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Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high-volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19-9 independently indicated surgical response in pancreatic cancer. Patients with CA19-9 ≥1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19-9 levels decreased postoperatively. CEA and CA125 in the presence of CA19-9 ≥1000 U/mL could independently predict the non-decrease of CA19-9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p

Purpose The main objectives of this retrospective study were to survey the genetic landscape of PNETs in a clinical cohort by using the high throughput gene sequencing method and to determine cellular signaling networks affected by the uncovered gene mutations. Materials and methods We retrieved the demographics and tumor characteristics of 13 patients. Cellular DNA was extracted from fresh snap frozen tumor tissues and was subject to high throughput gene sequencing analysis using the Illumina NextSeq500 System. Furthermore, the interaction network was constructed from the input gene set by Reactome and performed gene set enrichment analysis was performed with a cutoff FDR of ≤0.01. Results Totally 74 mutated genes and 93 mutations were identified. The median number of mutations was 7 (range 1–20) and that of mutated genes was 6 (range 1–17). Among these mutations, 48 (51.6%) were substitution mutations, nine (9.7%) were duplication mutations, 28 (30.1%) were deletion mutations and eight (8.6%) were deletion/insertion mutations. Gene set enrichment analysis generated a network of 21 interactions, 10 of which were associated with DNA repair like the Fanconi anemia pathway, nucleotide excision repair, and homologous recombination repair, or chromosome maintenance. Moreover, 9 patients had one or more mutations in DNA repair genes including the mismatch repair genes MSH2/MSH6. Conclusions The study has uncovered genetic alterations of genes implicated in DNA damage responses and chromatin remodeling. Our findings will prompt further studies into the role of these mutated genes in the oncogenesis and molecular stratification of PNETs.

To examine potential biomarkers in Lewis negative patients with pancreatic cancer.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.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.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.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.

Although a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a predictor of poor survival in patients with pancreatic cancers, its prognostic role in patients with advanced pancreatic cancer undergoing chemotherapy remains unclear. This study was performed to determine the prognostic role of NLR in patients with advanced pancreatic cancer undergoing chemotherapy.We retrospectively enrolled 403 patients undergoing chemotherapy for advanced pancreatic adenocarcinoma from 2002 to 2013. Univariate and multivariate analyses were performed to identify clinicopathological predictors of overall survival including baseline NLR (NLR before chemotherapy) and postchemotherapy NLR change (NLR change before and after one cycle of chemotherapy), using the Cox proportional hazards model. Clinicopathological characteristics related to baseline NLR and postchemotherapy NLR change were evaluated.Univariate and multivariate analyses showed that both baseline NLR (NLR ≥ 3.1 vs. NLR 3.1, hazard ratio [HR] = 1.42; P = 0.001) and postchemotherapy NLR change (NLR ≥ 3.1 and increased vs. NLR 3.1 and decreased, HR = 2.39; P = 0.000) were independent prognostic factors in overall survival. NLR ≥ 3.1 before chemotherapy and NLR postchemotherapy change were significantly correlated with distant metastasis, serum CA19-9 levels, and serum albumin levels.Baseline NLR and postchemotherapy NLR change may serve as potential biomarkers for overall survival in patients with advanced pancreatic cancer undergoing chemotherapy.

18F-Fluorodeoxyglucose positron emission tomo-graphy and computed tomography (18F-FDG PET/CT) has limited value in well-differentiated neuroendocrine tumors. The value of 18F-FDG PET/CT in non-functioning pancreatic neuroendocrine tumors, which are often poorly differentiated, malignant, and present at an advanced stage, was also thought to be limited. This study was performed to evaluate the clinical value of 18F-FDG PET/CT in assessing non-functioning pancreatic neuroendocrine tumors. From January 2010 to February 2014, a comparable large cohort of patients (31 cases) with non-functioning pancreatic neuroendocrine tumors from Shanghai Cancer Center underwent 18F-FDG PET/CT scans. Demographics and clinical characteristics were retrospectively collected and analyzed for all the patients. Twenty-eight of 31 (90.3%) patients with non-functioning endocrine pancreatic tumors had an elevated 18F-FDG uptake (SUVmax ≥2.5). In addition, 18F-FDG PET/CT visualized 38 of 42 (90.5%) distant metastatic lesions. The 18F-FDG uptake had significant association with tumor size (P=0.012) and TNM stage (P=0.004). The application of 18F-FDG PET/CT has changed the management of 8 cases (8/31, 25.8%). In conclusion, 18F‑FDG PET/CT plays an important role in detecting and staging non-functioning pancreatic neuroendocrine tumors.

Background: Pathophysiologic actions of Helicobacter pylori colonization on gastric acidity have been hypothesized to modulate the effect of pancreatic carcinogens, through CagA-negative organism strain type, hyperchlorhydria and increased risk of pancreatic cancer, or CagA-positive strain, hypochlorhydria and decreased risk of pancreatic cancer. We aimed to determine H. pylori strain–specific associations with pancreatic cancer in a population in which colonization by CagA-positive strains is common. Methods: We carried out a large population-based case–control study of pancreatic carcinoma in Shanghai, China. Venipuncture specimens were obtained from a representative sample of 761 case patients and 794 randomly selected control subjects matched by category of age and gender. Antibody seropositivity for H. pylori and its virulence protein CagA were determined by commercial enzyme-linked immunosorbent IgG assays. Results: Compared with individuals seronegative for both H. pylori and CagA, decreased pancreas-cancer risk was seen for CagA seropositivity [adjusted OR, 0.68; 95% confidence interval (CI), 0.54–0.84], whereas some increased risk was suggested for CagA-negative H. pylori seropositivity (OR, 1.28; 95% CI, 0.76–2.13). No risk interactions were observed between CagA seropositivity and gender, cigarette smoking, or age-21 body mass index. Conclusions: Similar to what has been seen in animal models, our results provide suggestive evidence in humans for the involvement of gastric acidity, through its bidirectional modification according to colonization by H. pylori CagA strain type, in the risk of pancreatic carcinoma. Impact:H. pylori colonization may have diverse effects on cancer risk, depending on the organism strain type as well as on the particular cancer site. Cancer Epidemiol Biomarkers Prev; 23(1); 172–8. ©2013 AACR.

N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1α level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1α, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC.

Although carbohydrate antigen 19-9 (CA19-9) has been reported as a biomarker to predict the resectability of pancreatic cancer, several limitations have restricted its clinical use. The potential of several serum tumor markers (CA19-9, CA125, CA50, CA242, CA724, carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP)) to predict the resectability of pancreatic cancer was evaluated by receiver operating characteristic (ROC) analysis in a series of 212 patients with proven pancreatic cancer. Compared with other tumor markers including CA19-9, CA125 has a superior predictive value (CA19-9, ROC area 0.66, cutoff value 289.40 U/mL; CA125, ROC area 0.81, cutoff value 19.70 U/mL). In addition, for patients with unresectable diseases misjudged by CT as resectable, the percentage of CA125 over selected cutoff value was higher than that of CA19-9 (CA19-9, 70.27 %; CA125, 81.08 %). CA125 is superior to CA19-9 in predicting the resectability of pancreatic cancer. Aberrant high levels of CA125 may indicate unresectable pancreatic cancer.

Caveolin-1 exhibits a stage-dependent, functional fluctuation during pancreatic cancer development, but the underlying mechanisms remain unclear. Here, we report that cavin-1, a structural protein of caveolae, modulates the oncogenic function of caveolin-1 and cooperates with caveolin-1 to enhance pancreatic cancer aggressiveness. Cavin-1 expression is associated with caveolin-1 in pancreatic cancer tissue samples and cell lines, and predicts the metastatic potential of pancreatic cancer. Interactome analyses further revealed the physical interaction of cavin-1 and caveolin-1 and their colocalization in pancreatic cancer cells. Cavin-1 stabilizes caveolin-1 expression or activity by inhibiting its internalization and subsequent lysosomal degradation. More in-depth functional experiments showed that caveolin-1-enhanced aggressiveness of pancreatic cancer cells is dependent on the presence of cavin-1. In contrast, cavin-1 depletion inhibited the invasion and metastasis of pancreatic cancer cells, which could not be restored by caveolin-1-rescue construct. Tissue microarray analyses in two independent clinic cohorts also supported the augment of cavin-1 on the prognostic potency of caveolin-1, and showed that combination of cavin-1 with caveolin-1 predicted worse survival in pancreatic cancer patients. Of note, the phenotypes because of cavin-1 could not be achieved by other cavins such as cavin-2, and the tumor-promoting role of cavin-1 in pancreatic cancer was found to be largely dependent on caveolin-1 expression, which highlights the critical role of cavin-1/caveoin-1 in pancreatic cancer progression, and suggests that the interruption of cavin-1/caveolin-1 interaction is a promising therapeutic strategy for pancreatic cancer.

Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.

The study was performed to identify unique subtype from the long-term survival (24 months) patients with advanced pancreatic cancer (1039 cases). Long-term survival patients had higher proportion of low secretion of carbohydrate antigen 19-9 (CA19-9) than that of patients with non long-term survival (P 0.001). Considering the impact of Lewis status on CA19-9 secretion, Lewis genotypes were further determined by Sanger sequencing. The prognosis of CA19-9-LowLewis (-) patients was worse than that of CA19-9-LowLewis (+) (hazard ratio (HR) = 0.37, P 0.001). The proportion of epidermal growth factor receptor (EGFR) (-) cases was lower in the CA19-9-LowLewis (+) subgroup than that in other patients (P = 0.047). For the CA19-9-LowLewis (+) subgroup, chemotherapy plus radiotherapy but not chemotherapy was found to be an independent prognostic factor (versus best supportive care, chemotherapy, HR = 0.71, P = 0.267; chemotherapy plus radiotherapy, HR = 0.33, P = 0.022). We conclude that CA19-9-LowLewis (+) pancreatic cancer is a unique subtype with special biological properties.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with the 5-year survival rate less than 6%. Previous results indicated that serum levels of CA125 (encoded by MUC16) could be used to predict which groups of pancreatic cancer patients may benefit from surgery. However, the underlying mechanism remains elusive. Herein, using the Cancer Genome Atlas and clinicopathologic data obtained from our center, we demonstrate that high CA125 serum levels and expression levels of MUC16 are predictive of poor prognosis. MUC16 is also validated as a downstream target of KRAS, and their expression strongly correlated with each other in vitro and in vivo. Mechanistically, the KRAS/ERK axis induced upregulation of MUC16 and shedding of CA125 via its effector c-Myc in SW1990 and PANC-1 pancreatic cancer cells. Notably, proto-oncogene c-Myc could bind to the promoter of MUC16 and transcriptionally activate its expression. Taken together, these data establish CA125 as a prognostic marker for pancreatic cancer, and mechanistic studies uncovered the KRAS/c-Myc axis as a driving factor for upregulation of MUC16. Implications: The current study uncovers the contribution of oncogenic KRAS to serum marker CA125 production through a mechanism that involves the ERK/c-Myc axis. Mol Cancer Res; 15(2); 201–12. ©2016 AACR.

Cell-free circulating tumor DNA (ctDNA) in plasma has been used as a potential noninvasive biomarker for various tumors. Our study was performed to evaluate the clinical implications of ctDNA detection in patients with metastatic pancreatic cancer. First, we attempted to prospectively screen a panel of 60 genes in cell-free DNA (cfDNA) from ten metastatic pancreatic cancer patients via exome sequencing. Second, droplet digital PCR (ddPCR) was used to identify potential mutations in a cohort of 188 patients with metastatic pancreatic cancer. Finally, to preliminary evaluate the potential role of ctDNA in monitoring tumor responses following chemotherapy, we detected the presence of ctDNA in serial plasma samples from 13 metastatic pancreatic cancer patients (Clinical trial: NCT02017015). The analysis revealed five somatic mutations at BRCA2, EGFR, KDR and ERBB2 gene loci. The frequencies of ctDNA mutation at BRCA2, KDR, EGFR, ERBB2 exon17 and ERBB2 exon27 were 11.7%, 13.8%, 13.3%, 13.3% and 6.4% respectively. Univariate and multivariate analyses identified the ERBB2 exon17 mutation (p = 0.035, HR = 1.61) as an independent factor associated with overall survival among metastatic pancreatic cancer patients. Furthermore, the rate of coincident detection of ctDNA and response to treatment as assessed by CT imaging was 76.9% (10 of 13 cases), and the presence of ctDNA provided the earliest measure of treatment in 6 of 10 patients (60%). ctDNA sequencing may have clinical value for determining metastatic pancreatic cancer treatment and monitoring the tumor response.

Pancreatic neuroendocrine neoplasms (p-NENs) are slowly growing tumors with frequent liver metastasis. There is a variety of approaches to treat non-functional p-NENs with synchronous liver metastasis (LM) which complicates the determination of optimal treatment. Based on updated literature review, we discussed the treatment strategy determinants for p-NEN with LM. According to the resectability of primary tumor, the WHO 2010 grade classification and the radiological type of liver metastasis, the CSNET group reached agreements on a number of issues, including the following. Prior to treatment, biopsy is required to confirm pathology. Liver biopsy is important for more accurate grading of tumor and percutaneous core needle biopsy is more available than EUS-FNA. In patients with unresectable primary, surgical resection for liver-metastatic lesions should be avoided. Curative surgery is recommended for G1/G2 p-NET with type I LM and R1 resection also seems to improve overall survival rate. Cytoreductive surgery is recommended for G1/G2 p-NET with type II LM in select patients, and should meet stated requirements. Surgical resection for G1/G2 p-NET with type III LM and p-NEC with LM should be avoided, and insufficient evidence exists to guide the surgical treatment of G3 p-NET with LM. Liver transplantation may be an option in highly select patients. In addition, the optimal time for surgical approach is still required for more evidence.

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.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignant neoplasms. The recognized hallmarks of PDA are regarded to be downstream events of metabolic reprogramming. Because PDA is a heterogeneous disease that is influenced by genetic polymorphisms and changes in the microenvironment, metabolic plasticity is a novel feature of PDA. As intrinsic factors for metabolic plasticity, K-ras activation and mutations in other tumor suppressor genes induce abnormal mitochondrial metabolism and enhance glycolysis, with alterations in glutamine and lipid metabolism. As extrinsic factors, the acidic and oxygen/nutrient-deprived microenvironment also induces cancer cells to reprogram their metabolic pathway and hijack stromal cells (mainly cancer-associated fibroblasts and immunocytes) to communicate, thereby adapting to metabolic stress. Therefore, a better understanding of the metabolic features of PDA will contribute to the development of novel diagnostic and therapeutic strategies.

Background Carbohydrate antigen 19-9 (CA19-9) is currently the most widely used biomarker for pancreatic cancer. It is well-known that Lewis and Secretor status can affect CA19-9 biosynthesis. This study was performed to optimize CA19-9 in detecting pancreatic cancer using Lewis and Secretor dependent cut-off values. Methods Lewis and Secretor genotypes were determined by Sanger sequencing in a large cohort of subjects (578 cases with pancreatic cancer, 210 cases with benign pancreatic disease, 315 normal subjects). The effectiveness of CA19-9 for detecting pancreatic cancer using Lewis and Secretor group dependent cut-off values was evaluated. Results The Lewis (-), Mixed, and Secretor (-) groups had low, medium, and high CA19-9 biosynthesis, respectively. In Lewis (-) pancreatic cancer (all stages), CA19-9 had a sensitivity of 48.6% and a specificity of 95.9% when 1.8 U/mL was used as the cut-off value. The sensitivity of CA19-9 in detecting all stages of pancreatic cancer improved from 80.1% to 88.0% and the negative predictive value increased from 81.2% to 87.1% without compromising other values when using group dependent cut-off values. The sensitivity of CA19-9 for the detection of stage I, II pancreatic cancer increased from 76.1% to 87.2%. Conclusions The value of CA19-9 in detecting pancreatic cancer was optimized by using group dependent cut-off values based on Lewis and Secretor genotypes. CA19-9 can be applied as an early detector of pancreatic cancer using group dependent cut-off values.

Lymphatic metastasis of pancreatic cancer is a predictor of poor prognosis. However, the molecular mechanisms are largely unknown, thus, making the development of appropriate cell lines and experimental models critically important for future investigations. The purpose of the present study was to establish a 'pancreatic cancer cell and mouse model with high lymphatic metastasis potential' for in-depth study of the underlying mechanisms. The BxPC-3-LN subline, derived from the BxPC-3 human pancreatic cancer cell line, was established through serial passages in nude mice via footpad injections. The subline was able to develop notable lymphatic metastases in 100% of the recipient mice 8 weeks after tumor cell implantation. Compared with the parental BxPC-3 cells, BxPC-3-LN cells were more aggressive, displaying invasive ultrastructure, increased migration and invasion ability, and chemoresistance. Metastasis-related gene alteration including upregulation of MMP14, MMP24, MIF and ADRM1, and downregulation of TGFB2 and ROBO1 were also observed in BxPC-3-LN cells by cDNA microarrays. Thus, the newly selected BxPC-3-LN subline can serve as a unique model for further study of lymphatic metastasis of pancreatic cancer.

Integrin αvβ3 receptor is expressed on several types of cancer cells, including pancreatic cancer cells, and plays an important role in tumor growth and metastasis. The ability to target the integrin αvβ3 receptor on cancer cells increases the efficacy of targeted therapy and reduces the side effects. The aim of this study is to develop a novel arginine-glycine-aspartic acid (RGD) peptide -conjugated albumin nanoparticle to enhance the intracellular uptake of anticancer drug into the pancreatic cancer cells through receptor-mediated endocytosis. In the cellular uptake studies, the fluorescent signal of RGD-conjugated BSANPs in BxPC3 cells was higher than that of BSANPs without RGD conjugation as determined by fluorescence spectrophotometer. We also found that BSANPs bound to BxPC3 cells in a time- and concentration-dependent manner. The uptake of RGD-conjugated BSANPs by pancreatic cancer cells was inhibited by an excess amount of free RGD peptide, indicating that the binding and/or uptake were mediated by the αvβ3 receptor. Furthermore, the nanoparticles were found to be located close to the nuclei by using laser scanning confocal microscopy. Besides, no significant in vitro cytotoxicity was observed as measured with MTT assay. Both in vitro and in vivo antitumor efficacy was improved by targeting gemcitabine-loaded nanoparticles to BxPC-3 cells using RGD peptides. Therefore, the RGD-conjugated BSANPs hold great potential as an effective drug delivery system to deliver therapeutic agents to pancreatic cancer.

Background Pancreatic anastomotic failure remains the main reason for morbidity and mortality after pancreaticoduodenectomy, and there is no existing flawless pancreaticojejunal reconstruction approach to this date, especially for the normal soft pancreas cases. Methods We compared a pancreatic stump-closed pancreaticojejunostomy technique (group B; n = 33) with conventional duct-to-mucosa fashion (group A; n = 30) retrospectively in 63 normal soft pancreatic texture cases. Some operative related data including postoperative complications, anastomosis time, hospital stay days, mortality rate, and relaparotomy rate were analyzed. Results There was no difference concerning the incidences of postoperative morbidity, including pancreatic fistula, postpancreatectomy hemorrhage, delayed gastric emptying, intra-abdominal abscess, and remnant pancreatitis between two groups. The differences of anastomosis time, hospitalization days, relaparotomy rate, and mortality rate were also not significant. However, group B patients had a shorter duration (d) for healing of postoperative pancreatic fistula than group A (15.3 ± 8.5 versus 33.0 ± 14.1 d, P Conclusion For the normal soft pancreas cases, pancreatic stump-closed pancreaticojejunostomy technique is quite safe and convenient according to our experience; ideal clinical results could be achieved with its application in the future.

Standard pancreatectomy for benign and borderline pancreatic lesions involves resecting a substantial amount of normal pancreatic parenchyma and leads to a subsequent impairment of both exocrine and endocrine pancreatic functions. A limited resection such as enucleation is the preferred option for such neoplasms. However, enucleation is associated with a high risk of postoperative complications in some cases. This study evaluated the feasibility and outcomes of performing deep enucleation with Roux-en-Y pancreaticojejunostomy reconstruction.This study included patients who underwent pancreatic lesion enucleation from February 2010 to April 2014 in our hospital. The clinical data were collected and retrospectively analyzed.This study examined 53 patients who underwent enucleation, 33 of the procedures included deep enucleation with Roux-en-Y pancreaticojejunostomy reconstruction. There was no mortality, and the morbidity rate was 66.7% in this group. No patients developed grade C pancreatic fistulas in both group. None of the patients developed tumor recurrence or exocrine or endocrine insufficiency at a median follow-up of 25 months.Enucleation with Roux-en-Y pancreaticojejunostomy reconstruction is a safe and feasible procedure for the treatment of benign and borderline pancreatic neoplasms adjacent to the common pancreatic duct. This procedure can effectively mitigate the limitations of simple enucleation.

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.

The prognosis for pancreatic cancer (PC) is poor; however, the timely and accurate treatment of this disease will significantly improve prognosis. Serum biomarkers involve non-invasive tests that facilitate the early detection of tumors, predict outcomes and assess responses to therapy, so that the patient can be continuously monitored and receive the most appropriate therapy. Studies have reported that cancer antigen (CA)125 [also known as mucin 16 (MUC16)] has functional significance in the tumorigenic, metastatic and drug resistant properties of PC. Our aim was to use this biomarker in the diagnosis, detection of metastasis, prognosis and in the monitoring of the treatment effects of PC. Members of the Chinese Study Group for Pancreatic Cancer (CSPAC) reviewed the literature on CA125/MUC16 and developed an objective consensus on the clinical utility of CA125/MUC16 for PC. They confirmed the role of CA125/MUC16 in tumorigenesis and the progression of PC, and recommended monitoring CA125/MUC16 levels in all aspects of the diagnosis and treatment of PC, particularly those that involve the monitoring of treatments. In addition, they suggested that the combination of other biomarkers and imaging techniques, together with CA125/MUC16, would improve the accuracy of the clinical decision-making process, thereby facilitating the optimization of treatment strategies. Periodic clinical updates of the use of CA125/MUC16 have been established, which are important for further analyses and comparisons of clinical results from affiliates and countries, particularly as regards the in-depth biological function and clinical translational research of this biomarker.

Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras–Raf–MEK–ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy. Experimental Design: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways. Results: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc–dependent manner. Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950–60. ©2016 AACR.

Despite rapid advances in cancer diagnosis and treatment, pancreatic cancer remains one of the most difficult human malignancies to be treated, with a mortality rate nearly equal to its incidence. Although gemcitabine has been established as the standard first-line treatment for advanced pancreatic cancer, gemcitabine-based combination chemotherapy showed either marginal or no improvement in survival. Developments in liposomal delivery systems have facilitated the targeting of specific agents for cancer treatment. Such systems could be developed as platforms for future multi-functional theranostic nanodevices tailor-made for the combined detection of early cancer and functional drug delivery. We systemically review liposome based drug-delivery systems, which can provide improved pharmacokinetics, reduced side effects and potentially increased tumor uptake, for pancreatic cancer therapy. Novel liposomal formulations allowing for higher tumor targeting efficiencies and used in current clinical trials to treat this challenging disease are emphasized.

Strategies using carbon-based nanomaterials as carriers for delivering chemotherapeutic drugs to cancers have been described well. Here a novel magnetic lymphatic-targeting drug-delivery system, based on functionalised carbon nanotubes (fCNTs), is presented with the aim of improving the outcome of cancer with lymph node involvement. The potential therapeutic effect of gemcitabine (GEM) loading magnetic multiwalled carbon nanotubes (mMWNTs) was compared with that of GEM loading magnetic-activated carbon particles (mACs) in vitro and in vivo. mMWNTs-GEM and mACs-GEM both had high anti-tumour activity in vitro similar to free drug. Subcutaneous administration of GEM loading magnetic nanoparticles resulted in successful regression and inhibition of lymph node metastasis under the magnetic field, with mMWNTs-GEM superior to mACs-GEM, and more effectively in the high-dose versus low-dose groups. The successful application of intra-lymphatic delivery of chemotherapeutics using mMWNTs highlights the clinical potential of fCNTs for future cancer metastasis treatment with high efficacy and minimum side-effects.

Amino-carbon nanotubes (amino-CNTs) can conjugate with the DNA by electrostatic interactions and shuttle the DNA to the cell cytoplasm or even the nucleus. Here we report a new approach to produce amino-CNTs by cycloaddition of nitrenes. Fourier transform infrared spectroscopy was used to verify the success of the functionalization, and the functionalization degree was calculated by thermal gravity analysis. Transmission electron microscope (TEM) was used to observe the solubility of the CNTs and the interactions of the amino-CNTs with the plasmids. Cell ultrathin sections were made and observed under the TEM to confirm the amino-CNTs enter the cells. Transfection experiments ultimately verify the amino-CNTs produced through cycloadditions of nitrenes can serve as plasmid vector.

Objectives Decreased deoxycytidine kinase (dCK) expression is a reported indicator of gemcitabine efficacy in pancreatic cancer, due to the impact of this kinase on gemcitabine metabolism. The transcription factor NF‐E2 p45‐related factor 2 (NRF2, also called Nfe2l2), a master regulator of redox homoeostasis, has been reported to tightly control the expression of numerous ROS‐detoxification genes and participates in drug resistance. However, the contribution of dCK to the NRF2 signalling axis has seldom been discussed and needs investigation. Materials and methods By overexpressing dCK in pancreatic cancer cells, we assessed the impact of dCK on NRF2 transcriptional activity. Furthermore, we measured the impact of dCK expression on the intracellular redox balance and reactive oxygen species (ROS) production. By utilizing immunohistochemical staining and tissues from pancreatic cancer patients, we assessed the correlation between dCK and NRF2 expression. Through proliferation and metastasis assays, we examined the impact of dCK expression on cell proliferation and metastasis. Results dCK negatively regulates NRF2 transcriptional activity, leading to the decreased expression of ARE‐driven antioxidant genes. In addition, dCK negatively regulates intracellular redox homoeostasis and ROS production. Negative correlations between dCK and NRF2 levels in pancreatic cancer cell lines and patient samples were observed. In vitro cell line studies suggested that dCK negatively regulated proliferation and metastasis. Conclusion Decreased dCK expression promotes NRF2‐driven antioxidant transcription, which further enhances gemcitabine treatment resistance, forming a feedback loop.

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.

Understanding and formulating an appropriate strategy for the para-aortic lymph nodes (LN16) during curative surgery for pancreatic head cancer have been controversial for some time. This study intended to provide a recommendation for surgeons to perform an optimal curative surgery on pancreatic cancer patients with or without LN16 involvement. Based on an updated literature search and review, the members of the Chinese Study Group for Pancreatic Cancer (CSPAC) from high-volume centers reached a consensus on the issue of LN16 in pancreatic head cancer. Metastasis to LN16 is quite common in pancreatic head cancer cases. Depending on the location of the tumor, including the ventral and dorsal pancreas, there could be various lymph node drainage pathways whereby LN16 does not necessarily belong to the Group 3 lymph node stations for all cases of pancreatic head cancer. Although LN16 involvement generally indicates a poor prognosis, some cohorts of LN16-involved cases have benefited from a curative surgery, and there is still a lack of level I evidence to convince surgeons to abandon all resectable cases with LN16 positivity. Resection of LN16 combined with a standard lymphadenectomy during pancreatoduodenectomy is recommended by CSPAC, except in patients with both positive LN16 and criteria based on: i) the resectability status of primary tumor; ii) the extent of involved para-aortic lymph nodes; and iii) the serum tumor burden assessed preoperatively.

Pancreatic Adenocarcinoma (PDAC) is one of the most deadly malignant tumors worldwide. A variety of mechanisms are involved in PDAC biological behaviors, of which, the mechanisms of immune escape may be a pivotal hallmark. HLA-G is a tolerant molecule implicated in tumor escape and serves as a prognostic biomarker in tumors. Our study evaluated the expression of HLA-G in PDAC and explored its clinical significance. In a cohort of 122 PDAC patients, 78 patents (63.9%) exhibited high level of HLA-G tumor tissues. Multivariate analysis suggested that HLA-G level was an independent predictor for OS (HR = 3.894, 95% CI = 2.380-6.370, p

Pancreatic cancer is an aggressive and lethal disease with an overall 5-year survival rate of only 5%. Studies have demonstrated the ability of (18)F-fludrodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) to measure the metabolic tumor burden in patients with various tumors, including pancreatic cancer. In a previous study, we investigated the predictive significance of the metabolic tumor burden in terms of the metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this study, we analyzed the correlation between metabolic tumor burden and the status of the KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4 genes. Our results showed that the metabolic tumor burden was associated with oncogenomic alterations that reflected the abnormal expression of carbohydrate metabolic enzymes (GLUT1, ALDOA and FBP1). We also identified a linear correlation between serum tumor markers and the metabolic tumor burden. To estimate the metabolic tumor burden when (18)F-FDG PET/CT is not available, we used the linear regression models to establish equations for MTV and TLG using CA19-9 and CA125 as independent variables. Our results suggest that the metabolic tumor burden, as evaluated by (18)F-FDG PET/CT or estimated by serum tumor markers, may be suitable for monitoring treatment response and disease progression of pancreatic cancer. Further research is needed to better understand why pancreatic cancer patients with abnormal expressions of TP53, CDKN2A/p16, and SMAD4/DPC4 get high metabolic tumor burden.

Pancreatic cancer has been increasing in importance in Shanghai over the last four decades. The etiology of the disease is still unclear. Evidence suggests that the COX-2 pathway, an important component of inflammation, may be involved in the disease. We aimed to evaluate the association between urinary prostaglandin E2 metabolite (PGE-M) level and risk of pancreatic cancer. From a recent population-based case-control study in Shanghai, 200 pancreatic ductal adenocarcinoma cases and 200 gender- and age- frequency matched controls were selected for the present analysis. Urinary PGE-M was measured with a liquid chromatography/mass spectrometric assay. Adjusted unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A positive association was observed between PGE-M leve and pancreatic cancer risk: OR = 1.63 (95% CI 1.01–2.63) for the third tertile compared to the first. Though the interactions were not statistically significant, the associations tended to be stronger among subjects with diabetes history (OR = 3.32; 95% CI 1.20–9.19) and higher meat intake (OR = 2.12; 95% CI 1.10–4.06). The result suggests that higher urinary PGE-M level may be associated with increased risk of pancreatic ductal adenocarcinoma.

Patients with pancreatic cancer (PC) are usually diagnosed at late stages, when the disease is nearly incurable. Sensitive and specific markers are critical for supporting diagnostic and therapeutic strategies. The aim of this study was to use a metabonomics approach to identify potential plasma biomarkers that can be further developed for early detection of PC. In this study, plasma metabolites of newly diagnosed PC patients (n = 100) and age- and gender-matched controls (n = 100) from Connecticut (CT), USA, and the same number of cases and controls from Shanghai (SH), China, were profiled using combined gas and liquid chromatography mass spectrometry. The metabolites consistently expressed in both CT and SH samples were used to identify potential markers, and the diagnostic performance of the candidate markers was tested in two sample sets. A diagnostic model was constructed using a panel of five metabolites including glutamate, choline, 1,5-anhydro-d-glucitol, betaine, and methylguanidine, which robustly distinguished PC patients in CT from controls with high sensitivity (97.7%) and specificity (83.1%) (area under the receiver operating characteristic curve [AUC] = 0.943, 95% confidence interval [CI] = 0.908-0.977). This panel of metabolites was then tested with the SH data set, yielding satisfactory accuracy (AUC = 0.835; 95% CI = 0.777-0.893), with a sensitivity of 77.4% and specificity of 75.8%. This model achieved a sensitivity of 84.8% in the PC patients at stages 0, 1, and 2 in CT and 77.4% in the PC patients at stages 1 and 2 in SH. Plasma metabolic signatures show promise as biomarkers for early detection of PC.

Background The role of adjuvant chemoradiotherapy in pancreatic cancer remains limited. The primary aim of this study was to determine the prediction of lymph node (LN) status to the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic adenocarcinoma. Methods Between December 2010 and December 2012, a total of 152 patients undergoing curative R0 resection for pancreatic adenocarcinoma from multi-institutions were retrospectively analyzed. Results Overall median survival was 16.3 months. Sixty-four patients (42.1%) received adjuvant chemoradiotherapy, whereas 88 (57.9%) did not receive adjuvant therapy after surgery. Patients who received chemoradiotherapy could achieve an improved median OS compared with surgery alone (20.3 versus 13.9 months, p =0.027). Stratified by different lymph node status, multivariate analysis demonstrated the benefit of adjuvant chemoradiotherapy was only seen among patients with lymphatic positive disease (HR = 0.54, 95% CI, 0.33–0.88; p =0.014), not lymphatic negative disease (HR = 0.80, 95% CI, 0.44–1.46; p =0. 468). Conclusions This study suggests adjuvant chemoradiotherapy is associated with a significant improvement of survival only in patients with LN-positive disease, while the effects of chemoradiotherapy on patients with LN-negative disease may be limited. This study may add incremental knowledge of the role of lymph node status in offering treatment with adjuvant chemoradiotherapy.

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

To investigate the association between urinary levels of isothiocyanates (ITCs) and the risk of pancreatic cancer in urban Shanghai.A case-control study has been conducted in urban Shanghai. The cases (from December 2006 to December 2008) were identified through an newly established "instant case reporting" system. The high performance liquid chromatography (HPLC) method was applied to determine the urinary levels of isothiocyanates in 390 cases and 414 controls. A food-frequency questionnaire was administered to estimate cruciferous vegetables consumption and dietary ITC exposure.Non-conditional logistic regression model was used to analyze the relationship between dietary and urinary levels of isothiocyanates and the risk of pancreatic cancer.The cruciferous vegetables intake and ITC consumption, urinary ITC levels (median (P25, P75)) were 95.0 (66.9, 135.8) g/d, 11.0 (7.1, 16.0) µmol/d, 0.95 (0.12, 2.92) µmol/g Cr respectively in cases, all lower than those in controls, separately 107.4 (80.1, 154.1) g/d, 12.3 (8.0, 18.0) µmol/d, 1.78 (0.53, 5.28) µmol/g Cr. The differences were statistically significant (t = 3.75, 3.03, 4.40, all P values0.01). Urinary levels of ITCs in controls were correlated with cruciferous vegetables consumption and dietary ITC exposure (r = 0.189, 0.201, all P values0.01). There was inverse association between urinary ITCs and the risk of pancreatic cancer after adjusting for possible confounding factors such as age, sex, history of diabetes and pancreatitis. Compared with the first tertile (0.825 µmol/g Cr), the odds ratio (95%CI) for the second (0.825-3.342 µmol/g Cr) and third tertiles ( ≥ 3.343 µmol/g Cr) were 0.69 (0.49-0.97) and 0.47(0.33-0.68), respectively, Ptrend0.01.High levels of cruciferous vegetables or ITC consumption were associated with a reduced risk of pancreatic cancer (all P trend0.05).indicated that high levels of dietary ITC exposure might reduce the risk of pancreatic cancer.

Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high-volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19-9 independently indicated surgical response in pancreatic cancer. Patients with CA19-9 ≥1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19-9 levels decreased postoperatively. CEA and CA125 in the presence of CA19-9 ≥1000 U/mL could independently predict the non-decrease of CA19-9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p 0.001) for the training cohort and 7.0 months vs. 18.2 months (p 0.001) for the validation cohort and also suggested a higher prevalence of early distant metastasis after surgery. Resected patients with this proposed signature showed no survival advantage over patients in the locally advanced group who did not receive pancreatectomy. Therefore, a preoperative serum signature of CEA(+)/CA125(+)/CA19-9 ≥1000 U/mL is associated with poor surgical outcome and can be used to select appropriate patients with pancreatic cancer for pancreatectomy.

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 exact mechanisms 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.

Pancreatic cancer has an extremely poor prognosis mainly due to lack of effective treatment options. Radiotherapy is mostly applied to locally advanced cases, although tumor radioresistance limits the effectiveness. Profilin1, a novel tumor suppressor gene, was reported to be down-regulated in various cancers and associated with tumor progression. The objective of this study was to demonstrate how profilin1 affected pancreatic cancer radiosensitivity. We showed profilin1 was down-regulated in pancreatic cancer cells after exposure to radiation, and re-expression of profilin1 suppressed tumor cell viability and increased DNA damage following irradiation. Further studies revealed that up-regulation of profilin1 facilitated apoptosis and repressed autophagy induced by irradiation, which might sensitize pancreatic cancer cells to radiation treatment. Our findings may provide a novel therapeutic strategy for sensitizing pancreatic cancer to radiotherapy.

Studies over 5 decades have examined ABO blood groups and risk of pancreatic cancer in Western, Asian, and other populations, though no systematic review has been published. We studied data from 908 pancreatic cancer cases and 1,067 population controls collected during December 2006–January 2011 in urban Shanghai, China, and reviewed the literature for all studies of this association. Random-effects meta-analysis provided summary odds ratio estimates according to blood group and by populations endemic versus nonendemic for cytotoxin-associated gene A (CagA)-positive Helicobacter pylori. In our Shanghai study, versus group O, only ABO group A was associated with risk (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.27, 2.03). In 24 pooled studies, group A showed increased risk in both CagA-nonendemic and -endemic populations (ORpooled = 1.40, 95% CI: 1.32, 1.49). In nonendemic populations, groups B and AB were also associated with higher risk (OR = 1.38, 95% CI: 1.16, 1.64; and OR = 1.52, 95% CI: 1.24, 1.85, respectively). However, in CagA-endemic populations, groups B and AB were not associated with risk (OR = 1.05, 95% CI: 0.92, 1.19; and OR = 1.13, 95% CI: 0.92, 1.38, respectively). These population differences were significant. One explanation for contrasts in associations of blood groups B and AB between CagA-endemic and -nonendemic populations could involve gastric epithelial expression of A versus B antigens on colonization behaviors of CagA-positive and CagA-negative H. pylori strains.

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.

The correlation between the loss of Profilin 1 (Pfn1) with tumor progression indicated that Pfn1 is a tumor suppressor in human carcinoma. The molecular mechanisms underlying Pfn1 tumor suppression has yet to be elucidated. In this study, we showed that Pfn1 overexpression sensitizes cancer cells to apoptosis through the typical intrinsic apoptotic pathway. Mechanistically, the increased Pfn1 expression mediated the upregulation of p53R273H, one of the most common tumor-associated hotspot mutations of p53, with transactivation deletion in tumorigenesis and increased localization of p53R273H in cytoplasm. Further studies showed that mutant p53R273H was involved in apoptosis induced by Staurosporine (STS) via transcription-independent mitochondrial functions. We observed (i) the increased cytosolic localization of p53R273H, (ii) the activation of phosphorylation at Ser15, (iii) its mitochondrial localization; Pfn1 acted as a positive regulator of these processes. We also found that Pfn1 interacted with p53R273H and thus facilitated its exertion over the transcription-independent activity in the cytoplasm during drug action. Our results define a new function and mechanism of Pfn1 demonstrating that the combined effect with apoptotic agents led to a synergistic increase in apoptosis. In addition, p53R273H abrogating DNA binding was found to play a major role in the Pfn1- sensitized apoptosis through a transactivation-independent and cytosolic activity.

Methyl-CpG binding domain protein 1 (MBD1) has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression and development. It is also predicted that MBD1 might be involved in tumor development and progression. However, whether and how MBD1 is involved in tumorigenesis, especially in pancreatic cancer (PC), is currently unknown. We found that MBD1 was significantly up-regulated in PC tissues compared with the surrounding normal tissues according to RT-PCR data. Tissue microarray (TMA) based immunohistochemical study from 58 surgically resected PC specimens indicated that higher MBD1 expression correlated with lymph node metastasis and poor survival in PC patients. Gain- and loss-of-function studies in vitro validated MBD1 as a potent oncogene promoting PC cell invasion as well as epithelial-mesenchymal transition (EMT). Mechanistically, MBD1 is associated with Twist and NAD-dependent deacetylase sirtuin-1 (SIRT1), thereby forming the Twist-MBD1-SIRT1 complex on the CDH1 promoter, which resulted in reduced E-cadherin transcription activity and increased cell EMT ability. Significantly, targeting MBD1 reversed the EMT phenotype of PC and restored sensitivity to chemotherapy. Taken together, the results of our study revealed a novel function of MBD1 in PC invasion and metastasis by providing a molecular mechanism underlying MBD1-promoted EMT. Thus MBD1 may serve as a potential therapeutic target for PC.

Solid pseudopapillary tumor of the pancreas is a rare neoplasm with low malignant potential, which affects predominantly young females. Only approximately 10% to 15% cases of solid pseudopapillary tumors (SPTs) are malignant. We present the case of a 57-year-old woman who developed malignant SPT of the pancreas. Meanwhile, a literature review was carried out. Some clinicopathological features and strategies of management of malignant SPT are presented. In general, surgical removal of the tumor even in case of metastases or recurrence offers an excellent prognosis. Chemotherapy and radiotherapy should be taken into consideration in patients with unresectable tumor.

Pancreatic ductal adenocarcinom a (PDA) has two exceptional features. First, it is a highly lethal disease, with a median survival of less than 6 months and a 5-year survival rate less than 5%. Second, PDA tumor cells are surrounded by an extensive stroma, which accounts for up to 90% of the tumor volume. It is well recognized that stromal microenvironment can accelerate malignant transformation, tumor growth and progression. More importantly, the interaction loop between PDA and its stroma greatly contributes to tumor growth and progression. We propose that the extensive stroma of PDA is closely linked to its poor prognosis. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed. Targeting the stroma may thus provide novel prevention, earlier detection and therapeutic options to this deadly malignancy. Accordingly, in this review, we will summarize the mechanism of PDA stroma formation, the role of the stroma in tumor progression and therapy resistance and the potential of stroma-targeted therapeutics strategies.