Pancreatic Cancer Group Research Articles

Effect of chemotherapy and longitudinal analysis of circulating extracellular vesicle tissue factor activity in patients with pancreatic and colorectal cancer

IntroductionWe conducted a longitudinal study in patients with pancreatic and colorectal cancer. We determined the effect of chemotherapy on extracellular vesicle tissue factor (EVTF) activity and the association of plasma EVTF activity with venous thromboembolism (VTE) and survival. Material and MethodsWe enrolled 13 patients with pancreatic and 22 patients with colorectal cancer. Plasma samples were collected during the 85‐day study period. Patients were followed for 3 months after the study period. We recorded symptomatic VTE during the study period (3 months) or asymptomatic deep vein thrombosis detected by ultrasound at day 85. We measured EVTF activity before and after chemotherapy. Results and ConclusionsIn the pancreatic cancer group, 2 patients had elevated levels of EVTF activity. One of these patients developed symptomatic VTE and died, and the second patient did not have a VTE but died. Chemotherapy decreased EVTF activity in 2 pancreatic patients with high levels. In the colorectal cancer group, 4 patients developed VTE, but EVTF activity was not elevated in any patient and no patient died. We observed a borderline significant correlation between EVTF activity and D‐dimer in the patients with pancreatic but not colorectal cancer. In this small descriptive study, 2 patients with pancreatic cancer had an elevated level of EVTF activity. Both patients died during the study period, and one had a VTE. Chemotherapy decreased EVTF activity in these patients. In contrast, elevated levels of EVTF activity were not observed in patients with colorectal cancer with or without VTE.

Establishing and Coordinating a Nationwide Multidisciplinary Study Group: Lessons Learned by the Dutch Pancreatic Cancer Group.

Establishing and Coordinating a Nationwide Multidisciplinary Study Group: Lessons Learned by the Dutch Pancreatic Cancer Group.

Treatment and survival of locally advanced pancreatic cancer: A prospective multicenter cohort

Background: About 30-40% of patients with a pancreatic malignancy present with locally advanced pancreatic cancer (LAPC). Clinical outcomes are mostly described in highly selected patient cohorts. This study aims to provide an overview of treatment and survival within an unselected, consecutive cohort of patients with LAPC. Methods: Prospective multicenter study including consecutive patients with LAPC according to Dutch Pancreatic Cancer Group (DPCG) criteria between 04/2015-12/2017 from 14 centers. The decision to start treatment was based on the advice of the multidisciplinary team meeting followed by patient consultation of a medical oncologist. Restaging of CT-scans was performed by a nationwide expert panel after two months of systemic treatment. The panel evaluated response according to RECIST criteria, resectability and eligibility for clinical trials. Results: In total, 424 patients were included, of whom 326 (77%) started chemotherapy, 83 (20%) received best supportive care (BSC) and 15 (4%) started other primary treatments. Most patients started FOLFIRINOX (n=255, 78%), 31 patients (10%) were treated with gemcitabine plus nab-paclitaxel and 40 (12%) with gemcitabine monotherapy. 301 patients were restaged of whom 35 (12%) showed partial response, 216 (72%) had stable disease and 50 (17%) demonstrated progression. A total of 33/424 patients (8%) underwent a resection, of which 49% (n=16) were R0. Median overall survival (mOS) in all patients was 11 months (95%CI 10-12). In patients treated with FOLFIRINOX, gemcitabine with nab-paclitaxel, or gemcitabine monotherapy, mOS was 14 (95%CI 12-16), 10 (95%CI 8-12), and 9 months (95%CI 7-11), respectively. Resected patients had a mOS of 22 months (95%CI 14-30). Conclusion: In a national prospective cohort of LAPC, median overall survival was 11 months. 60% of patients received FOLFIRINOX treatment, and 8% underwent resection after neoadjuvant chemotherapy with promising survival. Since treatment allocation bias cannot be excluded future randomized studies are needed.

Expressions of serum miRNA-126 and miRNA-30c in patients with pancreatic cancer and their clinical significances

Objective To investigate the expressions of serum miRNA-126 (miR-126) and miRNA-30c (miR-30c) in patients with pancreatic cancer, and to analyze the relationship with the occurrence of pancreatic cancer as well as the diagnostic value. Methods A total of 110 patients with pancreatic cancer diagnosed at the 928th Hospital of the Joint Service Support Force of PLA from January 2014 to December 2018 were selected, and 110 healthy people were also selected as the control group. The expression levels of serum miR-126 and miR-30c of 110 patients and the healthy controls were detected by using real-time quantitative polymerase chain reaction (qRT-PCR), and their relationship with clinicopathological features of pancreatic cancer was analyzed. Results The levels of serum miR-126 and miR-30c in pancreatic cancer group were lower than those in the healthy control group (0.43±0.12 vs. 1.02±0.27, t = 19.394, P 0.05), but related with tumor size, differentiation degree, TNM stage and lymph node metastasis (all P < 0.05). High expression levels of serum miR-126 and miR-30c were protective factors for pancreatic cancer (all P < 0.05), while smoking, drinking and gallstones were risk factors for pancreatic cancer (all P < 0.05). The area under the curve of combined detection of serum miR-126 and miR-30c for diagnosis of pancreatic cancer was 0.906, the sensitivity was 90.80%, and the specificity was 82.20%. Conclusions The expression levels of serum miR-126 and miR-30c in patients with pancreatic cancer are low. Both of them may be involved in the occurrence and development of pancreatic cancer, and may be used as early diagnostic markers of pancreatic cancer. Key words: Pancreatic neoplasms; miRNA-126; miRNA-30c; Diagnosis

Long non-coding RNA HULC as a diagnostic and prognostic marker of pancreatic cancer.

BACKGROUNDLong non-coding RNA (lncRNA) is abnormally expressed in various malignant tumors. In recent years, it has been found that IncRNA HULC is increasingly expressed in pancreatic cancer tissues and is involved in the development and progression of pancreatic cancer. However, the clinical value of serum HULC in pancreatic cancer remains unclear, and there are few studies on how HULC regulates the biological function of pancreatic cancer cells.AIMTo determine the value of lncRNA HULC in the diagnosis and prognosis of pancreatic cancer, and its possible biological potential.METHODSSixty patients with pancreatic cancer and sixty patients with benign pancreatic diseases admitted to Xiangya Hospital, Central South University were assigned to the pancreatic cancer group and the benign disease group, respectively, and another 60 healthy subjects were enrolled as the normal group during the same period. HULC-siRNA and NC-siRNA were transfected into pancreatic cancer cells. Quantitative real-time polymerase chain reaction was performed to determine the expression of HULC in tissues, serum, and cells. Western Blot was carried out to determine the expression of β-catenin, c-myc, and cyclin D1 in cells, and the cell counting kit-8, flow cytometry, and Transwell assay were conducted to determine the proliferation, apoptosis and invasion of cells.RESULTSHighly expressed in the tissues and serum of pancreatic cancer patients, HULC showed good clinical value in distinguishing between patients with pancreatic cancer, patients with benign pancreatic diseases and healthy subjects. HULC was related to pathological parameters including tumor size, T staging, M staging and vascular invasion, and the area-under-the-curve for evaluating these four parameters was 0.844, 0.834, 0.928 and 0.818, respectively. Patients with low expression of HULC had a significantly higher 3-year overall survival (OS) and 5-year OS than those with high expression. T staging, M staging, vascular invasion, and HULC were independent prognostic factors affecting the 3-year OS of patients with pancreatic cancer. Inhibition of HULC expression prevented the proliferation and invasion of pancreatic cancer cells, promoted apoptosis, and inhibited the expression of Wnt/β-catenin signaling pathway-related proteins, β-catenin, c-myc, and cyclin D1. The Wnt/β-catenin signaling pathway agonist (LiCl) restored proliferation, apoptosis, and invasion of pancreatic cancer cells with inhibited expression of HULC.CONCLUSIONHULC is an effective marker for the diagnosis and prognosis of pancreatic cancer, which may affect the biological function of pancreatic cancer cells through the Wnt/β-catenin signaling pathway.

Hic-5 in pancreatic stellate cells affects proliferation, apoptosis, migration, invasion of pancreatic cancer cells and postoperative survival time of pancreatic cancer

Pancreatic cancer is one of the most severe types of tumors, with a 5-year survival rate of less than 7%. The prognosis and treatment of pancreatic cancer are largely limited by the extent of tumor invasion and the presence of lymph node and distant metastases. Therefore, exploring the biological behavior of pancreatic cancer cells (PCCs) is extremely important for the understanding, diagnosis, and treatment of pancreatic cancer. Current studies have shown that pancreatic stellate cells (PSCs) regulate the biological behavior of PCCs, such as their proliferation, apoptosis, invasion, and migration, by remodeling the extracellular matrix. Though Hic-5 is an important gene in PSCs, no study has investigated the regulation of PCCs by Hic-5. Here, we demonstrate that Hic-5 expression is upregulated in pancreatic cancer and that siRNA transfection can effectively inhibit Hic-5 expression. Compared to the control group, Hic-5 inhibition significantly reduced proliferation, increased apoptosis, and reduced invasion and migration of PCCs. Moreover, the inhibition of Hic-5 expression simultaneously reduced matrix metalloproteinase-9 (MMP-9) expression. Statistical analysis revealed that Hic-5 expression was higher among the pancreatic cancer group than among the normal group and was negatively correlated with postoperative survival time among patients with pancreatic cancer. These results have important clinical significance for further exploring the molecular mechanism involved in Hic-5-mediated invasion and metastasis of pancreatic cancer and ameliorating the prognosis of patients with pancreatic cancer.

Significance of IL28RA in diagnosis of early pancreatic cancer and its regulation to pancreatic cancer cells by JAK/STAT signaling pathway - effects of IL28RA on pancreatic cancer.

To explore the significance of IL28RA in diagnosis of early pancreatic cancer and its regulation to pancreatic cancer cells by the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. A total of 81 patients with early pancreatic cancer were enrolled as a pancreatic cancer group, and 81 patients with benign pancreatic diseases were enrolled as a benign disease group. Western blot was adopted to analyze the serum IL28RA expression of the two groups and its diagnostic value in early pancreatic cancer. A pancreatic cancer cell model was constructed, and the IL28RA expression in pancreatic cancer cells, PANC-1 and BXPC-3, was up-regulated to explore the biological function of pancreatic cancer cells after up-regulation of IL28RA and the effects on JAK-STAT signaling pathway. Lowly expressed in serum of patients with pancreatic cancer, IL28RA showed a sensitivity of 80.25%, specificity of 75.31%, and area under the curve (AUC) of 0.846 in diagnosis of early pancreatic cancer. It was found that up-regulation of IL28RA expression in pancreatic cancer cells inhibited proliferation and invasion abilities of pancreatic cancer cells, increased apoptosis rate and expression of pro-apoptotic protein bax, decreased expression of anti-apoptosis protein bcl-2, and significantly inhibited phosphorylation level of JAK2 and STAT3 proteins. IL28RA is lowly expressed in pancreatic cancer patients, and has certain diagnostic value for early pancreatic cancer. Its up-regulated expression can inhibit the proliferation and invasion of pancreatic cancer cells, and promote their apoptosis by inhibiting the activation of JAK-STAT signaling pathway.

International Validation of Reduced Major Morbidity After Minimally Invasive Distal Pancreatectomy Compared With Open Pancreatectomy.

To quantify the nationwide impact of minimally invasive distal pancreatectomy (MIDP) on major morbidity as compared with open distal pancreatectomy (ODP). A recent randomized controlled trial (RCT) demonstrated significant reduction in time to functional recovery after MIDP compared with ODP, but was not powered to assess potential risk reductions in major morbidity. International cohort study using the American College of Surgeons' National Quality Improvement Program (ACS-NSQIP) (88 centers; 2014-2016) to evaluate the association between surgical approach (MIDP vs ODP) and 30-day composite major morbidity (CMM; death or severe complications) with external model validation using Dutch Pancreatic Cancer Group data (17 centers; 2005-2016). Multivariable logistic regression assessed the impact of nationwide MIDP rates between 0% and 100% on postoperative CMM at conversion rates between 0% and 25%, using estimated marginal effects. A sensitivity analysis tested the impact at various scenarios and patient populations. Of 2921 ACS-NSQIP patients, 1562 (53%) underwent MIDP with 18% conversion, and 1359 (47%) underwent ODP. MIDP was independently associated with reduced CMM [odds ratio (OR) 0.50, 95% confidence interval (CI) 0.42-0.60, P < 0.001], confirmed by external model validation (n = 637, P < 0.003). The association between rising MIDP implementation rates and falling postoperative morbidity was linear between 0% (all ODP) and 100% (all MIDP). The absolute risk reduction for CMM was 11% (95% CI 7.3%-15%) at observed conversion rates and improved to 14% (95% CI 11%-18%) as conversion approached 0%. Similar effects were seen across subgroups. This international study predicted a nationwide 11% risk reduction for CMM after MIDP versus ODP, which is likely to improve as conversion rates decrease. These findings confirm secondary outcomes of the recent LEOPARD RCT.

Association between GSTT1 Homozygous Deletion and Risk of Pancreatic Cancer: A Meta Analysis.

Objective To clarify the possible association of GSTT1 homozygous deletion with the susceptibility to pancreatic cancer. Methods We searched PubMed database, Chinese Journal Full Text Database (CNKI), and EMBASE to find the eligible studies published up to April 18, 2018 for evaluating the relationship between GSTT1 homozygous deletion and pancreatic cancer. The frequency of null genotype for GSTT1 between the pancreatic cancer group and the healthy control group was compared with Chi-square test, and odds ratios (ORs) value and 95% confidence interval (95% CI) were calculated. Results A total of 9 studies met the inclusion criteria, and 5952 cases consisting of 2387 pancreatic cancer patients and 3565 healthy controls were included in the meta analysis. Compared with the control group, frequency of null genotype for GSTT1 in the pancreatic cancer group was higher (33.4% vs. 38.7%, OR = 1.26, 95%CI = 1.01-1.58, P = 0.04). Conclusion GSTT1 homozygous deletion individuals may have higher susceptibility to pancreatic cancer.

Combined detection of CA19-9 and B7-H4 in the diagnosis and prognosis of pancreatic cancer.

There were no specific indicators for the early detection of pancreatic cancer. To analyze the diagnostic and prognostic value of CA19-9 plus B7-H4 detection in preoperative serum or surgical tissues of patients with pancreatic cancer. One hundred and eighty-eight patients with pancreatic cancer and 25 controls were recruited. Their preoperative serum CA19-9 level was detected chemiluminescently, and B7-H4 expression in pancreatic cancer tissues was assessed immunohistochemically. The diagnostic and prognostic utility of detecting CA19-9, B7-H4 and their combination was evaluated. CA19-9 and B7-H4 levels were significantly upregulated in patients with pancreatic cancer compared with those in controls. The diagnostic value of combined CA19-9 plus B7-H4 detection was markedly better than that achieved from their separate detection analyzed with receiver operating characteristic curve. Sensitivity and specificity of the combined detection in the pancreatic cancer group was significantly increased compared with single detection. B7-H4 detection showed better prognostic value than detection of CA19-9. However, CA19-9 had high sensitivity and low specificity, while B7-H4 showed the opposite. The sensitivity of the combined prognosis was not significantly different to B7-H4 alone. The combined detection of CA19-9 and B7-H4 could become a new method for the clinical diagnosis and prognosis of pancreatic cancer.

Evaluation of fatty pancreas by proton density fat fraction using 3-T magnetic resonance imaging and its association with pancreatic cancer

PurposeTo evaluate whether pancreatic magnetic resonance imaging-proton density fat fraction (MRI-PDFF) correlates with histological pancreatic fat fraction and its possible usefulness as a biomarker of pancreatic cancer compared with pancreatic index (PI) using computed tomography (CT number of the pancreas divided by that of the spleen). MethodWe included 55 consecutive patients (24 with pancreatic cancer and 31 controls; median age, 72 years) who preoperatively underwent MRI-PDFF using IDEAL-IQ and unenhanced CT and did not receive preoperative therapy. Histologic pancreatic fat fraction was measured in non-tumorous pancreatic tissues at the resection stump. A board-certified radiologist evaluated MRI-PDFF and PI. Correlations were evaluated among MRI-PDFF, PI, and histologic pancreatic fat fraction; the usefulness of MRI-PDFF as a predictor of pancreatic cancer was assessed. ResultsHistologic pancreatic fat fraction significantly correlated with MRI-PDFF and PI (r = 0.802 and −0.534, respectively; P < 0.01). The absolute correlation coefficient was significantly higher for MRI-PDFF than for PI (P < 0.01). Compared with the control group, the pancreatic cancer group had higher MRI-PDFF and histologic pancreatic fat fraction (P < 0.01) but lower PI (P < 0.01). In multivariate analysis, MRI-PDFF was found to be the sole independent risk factor for pancreatic cancer (odds ratio: 1.19; P < 0.01). ConclusionsPancreatic fat, which was associated with pancreatic cancer, could be quantified by MRI-PDFF measurement; therefore, MRI-PDFF should be considered as a promising and superior imaging biomarker for estimating the probability of pancreatic cancer than PI.

Technique and audited outcomes of laparoscopic distal pancreatectomy combining the clockwise approach, progressive stepwise compression technique, and staple line reinforcement

Laparoscopic distal pancreatectomy (LDP) has proven advantages over its open counterpart and is becoming more frequently performed around the world. It still remains a difficult operation due to the retroperitoneal location of the pancreas and limited experience and training with the procedure. In addition, complications such as bleeding or postoperative pancreatic fistula (POPF) remain a problem. A standardized approach to LDP with stepwise graded compression technique for pancreatic transection has been utilized at a single center, and we sought to describe the technique and determine the outcomes. A review of all patients undergoing LDP by a clockwise approach including the graded compression technique from August 1, 2008 to December 31, 2017 was performed. An external audit was performed by the Dutch Pancreatic Cancer Group. Overall, 260 patients with a mean age and a BMI of 62.3 and 28, respectively, underwent LDP using this technique. Mean operative time and blood loss were 183min and 248mL, respectively,. Hand-assisted method and conversion to open were both 5%. Major morbidity and mortality were 9.2% and 0.4%, respectively,. POPF was noted in 8.1%. The technical steps include (1) mobilization of the splenic flexure of the colon and exposure of the pancreas, (2) dissection along the inferior edge of the pancreas and choosing the site for pancreatic division, (3) pancreatic parenchymal division using a progressive stepwise compression technique with staple line reinforcement, (4) ligation of the splenic vein and artery, (5) dissection along the superior edge of the pancreas and residual posterior attachments, and (6) mobilization of the spleen and specimen removal. LDP with a clockwise approach for dissection, combined with the progressive stepwise compression technique for pancreatic transection, resulted in excellent outcomes including a very low POPF rate.

Trefoil factor(s) and CA19.9: A promising panel for early detection of pancreatic cancer.

BackgroundTrefoil factors (TFF1, TFF2, and TFF3) are small secretory molecules that recently have gained significant attention in multiple studies as an integral component of pancreatic cancer (PC) subtype-specific gene signature. Here, we comprehensively investigated the diagnostic potential of all the member of trefoil family, i.e., TFF1, TFF2, and TFF3 in combination with CA19.9 for detection of PC.MethodsTrefoil factors (TFFs) gene expression was analyzed in publicly available cancer genome datasets, followed by assessment of their expression in genetically engineered spontaneous mouse model (GEM) of PC (KrasG12D; Pdx1-Cre (KC)) and in human tissue microarray consisting of normal pancreas adjacent to tumor (NAT), precursor lesions (PanIN), and various pathological grades of PC by immunohistochemistry (IHC). Serum TFFs and CA19.9 levels were evaluated via ELISA in comprehensive sample set (n = 362) comprised of independent training and validation sets each containing benign controls (BC), chronic pancreatitis (CP), and various stages of PC. Univariate and multivariate logistic regression and receiver operating characteristic curves (ROC) were used to examine their diagnostic potential both alone and in combination with CA19.9.FindingsThe publicly available datasets and expression analysis revealed significant increased expression of TFF1, TFF2, and TFF3 in human PanINs and PC tissues. Assessment of KC mouse model also suggested upregulated expression of TFFs in PanIN lesions and early stage of PC. In serum analyses studies, TFF1 and TFF2 were significantly elevated in early stages of PC in comparison to benign and CP control group while significant elevation in TFF3 levels were observed in CP group with no further elevation in its level in early stage PC group. In receiver operating curve (ROC) analyses, combination of TFFs with CA19.9 emerged as promising panel for discriminating early stage of PC (EPC) from BC (AUCTFF1+TFF2+TFF3+CA19.9 = 0.93) as well as CP (AUCTFF1+TFF2+TFF3+CA19.9 = 0.93). Notably, at 90% specificity (desired for blood-based biomarker panel), TFFs combination improved CA19.9 sensitivity by 10% and 25% to differentiate EPC from BC and CP respectively. In an independent blinded validation set, the combination of TFFs and CA19.9 (AUCTFF1+TFF2+TFF3+CA19.9 = 0.82) also improved the overall efficacy of CA19.9 (AUCCA19.9 = 0.66) to differentiate EPC from CP proving unique biomarker capabilities of TFFs to distinguish early stage of this deadly lethal disease.InterpretationIn silico, tissue and serum analyses validated significantly increased level of all TFFs in precursor lesions and early stages of PC. The combination of TFFs enhanced sensitivity and specificity of CA19.9 to discriminate early stage of PC from benign control and chronic pancreatitis groups.

Association between small intestinal bacterial overgrowth and toll-like receptor 4 in patients with pancreatic carcinoma and cholangiocarcinoma

Multiple factors have been linked to pathogenesis of pancreatic cancer and cholangiocarcinoma. Until now, few studies have investigated the role of small intestinal bacterial overgrowth (SIBO) and toll-like receptor 4 (TLR-4) signaling in these diseases. This study aimed to examine the relationship between the prevalence of SIBO and the TLR-4 expression in patients with pancreatic carcinoma and cholangiocarcinoma. A total of 90 human subjects suffering from pancreatic carcinoma (n=30), cholangiocarcinoma (n=30), and healthy controls (n=30) were enrolled in the study. A glucose hydrogen breath test (GHBT) was used to evaluate SIBO. The TLR4 protein expression was measured by immunohistochemistry (IHC). The positive rate of SIBO was 63.3% in the pancreatic cancer group and 46.7% in patients with cholangiocarcinoma, which was significantly greater than 13.3% in the healthy control group (p<0.05). An IHC analysis revealed that the TLR-4 protein expression in the SIBO-positive pancreatic carcinoma patients was significantly higher than that in the SIBO-negative patients (p<0.05), and the same result was in the cholangiocarcinoma subjects. In addition, a correlation analysis identified the positive relationship between the prevalence of SIBO and the TLR-4 protein expression in pancreatic carcinoma (r=0.489), and the same result was in the cholangiocarcinoma subjects. Our findings indicate a high prevalence of SIBO in pancreatic carcinoma and cholangiocarcinoma, and SIBO displays a positive correlation with the TLR-4 expression, suggesting that SIBO could be a risk factor for the pathogenesis of pancreatic carcinoma and cholangiocarcinoma, in which the TLR4 signaling may be involved.

Clinical significance of exosomal miR-1231 in pancreatic cancer

Objective: To investigate the expression and clinical significance of exosomal miR-1231 in plasma of pancreatic cancer (PC) patients and pancreatic cancer cells. Methods: A total of 16 patients who were diagnosed with pancreatic cancer in Hunan Cancer Hospital were collected from April 2016 to August 2017. Meanwhile, 16 healthy volunteers were recruited as the healthy control group at the same period. The plasma exosomes were extracted, and the levels of miR-1231 were detected by qRT-PCR in PC and healthy control groups. Moreover, the clinicopathological significance of exosomal miR-1231 expression was analyzed. Furthermore, the expression of exosomal miR-1231 was detected in several pancreatic cancer cells (MIA PaCa-2, PANC-1, SW1990, AsPC-1 and BxPc-3) and two normal pancreatic epithelial cells (HPDE and human primary pancreatic epithelial cell). Results: qRT-PCR results showed that the expression level of miR-1231 in plasma exosomes of pancreatic cancer patients (1.06±0.46) was significantly lower than that in healthy controls (2.30±0.99; P<0.05). The levels of exosomal miR-1231 in patients with stage Ⅰ-Ⅱ (1.515±0.531), no distant metastasis (1.236±0.461) and no lymph node metastasis (1.337±0.522) were significantly higher than those with stage Ⅲ-Ⅳ (0.848±0.224), distant metastasis (0.757±0.278) and lymph node metastasis (0.838±0.261), respectively (P<0.05 for all). In addition, there were no correlation between exosomal miR-1231 expression and age, sex, smoking history, CA19-9 levels and tumor sites (P>0.05). Furthermore, the expression level of exosomal miR-1231 in pancreatic cancer cell lines (0.142±0.135) was significantly lower than that in normal epithelial cells (1.127±0.179; P<0.05). Conclusions: The downregulation of exosomal miR-1231 in plasma of pancreatic cancer patients and pancreatic cancer cells suggests that it is related to the initiation and development of PC. It may be a new diagnostic and prognostic marker for PC.

A Comprehensive Proteome Analysis of Peripheral Blood Mononuclear Cells (PBMCs) to Identify Candidate Biomarkers of Pancreatic Cancer.

Pancreatic cancer (PC) is currently the fourth leading cause of cancer-related mortality worldwide. Peripheral blood mononuclear cells (PBMCs) is a subpopulation of accessible and functional immune cells. Comparative analysis of the proteome of PBMCs can help us elucidate the mechanism of disease and find potential biomarkers for diagnosis. PBMCs were collected from healthy individuals, patients with benign diseases, and pancreatic cancer. iTRAQ-2DLC-MS/MS and SWATH methodologies were applied to make a comparative proteomics analysis of PBMCs. A total of 3,357 proteins with a false discovery rate (FDR) <1% were identified, of which 114 proteins were found dysregulated in the PC group. An extensive SWATH library was constructed which showed a potential application for large scale clinical sample analysis. A PBMCs proteome with extensive protein representation was achieved, which will potentially allow the identification of novel biomarkers for PC.

Characteristics of postoperative pancreatic fistula on abdominal CT: a multicenter cohort study

Introduction: Pancreatic fistula is a potentially severe complication after pancreatic resection. Our aim was to describe the characteristics of clinically relevant postoperative pancreatic fistula on abdominal imaging Methods: Consecutive patients undergoing computed tomography (CT) scan for (suspected) pancreatic fistula after pancreatoduodenectomy in 2015–2016 in 4 centres of the Dutch Pancreatic Cancer Group were included. Scans were systematically re-evaluated by two expert radiologists according to a predefined form. Scans were considered positive for clinically relevant pancreatic fistula when followed by an invasive intervention for pancreatic fistula, an intensive care unit admission or death due to abdominal sepsis. Results: This preliminary analysis included outcomes of 213 scans performed in 150 patients: 72 scans were positive and 141 scans were negative for clinically relevant pancreatic fistula. The pancreatic anastomosis was dehiscent in 38/72 positive and 51/141 negative scans (53% vs. 36%; P=0,03; positive predictive value [PPV]0.42, negative predictive value [NPV]0.72). Fluid in direct contact to the pancreatic anastomosis was seen in 57/72 positive and 94/141 negative scans (80% vs. 67%; P=0.06; PPV0.38; NPV0.76), these collections contained gas in 40/57 positive and 52/94 negative scans (70% vs. 55%; P=0.10; PPV0.43; NPV0.70). Conclusion: Characteristics of clinically relevant pancreatic fistula after pancreatoduodenectomy include dehiscence of the pancreatic anastomosis and fluid in direct contact to the anastomosis containing gas, although diagnostic accuracy of these individual variables is low. Further analysis will be focused on combining radiological and clinical data to ultimately create a model for early identification of patients with clinically relevant postoperative pancreatic fistula.

Predicting successful catheter drainage in patients with severe pancreatic fistula after pancreatoduodenectomy: a multicenter cohort study

Introduction: Catheter drainage appears to be superior to relaparotomy in the management of postoperative pancreatic fistula, but is not successful in all patients. The aim of this study is create a prognostic model for successful catheter drainage in patients with pancreatic fistula after pancreatoduodenectomy. Methods: This is multicenter cohort study on patients undergoing catheter drainage as first intervention for pancreatic fistula after pancreatoduodenectomy (January 2005 to September 2013) in 9 Dutch Pancreatic Cancer Group centers. Possible prognostic factors for successful catheter drainage (i.e. survival without relaparotomy) were evaluated using logistic regression and selected using the Akaike Information Criterion. The model was internally validated and definitive predictors were combined in a nomogram. Results: Of 2196 patients undergoing pancreatoduodenectomy, catheter drainage was the first intervention for pancreatic fistula in 227 patients. Primary catheter drainage was successful in 175/227 patients (77%). Multivariable logistic regression revealed the following negative prognostic factors for success: male sex (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.21-1.00, P=0.049), higher age (for every 5 years over 50; OR0.69 95%CI0.57-0.84; P< 0.001) and respiratory failure in 24h before catheter drainage (OR0.10, 95%CI0.03-0.33, P< 0.001). A prognostic model incorporating these factors yielded an c-statistic of 0.76. The prognostic nomogram demonstrated a success range from 98-14%. Conclusions: Male sex, higher age and respiratory failure are negative prognostic factors for successful catheter drainage in patients with pancreatic fistula after pancreatoduodenectomy. Future prospective trials should determine whether early detection and management of pancreatic fistula can prevent respiratory failure and ultimately improve clinical outcome.

Mo1346 THERAPEUTIC EFFECTS OF ENDOSCOPIC ULTRASOUND-GUIDED CELIAC NEUROLYSIS (EUS-CPN) IN PATIENTS WITH UPPER ABDOMINAL-ASSOCIATED PAIN (UAP)

EUS-CPN has been shown to have a therapeutic effect on pancreatic cancer (PC) pain. However, little information is available about the use of EUS-CPN for UAP arising from non-pancreatic forms of cancer (nPC). The objective of the study was to compare the efficacy and safety of EUS-CPN in patients with PC and those with nPC. Clinical information was obtained retrospectively from the medical records and endoscopy reporting system. The follow-up period was until the patient died or was lost to follow-up. Patients were excluded from the study if they died or were lost to follow-up within 2 weeks of undergoing EUS-CPN. Patients who underwent biliary drainage within 1week before or after EUS-CPN were also excluded. Between November 2014 and October 2017, 80 patients were enrolled (PC: 68, nPC: 12). The nPC classifications were 6 bile duct cancer (CA) patients, 1 gastric CA patient, 2 colon CA patients, 1 germ cell tumors patient, 1 gallbladder CA patient, and 1 esophageal CA patient. We used the same EUS-CPN method in both groups: 5 mL of bupivacaine mixed with 15 mL of pure ethanol was injected into the celiac plexus and superior mesenteric plexus with or without ganglion ablation using a 22G endoscopic ultrasound-guided fine needle aspiration needle. The amount of narcotic analgesics consumption was converted into morphine dosage level. Treatment response was defined by the patients rational symptoms and the amount of morphine consumption. Treatment response using morphine was defined as a decreased or stable amount of morphine consumption after EUS-CPN. If morphine consumption was temporarily elevated within 2 weeks after the procedure because of the delayed response of EUS-CPN but achieved a stable dosage level for 4 weeks after elevation, it was defined treatment response. The overall response rate (RR) was 72.5% (58/80) in all patients. The median duration of pain relief was 4.6 months. Temporary diarrhea (16/80, 20.0%), low blood pressure (14/80, 17.5%) and tachycardia (4/80, 5.0%) were seen after the procedure but self-limited. The RR did not differ between the PC and nPC groups (73.5% vs. 66.7%, p=0.63). The median duration of response was 4.6 months for both. Diarrhea was significantly more frequent in nPC (41.6% vs. 16.1%, p=0.04). As for the patient characteristics, nPC had a larger percentage of lymph node metastasis around the celiac plexus (100% vs. 57.4%, p<0.01). EUS-CPN had a similar therapeutic effect on intractable UAP on PC and nPC patients in our study. There is a possibility that EUS-CPN can become a useful approach for pain relief in nPC patients with UAP. Although more cases are needed to assess the potential long-term benefits of EUS-CPN in this patient population.

Characterization of the duodenal bacterial microbiota in patients with pancreatic head cancer vs. healthy controls

An increasing number of reports have demonstrated that there is an association between the presence of pathogenic microorganisms and pancreatic cancer. However, the role of the duodenal microbiota in pancreatic carcinogenesis remains unknown. In this study, duodenal mucosal microbiota was analyzed in 14 patients with pancreatic head cancer and 14 healthy controls using 16S rRNA gene pyrosequencing methods. Plasma endotoxin activity and the concentrations of the proinflammatory cytokine IL-6 and C-reactive protein (CRP) were measured in blood samples. The urea breath test was used to detect Helicobacter pylori infections. Endoscopic duodenal mucosal biopsies were evaluated by histological examinations. Statistical comparisons of inflammatory factors revealed significantly higher levels of CRP and IL-6 in the pancreatic cancer group as compared to healthy controls. Patients with pancreatic cancer also had a higher incidence of H. pylori infections and showed mucosal changes, including villous abnormalities and diffuse inflammatory cell infiltration in the lamina propria. The sequences analysis showed that based on linear discriminant analysis effect size (LEfSe) analysis at the genus level, Acinetobacter, Aquabacterium, Oceanobacillus, Rahnella, Massilia, Delftia, Deinococcus, and Sphingobium were more abundant in the duodenal mucosa of pancreatic cancer patients, whereas the duodenal microbiotas of healthy controls were enriched with Porphyromonas, Paenibacillus, Enhydrobacter, Escherichia, Shigella, and Pseudomonas. These results reveal a picture of duodenal microbiota in pancreatic head cancer patients that could be useful in future trials investigating the role of gut microbiota in pancreatic cancer.