by quantitative real-time PCR. PC cell lines were transfected with lentivirus targeting lncRNA CASC9, and cells proliferation, migration and invasion tests were conducted. Dual luciferase reporter assays were also carried out to explore the relationship between lncRNA CASC9, miR-497-5p and Cyclin D1 (CCND1). RESULTS: LncRNA CASC9 was significantly up-regulated in PC tissues, while miR-497-5p expression was down-regulated. Down-regulation of lncRNA CASC9 in PC cells can significantly suppress the cell aggressiveness both in vitro and in vivo; moreover, knock-down of miR-497-5p could neutralize this impact. Additionally, the luciferase activity assay has assured that CCND1 was a downstream target of miR-497-5p. CONCLUSION: LncRNA CASC9 can promote the PC progression by modulating miR-497-5p/CCND1 axis, which is potential target for PC treatment.

Low aspartate aminotransferase/alanine aminotransferase (DeRitis) ratio assists in predicting diabetes in Chinese population.

Background: Few studies discussed the predictive ability of aspartate aminotransferase/alanine aminotransferase (AST/ALT, DeRitis) ratio for diabetes risk. The aim of this study was to characterize the role of AST/ALT ratio in the prediction of Chinese diabetes. Methods: This retrospective cohort study analyzed a Chinese population comprising 87,883 participants without diabetes at baseline between 2010 and 2016. Cox proportional hazards regression was used to identify independent risk factors. Restricted cubic spline (RCS) was performed to investigate the non-linear correlation between AST/ALT ratio and diabetes risk. Results: During a median follow-up period of 3.01 years, 1,877 participants developed diabetes. Comparing the baseline characteristics, diabetes group exhibited lower AST/ALT ratio. The Kaplan-Meier curve showed that participants with low AST/ALT ratio had higher cumulative incidence, and Cox regression also demonstrated that the lower AST/ALT ratio, the higher diabetes risk (HR: 0.56, 95% CI: 0.37-0.85, P = 0.006). The RCS model revealed a non-linear correlation between AST/ALT ratio and diabetes risk. In the condition of AST/ALT ratio ≤1.18, diabetes risk increased as it decreased (HR: 0.42, 95% CI: 0.19-0.91, P = 0.028). In contrast, AST/ALT ratio did not independently affect diabetes when beyond 1.18. Conclusion: AST/ALT ratio is a valuable predictor of diabetes. Diabetes risk increases rapidly in the condition of AST/ALT ratio ≤1.18.

A novel refined pyroptosis and inflammasome-related genes signature for predicting prognosis and immune microenvironment in pancreatic ductal adenocarcinoma.

Pyroptosis is an inflammatory form of cell death, which plays a key role in the development of auto-inflammation and cancer. This study aimed to construct a pyroptosis and inflammasome-related genes for predicting prognosis of the pancreatic ductal adenocarcinoma (PDAC). This study was based primarily on the one-way analysis of variance, univariate Cox regression analysis, Least absolute shrinkage and selection operator (LASSO) Cox regression, a risk-prognostic signature, gene set variation analysis (GSVA), and immune microenvironment analysis, using PDAC data from The Cancer Genome Atlas and International Cancer Genome Consortium databases for the analysis of the role of 676 pyroptosis and inflammasome-related genes in PDAC retrieved from the Reactome and GeneCards databases. Lastly, we collected six paired PDAC and matched normal adjacent tissue samples to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR). We identified 18 candidate pyroptosis and inflammasome-related genes that differed significantly between pathologic grades (stages) of PDAC patients. The univariate Cox and LASSO analyses pointed to six genes as the best variables for constructing a prognostic signature, including ACTA2, C1QTNF9, DNAH8, GATM, LBP, and NGF. The results of the risk prognostic model indicated that the AUCs at 1, 3, and 5 years were greater than 0.62. GSVA revealed that 'GLYCOLYSIS', 'P53 PATHWAY', 'KRAS SIGNALING UP', and 'INFLAMMATORY RESPONSE' hallmark gene sets were associated with the risk score. The high-risk group was associated with poor prognosis and was characterized by a lower infiltration of cells involved in anti-tumor immunity; whereas the low-risk group with higher T cells, NK cells, and macrophages showed relatively better survival and significantly higher upregulation of cytolytic scores and inflammation scores. Additionally, crucial pyroptosis and inflammasome-related genes were further validated by qRT-PCR. Our study revealed the prognostic role of the pyroptosis and inflammasome-related genes in PDAC for the first time. Simultaneously, the biological and prognostic heterogeneity of PDAC had been demonstrated, deepening our molecular understanding of this tumor.

Gamma-glutamyl transferase to high-density lipoprotein cholesterol ratio: A valuable predictor of type 2 diabetes mellitus incidence.

Background: Gamma-glutamyl transferase (GGT) and high-density lipoprotein cholesterol (HDL-C) have been proven to be valuable predictors of type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the association between GGT/HDL-C ratio and incident T2DM. Methods: The study retrospectively analyzed 15453 participants from 2004 to 2015. Cox proportional hazards regression models and Kaplan-Meier curves were used to elucidate the effect of GGT/HDL-C ratio on T2DM. Restricted cubic spline (RCS) analysis was performed to explore any non-linear correlation between GGT/HDL-C ratio and the risk of T2DM. The predictive performance of GGT, HDL-C and GGT/HDL-C ratio for T2DM was evaluated utilizing receiver-operating-characteristic (ROC) curves. Results: During a median follow-up of 5.39 years, 373 cases of incident T2DM were observed. Kaplan-Meier curves showed that the cumulative probabilities of T2DM increased in the participants with higher GGT/HDL-C ratio significantly (P < 0.001). Cox models further clarified that high GGT/HDL-C ratio was an independent risk factor for T2DM (HR = 1.01, 95% CI = 1.00-1.01, P = 0.011). Linear positive correlation between GGT/HDL-C ratio and the risk of T2DM was demonstrated through RCS analysis. In the ROC analysis, GGT/HDL-C ratio (AUC = 0.75, 95% CI = 0.73-0.77) showed competitive role in the prediction of T2DM compared with single GGT and HDL-C. Conclusions: The GGT/HDL-C ratio could serve as a valuable predictor of T2DM, and the risk of T2DM increases in the condition of higher GGT/HDL-C ratio.

Chinese and Global Burdens of Gastrointestinal Cancers From 1990 to 2019.

Background: Gastrointestinal (GI) cancers are an important component of the tumor. This study aimed to investigate the burden of six major GI cancers in China and globally from 1990 to 2019. Methods: We conducted a cross-sectional study based on the Global Burden of Disease Study (GBD) 2019. Indicators on incidence, deaths, disability-adjusted life-years (DALYs), and risk factors for esophageal, stomach, liver, pancreatic, colon and rectum, and gallbladder and biliary tract cancers were collected and analyzed for time trends. The contribution of each cancer and the proportion of cases in China among global cases were further reported. Results: Global incidence cases, death cases, and DALYs of GI cancers showed an overall ascending trend over the past 30 years, but there was temporal and geographical variation across cancer types. By 2019, colon and rectum cancer had overtaken stomach cancer as the most burdensome GI cancer globally. However, stomach cancer narrowly continued to be the most burdensome GI in China. In addition, the proportion of incidence and death cases of stomach, pancreatic, colon and rectum, and gallbladder and biliary tract cancers among global cases had further increased. It was noteworthy that the burden of liver cancer in China has been alleviated significantly. Conclusion: GI cancers remain a major public health problem in China and globally. Despite the temporal and geographic diversity of different cancers, targeted primary and secondary prevention are still necessary for the future to face these unknown challenges.

A nomogram for predicting stones recurrence in patients with bile duct stones undergoing laparoscopic common bile duct exploration.

Background: The recurrence of bile duct stones is a long-term outcome for patients undergoing laparoscopic common bile duct exploration (LCBDE) that is worthy of attention. This study aimed to investigate long-term risk factors for stones recurrence after LCBDE and develop a nomogram for predicting the risk. Methods: The clinical data on consecutive patients with bile duct stones undergoing LCBDE at Shanghai Tenth People's Hospital between January 2014 and February 2019 with a follow-up period longer than 2 years were reviewed. Independent risk factors of stones recurrence identified by the Cox regression model were used to develop a nomogram in predicting stones recurrence after LCBDE. Results: Eight hundred and twenty-two patients were eventually included in this study. Of these patients, 42 (5.11%) developed stones recurrence. The cumulative incidences of stones recurrence at 1, 3, and 5 years after LCBDE were 1.34%, 4.36%, and 7.14%, respectively. Independent risk factors of stones recurrence were identified to be age (HR = 1.04, 95% CI = 1.02-1.07), T-tube drainage (HR = 3.28, 95% CI = 1.23-8.72), fatty liver (HR = 2.69, 95% CI = 1.39-5.20), urinary calculus (HR = 4.68, 95% CI = 2.29-9.56), post-cholecystectomy (HR = 5.21, 95% CI = 2.39-11.33), and post-ERCP + EST (HR = 2.87, 95% CI = 1.18-6.96). By these factors, a developed nomogram showed a C-index of 0.770 to predict stones recurrence. Conclusions: The nomogram, based on identified risk factors, showed good accuracy for predicting stones recurrence, which is valuable to guide these patients' follow-up and prevention.

Laparoscopic common bile duct exploration with primary closure is beneficial for patients with previous upper abdominal surgery.

BACKGROUND: Previous upper abdominal surgery (PUAS) is considered a contraindication to laparoscopic surgery. Whether LCBDE-PC is feasible and beneficial for patients with PUAS remains unclear. This study aimed to evaluate the feasibility and benefits of LCBDE-PC for patients with PUAS. METHODS: From June 2011 to September 2019, 1167 patients who underwent laparoscopic procedures for choledocholithiasis were reviewed retrospectively. Perioperative outcomes were compared between patients with and without PUAS in un-matched and matched cohorts. RESULTS: LCBDE-PC was performed successfully in 88.3% of patients with PUAS, and 92.5% of patients without PUAS (P > 0.05). Multivariate analysis showed that PUAS was not a risk factor that affected successful performance of LCBDE-PC. Although a higher rate of conversion to open surgery and longer operative time were observed in patients with PUAS, no significant differences were found between patients with and without PUAS in multivariate and propensity score analysis (P > 0.05). A predictive nomogram for LCBDE-PC failure was developed based on potential predictors from the least absolute shrinkage and selection operator (LASSO) regression model. Successful performance of LCBDE-PC was associated with operative time. A linear regression model for operative time showed impacted stone in the CBD and intraoperative laser use was the most important factor in determining the operative time. CONCLUSION: LCBDE-PC is feasible and beneficial for patients with PUAS. However, patients with PUAS with a high possibility of LCBDE-PC failure from the nomogram and a longer operative time from the linear regression model should be cautious when undergoing LCBDE-PC.

Safety and efficacy of laparoscopic common bile duct exploration for the patients with difficult biliary stones: 8 years of experiences at a single institution and literature review.

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) has gained wide popularity for the treatment of choledocholithiasis. However, it remains unclear whether LCBDE is a better alternative option for the patients with difficult biliary stones. Thus, the aim of the present study was to explore the safety and efficacy of LCBDE for these patients by retrospectively analyzing our data and combing with literature review. METHODS: Between September 2011 and February 2019, 1064 consecutive patients who underwent LCBDE at Shanghai Tenth People's Hospital were reviewed. The clinical data of patients with difficult biliary stones were selected and retrospectively analyzed. RESULTS: Of these patients, 334 cases were confirmed with difficult biliary stones, and the overall complete stone clearance rate was 98.8% (330/334). 34 cases (10.2%) were performed with laser lithotripsy. A total of 296 patients (88.6%) underwent primary closure of common bile duct, and T-tube drainage was indwelled in 38 patients (11.4%). No bile duct injury, bleeding, perforation and surgery-related deaths were observed. The overall morbidity rate was 6.6%. 16 cases (4.8%) occurred in bile leakage with primary closure procedure, and all of them were managed successfully with conservative therapy. The median follow-up period was 9 months with stone recurrence occurring in 9 patients (2.7%). There was no evidence of bile duct stricture in all cases. CONCLUSIONS: The current study suggests that LCBED is a considerable safe and effective option for the patients with difficult biliary stones. A randomized clinical trial is needed to further evaluate the benefit of LCBDE in this subgroup.

A Modified T-Stage Classification for Gastric Neuroendocrine Tumors.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer (AJCC) staging manual's TNM staging classification for gastric neuroendocrine tumors has been shown to have poor prognostic discriminability. The aim of present study was to propose a modified T-stage classification, and externally validate its performance in a separate population data registry. METHODS: A modified T-stage classification with tumor size and extent of tumor invasion was generated from the National Cancer Database between 2004 and 2014 (n = 1249). External validation was performed using the Surveillance, Epidemiology, and End Results registry between 1973 and 2013 (n = 539). RESULTS: In the National Cancer Database population, using the AJCC T-stage classification, the 5-y survival rates were 85.7%, 80.8%, 64.5%, and 46.1% in T1, T2, T3, and T4 patients respectively (P < 0.001). These rates were more contrasting with the modified T-stage (mT) classification at 87.0%, 78.2%, 59.0%, and 40.3% respectively (P < 0.001). When patients within each of the AJCC T stages were stratified by mT stages, significant survival heterogeneity was observed within each of the AJCC T2 to T4 stages (P < 0.01). Conversely, when mT stages were stratified by AJCC T stage, no survival difference was observed in any of the mT stages (P > 0.05). The same analyses were performed using Surveillance, Epidemiology, and End Results data, and all the observed results were validated. CONCLUSION: The current AJCC T stage classification categorizes patients into groups with heterogenous prognosis, thus failing to serve as an effective staging tool. A modified T-stage classification demonstrated significantly improved stratification for patients with gastric neuroendocrine tumors.

Mesenchymal stromal cell therapy for pancreatitis: Progress and challenges.

Pancreatitis is a common gastrointestinal disease with no effective therapeutic options, particularly for cases of severe acute and chronic pancreatitis (CP). Mesenchymal stromal cells (MSCs) are multipotent cells with diverse biological properties, including directional migration, paracrine, immunosuppressive, and antiinflammatory effects, which are considered an ideal candidate cell type for repairing tissue damage caused by various pathogenies. Several researchers have reported significant therapeutic efficacy of MSCs in animal models of acute and CP. However, the specific underlying mechanisms are yet to be clarified and clinical application of MSCs as pancreatitis therapy has rarely been reported. This review mainly focuses on the potential and challenges in clinical application of MSCs for treatment of acute and CP, along with discussion of the underlying molecular mechanisms.

Long noncoding RNA H19 regulates the therapeutic efficacy of mesenchymal stem cells in rats with severe acute pancreatitis by sponging miR-138-5p and miR-141-3p.

BACKGROUND: Patients with severe acute pancreatitis (SAP), which is characterized by high morbidity and mortality, account for an increasing medical burden worldwide. We previously found that mesenchymal stem cells (MSCs) could attenuate SAP and that expression of long noncoding RNA H19 (LncRNA H19) was upregulated in rats receiving MSCs. In the present study, we investigated the mechanisms of LncRNA H19 regulating the therapeutic efficacy of MSCs in the alleviation of SAP. METHODS: MSCs transfected with LncRNA H19 overexpression and knockdown plasmids were intravenously injected into rats 12 h after sodium taurocholate (NaT) administration to induce SAP. RESULTS: Overexpressing LncRNA H19 in MSCs significantly enhanced the anti-inflammatory capacity of the MSCs, inhibited autophagy via promotion of focal adhesion kinase (FAK)-associated pathways, and facilitated cell proliferation by increasing the level of ß-catenin in rats with SAP. LncRNA H19 functioned as a competing endogenous RNA by sponging miR-138-5p and miR-141-3p. Knocking down miR-138-5p in MSCs increased the expression of protein tyrosine kinase 2 (PTK2, encoding FAK) to suppress autophagy, while downregulating miR-141-3p enhanced the level of ß-catenin to promote cell proliferation. CONCLUSIONS: In conclusion, LncRNA H19 effectively increased the therapeutic efficacy of MSCs in rats with SAP via the miR-138-5p/PTK2/FAK and miR-141-3p/ß-catenin pathways.

Resveratrol improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in rats with severe acute pancreatitis.

OBJECTIVE: Bone marrow-derived mesenchymal stem cells (BMSCs) are effective in the treatment of severe acute pancreatitis (SAP), but their therapeutic effects could still be improved. In order to optimize the clinical application of BMSCs, we adopted the strategy of resveratrol (Res) pretreatment of BMSCs (Res-BMSCs) and applied it to a rat model of sodium taurocholate (NaT)-induced acute pancreatitis. METHODS: SAP was induced by injection of 3% NaT into the pancreatic duct and successful induction of SAP occurred after 12 h. Rats were treated with BMSCs, Res or BMSCs primed with Res at 40 mmol/L, Vandetanib (ZD6474) daily oral dosages of 50 mg/kg vandetanib. RESULTS: Res stimulated BMSCs to secrete vascular endothelial growth factor A (VEGFA), activated the downstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and inhibited pancreatic cell apoptosis. In addition, conditioned medium (CM) from Res-BMSCs enhanced the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro, increased resistance to apoptosis and promoted the expression of angiogenesis-related proteins CD31, VEGF and VEGFR2 in pancreatic tissue, but Vandetanib partly abolished these effects by blocking the VEGFA- mediated pathway. CONCLUSION: Resveratrol-preprocessed BMSCs can activate the PI3K/AKT signaling pathway in pancreatic cells and HUVECs through paracrine release of VEGFA; thus, achieving the therapeutic effect of resisting apoptosis of pancreatic cells and promoting regeneration of damaged blood vessels. Res pretreatment may be a new strategy to improve the therapeutic effect of BMSCs on SAP.

Optimal treatment for elderly patients with resectable proximal gastric carcinoma: a real world study based on National Cancer Database.

BACKGROUND: High perioperative morbidity, mortality, and uncertain outcome of surgery in octogenarians with proximal gastric carcinoma (PGC) pose a dilemma for both patients and physicians. We aim to evaluate the risks and survival benefits of different strategies treated in this group. METHODS: Octogenarians (≥80 years) with resectable proximal gastric carcinoma who were recommended for surgery were identified from National Cancer Database during 2004-2013. RESULTS: Patients age ≥ 80 years with PGC were less likely to be recommended or eventually undergo surgery compared to younger patients. Patients with surgery had a significantly better survival than those without surgery (5-year OS: 26% vs. 7%, p < 0.001), especially in early stage patients. However, additional chemotherapy (HR: 0.94, 95% CI: 0.82-1.08, P = 0.36) or radiotherapy (HR: 0.97, 95% CI: 0.84-1.13, P = 0.72) had limited benefits. On multivariate analysis, surgery (HR: 0.66, 95% CI: 0.51-0.86, P = 0.002) was a significant independent prognostic factor, while extensive surgery had no survival benefit (Combined organ resection: HR: 1.88, 95% CI: 1.22-2.91, P = 0.004; number of lymph nodes examined: HR: 0.99, 95% CI: 0.97-1.00, P = 0.10). Surgery performed at academic and research (AR) medical center had the best survival outcome (5-year OS: 30% in AR vs. 18-27% in other programs, P < 0.001) and lowest risk (30-day mortality: 1.5% in AR vs. 3.6-6.6% in other programs, P < 0.001; 90-day mortality: 6.2% in AR vs. 13.6-16.4% in other programs, P < 0.001) compared to other facilities. CONCLUSIONS: Less-invasive approach performed at academic and research medical center might be the optimal treatment for elderly patients aged ≥80 yrs. with early stage resectable PGC.

Clinical role of frequency-doubled double-pulse neodymium YAG laser lithotripsy for removal of difficult biliary stones in laparoscopic common bile duct exploration.

BACKGROUND: The optimal methods for patients with difficult biliary stones remain under debate. The aim of this study was to evaluate the role of frequency-doubled double-pulse neodymium YAG (FREDDY) laser lithotripsy for removing difficult biliary stones during laparoscopic common bile duct exploration (LCBDE). METHODS: Between March 2013 and January 2015, 42 consecutive patients with difficult biliary stones who underwent LCBDE with FREDDY laser lithotripsy were included in this study. The clinical data of all patients were retrospectively collected and analysed. RESULTS: Bile ducts were completely cleared in all patients. The complications related to laser lithotripsy were not noted. A total of 38 patients (90.5%) underwent primary closure of common bile duct, and T-tube drainage was applied to four patients (9.5%). No bile duct injury, bleeding and perforation were observed. There were no post-operative surgery-related deaths. Bile leakage occurred in four patients (9.5%) with primary closure procedure, and all of them were managed successfully with conservative therapy. The median follow-up period was 42.8 months, with no evidence of bile duct stricture and stone recurrence in all patients. CONCLUSIONS: The LCBDE combined with FREDDY laser lithotripsy appear to be effective and safe for the treatment of difficult biliary stones.