Outcomes In Pancreatic Ductal Adenocarcinoma Patients Research Articles

Abstract 4162: The identification of biomarker for the early diagnosis of IPMN associated PDAC based on serum protein profiling

Abstract Background: Most of pancreatic cancer patients are diagnosed at late stage due to the inability of early diagnosis for pancreatic ductal adenocarcinoma (PDAC), finally leading to a very high mortality. Therefore the identification of effective biomarkers for the early diagnosis of PDAC has a critical significance for improving the outcome of PDAC patients at early stage. Up to 15% of PDACs are thought to come from Mucinous pancreatic cysts, most of which belong to intraductal papillary mucinous neoplasm (IPMN). Consequently, screening and detecting high-risk IPMN patients at early stage by potential biomarkers can help a lot to prevent these patients from developing into invasive PDAC at late stage. Methods: We collected 38 normal serum sample as control and 243 IPMN serum samples with different progression stages including 83 adenomas, 73 borderlines, 40 carcinoma in situs and 47 invasive carcinomas. Then we performed antibody microarray experiment on all serum samples and implemented data analysis on serum protein profiling by R programming. After that, we divided the protein expression data into discovery set and validation set. With data pre-progressing, quality control, differential expression analysis and feature selection, we screened some protein panels for the construction of diagnostic model including logistic regression (LR) model and support vector machine (SVM) model based on discovery set. Finally, we further confirmed the diagnostic performance of these protein panels on IPMN associated PDAC based on validation set. Results: By data analysis, we finally constructed a stepwise diagnostic model of IPMN associated PDAC based on 11 protein panels with high sensitivity and specificity. For example, protein panel 1 containing 2 proteins can separate the normal and IPMN at all stages with sensitivity of 0.988 and specificity of 0.946 by SVM model; protein panel 2 containing 15 proteins can separate invasive carcinoma and non invasive carcinoma (adenoma, borderline and carcinoma in situ) with AUC of 0.99 by LR model; protein panel 3 containing 16 proteins can specifically separate invasive carcinoma from the normal with AUC of 0.978 by SVM model; protein panel 4 containing 8 proteins can specifically separate serum samples at early stages (adenoma and borderline) from the normal with AUC of 0.969 by SVM model, which is useful for the early diagnosis of IPMN associated PDAC; protein panel 5 containing 7 proteins can specifically separate serum samples at early-middle stage (adenoma, borderline and carcinoma in situ) from the normal with AUC of 0.987 by SVM model. In summary, this comprehensive diagnostic model can effectively accomplish IPMN serum samples classification for different tumor stages with high accuracy. Further validation on these protein panels with more IPMN serum samples by ELISA is in progress. Citation Format: Chaoyang Zhang, Mohamed Alhamdani, Andrea Bauer, Li Peng, Jörg Hoheisel. The identification of biomarker for the early diagnosis of IPMN associated PDAC based on serum protein profiling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4162.

Loss of Wasl improves pancreatic cancer outcome.

Several studies have suggested an oncogenic role for the neural Wiskott-Aldrich syndrome protein (N-WASP, encoded by the Wasl gene), but thus far, little is known about its function in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed in silico analysis of WASL expression in PDAC patients and found a correlation between low WASL expression and prolonged survival. To clarify the role of Wasl in pancreatic carcinogenesis, we used 2 oncogenic Kras-based PDAC mouse models with pancreas-specific Wasl deletion. In line with human data, both mouse models had an increased survival benefit due to either impaired tumor development in the presence of the tumor suppressor Trp53 or the delayed tumor progression and senescent phenotype upon genetic ablation of Trp53. Mechanistically, loss of Wasl resulted in cell-autonomous senescence through displacement of the N-WASP binding partners WASP-interacting protein (WIP) and p120ctn; vesicular accumulation of GSK3β, as well as YAP1 and phosphorylated β-catenin, which are components of the destruction complex; and upregulation of Cdkn1a(p21), a master regulator of senescence. Our findings, thus, indicate that Wasl functions in an oncogenic manner in PDAC by promoting the deregulation of the p120-catenin/β-catenin/p21 pathway. Therefore, strategies to reduce N-WASP activity might improve the survival outcomes of PDAC patients.

The landscape of immune cell infiltration and its clinical implications of pancreatic ductal adenocarcinoma

The details of the immunological microenvironment and its clinical implications for pancreatic cancer are still unclear. In this study, we obtained data from public databases, such as the Gene Expression Omnibus, the Cancer Genome Atlas Program, the International Cancer Genome Consortium Data Portal, the ArrayExpress Data Warehouse, and the cBioPortal for Cancer Genomics. We used these data to evaluate the pattern of immune cells infiltration in pancreatic ductal adenocarcinoma (PDAC) tissues. We observed that the levels of M0 macrophages and activated dendritic cells in tumor tissues were significantly higher than that in para-tumor tissues. M0 macrophages, gamma delta T cells and naive CD4 T cells were independent predictive factors of a poor outcome for PDAC patients. An immune score determined by M0 macrophages, gamma delta T cells and naive CD4 T cells could predict the survival of patients. The results of this study suggest that the infiltration of immune cells, such as M0 macrophages, may be a possible target for the treatment of PDAC. However, these findings need to be confirmed by additional studies.

Association of ABO blood group with survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma

BackgroundExisting research suggests patients with blood group O are less likely to develop pancreatic ductal adenocarcinoma (PDAC) compared to those with non-O blood groups, and that survival from PDAC may be affected by ABO blood type. This study assessed survival outcomes in PDAC patients who underwent pancreatoduodenectomy (PD) in one health system. MethodsFrom 2010 to 2017, demographic, operative, chemotherapy and survival data for patients undergoing PD at Emory Healthcare were reviewed. Patients with blood type AB were excluded due to small sample size. The relationship between ABO blood group and survival was analyzed using Kaplan–Meier survival curves and multivariate cox proportional regression analysis. ResultsOf 449 PDAC patients assessed, 204 (45.4%), 60 (13.4%) and 185 (41.2%) were blood groups A, B and O, respectively. Patients were well matched in clinicopathologic characteristics. Median survival did not differ by blood group (p = 0.82), and this relationship remained insignificant on cox regression analysis (p = 0.15). On multivariate analysis, lymph node positivity (p < 0.001) and increasing age (p = 0.001) were associated with reduced survival. ConclusionIn contrast to recent reports, this larger study found that blood group did not impact overall survival among patients undergoing PD for PDAC.

Changes in glucose tolerance after pancreatectomy in patients with pancreatic ductal adenocarcinoma.

668 Background: Diabetes mellitus (DM) is reported to be related to pancreatic ductal adenocarcinoma (PDAC). Long-standing DM is a risk factor for PDAC, meanwhile, quite a few patients with PDAC develop DM as a paraneoplastic disorder and some papers reported that DM affected prognosis for PDAC. In this study, we investigated pre- and post-operative glucose tolerance in patients with pancreatectomy for PDAC or other disease. Methods: This single-center prospective study included 69 patients with pancreatectomy (40 pancreaticoduodenectomy (PD) and 29 distal pancreatectomy (DP) ) who received 75-g oral glucose tolerance test (OGTT) and glucagon test pre- and one month postoperatively. Plasma glucose, insulin, and C-peptide (CPR) at 0-, 30-, 60-, and 120-min during OGTT; and 0- and 6-min during glucagon test were obtained. These data and survival outcomes were analyzed. Results: There were 20 (29%) PDAC patients: 12 (30%) in PD group and eight (28%) in DP group. Nine patients with PDAC (45%) and seven patients (18%) without PDAC demonstrated DM type in preoperative OGTT. After pancreatectomy, 11 patients (55%) with PDAC and seven patients (15%) without PDAC experienced improvement in OGTT (P=0.0005). Greater improvement in homeostasis model assessment insulin resistance that were obtained by OGTT and used to measure insulin resistance, was noted after surgery in PDAC patients compared with non-PDAC patients (-1.4 vs -0.5 in PD group, P=0.07; -0.8 vs +0.06 P=0.05 in DP group). Delta CPRs obtained by glucagon test were significantly decreased postoperatively (3.0 to 1.1 ng/mL, P&lt;0.0001 in PD group; 3.3 to 1.8 ng/mL, P&lt;0.0001 in DP group). In survival analysis, fasting plasma glucose &gt;110 mg/dL (HR 3.9, 95%CI 1.5-10, P=0.005) and the average of plasma insulin &gt; 25 µIU/mL during OGTT (HR 0.36, 95%CI 0.14-0.93, P=0.035) were significant prognostic factor for PDAC. Conclusions: Pancreatectomy impaired insulin secretion and improve insulin resistance especially in PDAC patients. About half of PDAC patients demonstrated the improvement of glucose tolerance after surgery. Of note, glucose tolerance differed between PDAC and other disease, and affect the survival outcome for PDAC patients.

Aspartate \u03b2-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway

BackgroundSignaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate β-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis.MethodsTo demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH’s β-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models.ResultsASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial–mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0–2 (n = 4), 3–5 (n = 8), 6–8 (n = 24), and 9–12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001).ConclusionTargeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

MCOLN1 Promotes Proliferation and Predicts Poor Survival of Patients with Pancreatic Ductal Adenocarcinoma.

Background MCOLN1 (mucolipin subfamily, member 1) was first identified as an autophagic regulator, which was essential for efficient fusion of both autophagosomes and late endosomes with lysosomes. This study is aimed at investigating the role of MCOLN1 in the development of pancreatic ductal adenocarcinoma (PDAC). Methods Immunohistochemistry (IHC) assay was conducted to evaluate the expression level of MCOLN1 in 82 human PDAC tumor tissues. Overall survival (OS) and recurrence-free survival (RFS) analysis was performed to assess the prognosis of patients. Colony formation and MTT assays [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] were performed to measure the proliferation capacity of tumor cells. The expression level of related genes was measured by RT-PCR (reverse transcription polymerase chain reaction) and western blot assays. The animal model was used to examine the effects of indicated protein on tumorigenesis in vivo. Results The results of IHC showed that a high level of MCOLN1 expression was associated with the poor clinical characteristics of PDAC patients. OS and RFS were significantly worse in patients with high MCOLN1 expression. Silencing of MCOLN1 dramatically blocked the proliferation of PDAC cells. Mechanism studies confirmed that knockdown of MCOLN1 decreased the expression of Ki67 and PCNA (proliferating cell nuclear antigen), two markers of cell proliferation. In vivo, MCOILN1 depletion reduced the formation and growth of tumors in mice. Conclusion The high level of MCOLN1 expression was associated with poor clinical outcomes of PDAC patients. MCOLN1 ablation could inhibit PDAC proliferation of both in vitro and in vivo, which provide a new insight and novel therapeutic target for the treatment of PDAC.

Abstract 2579: Genomewide transcriptomic profiling identifies a novel miRNA signature for predicting lymph node metastasis in patients with pancreatic ductal adenocarcinoma

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer, and is projected to become the second leading cause of cancer-related deaths in the US by 2030. The lymph node (LN) status is an important predictor of survival outcomes in PDAC patients undergoing curative resection. The National Comprehensive Cancer Network guidelines recommend neoadjuvant therapy in patients with high-risk features such as large regional LNs, elevated CA-19-9 levels, large primary tumors, excessive weight loss, and extreme pain. Therefore, a pre-treatment diagnosis of LN metastasis (LNM) is critical in developing a more personalized treatment strategy in PDAC patients. Herein, for the first time, we performed a genomewide analysis to identify and develop a miRNA signature for the detection of LNM in PDAC patients. Methods: We analyzed a total of 518 PDAC patients, which included 269 patients from three genomewide miRNA-expression datasets (TCGA, GSE24279 and GSE35688) and 249 from two, independent clinical patient cohorts. During the biomarker discovery phase, we used rigorous computational and bioinformatic approaches to identify candidate miRNA biomarkers, which later were subjected to in-silico validations. The robustness and performance of this miRNA-signature was subsequently interrogated in two independent clinical cohorts (training cohort: n=150, validation cohort: n=99) using qRT-PCR assays. Furthermore, the clinical potential value of the miRNA signature was evaluated and compared to several clinicopathological factors using logistic regression analysis. Results: Through a comprehensive miRNA expression profiling analysis of LNM-positive and negative patients, we identified a panel of 7 miRNAs that significantly predicted LNM [the area under curve (AUC)=0.76, 0.75 and 0.92, respectively]. Using logistic regression analysis, we then optimized and trained a 6-miRNA risk-prediction model in the training cohort of patients, which robustly distinguished PDAC patients with LNM (AUC: 0.84, 95%CI: 0.76-0.89). The performance of this trained model was subsequently confirmed in an independent, large clinical validation cohort (AUC: 0.73, 95%CI: 0.64-0.82). Interestingly, multivariate analysis which incorporated several pre-operative clinical factors, revealed that our 6-miRNA signature was as an independent predictor of LNM in both patient cohorts (training cohort: OR=34.97; P&amp;lt;0.01, validation cohort: OR=10.11; P&amp;lt;0.01, respectively). Conclusion: We identified and developed a novel 6-miRNA signature that is highly robust in predicting presence of LNM in PDAC patients; highlighting the clinical impact of these findings in more appropriate patient selection and development of improved individualized treatment strategies for PDAC patients. Citation Format: Satoshi Nishiwada, Kensuke Yamamura, Raju Kandimalla, Takahiro Akahori, Kota Nakamura, Hideo Baba, Masayuki Sho, Ajay Goel. Genomewide transcriptomic profiling identifies a novel miRNA signature for predicting lymph node metastasis in patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2579.

Association of pancreatic cancer stem cells with tumor stroma type.

e15771 Background: Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease with distinct stroma features. Cancer stem cells (CSC) in PDA may express CD44 (C) +/- Epithelial Specific Antigen (E). We investigated the relationship of CSC markers with tumor stroma and clinical outcomes in PDA patients (pts) who had surgical resection. Methods: Pts who underwent PDA resection with IRB #00-032/#06-107 consent between 01/2012-06/2014 at Memorial Sloan Kettering were identified. C and E immunohistochemical (IHC) expression scored as follow: 0, none; 1, 1%–10%; 2, 11%–50%; 3, 51%–80%; 4, 81%–100%. Staining intensity was scored as 0, none; 1, weak; 2, moderate; 3, strong. The total scores (0-12) were averaged and was considered positive when average score &gt; median. Stroma was classified as loose, moderate and dense based on fibroblast content using H&amp;E stain. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier and compared by log-rank test; association between CSC markers and stroma type was assessed by Fisher`s exact test. Results: N = 93 PDA pts identified. PDA with C(+) E(-) had significantly higher loose stroma and PDA with C(-) E(+) and C(-) E(-) had more moderate and dense stroma (p = 0.0033). The number of PDA pts with dense, moderate, and loose stroma was: 11, 31, and 51 respectively. No local recurrence in pts with dense stroma observed and 8/11 had either lung or liver recurrence. Six of 31pts with loose stroma had a local recurrence and 13/31 pts had either liver or lung recurrence. No statistically significant difference in OS and RFS were observed among subgroups (P = 0.089). Median time from relapse to death was: 2, 11.5, 10,5 and months 7 in C+/E-, C-/E+, C+/E+, and C-/E- groups respectively. Conclusions: PDA CSCs appears to have an association with PDA stroma type. We also observed different recurrence patterns among stroma subgroups. Respecting small sample size, these data indicate CSCs may have an important role in stroma differentiation in PDA. CSC markers do not predict OS and RFS, however, resected PDA with C(+) E(-) may have more aggressive behavior following recurrence. [Table: see text]

The systemic inflammation response index predicts survival and recurrence in patients with resectable pancreatic ductal adenocarcinoma.

Purpose: The systemic inflammation response index (SIRI), based on peripheral neutrophil, monocyte, and lymphocyte counts, was recently emerged and used as a novel tool in predicting prognosis in different types of cancer. Our aim was to investigate the clinical significance of preoperative SIRI in patients with resectable pancreatic ductal adenocarcinoma (PDAC).Materials and methods: The SIRI was developed in a training cohort of 371 PDAC patients undergoing radical surgery between 2010 and 2013 and validated in a validation cohort of 310 patients from 2014 to 2015. Baseline clinicopathologic characteristics, preoperative laboratory parameters and follow-up information were collected. The optimal cutoff value of SIRI was determined by receiver operating characteristic curve. Univariate and multivariate analysis were performed to analyze the prognostic value of SIRI.Results: The optimal cutoff value of SIRI stratified patients into low SIRI group (≤0.69) and high SIRI group (>0.69). Survival analysis showed that the median overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients with low SIRI. The SIRI was an independent predictor of OS and RFS in multivariate analysis. In addition, SIRI remained its prognostic significance both in patients with early-stage diseases and in patients with normal carbohydrate antigen 19-9 levels. High SIRI indicated poor treatment response for patients who received postoperative adjuvant chemotherapy.Conclusion: Preoperative SIRI was an independent prognostic indicator of poor outcomes in PDAC patients after radical resection. It might assist clinicians to identify high-risk patients and choose the optimal individualized treatment strategy.

The oncological safety in minimally invasive versus open distal pancreatectomy for pancreatic ductal adenocarcinoma: a systematic review and meta-analysis

The safety of minimally invasive distal pancreatectomy (MIDP) and open distal pancreatectomy (ODP) regarding oncological outcomes of pancreatic ductal adenocarcinoma (PDAC) remains inconclusive. Therefore, the aim of this study was to examine the oncological safety of MIDP and ODP for PDAC. Major databases including PubMed, Embase, Science Citation Index Expanded, and the Cochrane Library were searched for studies comparing outcomes in patients undergoing MIDP and ODP for PDAC from January 1994 to August 2018. In total, 11 retrospective comparative studies with 4829 patients (MIDP: 1076, ODP: 3753) were included. The primary outcome was long-term survival, including 3-year overall survival (OS) and 5-year OS. The 3-year OS (hazard ratio (HR): 1.03, 95% confidence interval (CI): 0.89, 1.21; P = 0.66) and 5-year OS (HR: 0.91, 95% CI: 0.65, 1.28; P = 0.59) showed no significant differences between the two groups. Furthermore, the positive surgical margin rate (weighted mean difference (WMD): 0.71, 95% CI: 0.56, 0.89, P = 0.003) was lower in the MIDP group. However, patients in the MIDP group had less intraoperative blood loss (WMD: −250.03, 95% CI: −359.68, −140.39; P < 0.00001), a shorter hospital stay (WMD: −2.76, 95% CI: −3.73, −1.78; P < 0.00001) and lower morbidity (OR: 0.57, 95% CI: 0.46, 0.71; P < 0.00001) and mortality (OR: 0.50, 95% CI: 0.31, 0.81, P = 0.005) than patients in the ODP group. The limited evidence suggested that MIDP might be safer with regard to oncological outcomes in PDAC patients. Therefore, future high-quality studies are needed to examine the oncological safety of MIDP.

Prognostic value of γ-glutamyltransferase-to-albumin ratio in patients with pancreatic ductal adenocarcinoma following radical surgery.

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

Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality.

Although genomic analysis have recently discovered the malignant subtype of human pancreatic ductal adenocarcinoma (PDAC) characterized by frequent mutations of histone demethylase KDM6A, the biological and molecular roles still remain obscure. We herein elucidated the clinical and biological impacts of KDM6A deficiency on human PDAC and identified the therapeutic potential by pathological and molecular evaluation. Immunohistochemical analysis suggested that loss of KDM6A in cancerous tissues was an independent prognostic factor for both recurrence-free and overall survival in the 103 tumor specimens surgically resected from patients with PDAC. We established KDM6A knocked out cells by using the CRISPR/Cas9 system and KDM6A-expressed cells by doxycycline-inducible system from each two human PDAC cell lines, respectively. KDM6A knockout enhanced aggressive traits of human PDAC cell lines, whereas KDM6A overexpression suppressed them. Microarray analysis revealed reduced expression of 22 genes including five well-known tumor suppressors, such as CDKN1A, and ChIP-PCR analysis displayed depleted enrichment of histone H3 lysine 27 acetylation (H3K27ac) at the promoter regions of the five candidates. The epigenetic alterations were induced by the impaired recruitment of histone acetyltransferase p300, which cooperatively interacted with KDM6A. Consistent with these results, the KDM6A knockout cells demonstrated higher vulnerability to histone deacetylase (HDAC) inhibitors through the reactivation of CDKN1A in vitro and in vivo than the KDM6A wild-type. In conclusion, KDM6A exhibited essential roles in human PDAC as a tumor suppressor and KDM6A deficiency could be a promising biomarker for unfavorable outcome in PDAC patients and a potential surrogate marker for response to HDAC inhibitors.

Thrombospondin-2 is a Highly Specific Diagnostic Marker and is Associated with Prognosis in Pancreatic Cancer.

Thrombospondin-2 (TSP-2) has been reported as an early diagnostic marker for pancreatic ductal adenocarcinoma (PDAC) in Caucasian populations. This study was designed to validateTSP-2 as a diagnostic marker in a large Taiwan cohort and to investigate the association of TSP-2 with the clinical outcomes of PDAC patients. The serum TSP-2 levels in 263 PDAC patients and 230 high-risk individuals (HRIs) were measured via an enzyme-linked immunosorbent assay. The sensitivity, specificity, and accuracy of TSP-2 as a diagnostic marker to discriminating PDAC patients from HRIs and correlations between TSP-2 levels and prognosis of PDAC patients were analyzed. Serum TSP-2 levels were significantly higher in patients with PDAC (44.90 ± 40.70ng/ml) than in the HRIs (17.52 ± 6.23ng/ml). At a level of ≥ 29.8ng/ml, TSP-2 exhibited 100% specificity, 55.9% sensitivity, 100% positive predictive value (PPV), and 66.5% negative predictive value (NPV) for discriminating PDAC patients from HRIs. The Cox regression analysis showed that higher serum TSP-2 levels were significantly associated with poor outcomes in PDAC patients (hazard ratio = 1.54, 95% confidence interval = 1.143-2.086, P = 0.005). Combining the carbohydrate antigen 19-9 (CA19-9) (cutoff value of 62.0 U/ml) and TSP-2 (cutoff value of 29.8ng/ml) levels yielded 98.7% specificity, 90.5% sensitivity, 98.8% PPV, and 90.1% NPV for discriminating patients with PDAC from HRIs. TSP-2 is a highly specific diagnostic marker and an independent prognostic marker in patients with PDAC. A combined biomarker panel, including TSP-2 and CA19-9, may facilitate future PDAC screening.

11. Is age a barrier to optimal treatment, with curative intent, for pancreatic ductal adenocarcinoma?

Introduction: Surgery with adjuvant chemotherapy (aCT) is the standard of care for resectable pancreatic ductal adenocarcinoma (PDAC). The impact of age on curative management and outcomes of PDAC patients was investigated.

Serum Marker Score Based on Prognostic Nutrition Index, Carcinoembryonic Antigen, and Carbohydrate Antigen 19-9 Is Associated With Recurrence for Patients Undergoing Surgery for Pancreatic Ductal Adenocarcinoma.

The prognostic value of the prognostic nutrition index (PNI) in pancreatic ductal adenocarcinoma (PDAC) is still controversial. This study aimed to assess the correlation between PNI and the outcome for PDAC patients and to generate a new score from PNI and serum markers. This study investigated 151 patients who underwent pancreatic resection for PDAC between April 2002 and June 2012. Disease-free survival (DFS), overall survival, and clinicopathological parameters were analyzed according to the PNI value. The low PNI patients had poorer 5-year DFS rate than high-PNI patients (10.7% and 34.8%, respectively). Multivariate analyses revealed that independent risk factors for poor DFS were high carcinoembryonic antigen (hazard ratio [HR], 1.53; P = 0.038), high carbohydrate antigen 19-9 (HR, 1.67; P = 0.017), positive lymph node metastasis (HR, 1.98; P = 0.017), R1 or 2 resection (HR, 3.50; P < 0.001), and low PNI (HR, 0.37 [high/low]; P = 0.029]. Scoring based on the formula -0.49 × (PNI) + 0.41 × (carcinoembryonic antigen) + 0.67 × (carbohydrate antigen 19-9) was significantly associated with poor DFS (P < 0.001) and overall survival (P = 0.0019). Low PNI and serum marker score are significantly associated with poor DFS.

Abstract 3011: Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma

Abstract Background Quality of life (QOL) is impaired in pancreatic cancer patients. Our aim was to investigate the determinants and prognostic value of QOL after diagnosis in a hospital-based cohort of racially/ethnically diverse patients with pancreatic ductal adenocarcinoma (PDAC). Patients and methods QOL was prospectively assessed using the Short Form-12 version 1 in 2478 PDAC patients. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were categorized into tertiles based on their distribution. Ordered logistic regression was adopted to compare the risk of having lower PCS and MCS by patient sociodemographic and clinical characteristics. The association of PCS and MCS with mortality was assessed by Cox regression. Results Compared with non-Hispanic whites, Hispanics were at significantly higher risk of having lower PCS (odds ratio [95%CI], 1.69 [1.26-2.26]; P &amp;lt; .001) and lower MCS (1.66 [1.24-2.23]; P &amp;lt; .001). Patients diagnosed with stage III (1.80 [1.10-2.94]; P = .02) and stage IV (2.32 [1.50-3.59]; P &amp;lt; .001) were more likely to have lower PCS than were patients diagnosed with stage I. Other determinants included sex, age, drinking, smoking, education level, and comorbidities. The low tertile of PCS (hazard ratio [95%CI], 1.94 [1.72-2.18]; P &amp;lt; .001) and MCS (1.42 [1.26-1.59]; P &amp;lt; .001) were each related to poor prognosis. Similar results were found for non-Hispanic Whites as compared to African Americans/Hispanics/others. Conclusion QOL after diagnosis is a significant prognostic indicator for patients with PDAC, and multiple factors determine QOL, suggesting possible means of intervention to improve QOL and outcomes of PDAC patients. Citation Format: Yang Deng, Huakang Tu, Jeanne A. Pierzynski, Ethan Miller, Maosheng Huang, Xiangjun Gu, David W. Chang, Yuanqing Ye, Michelle A. Hildebrandt, Alison P. Klein, Scott M. Lippman, Xifeng Wu. Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3011.

Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma

Tumor-associated macrophages (TAMs) are frequently found near pancreatic cancer cells, but it is uncertain whether they are involved in pancreatic cancer progression and the Warburg effect. Here, we show that CCL18 secreted by TAMs facilitates malignant progression and induced a glycolytic phenotype in pancreatic cancer, partially owing to paracrine induction of VCAM-1 in pancreatic cancer cells. Reciprocally, VCAM-1-induced lactate production from pancreatic cancer cells with enhanced aerobic glycolysis activates macrophages to a TAM-like phenotype, forming a positive feedback loop. VCAM-1 was found to be highly expressed in human pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines, and is associated with disease progression and predicts clinical outcome in PDAC patients. Flow cytometry analysis further demonstrated that VCAM-1 downregulation induced an accumulation of PDAC cells in G0/G1 phase, accompanied by a significant decrease in S phase. Downregulation of VCAM-1 significantly inhibited proliferation, colony formation, migration, and invasion of PDAC cells in vitro, whereas the ectopic expression of VCAM-1 had the opposite effect. VCAM-1 on pancreatic cancer cells might tethers THP-1 monocytes to cancer cells via counter–receptor interaction, providing a survival advantage to pancreatic cancer cells that infiltrate leukocyte-rich microenvironments. Furthermore, downregulation of VCAM-1 could repress tumor growth in mouse xenograft models. In particular, our results highlighted the contribution of VCAM-1 to the maintenance of the Warburg effect in PDAC cells. Finally, we investigated the clinical correlations of CCL18 and VCAM-1 in human PDAC specimens. In summary, these findings indicate that the CCL18/PITPNM3/NF-kB/VCAM-1 regulatory network might provide a potential new therapeutic strategy for PDAC.

Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma

BackgroundQuality of life (QOL) is impaired in pancreatic cancer patients. Our aim was to investigate the determinants and prognostic value of QOL after diagnosis in a hospital-based cohort of racially/ethnically diverse patients with pancreatic ductal adenocarcinoma (PDAC). Patients and methodsQOL was prospectively assessed using the Short Form-12 in 2478 PDAC patients. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were categorised into tertiles based on their distribution. Ordered logistic regression was adopted to compare the risk of having lower PCS and MCS by patient sociodemographic and clinical characteristics. The association of PCS and MCS with mortality was assessed by Cox regression. ResultsCompared with non-Hispanic whites, Hispanics were at significantly higher risk of having lower PCS (odds ratio [95% CI], 1.69 [1.26–2.26]; P < 0.001) and lower MCS (1.66 [1.24–2.23]; P < 0.001). Patients diagnosed with stage III (1.80 [1.10–2.94]; P = 0.02) and stage IV (2.32 [1.50–3.59]; P < 0.001) PDAC were more likely to have lower PCS than stage I patients. Other determinants of QOL included sex, age, drinking, smoking, education level, comorbidities and time since diagnosis. The low tertile of PCS (hazard ratio [95% CI], 1.94 [1.72–2.18]; P < 0.001) and MCS (1.42 [1.26–1.59]; P < 0.001) were each related to poor prognosis. Similar results were found for non-Hispanic whites as compared with African-Americans/Hispanics/others. ConclusionQOL after diagnosis is a significant prognostic indicator for patients with PDAC. Multiple factors determine QOL, suggesting possible means of intervention to improve QOL and outcomes of PDAC patients.

FEZF1-AS1/miR-107/ZNF312B axis facilitates progression and Warburg effect in pancreatic ductal adenocarcinoma

Long non-coding RNAs (lncRNAs) play a pivotal role in pathological processes. However, little information has been published regarding the underlying functions and mechanisms of lncRNAs in pancreatic ductal adenocarcinoma (PDAC). A novel lncRNA FEZF1-AS1 and its sense-cognate gene ZNF312B were found to be highly expressed in human PDAC tissues and cell lines, which is associated with disease progression and predicts clinical outcome in PDAC patients. Of note, bioinformatics analysis, luciferase assays and RNA immunoprecipitation assays indicated that FEZF1-AS1 may act as an endogenous sponge by competing for miR-107, thereby modulating the derepression of ZNF312B. Downregulation of FEZF1-AS1 or ZNF312B significantly inhibited proliferation, colony formation, migration, and invasion of PDAC cells in vitro, whereas the miR-107 inhibitor abrogated the effect of dow-regulation of FEZF1-AS1 or ZNF312B in reducing oncogenic capacities of PDAC cells. In addition, FEZF1-AS1/miR-107/ZNF312B axis-induced promotion of PDAC cells proliferation appeared to be mediated by modulation of the apoptosis and the G1-S checkpoint. Furthermore, downregulation of FEZF1-AS1 repressed tumor growth in mouse xenograft models. In particular, our results highlight the contribution of FEZF1-AS1/miR-107/ZNF312B axis to Warburg effect maintenance of PDAC cells. Collectively, our findings demonstrate that the FEZF1-AS1/miR-107/ZNF312B axis regulatory network might provide a potential new therapeutic strategy for PDAC.