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Abstract Background Carbohydrate antigen 19–9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in pancreatic cancer, the deciphering of CA19-9 biosynthesis provides a potential clue for treatment. Methods Concentration of amino acids was detected by ultrahigh-performance liquid chromatography tandem mass spectrometry. Metabolic flux of glutamine was examined by isotope tracing untargeted metabolomics. Label-free quantitative n-glycosylation proteomics was used to examine n-glycosylation alterations. Results Among all amino acids, glutamine was higher in CA19-9-high pancreatic cancers (> 37 U/mL, 66 cases) than in CA19-9-normal clinical specimens (≤ 37 U/mL, 37 cases). The glutamine concentration in clinical specimens was positively correlated with liver metastasis or lymphovascular invasion. Glutamine blockade using diazooxonorleucine suppressed pancreatic cancer growth and intraperitoneal and lymphatic metastasis. Glutamine promotes O-GlcNAcylation, protein glycosylation, and CA19-9 biosynthesis through the hexosamine biosynthetic pathway. UDP-n-acetylglucosamine (UDP-GlcNAc) levels correlated with the glutamine influx through hexosamine biosynthetic pathway and supported CA19-9 biosynthesis. Conclusions Glutamine is a substrate for CA19-9 biosynthesis in pancreatic cancer. Glutamine blockade may be a potential therapeutic strategy for pancreatic cancer.

Abstract Background Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which plays a pivotal role in the progression of pancreatic ductal adenocarcinoma (PDAC). Therefore, we investigated the prognostic significance of GFPT1 expression in patients with resectable PDAC. Methods We analyzed public datasets to compare GFPT1 expression in tumor tissues and normal/adjacent pancreatic tissues. We measured the relative GFPT1 expression of 134 resected PDAC specimens in our institution, using real-time polymerase chain reaction (PCR). Survival was compared between high and low GFPT1 expression groups using Kaplan-Meier curves and log-rank tests. Multivariate analyses were estimated using Cox regression and logistic regression models. Results GFPT1 is generally upregulated in PDAC tissues, according to the analysis of public datasets. The data from our institution shows that high GFPT1 expression was correlated with a high rate of lymph node (LN) metastasis (p = 0.038) and was an independent risk factor for LN metastasis (odds ratio (OR) = 3.14, 95% confidence interval (CI) = 1.42 to 6.90, P = 0.005). High GFPT1 expression was significantly associated with poor overall survival (OS; P = 0.019) in patients with resected PDAC. The multivariable-adjusted hazard ratio (HR) for mortality when comparing patients with high and low GFPT1 expression was 2.54 (95% CI = 1.35 to 4.79, P = 0.004). Conclusions GFPT1 is generally upregulated in PDAC tissue and is associated with a high risk of LN metastasis and an unfavorable outcome in patients with resectable PDAC, suggesting its crucial role in PDAC progression.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

Abstract Background Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging systems have been introduced for pancreatic adenocarcinoma. However, the applicability of these classifications for invasive intraductal papillary mucinous neoplasms (IPMN) has not been systematically examined. Methods Patients with invasive IPMN were retrieved from a cohort of 18 geographical sites (1973–2014 varying) in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The 7th and 8th editions of the AJCC staging were compared. Survival rates and multivariate analyses were computed. Results In total, 1216 patients with resected invasive IPMN were included. A major difference between the 7th and 8th systems is the definition of stage IIA (7th, beyond the pancreas without involvement of major arteries; 8th, maximum tumor diameter > 4 cm). The hazard ratio (HR) of stage IIA disease (versus stage IA, HR = 2.33, P 2 cm (size > 4 cm versus > 2 ≤ 4 cm, HR = 0.91, P = 0.420). Conclusions The AJCC 7th edition staging classification is more applicable than the 8th edition classification for invasive IPMN.

Abstract Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy. The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated. Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.

Abstract Background The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism. Methods Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of 18F-FDG (fluorodeoxyglucose) uptake by PET/CT (positron emission tomography/computed tomography) imaging were used to verify the role of PRMT5 in aerobic glycolysis, which sustains cell proliferation. The regulatory effect of PRMT5 on cMyc, a master regulator of oncogenesis and aerobic glycolysis, was explored by quantitative PCR and protein stability measurements. Results PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells. Conclusions The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with poor prognosis. Many preoperative biomarkers can predict postoperative survival of PDAC patients. In this study, we created a novel ratio index based on preoperative liver function test, γ‐glutamyltransferase‐to‐albumin ratio (GAR), and evaluated its prognostic value in predicting clinical outcomes of PDAC patients following radical surgery. We retrospectively enrolled 833 PDAC patients who had underwent radical surgery at our institution between January 2010 and January 2017. Patients were divided into two groups according to the cut‐off value of GAR. Univariate and multivariate survival analysis between the groups were evaluated. TNM stage, GAR, preoperative serum carbohydrate antigen 19‐9 (CA19‐9) and tumor differentiation were combined to generate a more accurate prognostic model. The optimal cut‐off value of GAR was 0.65. Significant correlations were found between GAR and tumor location, tumor size, vascular invasion, obstructive jaundice, biliary drainage and parameters of liver function test. Univariate and multivariate analysis showed that high level of GAR independently predicted poorer postoperative overall survival (OS, P < 0.001) and recurrence‐free survival (RFS, P < 0.001). Subgroup analysis demonstrated that GAR was predictive of survival in patients without biliary obstruction or severely impaired liver function. In addition, integration of GAR, preoperative serum CA19‐9, and tumor differentiation into TNM staging system could better stratify the prognosis for PDAC patients compared with TNM stage alone. Our study demonstrates that preoperative GAR is an independent prognostic factor for prediction of surgical outcomes in PDAC patients. Combination of TNM stage, GAR, preoperative serum CA19‐9, and tumor differentiation can enhance the prognostic accuracy.

Lymphatic metastasis is a major determinant of the outcome of resected pancreatic cancer. Gemcitabine-based adjuvant chemotherapy can improve the outcome of resected pancreatic cancer. However, the efficacy of gemcitabine against pancreatic cancer stratified by nodal involvement is unclear. In this study, patients who had undergone curative resection of pancreatic adenocarcinoma (612 cases) were included. The efficacy of adjuvant gemcitabine-based regimen, stratified by nodal status (negative, positive) or N substage (N0, no nodal involvement; N1, 1-3-node involvement; N2, ≥4-node involvement), was examined. Both the node-negative (hazard ratio [HR] = 0.62, 95% confidence interval [CI], 0.44-0.87, P = .006) and node-positive subgroups (HR = 0.45, 95% CI, 0.33-0.62, P < .001) benefited from gemcitabine-based adjuvant chemotherapy. Patients with N0 (ie, the node-negative subgroup) or N1 (HR = 0.36, 95% CI, 0.25-0.52, P < .001) disease benefited from gemcitabine-based chemotherapy. However, patients with N2 tumors (HR = 0.95, 95% CI, 0.50-1.78, P = .867) had poor response to gemcitabine-based treatment. Therefore, we postulate that resected pancreatic cancer with N2 node involvement is refractory to gemcitabine-based adjuvant chemotherapy. A more intensive adjuvant regimen may be required for N2 subgroup patients.

Solid pseudopapillary tumor of the pancreas (SPT) is a rare pancreatic disease with a unique clinical manifestation. Although CTNNB1 gene mutations had been universally reported, genetic variation profiles of SPT are largely unidentified. We conducted whole exome sequencing in nine SPT patients to probe the SPT-specific insertions and deletions (indels) and single nucleotide polymorphisms (SNPs). In total, 54 SNPs and 41 indels of prominent variations were demonstrated through parallel exome sequencing. We detected that CTNNB1 mutations presented throughout all patients studied (100%), and a higher count of SNPs was particularly detected in patients with older age, larger tumor, and metastatic disease. By aggregating 95 detected variation events and viewing the interconnections among each of the genes with variations, CTNNB1 was identified as the core portion in the network, which might collaborate with other events such as variations of USP9X, EP400, HTT, MED12, and PKD1 to regulate tumorigenesis. Pathway analysis showed that the events involved in other cancers had the potential to influence the progression of the SNPs count. Our study revealed an insight into the variation of the gene encoding region underlying solid-pseudopapillary neoplasm tumorigenesis. The detection of these variations might partly reflect the potential molecular mechanism.

The data regarding the prognostic significance of EGFR (epidermal growth factor receptor) expression and adjuvant therapy in patients with resected pancreatic cancer are insufficient. We retrospectively investigated EGFR status in 357 resected PDAC (pancreatic duct adenocarcinoma) patients using tissue immunohistochemistry and validated the possible role of EGFR expression in predicting prognosis. The analysis was based on excluding the multiple confounding parameters. A negative association was found between overall EGFR status and postoperative survival (p = 0.986). Remarkably, adjuvant chemotherapy and radiotherapy were significantly associated with favorable postoperative survival, which prolonged median overall survival (OS) for 5.8 and 10.2 months (p = 0.009 and p = 0.006, respectively). Kaplan–Meier analysis showed that adjuvant chemotherapy correlated with an obvious survival benefit in the EGFR-positive subgroup rather than in the EGFR-negative subgroup. In the subgroup analyses, chemotherapy was highly associated with increased postoperative survival in the EGFR-positive subgroup (p = 0.002), and radiotherapy had a significant survival benefit in the EGFR-negative subgroup (p = 0.029). This study demonstrated that EGFR expression is not correlated with outcome in resected pancreatic cancer patients. Adjuvant chemotherapy and radiotherapy were significantly associated with improved survival in contrary EGFR expressing subgroup. Further studies of EGFR as a potential target for pancreatic cancer treatment are warranted.

Objective: The aim of this study was to investigate the association of the strain ratio (SR) with clinicopathologic features and the prognostic value of the SR in local pancreatic cancer. Background: The SR as obtained by endoscopic ultrasonography elastography is useful in the differential diagnosis of pancreatic diseases. However, its role in the prognostic prediction of pancreatic cancer remains unknown. Methods: A total of 78 resected pancreatic cancer patients and 93 locally advanced pancreatic cancer (LAPC) patients were enrolled in this study according to the inclusion criteria. Masson trichrome staining was used to evaluate the stromal proportion. Survival rates were calculated according to the Kaplan--Meier method and were compared using the log rank test. Multivariate analysis was performed with a Cox regression model. Results: The SR was positively associated with the stromal proportion of resected pancreatic cancer (R = 0.768, P < 0.001). High SR was more likely in males (P = 0.039) and was related to perineural invasion (P = 0.022). High SR predicted unfavorable overall survival (OS) relative to low SR (15.4 vs. 25.8 mo, P = 0.017). SR was confirmed as an independent prognostic factor for resected pancreatic cancer based on multivariate analysis (hazard ratio = 1.939, P = 0.020). For LAPC patients who received nab-paclitaxel and gemcitabine, high SR was associated with improved prognosis (OS: 14.9 vs. 11.6 mo, P = 0.045), but this positive association was not observed in patients treated with other gemcitabine-based regimens (OS: 10.7 vs. 12.4 mo, P = 0.478). Conclusions: A high SR as obtained by endoscopic ultrasonography elastography was associated with poor prognosis of resected pancreatic cancer but predicted improved survival for LAPC patients treated with the nab-paclitaxel and gemcitabine regimen. [ABSTRACT FROM AUTHOR]

Carbohydrate antigen 19‑9 (CA19‑9) is not generally considered to be a biomarker in pancreatic neuroendocrine tumors (pNETs), as the majority of pNETs present with a normal range of CA19‑9. The present study aimed to evaluate the role of serum CA19‑9 levels as a prognostic factor in a relatively large number of patients with pNETs. Consecutive patients were retrospectively collected from a single institution between June 2006 and February 2015. The receiver operating characteristic (ROC) curve and the area under the ROC curve were used to select the cut‑off values for the baseline CA19‑9 levels. The primary end point was set as overall survival. Potential factors associated with the abnormal elevation of CA19‑9 expression levels in pNETs were also investigated. The cut‑off value for CA19‑9 was 16 U/ml as determined by the ROC curve, and for the area under the ROC curve it was 0.68. In total, 32.7% of patients (51/156) had CA19‑9 expression levels higher than the cut‑off value. Univariate analysis demonstrated that CA19‑9 >16 U/ml was an adverse prognostic factor for patients' overall survival. The CA19‑9 >16 U/ml group had a statistically higher proportion of tumor node metastasis (TNM) stage III or IV, as compared with the CA19‑9 ≤16 U/ml group. To the best of our knowledge, the present study is the first to demonstrate that CA19‑9 is a prognostic biomarker of pNETs, one that may reflect its aggressiveness and severity. [ABSTRACT FROM AUTHOR]

Background: Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers and is increased in 30%-60% of patients with pancreatic cancer. Although carbohydrate antigen 19-9 (CA19-9) is the most important serum biomarker in pancreatic cancer, the diagnostic and prognostic value of CEA is gradually being recognized. Materials and methods: The MEDLINE, EMBASE, and Web of Science databases were searched for related literature published until January 2017. Diagnostic accuracy variables were pooled using the Meta-Disc software. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software. Results: A total of 3,650 participants enrolled in 19 studies met our inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of a CEA-based panel were 0.45 (95% confidence interval [CI], 0.41-0.50), 0.89 (95% CI, 0.86-0.91), 5.39 (95% CI, 3.16-9.18), and 0.55 (95% CI, 0.41-0.72), respectively. The area under the curve (AUC, 0.90) and Q-value (0.84) of the CEA-based panel indicated a significantly higher diagnostic accuracy compared with CEA or CA19-9 alone. Moreover, there was also a significant association between high levels of CEA and worse overall survival (HR, 1.43; 95% CI, 1.31-1.56). Conclusion: Our meta-analysis indicated that elevated serum CEA level, as a vital supplementary to CA19-9, can play an important role in the clinical diagnosis of pancreatic cancer patients and predict poor prognosis. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the clinical, pathological and prognostic characteristics of Chinese patients with resected pancreatic neuroendocrine neoplasms (p-NENs). Data from patients who were surgically treated and pathologically diagnosed with p-NENs at the Department of Pancreatic Oncology of the Fudan University Shanghai Cancer Center (Shanghai, China), between January 2003 and July 2015, were evaluated using univariate and multivariate analyses. A total of 162 patients with p-NENs met the criteria of the present study and were included in the analysis. Patients with poorly differentiated pancreatic neuroendocrine carcinoma (p-NEC) exhibited a significantly increased rate of lymph node metastasis, as compared with patients with grade (G)1/G2 pancreatic neuroendocrine tumors (p-NETs) (62.5 vs. 20.5%, P=0.003). Univariate analysis identified that the following factors led to decreased overall survival (OS): Lymph node metastasis (P=0.001, vs. the absence of lymph node metastasis); distant metastasis (P=0.043, vs. the absence of distant metastasis); resection margin R1/R2 (P=0.030, vs. R0 resection); NEC G3 (P<0.001, vs. NET G1). Following the multivariate analysis, NEC G3 remained a statistically significant risk factor (HR=12.593; 95% CI, 3.476-45.622; P<0.001, vs. NET G1/G2). Furthermore, according to the proliferation marker protein Ki-67 staining index, assigning a grade using the proliferative index (G1, ≤5%; G2, >5-20%; G3, >20%) was more efficient for prognostic stratification compared with the European Neuroendocrine Tumor Society (Berlin, Germany)/World Health Organization (Geneva, Switzerland) 2010 grading classification. The present study indicated that p-NEC was an important predictor of decreased OS in Chinese patients. Furthermore, a Ki-67 staining index of 5% represented a more efficient value for the distinction between G1 and G2. [ABSTRACT FROM AUTHOR]

Objective: To examine potential biomarkers in Lewis negative patients with pancreatic cancer. Background: Carbohydrate antigen 19–9 (CA19–9) is currently the most important and widely used biomarker in pancreatic cancer. However, approximately 5 to 10% of the population are Lewis negative individuals, and they are documented to have scarce or no CA19–9 secretion. Therefore, it is necessary to explore potential biomarkers to compensate for this drawback. Methods: Lewis genotypes were determined in a large cohort of patients with pancreatic cancer (682 cases) and controls (525 cases) by sequencing the Fucosyltransferase 3 (FUT3) gene from genomic DNA. Potential biomarkers were examined in patients with Lewis negative genotypes and normal subjects. The impact of potential biomarkers on tumor burden and survival was analyzed. Results: Forty-seven (6.9%) patients with pancreatic cancer had Lewis negative genotypes. Carcinoembryonic antigen (CEA) and CA125 had greater sensitivity than other biomarkers in Lewis negative patients with pancreatic cancer [CEA, 63.8%; CA125, 51.1%; CA72–4, 25.5%; CA15–3, 21.3%; CA19–9, 19.1%; CA50, 12.8%; CA242, 10.6%; and alpha-fetoprotein (AFP), 0.0%]. In addition, both CEA (98.0%) and CA125 (93.8%) showed a high specificity. Compared with other biomarkers, CEA (60.9%) was sensitive for stage I, II diseases and CA125 (75.0%) was sensitive for stage III, IV diseases. CEA and CA125 were associated with tumor metastasis and therapeutic response. Conclusions: CEA and CA125 have the potential to be applied as biomarkers in Lewis negative patients with pancreatic cancer. CEA and CA125 should be routinely measured for all patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Although the prognostic role of neutrophil-lymphocyte ratio (NLR) has been confirmed in a variety of tumors, the prognostic role of NLR in pancreatic neuroendocrine tumors (PNETs) has not been examined. The present study was performed to assess the role of NLR as a prognostic factor in patients with PNETs. Clinical data were retrospectively retrieved from a single institution. The best cut-off value for baseline NLR levels was determined by the receiver operating characteristic (ROC) curve and area under the ROC curve. The primary event was overall survival and event times were assessed by the Kaplan-Meier method. Potential factors associated with the elevation of NLR in PNETs were examined. A total of 165 consecutive patients with pathologically confirmed PNETs were included in this study. The cutoff value of NLR was 2.4 by ROC curve (area under ROC curve, 0.70). NLR >2.4 was found to be a poor prognostic factor in the univariate and multivariate analyses. Patients with a NLR value >2.4 had a higher proportion of tumor size at >3 cm (P=0.001), TNM stage III or IV (P=0.019), and G2/G3 (P=0.003). We concluded that NLR is an independent predictor of overall survival for patients with PNETs. Aberrant elevation of NLR identifies high-risk patients with aggressive characteristics. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains a lethal disease that responds poorly to multiple types of treatment. Therefore, the identification of distinct subgroups that exhibit unique therapeutic responses is an urgent requirement. In the present multicenter study (1,912 cases), the differences between the therapeutic responses and clinical characteristics of two subgroups of pancreatic cancer, carbohydrate antigen 19-9 (CA19-9)-normal (baseline serum level, ≤37 U/ml) and CA19-9-elevated (baseline serum level, >37 U/ml), were analyzed. CA19-9-normal expression was identified to be an independent prognostic factor for patients with stage I-II [hazard ratio (HR)=0.77; P=0.037] and stage III-IV (HR=0.68; P<0.001) pancreatic cancer. The 5-year survival rate of the stage III-IV CA19-9-normal subgroup was increased compared with the stage I-II CA19-9-elevated subgroup (15.4 vs. 13.8%). In the stage I-II CA19-9-normal and CA19-9-elevated subgroups, gemcitabine-based chemotherapy was a significant positive prognostic factor for survival (CA19-9-normal, HR=0.54, P=0.013; CA19-9-elevated, HR=0.55, P<0.001). However, among stage III-IV patients, the CA19-9-normal subgroup exhibited a poor response to gemcitabine-based chemotherapy (HR=0.77; P=0.165), while the CA19-9-elevated subgroup exhibited a favorable response, resulting in a lower rate of mortality (HR=0.70; P<0.001) compared with no chemotherapy. It was concluded that CA19-9-normal pancreatic cancer is a less aggressive subgroup; however, advanced CA19-9-normal pancreatic cancer exhibits a poorer response to gemcitabine-based chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Few options besides the avoidance of smoking and obesity are available to prevent pancreatic cancer. The association between aspirin use and risk of pancreatic cancer has been inconsistent across studies. Methods: We performed a population-based study of 761 case and 794 control subjects frequency matched on sex and age during 2006 to 2011 in Shanghai, China. Participants were asked about episodes of regular use of aspirin, tablets per day or week, and ages that the use started and stopped. Data were analyzed by unconditional logistic regression, with adjustments for age, sex, education, body mass index, years of cigarette smoking, cigarettes smoked per day, Helicobacter pylori CagA seropositivity, ABO blood group, and history of diabetes mellitus. Meta-regression was carried out to summarize the literature. Results: Ever-regular use of aspirin was associated with lowered risk of pancreatic cancer: OR = 0.54; 95% confidence interval (CI), 0.40-0.73; P = 10-4.2. Risk decreased 8% per each cumulative year of use: ORtrend = 0.92; 95% CI, 0.87-0.97; P = 0.0034. Across this and 18 published studies of this association, the OR for ever-regular use decreased with increasingly more recent mid-study year, for any aspirin type (Ptrend = 10-5.1), and for low-dose aspirin (Ptrend = 0.0014). Conclusions: Regular use of aspirin thus appears to reduce risk of pancreatic cancer by almost half. Impact: People who take aspirin for prevention of other diseases likely also reduce their risk of pancreatic cancer. Aside from benefits for both cardiovascular disease and certain cancers, long-term aspirin use entails some risks of bleeding complications, which necessitates risk-benefit analysis for individual decisions about use. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a human malignancy with one of the highest mortality rates and little progress has been achieved in its treatment in recent decades. Further improvement to the understanding of the biological and molecular mechanisms underlying the initiation and development of pancreatic ductal adenocarcinoma (PDAC) is required. Previous studies using genetically engineered mouse models have demonstrated that oncogenic GTPase KRas (KRAS) mutation is involved in the formation of pancreatic intraepithelial neoplasia and promotes the progression of PDAC. However, attempts to target KRAS directly by pharmacological inhibition have been unsuccessful. This has resulted in increased efforts to identify pharmacological targets and nodes associated with the mutated KRAS. The present review discusses the recent progress and prospects of KRAS signaling in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Tumor cells exhibit abnormal actin remodeling profiles, which involve the altered expressions of several important actin-binding proteins. Profilin1 (Pfn1), originally identified as an actin-associated protein, has been linked to several human malignancies. Our recent studies suggested that Pfn1 facilitates apoptosis in pancreatic cancer cells. Here, we investigated the exact role of Profilin1 (Pfn1) in pancreatic adenocarcinoma (PDAC) and the underlying mechanisms. Methods: Pfn1 protein expression in PDAC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing PDAC tumor tissue and corresponding normal tissue samples from 72 patients. The effect of Pfn1 expression on cancer proliferation was assessed in cells by up- and down-regulation of Pfn1 in vitro and in vivo. Immunoprecipitation and mass spectrometry were used to identify the Pfn1-associated proteins and potential pathways. Results: Pfn1 was downregulated in clinical pancreatic adenocarcinoma specimens compared with the surrounding benign tissues. Univariate survival analysis of the PDAC cohorts showed that low expression of Pfn1 was significantly correlated with shortened patient survival (mean 14.2 months versus 20.9 months, P < 0.05). Restoration of Pfn1 in pancreatic cancer cells with low endogenous Pfn1 expression resulted in a nontumorigenic phenotype, suggesting that Pfn1 may be a negative regulator of pancreatic cancer progression. Overexpression of Pfn1 in vivo decreased the tumor volume in orthotopic xenograft nude mice models. Pfn1 upregulated the expression of SIRT3, leading to HIF1α destabilization. This data revealed that aberrant Pfn1 expression contributes to pancreatic cancer progression. Conclusions: Our data suggest that Pfn1 is a tumor suppressor in pancreatic cancer that acts via a novel mechanism of regulating the SIRT3-HIF1α axis, independently of its cytoskeleton-related activity. [ABSTRACT FROM AUTHOR]

The article presents a study which determined Helicobacter pylori strain-specific associations with pancreatic cancer in a population in which colonization by CagA-positive strains is common. Topics discussed include pathophysiologic actions of Helicobacter pylori colonization on gastric acidity, prevalence of pancreatic cancer and differences in Helicobacter pylori colonization.

As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs) and the microenvironments may act as a double-reed style in this crime. However, the exactmechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreaticojejunostomy is the key procedure of pancreaticoduodenectomy. Our study introduced a new pancreaticojejunal (PJ) anastomosis named "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy. Nighty-two patients underwent pancreaticojejunostomy with either conventional duct-to-mucosa pancreaticojejunostomy or the new "papillary-like main pancreatic duct invaginated" techniques were analyzed retrospectively from January 2010 to September 2012. The incidence of pancreatic fistula was 15.7% (8/51) for the "papillary-like main pancreatic duct invaginated" group and 19.5% (8/41) for the duct-to-mucosa fashion respectively. It is noteworthy that the rate of grade B/C postoperative pancreatic fistula (POPF) in the "papillary-like main pancreatic duct invaginated" group was significantly lower than that of the duct-to-mucosa group (P = 0.039). There were no differences in the incidence of postoperative morbidity and mortality such as postoperative hemorrhage, delayed gastric emptying or remnant pancreatitis. The "papillary-like main pancreatic duct invaginated" pancreaticojejunostomy could provide a feasible option to pancreatic surgeons for patients with normal soft pancreas. [ABSTRACT FROM AUTHOR]

With the development of nanotechnology, special attention has been given to the nanomaterial application in tumor treatment. Here, a modified desolvation-cross-linking method was successfully applied to fabricate gemcitabine-loaded albumin nanospheres (GEM-ANPs), with 110 and 406 nm of mean diameter, respectively. The aim of this study was to assess the drug distribution, side effects, and antitumor activity of GEM-ANPs in vivo. The metabolic viability and flow cytometry analysis revealed that both GEM-ANPs, especially 406-nm GEM-ANPs, could effectively inhibit the metabolism and proliferation and promote the apoptosis of human pancreatic carcinoma (PANC-1) in vitro. Intravenous injection of 406-nm GEM-ANPs exhibited a significant increase of gemcitabine in the pancreas, liver, and spleen of Sprague-Dawley rats (p < 0.05). Moreover, no signs of toxic side effects analyzed by blood parameter changes were observed after 3 weeks of administration although a high dose (200 mg/kg) of GEM-ANPs were used. Additionally, in PANC-1-induced tumor mice, intravenous injection of 406-nm GEM-ANPs also could effectively reduce the tumor volume by comparison with free gemcitabine. With these findings, albumin nanosphere-loading approach might be efficacious to improve the antitumor activity of gemcitabine, and the efficacy is associated with the size of GEM-ANPs. [ABSTRACT FROM AUTHOR]