Overall Survival Of Pancreatic Cancer Patients Research Articles

A Novel and Robust Long Noncoding RNA Panel to Predict the Prognosis of Pancreatic Cancer.

Pancreatic cancer (PC) is one of the most lethal malignancies with an extremely poor prognosis. In this study, we aim to construct a long noncoding RNA (lncRNA)-based panel biomarker to predict the overall survival of PC patients. The lncRNA expression profiles of PC samples were extracted from The Cancer Genome Atlas (TCGA-PAAD, n = 176) and International Cancer Genome Consortium (PACA-CA, n = 180). We then developed a risk score model according to the lncRNAs expressions from the TCGA-PAAD cohort and further validated it in the PACA-CA cohort. The potential biological functions for the prognostic lncRNAs were investigated using gene set enrichment analysis (GSEA). In the TCGA-PAAD cohort, three lncRNAs (AC009014.3, RP11-48O20.4, and UCA1) were found to be strongly associated with the prognosis of PC. These lncRNAs were integrated to build a three-lncRNA prognostic model that could divide individuals into low- and high-risk groups. Patients of TCGA-PAAD cohort in the high-risk group showed a poorer overall survival than those in the low-risk group (median: 17.3 months vs. 30.4 months, log-rank p < 0.001). Similar results were documented in the PACA-CA cohort (median: 15.2 months vs. 21.0 months, log-rank p < 0.001) and in the stratified analyses by patients' age and TNM stage. In addition, the signature exhibited an independent prognostic power and was significantly correlated with tumor relapse and patients' response to chemotherapy. GSEA indicated that the three-lncRNA signature may be involved in many known biological functions in cancer, especially the epithelial mesenchymal transformation. In conclusion, the identified three-lncRNA signature in our study may serve as a robust and useful prognostic biomarker in PC patients.

Pretreatment C-reactive protein/albumin ratio for predicting overall survival in pancreatic cancer: A meta-analysis.

Background:Inconsistent findings have been reported regarding the association of C-reactive protein to albumin ratio (CAR) with survival outcome in patients with pancreatic cancer. We conducted the current meta-analysis to assess the prognostic utility of elevated baseline CAR in predicting overall survival (OS) in pancreatic cancer patients.Methods:A comprehensively literature search was performed in the PubMed and Embase database until February 10, 2019. Studies evaluating the association between pretreatment CAR and OS among pancreatic cancer were selected. Study quality was evaluated by using the Newcastle-Ottawa Scale.Results:Nine retrospective studies involving 1534 pancreatic cancer patients were identified. A meta-analysis using a random-effect model indicated that elevated CAR was associated with poor OS (hazard ratio 1.98; 95% confidence interval 1.58–2.48). Subgroup analysis produced similar prognostic values for OS in different geographical regions, sample sizes, thresholds of CAR, treating methods, and Newcastle-Ottawa Scale points.Conclusion:Elevated pretreatment CAR may independently predict poor OS in pancreatic cancer patients. Pretreatment CAR is possibly a simple and cost-effective blood-derived indicator for predicting survival outcome in patients with pancreatic cancer.

Detection of pancreatic cancer using a novel blood-based DNA methylation signature.

e15546 Background: Pancreatic cancer (PC) is a high mortality malignancy typically found when curative surgery is not an option. Liquid biopsies are a minimally invasive option that may allow earlier detection of PC. Using a bioinformatic analysis of TCGA and GEO we identified a novel set of blood-based biomarkers to detect PC with high sensitivity and specificity (AUROC = 0.999) (Vrba et al, Epigenetics 2019). Here we tested the ability of this DNA methylation signature (MS) to distinguish metastatic PC from pancreatic cysts (Cy) and healthy controls (HC) through quantitative DNA methylation analysis of cell free DNA (cfDNA). Methods: A 10 gene DNA methylation marker set that identifies PC was used to evaluate the cfDNA component of the plasma of PC patients, Cy patients and HC. The ROC analysis and AUC calculations were performed using the R library pROC (Robin et al, BMC Bioinformatics 2011). Plasma samples were collected in cfDNA collection tubes from patients with benign Cy, PC, and HC. Clinical information was collected including age, gender, smoking history, CA 19-9 level, cyst size, presence of liver metastases, and survival status. After processing and cfDNA extraction, qRT-PCR methylation analysis was performed on these prospectively collected samples. The difference in median DNA MS per marker of the full 10-gene marker set between the above groups was analyzed by Wilcoxon rank sum test and ROC analysis. A Cox proportional hazard regression model was used to test the association between MS and survival. Results: A total of 66 samples were collected (PC = 10, Cy = 12, HC = 44). Clinical information was collected on all patients included in the analysis. Using liquid biopsies for cfDNA analysis and a novel set of DNA methylation biomarkers, MS was substantially stronger in PC (median, 13.2) patients than Cy (median, 3.5) patients (p = 0.0001). Importantly, while there was no clear association between MS and age, gender, smoking status, CA 19-9 levels, or presence of liver metastases, higher methylation levels were non-significantly associated with worse overall survival in PC patients (HR, 1.29; 95% CI, 0.97–1.72; p = 0.082). Conclusions: While this is a small sample size, early findings suggest that a DNA MS may reliably distinguish PC from benign Cy. The strength of signal may be a prognostic marker that could play a role in determining treatment approaches. Given its utility in predicting PC, future directions include testing this tool as a blood-based early detection mechanism as well as a predictor for recurrence or response to PC treatment.

Identification of Key Genes Involved in Diabetic Peripheral Neuropathy Progression and Associated with Pancreatic Cancer.

IntroductionDiabetes mellitus (DM) patients suffer from high morbidity and premature mortality due to various diabetic complications and even cancers. Therefore, this study aimed to identify key genes involved in the pathogenesis of diabetic peripheral neuropathy (DPN) and pancreatic cancer (PC).MethodsWe analyzed three gene expression profiles (GSE95849, GSE28735 and GSE59953) to obtain differentially expressed genes (DEGs). Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was then used to establish a protein–protein interaction (PPI) network. The MCODE and cytoHubba plug-ins of Cytoscape were used to select hub genes. Finally, survival analysis of the hub genes was performed using the Kaplan–Meier plotter and GEPIA online tool.ResultsWe first analyzed GSE95849 to obtain DPN-related genes. DEGs were obtained from three groups in GSE95849. The DEGs were enriched in the Toll-like receptor signaling pathway, hematopoietic cell lineage and chemokine signaling pathway. Importantly, we identified three shared genes as hub genes, including TLR4, CCR2 and MMP9. We then analyzed and integrated GSE95849 and GSE28735 to obtain genes common in DM and PC. A total of 58 mutual DEGs were identified, and these DEGs were enriched in the ECM-receptor interaction, focal adhesion and pathways in cancer. Five hub genes (including PLAU, MET, CLU, APOL1 and MMP9) were associated with the overall survival of PC patients. However, the results from the analysis of GSE59953 showed that hyperglycemia or TGF-β1 treatment did not affect the expression level of these hub genes, but the DEGs based on hyperglycemia or TGF-β1 treatment were mostly enriched in the ECM-receptor interaction, focal adhesion and pathways in cancer. Finally, functional enrichment analysis of MMP9 showed that significant genes correlated with MMP9 were associated with the tumorigenicity of cancers, insulin resistance, development of DM and inflammation.ConclusionIn summary, inflammation and immunity-related pathways may play an important role in DM and DPN, while the ECM-receptor interaction, focal adhesion and pathways in cancer pathways may play significant roles in DM and PC. MMP9 may be used as a prognostic marker for PC and may be helpful for the treatment of DM, DPN and PC.

The role of immunotherapy on the survival of pancreatic cancer patients.

714 Background: Immunotherapy has revolutionized the treatment landscape of many malignancies, but its therapeutic role in pancreatic cancer (PC) remains unclear. The objective of this study is to investigate the impact of immunotherapy on the overall survival of PC patients stratified by definitive surgery of the pancreas using the National Cancer Database (NCDB). Methods: Patients with pancreatic adenocarcinoma were identified from NCDB. Cox proportional hazard models were employed to assess the impact of immunotherapy on survival after being stratified by surgery and adjusted for age of diagnosis, race, sex, place of living, income, education, treatment facility type, insurance status, year of diagnosis, and treatment types such as chemotherapy and radiation therapy. Results: Of 252,280 patients who were analyzed, 214,632 (85.08%) had definitive surgery, and 37,638 (14.92%) did not get definitive surgery of the pancreas. In the surgery group, 351 (0.93%) received immunotherapy and 37,287 (99.07%) did not while in the no surgery group, 838 (0.39%) received immunotherapy and 213,804 (99.61%) did not. In the multivariable analysis, patients who received immunotherapy had significantly improved OS both in the no surgery group (HR: 0.886, CI: 0.655-0.714; P &lt; 0.0001) and in the surgery group (HR: 0.846, CI: 0.738-0.971; P &lt; 0.0001) compared to patients who did not receive immunotherapy. Treatment with chemotherapy plus immunotherapy was associated with significantly improved OS (HR: 0.871, CI: 0.784-0.967; P &lt; 0.009) compared to chemotherapy without immunotherapy in the no surgery group, while it was not significant in the surgery group. Chemoradiation plus immunotherapy was associated with significantly improved OS (HR: 0.787, CI: 0.684-0.906; P &lt; 0.0009) in the no surgery group and (HR: 0.799, CI: 0.681-0.938) in the surgery group compared to chemoradiation alone. Conclusions: In this study, the addition of immunotherapy to chemoradiation therapy was associated with significantly improved OS in PC patients with or without definitive surgery. The study warrants further future clinical trials of immunotherapy in PC.

TRIM59 predicts poor prognosis and promotes pancreatic cancer progression via the PI3K/AKT/mTOR-glycolysis signaling axis.

Aberrant expression of the tripartite motif containing 59 (TRIM59) has been reported to participate in the development and progression of various human cancers. However, its expression pattern and cellular roles in pancreatic cancer (PC) remains unclear. In our study, we found that TRIM59 expression was significantly increased in PC tissues and was positively correlated with several malignant behaviors and poor overall survival of PC patients based on bioinformatics analysis and immunohistochemistry staining. Functionally, small interfering RNA-mediated TRIM59 depletion inhibited cell proliferation and migration in vitro, whileTRIM59 overexpression promoted cell proliferation and migration in vitro and drove tumor growth and liver metastasis in vivo. Mechanically, TRIM59 was found to enhance glycolysis through activating the PI3K/AKT/mTOR pathway, ultimately contributing to PC progression. Taken together, our results demonstrate that TRIM59 may be a potential predictor for PC and promotes PC progression via the PI3K/AKT/mTOR-glycolysis signaling pathway, which establishes the rationale for targeting the TRIM59-related pathways to treat PC.

Postoperative Imaging and Tumor Marker Surveillance in Resected Pancreatic Cancer.

Background: Pancreatic cancer is a catastrophic disease with high recurrence and death rates, even in early stages. Early detection and early treatment improve survival in many cancer types but have not yet been clearly documented to do so in pancreatic cancer. In this study, we assessed the benefit on survival resulting from different patterns of surveillance in daily practice after curative surgery of early pancreatic cancer. Methods: Patients with pancreatic ductal adenocarcinoma who had received curative surgery between January 2000 and December 2013 at our institute were retrospectively reviewed. Patients were classified into one of four groups, based on surveillance strategy: the symptom group, the imaging group, the marker group (carbohydrate antigen 19-9 and/or carcinoembryonic antigen), and the intense group (both imaging and tumor marker assessment). Overall survival (OS), relapse-free survival (RFS), and post-recurrence overall survival (PROS) were evaluated. Results: One hundred and eighty-one patients with documented recurrence or metastasis were included in our analysis. The median OS for patients in the symptom group, imaging group, marker group, and intense group were 21.4 months, 13.9 months, 20.5 months, and 16.5 months, respectively (p = 0.670). Surveillance with imaging, tumor markers, or both was not an independent risk factor for OS in univariate and multivariate analyses. There was no significant difference in median RFS (symptom group, 11.7 months; imaging group, 6.3 months; marker group, 9.3 months; intense group, 6.9 months; p = 0.259) or median PROS (symptom group, 6.9 months; imaging group, 7.5 months; marker group, 5.0 months; intense group, 7.8 months; p = 0.953) between the four groups. Multivariate analyses identified poor Eastern Cooperative Oncology Group Performance Status (ECOG PS) (≥1), primary tumor site (tail), and tumor grade (poor differentiation) were poor prognostic factors for OS. Conclusions: Surveillance with regular imaging, tumor marker, or both was not an independent risk factor for OS of pancreatic cancer patients who undergo curative tumor resection.

Hypoxia-induced feedback of HIF-1α and lncRNA-CF129 contributes to pancreatic cancer progression through stabilization of p53 protein.

Rationale: Emerging evidences have highlighted the critical roles of lncRNAs in human cancer development. The work sought to assess the biological role and potential underlying mechanisms of lncRNA-CF129 (CF129) which is significantly reduced in pancreatic cancer (PC).Methods: CF129 expression and its association with multiple clinicopathologic characteristics in PC specimens were analyzed. The role of CF129 both in vitro and in vivo was assessed, with RNA pull-down and immunoprecipitation assays being performed to detect the interaction between CF129 and p53 and E3 ligase MKRN1. Chromatin immunoprecipitation and luciferase assays were utilized to identify the interaction between p53 and FOXC2 promoter, HIF-1α/HDAC1 complex and CF129 promoter, FOXC2 and HIF-1α promoter, respectively.Results: CF129 levels were markedly lower in PC compared with paired non-tumor adjacent tissues. Low CF129 expression predicted short overall survival in PC patients. CF129 inhibited invasion and metastasis of PC cells in a FOXC2-dependent manner. In addition, CF129 regulates FOXC2 transcription through association with mutant p53. CF129 directly binds to p53 and E3 ligase MKRN1, and such an interaction leading to p53 protein ubiquitination and degradation. Furthermore, CF129 is a hypoxia-responsive lncRNA, which is transcriptionally downregulated by binding between HIF-1α/HDAC1 complex and CF129 promoter. Finally, it is revealed that HIF-1α is reciprocally regulated by FOXC2 in transcriptional level. Clinically, CF129 downregulation coordinates overexpression of FOXC2.Conclusions: Our study suggests that CF129 inhibits pancreatic cell proliferation and invasion by suppression of FOXC2 transcription, which depends on MKRN1-mediated ubiquitin-dependent p53 degradation. The HIF-1α/CF129/ p53/FOXC2 axis may function as a potential biomarker and therapeutic target.

Pathological complete response to chemotherapy in pancreatic cancer: frequency, predictors and impact on overall survival

Background: While Pathological complete response (pCR) after neoadjuvant chemotherapy (NCT) in pancreatic cancer has been associated with improved overall survival (OS), the rate of pCR and its predictors have not been elucidated yet. Our aim was to study factors predicting rate of pCR in a large data set and the impact on OS. Methods: Patients listed in the National Cancer Data Base from 1998 to 2011 were studied. We included patients with NCT followed by surgery. Demographics, cancer characteristics, and treatment modalities including NCT to surgery (NCT-S) interval were studied. Results: A total of 2093 patients were included. Mean age was 62, 51% were male, and 71% had neoadjuvant radiotherapy (NRT). NCT-S was divided into time quintiles in weeks: 8–11, 12–14, 15–19, 20–29 and >29 weeks; as well as a continuous variable). Median follow up was 74 months. Rate of pCR was 2.1% (44/2093). OS in pCR vs non-pCR: 61 vs. 31 months, HR 0.3, 95% CI 0.1–0.9, p 0.03). There was a significant increase in pCR with longer NCT-S interval (quintiles: (5/510 = 1.0%, 9/551 = 1.6%, 8/462 = 1.7%, 12/403 = 3.0% and 10/167 = 6.0%, p < 0.001). In logistic regression: NRT (OR 2.5, 95% CI: 1.1–6.1, p = 0.03) and NCT-S interval per week increase (OR 1.1, 95% CI 1.03–1.09, p < 0.001) as well as NCT-S >29 weeks (OR 6.1, 95% CI 2.02–18.50, p < 0.001) were predictive of increased pCR rate. Multivariate Cox regression showed that age, pCR and NCT-S >29 weeks were significantly predictive of OS, while gender, race, facility type, tumor grade, cT, cN stage, single vs. multiple chemotherapy agents and NRT were not.. Conclusion: NCT-S interval >29 weeks and pCR were independent predictors of better OS in pancreatic cancer patients. NRT predicted increased pCR but not OS in the multivariate analysis. Further studies are needed to optimize multimodality regimens that best improve OS.

Prognostic implication of soluble programmed death-ligand 1 (sPDL1) and its dynamic changes during FOLFIRINOX chemotherapy in unresectable pancreatic cancer.

306 Background: Programmed death-ligand 1 (PD-L1) expressed on a tumor or in a tumor microenvironment has an important role in the tumor escaping from the immune system. The soluble form of PD-L1 (sPD-L1) has been suggested to have an immunosuppressive activity. In pancreatic cancer, the acquisition of a sufficient amount of tumor tissue is an obstacle. In this study, we measured the serum levels of sPD-L1 and evaluated its prognostic implications in unresectable pancreatic cancer. Methods: We prospectively enrolled 60 pancreatic cancer patients who were treated with FOLFIRINOX as the first-line palliative chemotherapy. We collected blood samples at the time of diagnosis, first response assessment and disease progression. Serum sPD-L1 was measured using an enzyme-linked immunosorbent assay. Results: The median sPD-L1 was 1.7ng/mL (range, 0.4-5.7ng/mL). The median overall survival (OS) and progression free survival (PFS) were 10.3 months (95% CI: 8.5-12.11) and 6.5 months (95% CI: 4.9-8.1), respectively. Patients with low levels of sPD-L1 at diagnosis ( &lt; 4.6 ng/mL) showed a better OS than the patients with a high sPDL1 (OS: 12.6 vs. 8.0 months HR 2.796, P = 0.015). In the multivariable analysis, sPD-L1 and the neutrophil-to-lymphocyte ratio were independent prognostic factors for OS. During chemotherapy, more patients achieved CR(complete response)/PR (partial response) as the best response when sPD-L1 was decreased at the first response assessment. (CR+PR rate; sPDL1 decreased group vs. sPD-L1 increased group: 14/29 (48.3%) vs. 5/24 (20.8%), P = 0.038). For patients who achieved CR/PR as the best response, sPD-L1 was significantly increased at disease progression compared with the first response assessment (mean 3.5 vs. 1.9 ng/mL, P = 0.025). Conclusions: sPD-L1 at diagnosis confers a prognostic value for OS in pancreatic cancer patients treated with chemotherapy. The dynamics changes of sPD-L1 during chemotherapy correlates with disease progression

MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer.

Migration and invasion inhibitory protein (MIIP) is recently identified as an inhibitor in tumor development. However, the regulatory mechanism and biological contributions of MIIP in pancreatic cancer (PC) have been not elucidated. In this study, we demonstrated a negative feedback of MIIP and hypoxia-induced factor-1α (HIF-1α), which was mediated by a hypoxia-induced microRNA. Compared with paracarcinoma tissues, MIIP was downregulated in PC tissues. Overexpression of MIIP significantly impeded the proliferation and invasion of PC cells both in vitro and in mouse xenograft models. We further verified MIIP was downregulated under hypoxia in a HIF-1α-mediated manner. Interestingly, although MIIP promoter containing two putative hypoxia response elements (HREs), the chromatin immunoprecipitation (ChIP) and luciferase reporter assays did not support an active interaction between HIF-1α and MIIP promoter. Meanwhile, microRNA array revealed a hypoxia-induced microRNA, miR-646, impaired stability of MIIP mRNA and consequently inhibited its expression by targeting the coding sequence (CDS). Coincidently, knockdown of miR-646 significantly repressed proliferation and invasion ability of PC cells both in vitro and in vivo by upregulating MIIP expression. Besides, ChIP and luciferase reporter assays further validated that HIF-1α activated transcription of miR-646 in hypoxia condition. Therefore, these results suggested HIF-1α indirectly regulated MIIP expression in post-transcriptional level through upregulating miR-646 transcription. Conversely, our results further revealed that MIIP suppressed deacetylase ability of histone deacetylase 6 (HDAC6) to promote the acetylation and degradation of HIF-1α, by which impairing HIF-1α accumulation. What is more, a specific relationship between downregulated MIIP and upregulated miR-646 expression was validated in PC samples. Moreover, the dysregulated miR-646 and MIIP expression was correlated with advanced tumor stage, lymphatic invasion, metastasis and shorter overall survival in PC patients. Together, our results highlight that the reciprocal loop of HIF-1α/miR-646/MIIP might be implemented as an applicable target for pancreatic cancer therapy.

Prognosis of Pancreatic Cancer Patients with Synchronous or Metachronous Malignancies from Other Organs Is Better than Those with Pancreatic Cancer Only.

PurposePancreatic cancer associated double primary tumors are rare and their clinicopathologic characteristics are not well elucidated.Materials and MethodsClinicopathologic factors of 1,352 primary pancreatic cancers with or without associated double primary tumors were evaluated.ResultsOf resected primary pancreatic cancers, 113 (8.4%) had associated double primary tumors, including 26 stomach, 25 colorectal, 18 lung, and 13 thyroid cancers. The median interval between the diagnoses of pancreatic cancer and associated double primary tumors was 0.5 months. Overall survival (OS) of pancreatic cancer patients with associated double primary tumors was longer than those with pancreatic cancer only (median, 23.1 months vs. 17.0 months; p=0.002). Patients whose pancreatic cancers were resected before the diagnosis of metachronous tumors had a better OS than patients whose pancreatic cancer resected after the diagnosis of metachronous tumors (48.9 months and 13.5 months, p=0.001) or those whose pancreatic cancers were resected synchronously with non-pancreas tumors (19.1 months, p=0.043). The OS of pancreatic cancer patients with stomach (33.9 months, p=0.032) and thyroid (117.8 months, p=0.049) cancers was significantly better than those with pancreas cancer only (17.0 months).ConclusionAbout 8% of resected pancreatic cancers had associated double primary tumors, and those from the colorectum, stomach, lung, and thyroid were common. Patients whose pancreatic cancer was resected before the diagnosis of metachronous tumors had better OS than those resected after the diagnosis of metachronous tumors or those resected synchronously.

Prognostic value of PD-L1 overexpression for pancreatic cancer: evidence from a meta-analysis.

Programmed death-ligand 1 (PD-L1) is an immune checkpoint that is often activated in cancer and plays a pivotal role in the initiation and progression of cancer. However, the clinicopathologic significance and prognostic value of PD-L1 in pancreatic cancer (PC) remains controversial. In this study, we conducted a meta-analysis to retrospectively evaluate the relationship between PD-L1 and PC. PubMed and other databases were searched for the clinical studies published up to March 21, 2017, to be included in the meta-analysis. Hazard ratios and their 95% CIs were calculated. Risk ratios (RRs) were extracted to assess the correlations between the clinicopathologic parameters and PD-L1 expression. Ten studies including 1,058 patients were included in the meta-analysis. The pooled results indicated that positive PD-L1 expression was correlated with a poor overall survival outcome in PC patients (hazard ratio =1.76, 95% CI: 1.43–2.17, P<0.00001). Interestingly, high PD-L1 expression was correlated with poor pathologic differentiation (RR =1.57, 95% CI: 1.25–1.98, P=0.0001) and neural invasion (RR =1.30, 95% CI: 1.03–1.64, P=0.03). However, there were no significant correlations between PD-L1 expression and other clinicopathologic characteristics. In summary, our meta-analysis implied that PD-L1 could serve as a negative predictor for the overall survival of PC patients, and high expression of PD-L1 was correlated with poor differentiation and neural invasion, indicating that anti-PD-L1 treatments should be evaluated in PC patients, especially in those who exhibit these two characteristics.

IL-8 as PD biomarker for TGF-b antisense (OT-101) therapy: Results of a phase II trial.

e15742 Background: Trabedersen (OT-101) is a phosphorothioate antisense specific for human TGF-β2 mRNA. In a Phase I/II study of OT-101 in patients with advanced pancreatic cancer (PAC) treated second line and beyond, improved Overall Survival (OS) was observed when OT-101 was followed with chemotherapy. Here, we examined the association between plasma levels of cyto-/chemokines and OS outcomes and identified IL-8 as a biomarker for improved OS. Methods: 37 patients with PAC were treated with OT-101 by IV infusion in escalating doses of 2 treatment schedules (7-days on, 7-days off and 4-days on, 10-days off). Plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of OT-101 therapy (140 mg/m2/day on a 4-days on, 10-days off cycle). IL-8 levels were measured in 12 patients before and during 3 cycles of treatment on Days 2 and 5. Maximum levels of IL-8 on Day 2 were subtracted from levels on Day 5 and these standardized scores were correlated with log10 transformed OS values. Feedback interactions with PK parameters were also investigated utilizing an ANCOVA model. Results: We observed OS of 14.5 months and 2.6 months for those treated with and without subsequent chemotherapies, respectively (p = 0.0009). Peak IL-8 levels were apparent after 2 days of OT-101 treatment. A significant regression and 95% CI was evident, whereby increasing difference of IL-8 following Day 2 vs Day 5 was positively correlated with OS (R2 = 0.58, F1,9 = 12.32, P = 0.0066). R- squared increased from 0.4955, p &lt; 0.0001, for all patients to 0.8524, p &lt; 0.0001, for patients without subsequent chemo and 0.9744, p &lt; 0.0001, for patients with subsequent chemo. The ANCOVA model for two PK parameters exhibited significant model fits (F3,7 = 7.89, P = 0.012 for Simulated Vz Mean; F3,7 = 8.18, P = 0.011 for Simulated Cl Mean) and the interaction effects resulted in lower p-values for the correlation of OS vs IL-8 levels. Conclusions: Peak of IL-8 response on Day 2 of OT-101 treatment was correlated with OS in PAC patients. The correlation existed between OS whether patients received subsequent chemo or not suggesting that the IL-8 spike is a PD biomarker for OT-101. Clinical trial information: NCT00844064.

WITHDRAWN: Prognostic role of anti-diabetic drugs in pancreatic cancer: A systematic review and meta-analysis

// Lei Zheng 1, * , Shinan Yin 1, * , Fenghua Yao 2 , Hua Bai 1 and Danqing Jing 1 1 Department of Endocrinology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China 2 Department of Nephrology, the First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China * These authors contributed equally to this work Correspondence to: Shinan Yin, email: zhenglei_1977@sina.com Keywords: anti-diabetic drug(ADD), metformin, pancreatic cancer, prognosis Received: March 31, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: April 27, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: May 09, 2017 ABSTRACT Anti-diabetic drugs (ADDs) have been reported to modify the risk and survival of several malignancies, but whether ADDs affect the prognostic outcomes for pancreatic cancer (PC) patients remains unclear. A systematic literature search was performed for studies published until September 2016 investigating the associations between ADD use and PC survival. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using the random-effects model. Overall survival (OS) and progression-free survival (PFS) were set as the main outcomes. Twelve cohorts and two randomized controlled trials (RCTs) for a total of 12,6158 subjects were identified for this meta-analysis. Pooled analysis of cohorts suggested that metformin use was significantly associated with improved OS in PC patients ( n = 11 studies; pooled HR 0.77, 95% CI 0.68 to 0.87), with no increased OS for insulin, sulfonylureas (SU) or thiazolidinedione (TZD) (all P values &gt; 0.05). For OS of PC patient using metformin, this effect remained constant by subgroup analyses and sensitivity analysis by trim and filled method. Meta-analysis of RCTs did not show survival benefits for PC patients ( n = 2; pooled HR 1.20, 95% CI 0.84 to 1.72). We also did not find significant association between metformin use and PFS in PC patients for cohort studies ( n = 2; pooled HR 1.22, 95% CI 0.76 to 1.95). Our findings provide evidence in cohort studies that metformin, not other ADDs is associated with impoved OS in PC patients; however, due to limited number of studies investigating other ADDs except metformin, further large-scale studies are warranted to determine this associations.

Prognostic significance of anti-diabetic medications in pancreatic cancer: A meta-analysis.

The role of anti-diabetic medications in pancreatic cancer remains conflicting. We carried out a systematic search of Pubmed and Embase databases for studies published before August 2016, which assessed the associations between anti-diabetic medications (metformin, sulfonylureas, thiazolidinediones and insulin) intake and pancreatic cancer prognosis. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using the random-effects model. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS). Fourteen studies enrolling 94778 participants were eligible for inclusion, with 12 cohort studies and 2 randomized controlled trials (RCTs). Significant association between metformin (adjusted HR=0.77, 95% CI=0.68-0.87) use and OS was found in cohort studies, whereas no significant association between metformin use and PFS (HR=1.22; 95% CI=0.76-1.95) or OS (HR=1.20, 95% CI=0.84-1.72) in RCTs. No significant survival benefits were identified for insulin (HR=1.18, 95% CI=0.83-1.69), sulfonylureas (HR=1.03, 95% CI=0.81-1.30), or thiazolidinediones (HR=0.84, 95% CI=0.58-1.22). The trim-and-fill method and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. Our findings provide strong evidence that metformin is associated with improved OS in pancreatic cancer patients in cohort studies. However, the effect of other anti-diabetic medications should be interpreted with caution owing to the limited number of studies.

MicroRNA-195 Suppresses the Progression of Pancreatic Cancer by Targeting DCLK1

Background/Aims: Doublecortin-like kinase 1 (DCLK1) is emerging as a tumor-specific stem cell marker in pancreatic cancer (PC). MicroRNA-195 (miR-195) plays an important role in many types of tumors. However, the roles of DCLK1 in cancer and miRNAs that directly regulate DCLK1 have not been elucidated. The goal of this study is to assess the effects of miR-195 on inhibiting DCLK1 and to clarify the regulating mechanism of miR-195-DCLK1 in PC cells. Methods: The expression of DCLK1 protein and miR-195 in PC tissues and adjacent healthy pancreatic tissues was detected by Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively and the correlation between overall survival of PC patients and expression of DCLK1 was measured by Kaplan-Meier analysis. Bioinformatics tools were used to identify the target gene of miR-195. Effects of miR-195 and DCLK1 on proliferation and cell cycle of PC cells were analyzed by MTT, colony formation assays and flow cytometry. Transwell and wound-healing experiments were employed to examine the cellular migration and invasion. A xenograft mouse model was also used to test the effects of miR-195 on tumor growth and metastasis in vivo. Results: The expression level of DCLK1 and miR-195 shows an inverse correlation in PC tissues and cell lines. A higher DCLK1 level is associated with higher TNM (tumor, node, and metastasis) stage, higher rate of lymph node metastasis, and poor survival. Luciferase reporter assay shows that miR-195 directly targets DCLK1. Overexpression of miR-195 inhibits proliferation, migration and invasion of PC cells, whereas downregulation of miR-195 has an opposite role. These actions were similar to the effects of knockdown and overexpression of DCLK1, respectively. Conclusions: These data suggest that miR-195 has tumor suppressor roles in PC by targeting DCLK1. MiR-195-DCLK1 pathway may provide insight into PC progression and represent a novel, promising diagnostic and therapeutic target for PC.

A panel of 13-miRNA signature as a potential biomarker for predicting survival in pancreatic cancer.

Some reports have evaluated the prognostic relevance of microRNAs (miRNAs) in patients with pancreatic cancer (PC). However, most studies focused on limited miRNAs with small number of patients. The aim of the study is to identify a panel of miRNA signature that could predict prognosis in PC with the data from The Cancer Genome Atlas (TCGA). A total of 167 PC patients with the corresponding clinical data were enrolled in our study. The miRNAs significantly associated with overall survival (OS) in PC patients were identified with Cox proportional regression model. A risk score formula was developed to evaluate the prognostic value of the miRNA signature in PC. Thirteen miRNAs were identified to be significantly related with OS in PC patients. Patients with high risk score suffered poor overall survival compared with patients who had low risk score. The multivariate Cox regression analyses showed that the miRNA signature could act as an independent prognostic indicator. In addition, the signature might serve as a predicator for treatment outcome. Our study identified a miRNA signature including 13 miRNAs which could serve as an independent marker in prognosis of PC.

Effect of Body Mass Index on Overall Survival of Pancreatic Cancer: A Meta-Analysis.

Although obesity has been identified as a risk factor for pancreatic cancer, the important question of whether obesity influences the prognosis of pancreatic cancer has not been explicated thoroughly. We therefore performed a meta-analysis to investigate the association between body mass index (BMI) and survival outcomes of patients with pancreatic cancer.Studies that described the relationship between BMI and overall survival (OS) of pancreatic cancer were searched in PubMed, Embase, Ovid, and Cochrane Library Databases from the earliest available date to May 12, 2015. Hazard ratios (HRs) for OS in each BMI category from individual studies were extracted and pooled by a random-effect model. Dose–response meta-analysis was also performed to estimate summary HR and 95% confidence interval (CI) for every 5-unit increment. Publication bias was evaluated by Begg funnel plot and Egger linear regression test.Ten relevant studies involving 6801 patients were finally included in the meta-analysis. Results showed that obesity in adulthood significantly shortened OS of pancreatic cancer patients (HR: 1.29, 95% CI: 1.17–1.41), whereas obesity at diagnosis was not associated with any increased risk of death (HR: 1.10, 95% CI: 0.78–1.42). For every 5-kg/m2 increment in adult BMI, the summary HR was 1.11 (95% CI: 1.05–1.18) for death risk of pancreatic cancer. However, no dose–response relationship was found in the BMI at diagnosis. Egger regression test and Begg funnel plot both revealed no obvious risk of publication bias.In conclusion, increased adult BMI is associated with increased risk of death for pancreatic cancer patients, which suggested that obesity in adulthood may be an important prognostic factor that indicates an abbreviated survival from pancreatic cancer. More studies are needed to validate this finding, and the mechanism behind the observation should be evaluated in further studies.

Diffusion-weighted MR imaging of pancreatic cancer and inflammation: Prognostic significance of pancreatic inflammation in pancreatic cancer patients.

Pancreatic cancer often accompanies chronic obstructive pancreatitis (COP) due to obstruction of the main pancreatic duct, and the inflammatory environment may enhance cancer progression. The purpose of this study is to evaluate COP using the apparent diffusion coefficient (ADC) value measured by diffusion-weighted MR imaging (DWI), and to assess its prognostic significance in pancreatic cancer. Twenty-eight patients (16 men, 12 women; mean age 67.1 years) with pancreatic cancers who underwent DWI followed by curative surgery were evaluated. The ADC value of pancreatic parenchyma upstream to the tumor (upstream pancreas) was measured and compared with the upstream pancreatic duct dilatation to assess whether DWI could reflect COP. The ADC values of tumor and upstream portion were compared with overall survival (OS) using Cox regression and Kaplan-Meier analysis. The ADC value of upstream pancreas was significantly lower in patients with greater dilated pancreatic duct than those with less (P = 0.03). In univariate Cox regression analysis, the ADC value of upstream pancreas showed a significant association with OS (P = 0.01), but that of tumor did not (P = 0.06). In Kaplan-Meier analysis, patients with lower ADC value of upstream pancreas (<1.36 × 10(-3) mm(2)/s) were significantly associated with poor OS (P = 0.0006). In multivariate analysis, the ADC value of upstream pancreas was identified as an independent prognostic factor (P = 0.01; hazards ratio, 0.05; 95% CI, 0.004-0.59). The ADC value of upstream pancreas was an independent prognostic factor for OS in pancreatic cancer patients. Inflammatory environment may play an important role in pancreatic cancer progression.