Risk factors of delayed gastric emptying in patients after pancreaticoduodenectomy: a comprehensive systematic review and meta-analysis.

BACKGROUND: Delayed gastric emptying (DGE) is a common complication after pancreaticoduodenectomy (PD) or pylorus-preserving pancreaticoduodenectomy (PPPD). However, its risk factors are still unclear. This meta-analysis aimed to identify the potential risk factors of DGE among patients undergoing PD or PPPD. MATERIALS AND METHODS: We searched PubMed, EMBASE, Web of Science, Cochrane Library, Google Scholar, and ClinicalTrial.gov for studies that examined the clinical risk factors of DGE after PD or PPPD from inception through 31 July 2022. We pooled odds ratios (ORs) with 95% CIs using random-effects or fixed-effects models. We also performed heterogeneity, sensitivity, and publication bias analyses. RESULTS: The study included a total of 31 research studies, which involved 9205 patients. The pooled analysis indicated that out of 16 nonsurgical-related risk factors, three risk factors were found to be associated with an increased incidence of DGE. These risk factors were older age (OR 1.37, P =0.005), preoperative biliary drainage (OR 1.34, P =0.006), and soft pancreas texture (OR 1.23, P =0.04). On the other hand, patients with dilated pancreatic duct (OR 0.59, P =0.005) had a decreased risk of DGE. Among 12 operation-related risk factors, more blood loss (OR 1.33, P =0.01), postoperative pancreatic fistula (POPF) (OR 2.09, P <0.001), intra-abdominal collection (OR 3.58, P =0.001), and intra-abdominal abscess (OR 3.06, P <0.0001) were more likely to cause DGE. However, our data also revealed 20 factors did not support stimulative factors influencing DGE. CONCLUSION: Age, preoperative biliary drainage, pancreas texture, pancreatic duct size, blood loss, POPF, intra-abdominal collection, and intra-abdominal abscess are significantly associated with DGE. This meta-analysis may have utility in guiding clinical practice for improvements in screening patients with a high risk of DGE and selecting appropriate treatment measures.

The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer.

Background: Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood. Methods: SIX1 expression was determined using immunohistochemistry in PC tissues and cell lines. Glucose consumption, lactate production, and ATP assays were used to detect the function of SIX1. PC cells and NK cells were cocultured to study the effect of SIX1 overexpression in PC cells on NK cell function. Chromatin immunoprecipitation (ChIP) assays were used to study the relationship between SIX1 and lactate dehydrogenase A (LDHA). A series of in vitro and in vivo assays were further applied to elucidate the important role of the SIX1/LDHA axis in metabolism and NK cell dysfunction in PC. Results: SIX1 was significantly upregulated in PC tissue; SIX1 overexpression promoted the glycolysis capacity of PANC-1 and CFPAC-1 cells and resulted in NK cell dysfunction after the NK cells had been cultured with PC cells. LDHA inhibitor partially restored the promotion of PC caused by SIX1 overexpression. According to ChIP assays, SIX1 directly binds to the LDHA promoter region. Moreover, LDHA inhibitor and lactate transporter blocker treatment promoted the function of NK cells cocultured with PC cells. In vivo experiments yielded the same results. Conclusion: The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC.

Impact of the time of surgical delay on survival in patients with muscle-invasive bladder cancer.

Background and objectives: Patients with muscle-invasive bladder cancer (MIBC) often experience a waiting period before radical surgery for numerous reasons; however, the COVID-19 outbreak has exacerbated this problem. Therefore, it is necessary to discuss the impact of the unavoidable time of surgical delay on the outcome of patients with MIBC. Methods: In all, 165 patients from high-volume centers with pT2-pT3 MIBC, who underwent radical surgery between January 2008 and November 2020, were retrospectively evaluated. Patients' demographic and pathological information was recorded. Based on the time of surgical delay endured, patients were divided into three groups: long waiting time (> 90 days), intermediate waiting time (30-90 days), and short waiting time (≤ 30 days). Finally, each group's pathological characteristics and survival rates were compared. Results: The median time of surgical delay for all patients was 33 days (interquartile range, IQR: 16-67 days). Among the 165 patients, 32 (19.4%) were classified into the long waiting time group, 55 (33.3%) into the intermediate waiting time group, and 78 (47.3%) into the short waiting time group. The median follow-up period for all patients was 48 months (IQR: 23-84 months). The median times of surgical delay in the long, intermediate, and short waiting time groups were 188 days (IQR: 98-367 days), 39 days (IQR: 35-65 days), and 16 days (IQR: 12-22 days), respectively. The 5-year overall survival (OS) rate for all patients was 58.4%, and that in the long, intermediate, and short waiting time groups were 35.7%, 61.3%, and 64.1%, respectively (P = 0.035). The 5-year cancer-specific survival (CSS) rates in the long, intermediate, and short waiting time groups were 38.9%, 61.5%, and 65.0%, respectively (P = 0.042). The multivariate Cox regression analysis identified age, time of surgical delay, pT stage, and lymph node involvement as independent determinants of OS and CSS. Conclusion: In patients with pT2-pT3 MIBC, the time of surgical delay > 90 days can have a negative impact on survival.

The mechanism underlying ICAM-1 and E-selectin-mediated hypertriglyceridemic pancreatitis-associated lung injury.

PURPOSE: To investigate the possible mechanism by which adhesion molecules ICAM-1 and E-selectin mediate hypertriglyceridemic pancreatitis (HTGP)-associated lung injury. METHODS: C57BL/6 mice were randomly divided into five groups: control group (Con), severe acute pancreatitis group (SAP), HTGP group (HTGP), A-205804 group (A-205804), and apocynin group (Apo). Serum biochemical markers related to pancreatitis, such as inflammatory cytokines, amylase and lipase, were measured by enzyme-linked immunosorbent assay (ELISA) kits. Hematoxylin and eosin (HE) staining was used to analyze the histopathology changes in the pancreas and lung, and myeloperoxidase (MPO) activity in lung was detected by immunohistochemistry (IHC). Molecules related to NF-κB signaling pathway and adhesion molecules were assessed by western blotting (WB), IHC and immunofluorescence staining. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) in lung tissues and serum were measured with reagent kits, respectively. RESULTS: The severity of pancreatitis and lung injury in HTGP group was more severe than that in SAP group, and the expression levels of adhesion molecules ICAM-1 and E-selectin in lung tissues of HTGP mice were significantly increased. After HTGP mice were treated with adhesion molecule inhibitor A-205804, the expression of ICAM-1 and E-selectin in A-205804 group significantly decreased, and the lung injury was alleviated. The HTGP group had higher levels of oxidative stress and NF-κB pathway-related protein p-p65 expression compared with the SAP group. Apocynin treatment resulted in suppression of p-p65, ICAM-1, and E-selectin expression. CONCLUSION: In HTGP, hypertriglyceridemia may exacerbate pancreatitis-related lung injury by regulating oxidative stress and activating the NF-κB proinflammatory pathway to upregulate ICAM-1 and E-selectin levels.

Identification of genomic instability related lncRNA signature with prognostic value and its role in cancer immunotherapy in pancreatic cancer.

Background: Increasing evidence suggested the critical roles of lncRNAs in the maintenance of genomic stability. However, the identification of genomic instability-related lncRNA signature (GILncSig) and its role in pancreatic cancer (PC) remains largely unexplored. Methods: In the present study, a systematic analysis of lncRNA expression profiles and somatic mutation profiles was performed in PC patients from The Cancer Genome Atlas (TCGA). We then develop a risk score model to describe the characteristics of the model and verify its prediction accuracy. ESTIMATE algorithm, single-sample gene set enrichment analysis (ssGSEA), and CIBERSORT analysis were employed to reveal the correlation between tumor immune microenvironment, immune infiltration, immune checkpoint blockade (ICB) therapy, and GILncSig in PC. Results: We identified 206 GILnc, of which five were screened to develop a prognostic GInLncSig model. Multivariate Cox regression analysis and stratified analysis revealed that the prognostic value of the GILncSig was independent of other clinical variables. Receiver operating characteristic (ROC) analysis suggested that GILncSig is better than the existing lncRNA-related signatures in predicting survival. Additionally, the prognostic performance of the GILncSig was also found to be favorable in patients carrying wild-type KRAS, TP53, and SMAD4. Besides, a nomogram exhibited appreciable reliability for clinical application in predicting the prognosis of patients. Finally, the relationship between the GInLncSig model and the immune landscape in PC reflected its application value in clinical immunotherapy. Conclusion: In summary, the GILncSig identified by us may serve as novel prognostic biomarkers, and could have a crucial role in immunotherapy decisions for PC patients.

Preoperative Free Ferrous Protoporphyrin and Reactive Oxygen Species Status of Voided Urine Predicts Potential Recurrence Risk in NMIBC.

Purpose: This study aimed to assess the relationship between the preoperative reactive oxygen species and free ferrous protoporphyrin (ROS and FH) combined test and the risk of recurrence in a pathologically confirmed non-muscular invasive bladder cancer (NMIBC) patients. Patients and Methods: The retrospective study included 218 patients, newly diagnosed with NMIBC between January 2019 and February 2022. According to the results of FH and ROS combined test of voided urine, all patients were classified as FH(-)/ROS(-), FH(+)/ROS(-), or FH(+) /ROS(+). We reviewed demographic information, pathological results, and the FH and ROS combined test status. The clinicopathological characteristics were evaluated, and the survival rates of each group were compared. Finally, we also analyzed the association between preoperative free ferrous protoporphyrin and reactive oxygen species status and the tumor stage and grade. Results: This study included 218 NMIBC patients with a median age of 68 years (interquartile range [IQR] 60-76 years). The number and proportion of patients in FH(-)/ROS(-), FH(+)/ROS(-) and FH(+) /ROS(+) were 95(43.6%), 79(36.2%) and 44(20.2%), respectively. And the pathological stages for those with FH(+) and ROS(+), FH(+) and ROS(-), FH(-) and ROS(-) at diagnosis were 0.5% Tis, 6.4% Ta, 13.3% T1; 2.3% Tis, 20.6% Ta, 13.3% T1; 5.5% Tis, 28.9% Ta, 9.2% T1, respectively. After adjusting for clinical factors, including tumor grade, tumor stage and FH/ROS status were independent risk factors for RFS In the multivariate Cox regression analysis. Through logistics regression analysis, FH(+)/ROS(+) were found to be corelated with high grade and more high stage (T1). Kaplan-Meier analysis showed that 1-year RFS of FH(+)/ROS(+), FH(+)/ROS(-) and FH(-)/ROS(-) were 46.0%, 87.8% and 93.4%, respectively (P=0.000). Conclusion: In newly diagnosed NMIBC patients, the status of FH(+)/ROS(+) has an association with a higher risk in recurrence. Furthermore, FH(+)/ROS(+) at diagnosis was correlated with high grade and higher stage (T1). Hence, the FH/ROS combined test can help specify treatment options for patients diagnosed with NMIBC.

[Corrigendum] miR­23a suppresses pancreatic cancer cell progression by inhibiting PLK­1 expression.

Subsequently to the publication of this paper, the authors have realized that they made an error during the sorting of the data panels shown for the migration and invasion assays shown in Fig. 2C; essentially, the 'Invasion/PLL3.7' panel was chosen from the same original data source as the panel selected to represent the 'Migration/Inhibitor­NC' experiment. The authors have consulted their original data, and realize that the 'Invasion/PLL3.7' data panel was inadvertently selected incorrectly for Fig. 2. The revised version of Fig. 2, showing the data appropriate for the 'Invasion/PLL3.7' experiment, is shown on the next page. Note that the errors made in assembling Fig. 2 did not significantly affect either the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused.[Molecular Medicine Reports 18: 105­112, 2018; DOI: 10.3892/mmr.2018.8941].

Clinical benefits of a modified Cryopiece system for cryopreservation of rare ejaculated and testicular spermatozoa for ICSI.

Cryopreservation of rare testicular-retrieved spermatozoa for intracytoplasmic sperm injection (ICSI) in patients with severe oligozoospermia and azoospermia remains a major challenge in clinical practice. This study evaluated the Cryopiece system as a potential technique to cryopreserve rare human spermatozoa for ICSI. Small numbers of ejaculated (24 patients) and testicular (13 patients) spermatozoa were cryopreserved using the Cryopiece system. The total number of recovered spermatozoa and motility were assessed after thawing. Thirty-seven couples underwent ICSI using spermatozoa cryopreserved by the Cryopiece system, and ICSI outcomes (rates of fertilization, embryo cleavage, and clinical pregnancy) were evaluated. The average sperm post-thaw retrieval rate was 79.1%, and motility was 29.7%. Ejaculated spermatozoa had a higher post-thaw motility (32.5%) than testicular spermatozoa (21.8%; P = 0.005). ICSI achieved a fertilization rate of 61.9%, embryo cleavage rate of 84.6%, and clinical pregnancy rate of 43.3%. The ICSI outcomes in the ejaculated and testicular frozen-thawed spermatozoa were similar. Assisted oocyte activation (AOA) after ICSI with motile (72.1%) or immotile (71.9%) spermatozoa resulted in a significantly higher fertilization rate than that when using motile spermatozoa without AOA (52.0%; P = 0.005). However, AOA did not enhance the clinical pregnancy rate (55.6% or 40.0% vs 35.3%; P = 0.703). The Cryopiece system is simple and useful for the cryopreservation of small numbers of ejaculated or testicular spermatozoa for ICSI in patients with severe oligozoospermia or nonobstructive azoospermia.

Development an Inflammation-Related Factor-Based Model for Predicting Organ Failure in Acute Pancreatitis: A Retrospective Cohort Study.

Several inflammation-related factors (IRFs) have been reported to predict organ failure of acute pancreatitis (AP) in previous clinical studies. However, there are a few shortcomings in these models. The aim of this study was to develop a new prediction model based on IRFs that could accurately identify the risk for organ failure in AP. Methods. 100 patients with their clinical information and IRF data (levels of 10 cytokines, percentages of different immune cells, and data obtained from white blood cell count) were retrospectively enrolled in this study, and 94 patients were finally selected for further analysis. Univariate and multivariate analysis were applied to evaluate the potential risk factors for the organ failure of AP. The area under the ROC curve (AUCs), sensitivity, and specificity of the relevant model were assessed to evaluate the prediction ability of IRFs. A new scoring system to predict the organ failure of AP was created based on the regression coefficient of a multivariate logistic regression model. Results. The incidence of OF in AP patients was nearly 16% (15/94) in our derivation cohort. Univariate analytic data revealed that IL6, IL8, IL10, MCP1, CD3+ CD4+ T lymphocytes, CD19+ B lymphocytes, PCT, APACHE II score, and RANSON score were potential predictors for AP organ failure, and IL6 (P = 0.038), IL8 (P = 0.043), and CD19+B lymphocytes (P = 0.045) were independent predictors according to further multivariate analysis. In addition, a preoperative scoring system (0-11 points) was constructed to predict the organ failure of AP using these three factors. The AUC of the new score system was 0.86. The optimal cut-off value of the new scoring system was 6 points. Conclusions. Our prediction model (based on IL6, IL8, and CD19+ B Lymphocyte) has satisfactory working efficiency to identify AP patients with high risk of organ failure.

CA9-Related Acidic Microenvironment Mediates CD8+ T Cell Related Immunosuppression in Pancreatic Cancer.

PURPOSE: This study aims to integrate pancreatic cancer TCGA, GEO, and single-cell RNA-sequencing (scRNA-seq) datasets, and explore the potential prognostic markers and underlying mechanisms of the immune microenvironment of pancreatic cancer through bioinformatics methods, in vitro and in vivo assays. METHODS: Expression data and clinicopathological data of pancreatic cancer TCGA, GEO (GSE131050), single cell sequencing (PAAD_CRA001160) dataset were downloaded. We used R/Bioconductor edgeR for differential expression analysis. ClusterProfiler was utilized to perform GO enrichment analysis on differentially expressed genes. The online software CIBERSORT was used to reanalyze the mRNA expression data of pancreatic cancer. CellRanger, RunPCA, FindNeighbors, FindClusters, RunTSNE and RunUMAP were used to perform preprocessing, cell clustering and expression profile analysis on single-cell sequencing data sets. We analyzed intracellular pH with or without CA9 inhibitor SLC-0111. Indirect co-culture model of human pancreatic cancer cell lines and healthy individual-derived PBMCs were used to determine the effect of CA9-related Acidic Microenvironment on CD8+ T cells. RESULTS: The CIBERSORT analysis of TCGA pancreatic cancer transcriptome sequencing data showed that among the 22 immune microenvironment components, CD8+ T cell infiltration was significantly correlated with the prognosis of pancreatic cancer patients. The differential expression analysis of the TCGA data grouped by the level of CD8+ T cell infiltration indicates that the expression of carbonic anhydrase 9 (CA9) is the most significant, and the survival analysis suggests that CA9 is associated with the overall survival of pancreatic cancer. TCGA data and GEO data set GSE131050 expression correlation analysis suggests that CA9 and CD8 expression are closely related. Pancreatic cancer single-cell sequencing data set PAAD_CRA001160 analysis results show that CA9 is mainly expressed in pancreatic cancer cell clusters, and the expression of the cancer cell subgroup CA9 in the single-cell data set is correlated with CD8+ T cell infiltration. CONCLUSION: Pancreatic cancer cells may inhibit the infiltration of CD8+ T cells through CA9. Further exploration of its related mechanisms can be used to explore the immune escape pathway of pancreatic cancer and provides new perspectives immune targeted therapy.

46, XX Ovotesticular disorder of sex development (true hermaphroditism) with seminoma: A case report.

RATIONALE: Ovotesticular disorder of sex development (DSD), previously known as true hermaphroditism, is a disorder in which individuals have both testicular and ovarian tissues. Instances of tumors arising in the gonads of individuals with 46,XX ovotesticular DSD are uncommon. PATIENT CONCERNS: We report a case of a 36-year-old phenotypical male with a chief complaint of an abdominal mass for 3 months. He reported normal erections and regular menses. Computerized tomography showed a large tumor measuring 15 × 10 cm in size, a uterus, and a cystic ovary. DIAGNOSIS: 46, XX ovotesticular DSD with seminoma. INTERVENTIONS: The patient was treated with neochemotherapy (etoposide and cisplatin), surgery, chemotherapy, and testosterone replacement. OUTCOMES: At the 13-month follow-up, the patient reported satisfactory erections, and no evidence of disease was found. CONCLUSION: Cases of 46,XX ovotesticular DSD with seminoma are uncommon. Our case reveals the importance of surgery combined with neochemotherapy, chemotherapy, and testosterone replacement in these patients to improve the prognosis.

Comparative bioinformatical analysis of pancreatic head cancer and pancreatic body/tail cancer.

This study is to analyze differentially expressed genes (DEGs) and mutation signatures of pancreatic head cancer and pancreatic body/tail cancer. Pancreatic Adenocarcinoma (PAAD) RNA-seq data, mutation data and clinical data were downloaded and collected from The Cancer Genome Atlas (TCGA), FireHose and CBioPortal. According to the anatomic location, the patients were divided into 146 cases of pancreatic head cancer and 28 cases of pancreatic body/tail cancer. Then survival analysis was performed by Kaplan-Meier and log-rank test. Furthermore, DEGs were screened by R package Deseq2. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) were then carried out by DAVID and String. Online tool TIMER was used to analyze the immune cells infiltration. R package maftools and GenVisR were applied to analyze frequently mutated genes and mutant-allele tumor heterogeneity (MATH) of PAAD. Survival of patients with pancreatic body/tail cancer was better than those with pancreatic head cancer (median survival, 24.05 vs 19.45 months, p = 0.048). And 496 significant DEGs (|log2 FoldChange| > 1.5,false discovery rate (FDR) < 0.05) were identified, including 253 downregulated genes and 243 upregulated genes. And there were 13 Go terms (4 biological processes, 6 cellular components and 3 molecular functions) and 3 KEGG pathways (Pancreatic secretion, Fat digestion and absorption, Protein digestion and absorption) (FDR < 0.05). B cells and CD4 + T cells infiltration were more significant in pancreatic head cancer. MATH scores of pancreatic body/tail cancer were higher than pancreatic head cancer, while χ2 test of top 10 frequently mutated genes showed little difference between them. There were prognostic and genetic differences between pancreatic head cancer and pancreatic body/tail cancer. PAAD originated from different location may have different biology natures and should not be treated with same strategy.

Management of the pancreatic transection plane after left (distal) pancreatectomy: Expert consensus guidelines by the International Study Group of Pancreatic Surgery (ISGPS).

BACKGROUND: The aim was to evaluate the various operative techniques and outcomes used to manage the pancreatic transection plane (or stump) during a left (distal) pancreatectomy and to develop expert consensus guidelines. METHODS: Evidence-based, clinically relevant questions were discussed and then were circulated among members of the International Study Group of Pancreatic Surgery. After agreement on the questions and statements, voting in a 9-point Likert scale was used to gauge the level of objective support for each. RESULTS: Studies using the International Study Group of Pancreatic Surgery definition of postoperative pancreatic fistula including 16 randomized trials were reviewed to generate a series of statements set into 14 domains. There was strong consensus in the following statements: there was no difference in the postoperative pancreatic fistula rate after left pancreatectomy between the handsewn and stapler techniques; a stapling technique could not be used in all cases of left pancreatectomy; the use of an energy-based tissue sealant or a chemical sealant device or combinations of these did not impact the postoperative pancreatic fistula rate; there was no difference in the postoperative pancreatic fistula rate between the open, laparoscopic, or robotic approaches; and there are 1 or more clinically important, patient-related risk factors associated with the postoperative pancreatic fistula rate. There was weak or conditional agreement on the use of prophylactic somatostatin analogs, stents, stump closure, stump anastomosis, and the role of abdominal drains. CONCLUSION: Areas of strong consensus suggests a change in clinical practice and priority setting. Eight domains with lower agreement will require novel approaches and large multicenter studies to determine future key areas of practice.

Glycolysis promotes the progression of pancreatic cancer and reduces cancer cell sensitivity to gemcitabine.

Previous studies have reported that increased glycolytic activity enhances chemotherapy resistance in some types of malignancies. However, whether glycolysis influences the curative effect of gemcitabine (GEM) on pancreatic cancer (PC) cells remains unclear. The aim of this study was to investigate the status of glycolysis in PC and its association with tolerance to GEM. Data from The Cancer Genome Atlas (TCGA) were used to analyze the correlation between glycolysis-related gene (GRG) expression and PC progression and prognosis. 2-Deoxy-D-glucose (2-DG) was applied to assess the effect of glycolysis inhibition on PC cell death and GEM tolerance. Expression of some GRGs, such as HK1, GAPDH, PKM2, and LDHA, was significantly associated with the prognosis of PC. Furthermore, HK1, PKLR, and LDHA expression correlated positively with PC progression. Further analysis revealed that cancer cell death was markedly enhanced following glycolysis inhibition and that the sensitivity of cancer cells to GEM was notably increased in the presence of 2-DG. Our findings indicate that abnormally increased glycolytic activity promotes the development of PC and enhances drug tolerance to GEM. 2-DG combined with GEM is a potential therapy for PC.

Diabetes and Younger Age Are Vital and Independent Risk Factors for Acute Pancreatitis in Patients with Severe Hypertriglyceridemia.

Background. The incidence of hypertriglyceridemia-induced acute pancreatitis (HIAP) is increasing worldwide, and now it is the third leading cause of acute pancreatitis in the United States. But, there are only 5% of patients with severe hypertriglyceridemia (>1000 mg/dl) which might generate acute pancreatitis. In order to explore which part of the patients is easy to develop into pancreatitis, a case-control study was performed by us to consider which patient population tend to develop acute pancreatitis in patients with severe hypertriglyceridemia. To perform a retrospective case-control study, we identified severe hypertriglyceridemia patients without AP (HNAP) and with HIAP with a fasting triglyceride level of >1000 mg/dl from The First Affiliated Hospital of Nanjing Medical University during January 1, 2014, to December 31, 2016. Baseline patient characteristics, comorbidities, and risk factors were recorded and evaluated by the univariate and multivariate logistic regression analysis for HIAP and HNAP patients. A total of 124 patients with severe hypertriglyceridemia were included in this study; of which, 62 patients were in the HIAP group and 62 were in the HNAP group. Univariate logistic regression analysis showed that there was no gender difference in both groups; however, there were more younger patients in the HIAP group than in the HNAP group ( P value < 0.001), and the HIAP group had low level of high-density lipoprotein compared to the HNAP group ( P < 0.05 ). Meanwhile, the presence of pancreatitis was associated with higher level of glycemia and a history of diabetes ( P < 0.05 ). Multivariate logistic regression analysis indicated that a history of diabetes and younger age were independent risk factors for acute pancreatitis in patients with severe hypertriglyceridemia. Uncontrolled diabetes and younger age are potential risk factors in patients with severe hypertriglyceridemia to develop acute pancreatitis.

Iguratimod (T-614) attenuates severe acute pancreatitis by inhibiting the NLRP3 inflammasome and NF-κB pathway.

Severe acute pancreatitis (SAP) is an acute abdominal disease that can develop locally to the multiple organs. It is characterized by pancreatic tissue self-digestion, and the rapid release of inflammatory cytokines, which play a dominant role in local or even systemic inflammation. In this study, we investigate the protective effect of T-614 against SAP induced by cerulein plus LPS in mice. Biochemical markers associated with pancreatitis in serum such as inflammatory cytokines, amylase and lipase activities were measured. Related proteins of NLRP3 inflammasome and NF-κB signaling pathway were evaluated by western blotting. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to evaluate changes of inflammation in pancreatic tissue. T-614 significantly alleviated the elevation markers of pancreatitis and suppresses the pancreatic tissue damage, including histopathological and molecular manifestations. In conclusion, T-614 plays a protective role in experimental SAP mice model via anti-inflammatory effects.

Insulin promotes invasion and migration of KRASG12D mutant HPNE cells by upregulating MMP-2 gelatinolytic activity via ERK- and PI3K-dependent signalling.

OBJECTIVES: Hyperinsulinemia is a risk factor for pancreatic cancer, but the function of insulin in carcinogenesis is unclear, so this study aimed to elucidate the carcinogenic effects of insulin and the synergistic effect with the KRAS mutation in the early stage of pancreatic cancer. MATERIALS AND METHODS: A pair of immortalized human pancreatic duct-derived cells, hTERT-HPNE E6/E7/st (HPNE) and its oncogenic KRASG12D variant, hTERT-HPNE E6/E7/KRASG12D /st (HPNE-mut-KRAS), were used to investigate the effect of insulin. Cell proliferation, migration and invasion were assessed using Cell Counting Kit-8 and transwell assays, respectively. The expression of E-cadherin, N-cadherin, vimentin and matrix metalloproteinases (MMP-2, MMP-7 and MMP-9) was evaluated by Western blotting and/or qRT-PCR. The gelatinase activity of MMP-2 and MMP-9 in conditioned media was detected using gelatin zymography. The phosphorylation status of AKT, GSK3ß, p38, JNK and ERK1/2 MAPK was determined by Western blotting. RESULTS: The migration and invasion ability of HPNE cells was increased after the introduction of the mutated KRAS gene, together with an increased expression of MMP-2. These effects were further enhanced by the simultaneous administration of insulin. The use of MMP-2 siRNA confirmed that MMP-2 was involved in the regulation of cell invasion. Furthermore, there was a concentration- and time-dependent increase in gelatinase activity after insulin treatment, which could be reversed by an insulin receptor tyrosine kinase inhibitor (HNMPA-(AM)3 ). In addition, insulin markedly enhanced the phosphorylation of PI3K/AKT, p38, JNK and ERK1/2 MAPK pathways, with wortmannin or LY294002 (a PI3K-specific inhibitor) and PD98059 (a MEK1-specific inhibitor) significantly inhibiting the insulin-induced increase in MMP-2 gelatinolytic activity. CONCLUSIONS: Taken together, these results suggest that insulin induced migration and invasion in HPNE and HPNE-mut-KRAS through PI3K/AKT and ERK1/2 activation, with MMP-2 gelatinolytic activity playing a vital role in this process. These findings may provide a new therapeutic target for preventing carcinogenesis and the evolution of pancreatic cancer with a background of hyperinsulinemia.

Central pancreatectomy for early-stage pancreatic ductal adenocarcinoma: a single-center case-control study.

PURPOSE: Central pancreatectomy (CP) has been applied for treating benign and low-grade malignant tumors in pancreatic neck, but studies regarding CP for pancreatic ductal adenocarcinoma (PDAC) are quite limited. We aimed to investigate the role of central pancreatectomy in the treatment of PDAC in the neck of the pancreas. METHODS: Patients who underwent CP at our hospital between 2009 and 2016 were identified. Patients treated by distal pancreatectomy (DP) were matched according to the tumor size, location, and staging. The surgical and survival outcomes were compared between the CP and DP groups. RESULTS: Nine patients had CP. Five (56%) had postoperative complications and three (33%) had clinically significant (grade B + C) fistula. No significant difference was found between the CP and DP groups for the rate of overall morbidity, pancreatic fistula, reoperation, and readmission. Tumor size was smaller in the CP group compared to the DP group. The mortality of both groups was zero. The median postoperative survival was similar between the two groups (20.4 months for CP vs 19.4 months for DP, P = 0.842). CONCLUSIONS: CP is safe for patients with small PDAC at the neck of the pancreas. Considering the good preservation of pancreatic endocrine and exocrine functions, CP could be considered as an alternative procedure for single small PDAC in pancreatic neck.

Gene polymorphisms in the interleukins gene and the risk of acute pancreatitis: A meta-analysis.

Single nucleotide polymorphisms (SNPs) within the interleukins (IL) gene may affect the risk of acute pancreatitis. Many epidemiological studies have reported an association between the IL gene and acute pancreatitis risk, but the results remain inconsistent. Given the controversial available data, we carried out a meta-analysis to systematically evaluate and clarify the association between IL gene polymorphisms and AP. A systematic search of studies for this association was obtained from the PubMed, EMBASE, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases until June 1, 2017. We also searched the references of the included studies to identify additional studies. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to pool the effect size. Stata12.0 was used for whole statistical analysis. Fifteen studies that contained 3371 AP cases and 3506 controls were included in final combination. Overall, a significant association was found between the IL-8-251 T/A (rs4073) polymorphism, the IL-10-1082 A/G (rs1800896) polymorphism and the AP risk in four genetic models (homozygote model, recessive model, dominant model, allele model). Meanwhile, individuals with IL-1ß+3954 C/T (rs1143634, (homozygote model, recessive model)), IL-1ß -511 C/T (rs16944, (dominant model)) and IL-6-634C/G (rs1800796, (allele model)) polymorphism were associated with an increased risk of AP. No evidence of an association was found between IL and 10-592 C/A (rs1800872) and IL-10-819 C/T (rs1800871) polymorphism and AP risk.

HHLA2 is a novel immune checkpoint protein in pancreatic ductal adenocarcinoma and predicts post-surgical survival.

HHLA2 is a newly identified member of the B7 immune checkpoint family, but its function and crosstalk with immune cells is not fully understood. To gain insights into the HHLA2 expression profile and to determine the clinical significance and function of HHLA2 in pancreatic cancer, we performed immunohistochemistry (IHC) analyses on tissue microarrays (TMAs) of pancreatic ductal adenocarcinoma (PDAC, n = 92) with matched peritumoral tissues as well as in cohorts of precancerous lesions: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). We found that HHLA2 was rarely detected in normal acinar, islet, and ductal cells but widely expressed from early pancreatic precancerous lesions to invasive PDAC. The overall HHLA2 positivity was 95% (19/20) in low grade PanIN and 70.73% (29/41) in IPMN. HHLA2 expression was detected in 77.17% (71/92) of the PDAC cases and was significantly associated with better prognosis in this cohort. Our findings suggest that HHLA2 may behave as a costimulatory ligand in pancreatic cancer, which differs from other B7 family members that are largely characterized as checkpoint inhibitors. Further investigation of the HHLA2 signaling pathway and its receptors is warranted by our data and may lead to novel therapeutic interventions.