Marker In Pancreatic Cancer Patients Research Articles

Is there any diagnostic value of serum caveolin-1 levels on the determination of pancreatic adenocarcinoma?

Caveolin-1 (CAV-1) is a vital component in cancer pathogenesis, as its expression determines the survival of patients with cancer. This study investigates CAV-1 serum levels in pancreatic adenocarcinoma (PA) patients and their role in tumor progression and prognostic factors. The trial included 33 patients with pathologically confirmed pancreatic cancer (PC). The enzyme-linked immunosorbent assay (ELISA) method was used to measure the concentrations of CAV-1 in the blood. The study also included 20 healthy subjects. The statistical analysis was two-sided, and a P value of ≤ 0.05 was determined as statistically significant. The median age of the subjects was 59 years (32-84 years) at the time of diagnosis. There were 13 (39%) female participants. In 21 (63%) patients, the primary focus was the pancreatic head. In 23 stage IV patients, hepatic metastasis (n = 19, 83%) was observed. Only one patient (3%) was still alive at the end of the study period. Palliative chemotherapy (CTx) was provided, with 39% of the 23 patients responding to it. The overall survival (OS) rate in this cohort was 41.3 ± 8.3 weeks at a 95% confidence interval (CI), after 25-58 weeks. Serum baseline CAV-1 values among patients with PA were significantly higher compared with controls (p = 0.009). Patients with poor performance status, a pancreatic head tumor, lower albumin levels, higher serum carcinoembryonic antigen (CEA) levels, and higher CA 19.9 levels had significantly higher serum CAV-1 levels (p = 0.01, P = 0.05, P = 0.03, P = 0.02, and P = 0.04, respectively). However, CAV-1 did not show any prognostic value (p = 0.75). Although serum CAV-1 is a useful diagnostic marker in PC patients, it is not a prognostic or predictive marker.

GK921, a transglutaminase inhibitor, strengthens the antitumor effect of cisplatin on pancreatic cancer cells by inhibiting epithelial-to-mesenchymal transition

Pancreatic adenocarcinoma (PAAD), a common digestive malignant tumor, presents high mortality rates and limited treatment methods. Currently, chemotherapy remains the main therapy method for patients with PAAD. As a classical chemotherapy drug, cisplatin (DDP) is limited by dose-related toxicity in patients with PAAD. In this study, we demonstrated that TGM2 may be a treatment and prognosis marker in pancreatic cancer patients. Co-treatment of low dose of DDP and GK921, a transglutaminase (TGM2) inhibitor, is capable of synergistically inhibiting the PAAD cell viability and proliferation in vitro and in vivo. Based on in vitro study, GK921 inhibited the epithelial-to-mesenchymal transition (EMT) induced by TGM2 as well as aggravated cell cycle arrest and apoptosis resulted from DDP, making pancreatic cancer cells more sensible to DDP. Our results showed that GK921 increased the protein levels regarding E-cadherin as well as decreased the protein level regarding Snail2, N-cadherin, which indicated that GK921 inhibited EMT in pancreatic cancer cells. Snail2 overexpression inhibited GK921/DDP-induced cell apoptosis, as well as mitigated the GK921/DDP-caused cell death and the EMT inhibition. In vivo studies also found GK921/DDP combination can further inhibit the growth of PAAD without significantly side effects. To sum up, we showed that GK921 increased PAAD cells sensitivity to DDP via inhibiting EMT. As revealed, DDP/GK921 co-treatment could promisingly serve for treating PAAD patients.

MicroRNA-593-3p Expression in Peritoneal Lavage Fluid as a Prognostic Marker for Pancreatic Cancer Patients Undergoing Staging Laparoscopy.

Some presumed resectable pancreatic cancer patients harbor radiographically occult metastases that are incidentally identified at the time of abdominal exploration. This study aims to identify novel diagnostic or predictive microRNA (miRNA) markers for subclinical peritoneal dissemination in patients with pancreatic cancer undergoing abdominal exploration. Peritoneal lavage fluid samples were harvested from 74 patients with pancreatic cancer at the time of staging laparoscopy. Microarray analysis was performed using peritoneal lavage fluids with positive and negative cytology. Candidate microRNA expression was quantified and validated by droplet-digital PCR assays. In the miRNA array analysis, miR-593-3p showed significant upregulation in peritoneal lavage fluids with positive cytology. Of the 74 patients validated, peritoneal lavage fluids with positive cytology had significantly higher expression of miR-593-3p than those with negative cytology (P < 0.001). Even in cases with no peritoneal dissemination and negative cytology, multivariate analysis revealed that elevated miR-593-3p expression was significantly correlated with worse overall survival than those with low expression (hazard ratio: 3.474, P = 0.042). Of the 48 patients who underwent pancreatectomy, multivariate analysis also demonstrated that higher expression of miR-593-3p in peritoneal lavage was the only significant poor prognostic marker influencing both overall survival (hazard ratio: 23.38, P = 0.005) and recurrence-free survival (hazard ratio: 5.700, P = 0.002). Elevated miR-593-3p expression in peritoneal lavage suggests the presence of subclinical micrometastasis even in cases with localized pancreatic cancer, and miR-593-3p could be a useful prognostic predictor for pancreatic cancer patients undergoing staging laparoscopy.

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Introduction: The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Methods: Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan–Meier curve, and both univariate and multivariate Cox proportional models. Results: BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively (p < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129–1.754, p = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10–1.82; p = 0.006) were identified as independent prognostic factors. Conclusion: Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.

Validation and clinical usefulness of pre- and postoperative systemic inflammatory parameters as prognostic markers in patients with potentially resectable pancreatic cancer

BackgroundSeveral preoperative systemic inflammatory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), and Glasgow prognostic score, have been reported to be associated with the prognosis of solid tumors. In this study, we compared pre- and postoperative hematological inflammatory parameters and validated their prognostic significance in pancreatic cancer patients who underwent surgical resection. MethodsClinical records from 211 consecutive pancreatic cancer patients who underwent surgical resection at our institution were retrospectively analyzed. The optimal cutoff values of hematological inflammatory parameters, including lymphocyte count, NLR, PLR, LMR, and PNI, were determined by time-dependent receiver-operating characteristic analysis. ResultsThe postoperative neutrophil count and serum albumin level were significantly decreased in patients who underwent pancreatoduodenectomy (PD group) and in those who underwent distal pancreatectomy (DP group) compared to the levels at baseline. The postoperative lymphocyte count, monocyte count, and platelet count were significantly increased in the DP group compared to those at baseline. As a result, the postoperative NLR and PNI significantly decreased in both groups. The multivariate analysis identified intraoperative peritoneal washing cytology, administration of adjuvant therapy, tumor size, extrapancreatic nerve plexus invasion, and preoperative PLR as independent prognostic factors for overall survival. ConclusionsSystemic inflammatory responses were altered after pancreatic resection in pancreatic cancer patients. Preoperative PLR may be a useful prognostic marker in pancreatic cancer patients undergoing surgical resection.

E‑cadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT.

The aim of the present study was to research the effect of microenvironmental change on epithelial‑mesenchymal transition (EMT) in pancreatic cancer cells and to determine the correlation between E‑cadherin expression and the prognosis of pancreatic cancer patients. We established hypoxic, serum‑deficient and TGF‑β‑induced microenvironment models of pancreatic cancer cells and studied the changes in the mRNA and protein expression of EMT‑related molecules, E‑cadherin and vimentin, using western blot analysis and real‑time PCR. Furthermore, immunohistochemistry was used to investigate E‑cadherin expression in pancreatic cancer tissues, and survival analysis and COX regression analysis were conducted. In pancreatic cancer cells under hypoxic, serum‑starved and TGF‑β‑induced microenvironments, E‑cadherin protein and mRNA levels were significantly decreased (P<0.05), while vimentin protein and mRNA expression levels were significantly increased (P<0.05). The results of immunohistochemistry showed that the protein level of E‑cadherin in pancreatic cancer tissues was positively correlated with overall survival (P<0.01). The results of Cox regression analysis showed that E‑cadherin was an independent prognostic factor in pancreatic cancer. In conclusion, E‑cadherin expression was significantly decreased by microenvironment changes, and this decrease induced EMT in pancreatic cancer cells. E‑cadherin is an independent prognostic marker in pancreatic cancer patients.

Combined use of CEMIP and CA 19-9 enhances diagnostic accuracy for pancreatic cancer

Carbohydrate antigen (CA) 19-9 is the only diagnostic marker used in pancreatic cancer despite its limitations. Here, we aimed to identify the diagnostic role of CEMIP (also called KIAA1199) combined with CA 19-9 in patients with pancreatic cancer. A retrospective analysis of prospectively collected patient samples was performed to determine the benefit of diagnostic markers in the diagnosis of pancreatic cancer. We investigated CEMIP and CA 19-9 levels in 324 patients with pancreatic cancer and 49 normal controls using serum enzyme-linked immunosorbent assay. Median CA 19-9 and CEMIP levels were 410.5 U/ml (40.8–3342.5) and 0.67 ng/ml (0.40–1.08), respectively, in patients with pancreatic cancer. The AUROC for CA 19-9 and CEMIP were 0.847 (95% confidence interval [CI]: 0.806–0.888) and 0.760 (95% CI: 0.689–0.831), respectively. Combination of CA 19-9 with CEMIP showed markedly improved AUROC over CA 19-9 alone in pancreatic cancer diagnosis (0.94 vs. 0.89; P < 0.0001). CEMIP showed a diagnostic yield of 86.1% (68/79) in CA 19-9 negative pancreatic cancer. Combined use with CEMIP showed significantly improved diagnostic value compared with CA 19-9 alone in pancreatic cancer. Especially, CEMIP may be a complementary marker in pancreatic cancer patients with normal CA 19-9 levels.

Aberrant expression of STYK1 and E-cadherin confer a poor prognosis for pancreatic cancer patients.

Previous studies showed that aberrant Serine/threonine/tyrosine kinase 1 (STYK1, also known as NOK) or/and E-cadherin were involved in the progression of some types of human cancers. However, whether they contributed to the development of pancreatic cancer was unknown. Here, we investigated the prognostic significance of aberrant STYK1 and E-cadherin in pancreatic cancer. Our results showed that STYK1 expression increased while E-cadherin decreased in pancreatic cancer tissues compared with normal pancreas tissues. STYK1 level was positively correlated with lymph node metastasis and clinical stage in pancreatic cancer patients. E-cadherin expression was inversely correlated with STYK1 expression in pancreatic cancer tissue samples. Patients with high STYK1 and low E-cadherin expression had the worst prognosis. In addition, STYK1 knockdown in pancreatic cancer cell lines inhibited cell proliferation, enhanced cell apoptosis, induced cell cycle arrest, and prohibited cell migration, while STYK1 over-expression showed the opposite effects. Silencing STYK1 also increased E-cadherin expression and inhibited epithelial-to-mesenchymal transition (EMT) and p-p38 expression in vitro. Over-expression had showed the opposite trends, and treatment with p38 inhibitor, SB203580, could reverse the trends. Thus, STYK1 repressed E-cadherin expression and promoted EMT, mediated by p38 MAPK signaling pathway, which was the possible mechanism for STYK1-mediated pancreatic cancer cell proliferation and migration. In summary, our results showed that STYK1 might be a prognostic marker for pancreatic cancer patients and might be a novel strategy for the treatment of pancreatic cancer.

Multiplex detection of pancreatic cancer biomarkers using a SERS-based immunoassay

Early diagnosis of pancreatic cancer (PC) is critical to reduce the mortality rate of this disease. Current biological analysis approaches cannot robustly detect several low abundance PC biomarkers in sera, limiting the clinical application of these biomarkers. Enzyme linked immunosorbent assay and radioimmunoassay are two common platforms for detection of biomarkers; however, they suffer from some limitation. This study demonstrates a novel system for multiplex detection of pancreatic biomarkers CA19-9, MMP7 and MUC4 in sera samples with high sensitivity using surface enhanced Raman spectroscopy. Measuring the levels of these biomarkers in PC patients, pancreatitis patients, and healthy individuals reveals the unique expression pattern of these markers in PC patients, suggesting the great potential of using this approach for early diagnostics of PCs.

Plasma miR-22-3p, miR-642b-3p and miR-885-5p as diagnostic biomarkers for pancreatic cancer.

Diagnosis of pancreatic cancer (PC) by using sensitive and specific biomarkers is considered necessary. MiRNAs are master regulators of gene expression and several biological processes, and they are dysregulated in various cancers, where they play a vital role in either cancer progression or suppression. So, this study was designed to investigate the role of plasma miR-22-3p, miR-642b-3p and miR-885-5p expression as possible diagnostic markers in PC patients as compared to serum CA19-9. In addition, the correlation of those miRNAs and CA19-9 with clinical characteristics of PC patients was analyzed. The expression levels of selected miRNAs and serum CA19-9 concentration were determined for 35 patients with PDAC and 15 healthy controls by quantitative real-time RT-PCR and electro-chemiluminescence immune assay, respectively. The sensitivities of miRNAs as biomarkers of PC were evaluated and compared with CA19-9 using a receiver operating characteristic analysis. The levels of three miRNAs (miR-22-3p, miR-642b-3p and miR-885-5p) and CA19-9 were significantly higher in PC patients, even those with early-stage disease (IB and IIB), than in healthy control. Both miRNAs and CA19-9 were associated with tumor stage. The high sensitivities of the three selected miRNAs and CA19-9 were observed. The measurement of miR-22-3p, miR-642b-3p and miR-885-5p may prove to have clinical utility in diagnosis of PC. Those miRNAs are ideal early biomarkers for PC diagnosis. So, they can effectively be used with serum CA19-9 for PC screening in early tumor stage.

The correlation between FDG uptake and biological molecular markers in pancreatic cancer patients

PurposeWe examined whether fluorine-18 fluorodeoxyglucose (FDG) uptake is related to the mammalian target of rapamycin (mTOR) signal pathway and its related proteins in pancreatic cancer patients. MethodsWe retrospectively studied 53 pancreatic cancer patients who underwent FDG positron emission tomography (PET) or FDG PET/CT, and complete curative surgical resection. The SUV max, the tumor to nontumor activity of pancreas [T/N (P)] ratio and the T/N of liver [T/N (L)] ratio were calculated. The expressions of glucose transporter-1(Glut-1) and mTOR pathway proteins in pancreas cell lines were examined by immune blots. Excised tumor tissue was analyzed by immunohistochemistry using monoclonal antibodies for Glut-1, epidermal growth factor receptor (EGFR), mTOR, p70S6kinase (p70S6) and S6 ribosomal protein (S6). ResultsThe expressions of Glut-1, EGFR and p70S6 were significantly correlated with the SUV max, T/N (P) ratio and T/N (L) ratio. The expressions of mTOR and S6 were not correlated with all parameters. The expression of Glut-1 was positively correlated with the expressions of EGFR and p70S6, but not with mTOR or S6. S6 was positively correlated with p70S6. ConclusionsGlut-1, EGFR and p70S6 expressions are associated with the FDG uptake mechanism of pancreatic cancer. FDG uptake may predict the levels of EGFR and p70S6 expressions, and FDG uptake reflects glucose metabolism and cancer progression.

Prognostic significance of neutrophil to lymphocyte ratio in pancreatic cancer: a meta-analysis.

To conduct a meta-analysis evaluating the association between the peripheral blood neutrophil to lymphocyte ratio (NLR) and the outcome of patients with pancreatic cancer. Studies evaluating the relationship between the peripheral blood NLR and outcome of patients with pancreatic cancer published up to May 2014 were searched using electronic databases, including PubMed, Web of Science, Embase and Ovid. A meta-analysis was performed to pool the hazard ratios (HRs) or odds ratios (ORs) and their 95% confidence intervals (CIs) using either a fixed-effects model or a random-effects model to quantitatively assess the prognostic value of NLR and its association with clinicopathological parameters. Eleven studies containing a total of 1804 patients were eligible according to our selection criteria, and combined hazard ratios indicated that high NLR was a poor prognostic marker for pancreatic cancer patients because it had an unfavorable impact on the overall survival (OS) (HR = 2.61, 95%CI: 1.68-4.06, P = 0.000) and cancer specific survival (HR = 1.66, 95%CI: 1.08-2.57, P = 0.021). Subgroup analysis revealed that high NLR was associated with poor OS in patients with mixed treatment (HR = 4.36, 95%CI: 2.50-7.61, P = 0.000), chemotherapy (HR = 2.08, 95%CI: 1.49-2.9, P = 0.000), or surgical resection (HR = 1.2, 95%CI: 1.00-1.44, P = 0.048). Additionally, high NLR was significantly correlated with tumor metastasis (OR = 1.69, 95%CI: 1.10-2.59, P = 0.016), poor tumor differentiation (OR = 2.75, 95%CI: 1.19-6.36, P = 0.016), poor performance status (OR = 2.56, 95%CI: 1.63-4.03, P = 0.000), high cancer antigen 199 (OR = 2.62, 95%CI: 1.49-4.60, P = 0.000), high C-reactive protein (OR = 4.32, 95%CI: 2.71-6.87, P = 0.000), and low albumin (OR = 3.56, 95%CI: 1.37-9.27, P = 0.009). High peripheral blood NLR suggested a poor prognosis for patients with pancreatic cancer, and it could be a novel marker of survival evaluation and could help clinicians develop therapeutic strategies for pancreatic cancer patients.

Prognostic value of several inflammatory markers in pancreatic cancer patients.

e15213 Background: Recent studies showed that the prognosis of cancer patients was strongly associated with pre-treatment systemic inflammation. Although several inflammatory markers were proposed,...

HENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: a systematic review.

High human equilibrative nucleoside transporter 1 (hENT1)-expression has shown a survival benefit in pancreatic cancer patients treated with gemcitabine in several studies. The aim of this systematic review was to summarize the results and try to assess the predictive value of hENT1 for determining gemcitabine outcome in pancreatic cancer. Relevant articles were obtained from PubMed, Embase and Cochrane databases. Studies evaluating hENT1-expression in pancreatic tumor cells from patients treated with gemcitabine were selected. Outcome measures were overall survival, disease-free survival (DFS), toxicity and response rate. The database searches identified 10 studies that met the eligibility criteria, and a total of 855 patients were included. Nine of 10 studies showed a statistically significant longer overall survival in univariate analyses in patients with high hENT1-expression compared to those with low expression. In the 7 studies that reported DFS as an outcome measure, 6 had statistically longer DFS in the high hENT1 groups. Both toxicity and response rate were reported in only 2 articles and it was therefore hard to draw any major conclusions. This review provides evidence that hENT1 is a predictive marker for pancreatic cancer patients treated with gemcitabine. Some limitations of the review have to be taken into consideration, the majority of the included studies had a retrospective design, and there was no standardized scoring protocol for hENT1-expression.

Quality of life in patients with pancreatic cancer during neoadjuvant chemotherapy using gemcitabine and bevazizumab: A pilot study.

330 Background: Neoadjuvant chemotherapy (nCT) for pancreatic cancer is increasing due to the fact that 75% of patients diagnosed with pancreatic cancer are borderline or non-resectable. The use of antibodies may improve the efficacy of nCT. The influence on quality of life is not clear. Methods: We prospectively evaluated quality of life in patients comparing nCT with gemcitabine (1000mg/m2; 1, 8, 15 for 4 cycles) and bevacizumab (nCT-GA; n=8) with patients with (aCT-G, n=15) or without adjuvant gemcitabine (noCT; n=14) using the EORTC-QLQ PAN26 modul. We also included patients operated due to benign disease as a control group (B; n=15). Quality of life was measured before as well as 3-7 months after surgery. Results: 52 patients were included in the study. There was no difference between the four groups before surgery in overall quality of life sores (p=0.280). Overall quality of life was also not impaired three months after surgery in any group (nCT-GA: 45 ± 23 vs. 65 ± 23 p=0.196; aCT-G: 42 ± 16 vs. 58 ± 22 p=0.104; noCT: 42 ± 16 vs. 49 ± 24 p=0.462; B: 60 ± 22 vs. 58 ± 21 p=0.894). There were no statistic significant differences between the four groups three to seven months after surgery (p=0.578). Similar function scores such as appetite loss, digestive symptoms or others did not differ significantly. Conclusions: Chemotherapy with or without bevacizumab seems to be well tolerated. The similar appetite score in patients comparing malignant (±chemotherapy) with benign disease is of importance as weight loss is a bad prognostic marker in pancreatic cancer patients. Thus, chemotherapy with or without bevacizumab may be safe in this respect. Further prospective trials with larger patient numbers are needed. [Table: see text]

Hypoxia inducible BHLHB2 is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma

Aims The cyclic adenosine monophosphate-inducible basic helix–loop–helix (bHLH) domain containing class-B2 transcriptional factor BHLHB2 is differentially expressed in a number of human malignancies. In the present study, the expression, regulation, functions and prognostic impact of BHLHB2 in pancreatic cancer were investigated. Methods Expression analyses were carried out in tissues of the normal pancreas ( n = 10) and pancreatic ductal adenocarcinoma ( n = 77) as well as in eight pancreatic cancer cell lines using quantitative RT-PCR, semiquantitative immunohistochemistry, and immunoblot analyses. In vitro functional experiments were conducted using siRNA transfection, hypoxia, serum starvation, apoptosis induction with gemcitabine and actinomycin-D, and invasion assays. Survival analysis was performed using the Kaplan–Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model. Results BHLHB2 mRNA and protein expressions were strongly induced by hypoxia and by serum starvation in pancreatic cancer cell lines. BHLHB2 silencing with RNAi had no significant effects on growth and invasion but increased apoptosis resistance against gemcitabine by reducing caspace-3 cleavage. In BHLHB2 silenced cells the ED50 of gemcitabine increased from 13.95 ± 1.353 to 38.70 ± 5.262 nM ( p < 0.05). Ex vivo, the weak/absent nuclear staining in normal pancreatic ducts and acinar cells was replaced by moderate to strong nuclear/cytoplasmic staining in PanIN lesions and pancreatic cancer cells. Patients with weak/absent nuclear BHLHB2 staining had significantly worse median survival compared to those with strong staining (13 months vs. 27 months, p = 0.03). In a multivariable analysis, BHLHB2 staining was an independent prognostic factor (Hazard-Ratio = 2.348, 95% CI = 1.250–4.411, p = 0.008). Conclusions Hypoxia-inducible BHLHB2 expression is a novel independent prognostic marker in pancreatic cancer patients and indicates increased chemosensitivity towards gemcitabine.

Tumour necrosis is a postoperative prognostic marker for pancreatic cancer patients with a high interobserver reproducibility in histological evaluation

Background:Tumour necrosis reflects the presence of hypoxia, which can be indicative of an aggressive tumour phenotype. The aim of this study was to investigate whether histological necrosis is a useful predictor of outcome in patients with pancreatic ductal carcinoma (PDC).Methods:We reviewed histopathological findings in 348 cases of PDC in comparison with clinicopathological information. We counted small necrotic foci (micronecrosis) as necrosis, in addition to massive necrosis that had been only defined as necrosis in previous studies. The reproducibility of identifying histological parameters was tested by asking five independent observers to blindly review 51 examples of PDC.Results:Both micronecrosis and massive necrosis corresponded to hypoxic foci expressing carbonic anhydrase IX detected by immunohistochemistry. Multivariate survival analysis showed that histological necrosis was an independent predictor of poor outcome in terms of both disease-free survival (DFS) and disease-specific survival (DSS) of PDC patients. In addition, metastatic status, and lymphatic, venous, and intrapancreatic neural invasion were independent prognostic factors for shorter DFS and metastatic status, margin status, lymphatic invasion, and intrapancreatic neural invasion were independent prognostic factors for DSS. The interobserver reproducibility of necrosis identification among the five independent observers was ‘almost perfect’ (κ-value of 0.87).Conclusion:Histological necrosis is a simple, accurate, and reproducible predictor of postoperative outcome in PDC patients.

Prognostic relevance of ribonucleotide reductase small subunit p53R2 in pancreatic cancer

e15655 Background: Pancreatic cancer has the worst survival of any solid tumor, with most patients presenting with metastatic disease. Even after surgical resection the median survival is only 20 months suggesting micrometastatic disease. Ribonucleotide reductase is a critical enzyme in DNA synthesis and repair. Previous studies have shown that ribonucleotide reductase M2 (RRM2) subunit is associated with invasion and metastasis. Even though p53R2 has 80% homology to RRM2, its role is quite different. Here we report on the prognostic relevance of p53R2 in pancreatic cancer. Methods: Archived pathology specimens were obtained from 30 patients and immunohistochemistry for p53R2 performed on an IRB approved protocol (#06253). Clinical data was obtained by chart review and log-rank and Cox hazard proportional models were used to analyze overall and disease-free survival. Cell culture analysis was performed to further evaluate the role of p53R2. Utilizing a Matrigel chamber, invasive MiaPaCa-2 cells were collected for comparison to parental cells. Results: The median overall survival (OS) was 13.2 months (p53R2+) vs 8.5 months (p53R2-) (p=0.01). Disease free survival (DFS) was 12.4 vs 8.5 months respectively (p&lt;0.05). By Western analysis, invasive cells have a higher protein level of RRM2 compared to parental cells. Interestingly, the protein level of p53R2 was low in the invasive cells suggesting an opposing role. To confirm this we inhibited p53R2 using siRNA which enhanced the migration ability of Mia PaCa-2 cells. Conclusions: Patients with p53R2 expression have improved disease-free and overall survival suggesting this may be used as a prognostic marker in pancreatic cancer patients. No significant financial relationships to disclose.

BRSK2 expression as a prognosis marker in pancreatic cancer patients

e15603 Background: The prognosis of pancreatic cancer remains dismal because of difficult early diagnosis, low resection rate and aggressive biological behavior. The research of factors related to oncogenesis, tumor infiltration and metastasis is valuable. AMPK(AMP-activated protein kinase)family is a group of regulators on the cellular energy metabolism which are sensitive to the cytoplasmic change of AMP/ATP ratio. As a member of AMPK, BRSK2 is found to be expressed in human pancreatic cell line and facilitate the tumor cell survival on glucose starving. In order to examine the expression of BRSK2 in human pancreatic cancer and explore the underline clinical implication, human pancreatic tissue was examined immunohistochemically Correlation of tumor biological behavior, prognosis and BRSK2 expression was examined. Methods: Seventy nine resected tumor specimens were collected. Immunochemical staining method was used to examine the expression pattern of BRSK2 translated protein. Semi-quantitative analysis was employed to compare the expression intensity and content of BRSK2 in tumor issues, peri-tumorous tissue and normal pancreatic tissue. Possible relationship of tumors differentiation, TNM stage, presence or absence of vessel and neural infiltration were explored with BRSK2 expression. The correlation of BRSK2 expression profile and patients survival was explored. Results: BRSK2 was weakly expressed in normal pancreatic tissues and peri-tumor tissues, including the islet and minor ducts. BRSK2 was strongly expressed in pancreatic cancer tissues, the expression intensity was correlated with extent of lymphatic metastasis, distant metastasis, TNM staging and neural invasion. Tumors with lymphatic metastasis, distant metastasis, neural invasion and later TNM stages showed stronger expression of BRSK2. The expression of BRSK2 in pancreatic cancer was closely correlated to the prognosis of patients, those with higher expression pattern showed bad prognosis. Conclusions: BRSK2 is up-regulated in pancreatic cancer; the expression of BRSK2 is correlated with tumor biological behavior and patient's prognosis. No significant financial relationships to disclose.

Specific Expression of Endoglin (CD105) in Endothelial Cells of Intratumoral Blood and Lymphatic Vessels in Pancreatic Cancer

Endoglin, a component of the transforming growth factor beta receptor expressed in embryonic vascular endothelial cells, is expressed in vascular endothelial cells in several types of cancer tissues and is involved in tumor angiogenesis. The aim of this study was to analyze the expression pattern of endoglin in pancreatic cancer and assess the involvement of this molecule in cancer progression. Pancreatic cancer and adjacent normal tissues obtained from 36 patients were subjected to immunostaining with anti-endoglin antibody, and the microvessel density (MVD) was assessed based on the number of endoglin-positive vessels. Endoglin was expressed in endothelial cells of small capillary-like vessels in pancreatic cancer tissues from all 36 patients, and lymphatic endothelial cells in the tumors also expressed endoglin. In contrast, endothelial cells of vascular and lymphatic vessels in normal pancreatic tissue did not express endoglin. Patients with a higher MVD of endoglin-positive vessels had shorter disease-free and overall survival. Endoglin is specifically expressed in endothelial cells of small vascular and lymphatic vessels in cancer tissues. The MVD of endoglin-positive vessels may also be a useful prognostic marker in pancreatic cancer patients.