Overall Survival In Pancreatic Cancer Research Articles

Cytokines as a prognostic biomarker of overall survival in pancreatic cancer.

e16753 Background: Pancreatic cancer is an aggressive malignancy with a dismal 5-year survival rate of only 9%. Novel biomarkers are urgently needed to improve the survival outcomes of patients with this dreaded disease. Cytokines serve a key role in tumor development and metastasis in pancreatic cancer, with each cytokine demonstrating unique functionality in the tumor microenvironment. This meta-analysis examined the role of cytokines in prognosticating overall survival (OS) of pancreatic cancer patients. Methods: Relevant literature were identified via electronic search of PubMed, EMBASE, Google Scholar and Cochrane Library databases up to January 1, 2020. Employing Review Manager 5.3, pooled hazard ratios and 95% confidence intervals were computed. Results: A total of 18 studies comprising 1920 patients were included. Pooled analysis showed worse OS among patients with high T-helper 1 (Th1) cytokines, with a hazard ratio of 1.48 (95% CI 1.27-1.74, p < 0.00001). High T-helper 2 (Th2) cytokines also demonstrated significant association with poor OS, with a hazard ratio of 1.62 (95% CI 1.12–2.34, p = 0.01). In terms of individual cytokines, high IL-6 correlated with inferior OS, with a hazard ratio of 2.73 (95% CI 2.18-3.43, p < 0.00001). Similarly, high IL-12 were linked with worse OS, with a hazard ratio of 1.85 (95% CI 1.26-2.72, p = 0.002). Other individual cytokines were not significantly associated with OS. Conclusions: Cytokines show promise as a prognostic biomarker in pancreatic cancer. Th1 and Th2 cytokines portend worse overall survival outcomes. In particular, high levels of IL-6 and IL-12 can potentially prognosticate patients with poor overall survival. Further prospective studies are encouraged to delineate the role of cytokines in mediating treatment outcomes in this deadly disease.

Development, Validation and Comparison of Artificial Neural Network Models and Logistic Regression Models Predicting Survival of Unresectable Pancreatic Cancer.

Background: Prediction models for the overall survival of pancreatic cancer remain unsatisfactory. We aimed to explore artificial neural networks (ANNs) modeling to predict the survival of unresectable pancreatic cancer patients.Methods: Thirty-two clinical parameters were collected from 221 unresectable pancreatic cancer patients, and their prognostic ability was evaluated using univariate and multivariate logistic regression. ANN and logistic regression (LR) models were developed on a training group (168 patients), and the area under the ROC curve (AUC) was used for comparison of the ANN and LR models. The models were further tested on the testing group (53 patients), and k-statistics were used for accuracy comparison.Results: We built three ANN models, based on 3, 7, and 32 basic features, to predict 8 month survival. All 3 ANN models showed better performance, with AUCs significantly higher than those from the respective LR models (0.811 vs. 0.680, 0.844 vs. 0.722, 0.921 vs. 0.849, all p < 0.05). The ability of the ANN models to discriminate 8 month survival with higher accuracy than the respective LR models was further confirmed in 53 consecutive patients.Conclusion: We developed ANN models predicting the 8 month survival of unresectable pancreatic cancer patients. These models may help to optimize personalized patient management.

The Impact of Prolonged Chemotherapy to Surgery Interval and Neoadjuvant Radiotherapy on Pathological Complete Response and Overall Survival in Pancreatic Cancer Patients.

Background:We aimed to study the impact of neoadjuvant chemotherapy to surgery (NCT-S) interval and neoadjuvant radiotherapy (NRT) on pathological complete response (pCR) and overall survival (OS) in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]).Methods:National Cancer Data Base (NCDB)–pancreatectomy patients who underwent NCT/NRT were included. The NCT-S interval was divided into time quintiles in weeks: 8 to 11, 12 to 14, 15 to 19, 20 to 29, and >29 weeks.Results:A total of 2093 patients with NCT were included with median follow-up of 74 months and 71% NRT. The pCR rate was 2.1% with higher median OS compared with non-pCR (41 vs 19 months, P = .03). The pCR rate increased with longer NCT-S interval (quintiles: 1%, 1.6%, 1.7%, 3%, and 6%, P < .001, respectively). In logistic regression, NRT (odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.1-6.1, P = .03) and NCT-S >29 weeks (OR = 6.1, 95% CI = 2.02-18.50, P < .001) were predictive of increased pCR. The prolonged NCT-S interval and pCR were independent predictors of OS, whereas NRT was not.Conclusions:Longer NCT-S interval and pCR were independent predictors of improved OS in patients with PDAC. The NRT predicted increased pCR but not OS.

In silico analysis of the prognostic value of FAS mRNA in malignancies

Background: FAS is a classical death receptor involved in the FAS/FAS ligand (FASL) apoptosis pathway and plays a role in anti-tumor activity. Some studies have recently reported that FAS can serve as an oncogene that promotes tumor proliferation and maintains the stemness of tumor cells. Hence, its prognostic value in malignancies remains controversial.Methods: we assessed the prognostic value of FAS mRNA in several types of tumors by online platforms including Kaplan-Meier Plotter and SurvExpress.Results: FAS mRNA was associated with better overall survival (OS) in breast cancer (Hazard ratio (HR): 0.59 [0.47, 0.73]; p=1.5e-06), gastric cancer (HR: 0.65 [0.54, 0.77]; p=8e-07) and non-small-cell lung cancer (NSCLC) (HR: 0.78 [0.69, 0.89]; p=0.00016), especially in lung adenocarcinoma (HR: 0.64 [0.51, 0.81], p=1.7e-04), female lung cancer (HR:0.72 [0.57, 0.9], p=0.0049) and patients who have never smoked (HR: 0.39 [0.21, 0.7], p=0.0012). However, a high level of FAS mRNA expression indicated poorer OS in pancreatic cancer (HR: 1.33 [1.06, 1.66]; p=0.01) and acute myeloid leukemia (AML) (HR: 1.57 [1.02, 2.41], p=0.04). Additionally, FAS showed no prognostic value in renal carcinoma, head and neck carcinoma, hepatic cancer, ovarian cancer, colorectal cancer or glioblastoma. The results from the Cell Miner tool revealed that FAS expression was associated with the sensitivity of tumor cells to cabozantinib and erlotinib.Conclusions: In summary, the dominant function of FAS may vary in different malignancies. FAS mRNA expression was correlated with better OS in breast cancer, gastric cancer and lung cancer, but worse OS in pancreatic cancer and AML. We also suggested that FAS mRNA expression could be a potential biomarker for cabozantinib and erlotinib.

Identification of a Nine-Gene Signature and Establishment of a Prognostic Nomogram Predicting Overall Survival of Pancreatic Cancer.

Background: Pancreatic cancer is highly lethal and aggressive with increasing trend of mortality in both genders. An effective prediction model is needed to assess prognosis of patients for optimization of treatment.Materials and Methods: Seven datasets of mRNA expression and clinical data were obtained from gene expression omnibus (GEO) database. Level 3 mRNA expression and clinicopathological data were obtained from The Cancer Genome Atlas pancreatic ductal adenocarcinoma (TCGA-PAAD) dataset. Differentially expressed genes (DEGs) between pancreatic tumor and normal tissue were identified by integrated analysis of multiple GEO datasets. Univariate and Lasso Cox regression analyses were applied to identify overall survival-related DEGs and establish a prognostic gene signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell's concordance index (C-index) and calibration curve. GSE62452 and GSE57495 were used for external validation. Gene set enrichment analysis (GSEA) and tumor immunity analysis were applied to elucidate the molecular mechanisms and immune relevance. Multivariate Cox regression analysis was used to identify independent prognostic factors in pancreatic cancer. Finally, a prognostic nomogram was established based on the TCGA PAAD dataset.Results: A nine-gene signature comprising MET, KLK10, COL17A1, CEP55, ANKRD22, ITGB6, ARNTL2, MCOLN3, and SLC25A45 was established to predict overall survival of pancreatic cancer. The ROC curve and C-index indicated good performance of the nine-gene signature at predicting overall survival in the TCGA dataset and external validation datasets relative to classic AJCC staging. The nine-gene signature could classify patients into high- and low-risk groups with distinct overall survival and differentiate tumor from normal tissue. Univariate Cox regression revealed that the nine-gene signature was an independent prognostic factor in pancreatic cancer. The nomogram incorporating the gene signature and clinical prognostic factors was superior to AJCC staging in predicting overall survival. The high-risk group was enriched with multiple oncological signatures and aggressiveness-related pathways and associated with significantly lower levels of CD4+ T cell infiltration.Conclusion: Our study identified a nine-gene signature and established a prognostic nomogram that reliably predict overall survival in pancreatic cancer. The findings may be beneficial to therapeutic customization and medical decision-making.

Dynamic serum alkaline phosphatase is an indicator of overall survival in pancreatic cancer

BackgroundThe prognostic role of serum alkaline phosphatase (ALP) has been found in several kinds of solid malignant tumor, but has never been extensively discussed in pancreatic cancer, especially through the application of dynamic survival model which incorporates the varying nature of ALP measurements.MethodsWe conducted a retrospective study which successfully collected 551 histopathologically confirmed pancreatic ductal adenocarcinoma (PDAC) patients from a cancer specialized hospital in southwest China. The association between variant ALP which measured during the whole survival period and the overall survival (OS) of PDAC patients was evaluated by using dynamic Anderson-Gill (AG) model. Exhaustive sensitivity analysis was performed by adopting continuous cut-offs of ALP.ResultsAfter adjusted for possible confounding of serum albumin, total bilirubin and leukocyte counts, AG model revealed that, serum ALP during the survival period was nonlinearly associated with the OS of PDAC: for resected patients, compared with those whose ALP results ranged within the first quartile (<P25), patients whose ALP measurements belonged to the second (P25-P50), the third (P50-P75), and the forth (>P75) quartiles were observed 1.14 (95% CI: 0.29–4.56), 3.93 (95% CI: 1.23–12.60), 3.87 (95% CI: 1.32–11.36) folds of death hazard; whereas in un-resected PDAC patients, the hazard ratios (HRs) were 1.15 (95% CI: 0.79–1.68), 1.92 (95% CI: 1.32–2.78), and 1.97 (95% CI: 1.30–2.98), respectively. Sensitivity analysis revealed that, for both resected and un-resected patients, the results of AG model were robust with regard to various cut-offs of ALP, and an increased ALP was in general associated with significantly increased hazard of death.ConclusionSerum ALP during the survival period was significantly associated with the OS of PDAC patients, especially for resected early stage PDAC patients. Future studies with expanded sample size and refined prospective design should be implemented to corroborate our major findings. Besides, the underlying mechanism for this possible hazardous role of ALP should also be investigated.

Abstract 1040: Characterization of extracellular vesicles in pancreatic cancer: Changing the way we think about tumorigenesis

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths by 2030. Patients diagnosed with PDAC have a 5-year survival rate ~9%. Detection of pre-neoplastic lesions has the potential to improve treatment and overall survival in pancreatic cancer (PC) by 4-5 fold. However, there is currently no validated screening test for the non-invasive and accurate detection of early stage PC. Extracellular vesicles (EVs) arise from invagination of, and secretion from, cells of all tissue types. Their role in mediating PC tumorigenesis however, is just beginning to be studied. We have found that EVs derived from PC cells (cancer-derived EVs, CDEVs), can impart significant phenotypic and metabolic transformational effects on normal human pancreas cells (hTERT-HPNE and H6c7), tantamount to an epithelial-to-mesenchymal transition (EMT). The goal of this study was to characterize the biochemical cargo of EVs toward understanding their role in PC tumorigenesis. Results: We isolated CDEVs from various established and PDX PC cell lines. After validating enrichment of EV fractions with quantitative ELISA, immunoblot and transmission electron microscopy (TEM), we added CDEVs to culture media of normal cells. We found that CDEVs induce a myriad of changes in normal cells, including significant morphological changes, increased proliferation and an uncharacteristic invasive capability. CDEVs also caused a bioenergetic switch in normal cells, from a quiescent, aerobic profile to a highly energetic and glycolytic profile. Comparative analyses of CDEVs and normal-derived EVs (NDEVs) using 1H- and 13C-NMR showed significantly different biochemical fingerprints. Interestingly, we found that NDEVs contained more amino acids than CDEVs, while CDEVs contained elevated amounts of urea and lactic acid. We next designed a 13C-isotope labeling flux experiment to trace the fate of carbon metabolized from 13C-glucose fed to cells in culture. Using UHPLC/Q-ToF-MS, we identified several differentially labeled isotopes in CDEVs, particularly surrounding lipid biosynthesis and folate. Conclusions: Our results indicate that CDEVs confer enormous transformational properties to normal human pancreas cells in vitro. We hypothesize that EVs could impart tumorigenic properties to normal cells in vivo and this influence could unveil novel mechanisms underpinning cancer onset and progression. We show that there are robust biochemical differences between CDEVs and NDEVs. Biochemical characterization of EV cargo can uncover abrogated pathways in which signaling is mediated by EVs. These signals may be detectable before progression of PC to PDAC, leading to the development of assays for earlier diagnosis in patients. Citation Format: Charles P. Hinzman, Michael Girgis, Yaoxiang Li, Meth Jayatilake, Meena Rajagopal, Partha P. Banerjee, Amrita K. Cheema. Characterization of extracellular vesicles in pancreatic cancer: Changing the way we think about tumorigenesis [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 1040.

Bioinformatics profiling utilized a nine immune-related long noncoding RNA signature as a prognostic target for pancreatic cancer.

To identify an immune-related long noncoding RNA (lncRNA) signature with potential prognostic value for patients with pancreatic cancer. Pancreatic cancer samples with available clinical information and whole genomic mRNA expression data obtained from The Cancer Genome Atlas (TCGA) were enrolled in our research. The immune score of each sample was calculated according to the expression level of immune-related genes and used to identify the most promising immune-related lncRNAs. According to the risk score developed from screened immune-related lncRNAs, the high- and low-risk groups were separated on the basis of the median risk score. The prediction reliability was further evaluated in the validation set and combination set. Both gene set enrichment analysis (GSEA) and principal component analysis (PCA) were performed for functional annotation, and the microenvironment cell population record was applied to evaluate the immune composition and purity of the tumor. A cohort of 176 samples was included in this study. A total of 163 immune-related lncRNAs were collected according to Pearson correlation analyses between immune score and lncRNA expression |R| > 0.5, P < 0.01). Nine immune-related lncRNAs (AL138966.2, AL133520.1, AC142472.1, AC127024.5, AC116913.1, AC083880.1, AC124016.1, AC008443.5, and AC092171.5) with the most significant prognostic values (P < 0.01) were identified. In the training set, it was observed that patients in the low-risk group showed longer overall survival (OS) than those in the high-risk group (P < 0.001); meanwhile, similar results were found in the validation set, combination set and various stratified sets (P < 0.05, P < 0.001, P < 0.05, respectively). Moreover, the signature was identified as an independent prognostic factor and significantly associated with the OS of pancreatic cancer. The area under curve (AUC) of the receiver operating characteristic curve (ROC curve) for the nine lncRNA signature in predicting the 2-year survival rate was 0.703. In addition, the low-risk and high-risk groups displayed different distributed patterns in PCA and different immune statuses in the GSEA. The signature indicated decreased purity of the tumor by implying a lower proportion of cancer cells along with an increasing enrichment of fibroblasts, myeloid dendritic cells, and monocytic lineage cells. Our research suggests that the immune-related lncRNA signature possesses latent prognostic value for patients with pancreatic cancer and may provide new information for immunological research and treatment in pancreatic cancer.

The IL-1/IL-1 receptor axis and tumor cell released inflammasome adaptor ASC are key regulators of TSLP secretion by cancer associated fibroblasts in pancreatic cancer

BackgroundThe thymic stromal lymphopoietin (TSLP), a key cytokine for development of Th2 immunity, is produced by cancer associated fibroblasts (CAFs) in pancreatic cancer where predominant tumor infiltrating Th2 over Th1 cells correlates with reduced patients’ survival. Which cells and molecules are mostly relevant in driving TSLP secretion by CAFs in pancreatic cancer is not defined.MethodsWe performed in vitro, in vivo and ex-vivo analyses. For in vitro studies we used pancreatic cancer cell lines, primary CAFs cultures, and THP1 cells. TSLP secretion by CAFs was used as a read-out system to identify in vitro relevant tumor-derived inflammatory cytokines and molecules. For in vivo studies human pancreatic cancer cells and CAFs were orthotopically injected in immunodeficient mice. For ex-vivo studies immunohistochemistry was performed to detect ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) expression in surgical samples. Bioinformatics was applied to interrogate published data sets.ResultsWe show in vitro that IL-1α and IL-1β released by pancreatic cancer cells and tumor cell-conditioned macrophages are crucial for TSLP secretion by CAFs. Treatment of immunodeficient mice orthotopically injected with human IL-1 positive pancreatic cancer cells plus CAFs using the IL-1R antagonist anakinra significantly reduced TSLP expression in the tumor. Importantly, we found that pancreatic cancer cells release alarmins, among which ASC, able to induce IL-1β secretion in macrophages. The relevance of ASC was confirmed ex-vivo by its expression in both tumor cells and tumor associated macrophages in pancreatic cancer surgical samples and survival data analyses showing statistically significant inverse correlation between ASC expression and survival in pancreatic cancer patients.ConclusionsOur findings indicate that tumor released IL-1α and IL-1β and ASC are key regulators of TSLP secretion by CAFs and their targeting should ultimately dampen Th2 inflammation and improve overall survival in pancreatic cancer.

PO-425 Combined administration of anti-IL6 and anti-PD-L1 antibodies prevents ketogenic failure, reduces tumour progression, and increases overall survival in an autochthonous murine pancreatic cancer model

IntroductionTumour associated IL-6 downregulates hepatic ketogenesis and thus predisposes to metabolic stress during caloric deficiency. Stress induced glucocorticoids are immune suppressive and can cause failure of cancer immunotherapy. Here, we investigate if this convergence of host metabolism and anti-tumour immunity offers a target for combination therapy with anti-IL-6 and anti-PD-L1 antibodies.Material and methodsCombined anti-IL-6 and anti-PD-L1 antibodies (n=13) or equimolar control antibodies (n=12) were administered to mice bearing autochthonous pancreatic cancer (KPC: KrasLSL.G12D/+; p53R172H/+; Pdx-Cre/+). Mice in both study arms received one day 1 dose of gemcitabine. Groups were matched with regard to tumour location and size, body weight, sex, and age. Tumour volumes were monitored by ultrasound. Body weight and food intake were recorded. Histopathological analyses of the liver and tumour were performed and the biochemical profile of mice was characterised. For statistical analysis, differences between groups were determined using an unpaired two-tailed Student’s t-test and were considered significant if p-value≤0.05. Overall survival (OS) was analysed on an intention-to-treat basis using the Kaplan-Meier method and by applying Log-rank (Mantel-Cox) statistics. The correlation between IL-6-JAK-STAT-3 pathway transcription and overall survival of patients from The Cancer Genome Atlas (TCGA) database was examined.Results and discussionsOverall survival increased significantly in anti-IL-6 and anti-PD-L1 treated mice compared to control mice (OS: 25 days vs. 11 days, p=0.04). Day 7 measurements revealed delayed tumour progression in the combination immunotherapy cohort (volume increase in%: 118+/-5.4 vs. 138+/-5.6, p=0.02). Detailed metabolic analyses are ongoing. The combined analysis of expression from 55 505 transcripts from 9345 patients using GSEA identified an association between IL-6 pathway transcription and shorter OS (p<0.0001). IL-6 expression was statistically significantly associated with shorter OS in non-small cell lung cancer (p=0.036, n=496) and associated with shorter OS in pancreatic cancer (p=0.064, n=178).ConclusionCombination treatment with anti-IL-6 and anti-PD-L1 antibodies significantly increased OS and slowed tumour growth in an autochthonous mouse model of pancreatic cancer. The results of our work provide further justification to explore this treatment combination in patients with cancer associated elevation of IL-6.

Genetic variability of the ABCC2 gene and overall survival in pancreatic cancer

It is widely accepted that postoperative pancreatic fistula (POPF) accompanied by bacterial infection results in a worse outcome than POPF alone. However, few studies evaluating predictive indicators of POPF have focused on bacterial infection.A consecutive 100 patients who underwent pancreaticoduodenectomy at our institute for periampullary disease were enrolled. POPF was assessed according to the International Study Group of Pancreatic Fistula consensus guidelines; grades B and C were defined as clinically relevant POPF (CR-POPF). The patients’ characteristics, perioperative surgical factors, and laboratory data including the results of culture and smear testing performed using drainage fluid on postoperative days (PODs) 1 and 3 were analyzed.The overall incidence of CR-POPF was 25%. Univariate analyses revealed that the factors associated with CR-POPF were male sex, soft pancreas, MPD diameter, higher serum C-reactive protein concentration and white blood cell count on POD 3, higher amylase concentration in drainage fluid, and culture and/or smear positivity of drainage fluid. Multivariate analysis newly revealed that the smear positivity of drainage fluid on POD 3 was the independent risk factors for CR-POPF (p = 0.027).Smear positivity of drainage fluid on POD 3 after pancreaticoduodenectomy may be a new predictor of CR-POPF.

Circulating and disseminated tumor cells in pancreatic cancer and their role in patient prognosis: a systematic review and meta-analysis.

BackgroundDisseminated tumor cells (DTCs) and circulating tumor cells (CTCs) have been postulated to seed metastases and contribute to poorer patient outcomes in many types of solid cancer. To date, no systematic reviews have examined the role of both DTCs and CTCs in pancreatic cancer. We aimed to determine the prognostic value of DTCs/CTCs in pancreatic cancer using a systematic review and meta-analysis.Materials and MethodsA comprehensive literature search identified studies examining DTCs and CTCs in the bone marrow and blood of pancreatic cancer patients at diagnosis with follow-up to determine disease-free/progression-free survival (DFS/PFS) and overall survival (OS). Statistical analyses were performed to determine the hazard ratio (HR) of DTCs/CTCs on DFS/PFS and OS.ResultsThe literature search identified 16 articles meeting the inclusion criteria. The meta-analysis demonstrated statistically significant HR differences in DFS/PFS (HR = 1.93, 95% CI 1.19–3.11, P = 0.007) and OS (HR = 1.84, 95% CI 1.37–2.45, P =< 0.0001), indicating patients with detectable DTCs/CTCs at diagnosis have worse prognoses. Subgroup analyses suggested CTCs in the peripheral blood (HR =2.03) were more indicative of poor OS prognosis than DTCs in the bone marrow (HR = 1.91), although the difference between these was not statistically significant. Positivity of the CellSearch detection method for DTC/CTC had the highest correlation with decreased OS (HR = 2.79) while immunodetection (HR = 1.91) and RT-PCR (HR = 1.25) were less effective in determining prognosis.ConclusionThe detection of DTCs/CTCs at diagnosis is associated with poorer DFS/PFS and OS in pancreatic cancer.

Positive relationship between subsequent chemotherapy and overall survival in pancreatic cancer: meta-analysis of postprogression survival for first-line chemotherapy.

To gain a better understanding of the impact of postprogression survival (PPS) and post-trial anticancer therapy on overall survival (OS) in first-line pancreatic cancer patients. A literature search identified 54 randomized trials, focusing on gemcitabine monotherapy to eliminate effects of heterogeneity of first-line regimens. We evaluated the relation between OS and either progression-free survival (PFS) or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment. For all 54 trials, PPS was strongly associated with OS (r = 0.844), whereas PFS was moderately associated with OS (r = 0.623). Average OS and PPS were significantly longer in recent trials than in older trials, (7.29 versus 6.15 months, p < 0.001) and (3.64 versus 2.86 months, p < 0.001), respectively. The correlation between OS and PPS in recent trials was much stronger than that in older trials (r = 0.846 versus 0.729). The relation between OS and PFS in recent and older trials did not differ (r = 0.595 versus 0.563). The percentage of patients with post-trial treatment was significantly higher in recent trials than in older trials (52.7 versus 39.7%, p < 0.001). The rate of post-trial anticancer therapy was significantly associated with OS (r = 0.910). We found an increase in median PPS in accordance with an increase in median OS in recent trials compared with older trials and that rate of post-trial anticancer therapy was strongly associated with median OS. It is important that researchers be aware of these findings in designing clinical trials of first-line chemotherapy for pancreatic cancer patients.

Predictive value of glucose transporter-1 and glucose transporter-3 for survival of cancer patients: A meta-analysis.

Background and ObjectiveThe role of glucose transporters in cancers remains contradictory. We conducted a systematic review and meta-analysis to assess the association between overall survival and glucose transporter s (GLUTs) 1 and 3 to find an accurate prognostic biomarker.MethodsWe systematically searched the PubMed, EMbase and Medline databases for relevant published studies that were consistent with the eligible criteria up to January 2016, and calculated pooled estimated hazard ratios of GLUT-1 and -3′s expressions in different cancer types and ethnic populations. Random-effects models were used to assess estimates from studies with significant heterogeneities.ResultsOverall, 12 studies concerning GLUT 1 and 2 studies concerning GLUT 3, which involved 2008 participants when combined, were included in this analysis. We found that overexpression of GLUTs were significantly correlated to poorer survival rates (HR=1.63, 95%CI=1.09-2.44 and HR=1.89, 95%CI=1.28-2.81). In the subgroup analysis, the GLUT 1 up-regulation was correlated with negative overall survival in pancreatic cancer and gastric cancer and with better overall survival in colorectal cancer. In addition, overexpression of GLUT 1 was associated with a poorer prognosis in the Asian population, while no significance was found in the non-Asian subgroup. However, limitations do exist, which could be handled better.ConclusionsA combination of GLUTs 1 and 3 might help predict malignancy of cancers and direct effective cancer therapy.

Pyruvate kinase M2 (PKM2) expression correlates with prognosis in solid cancers: a meta-analysis.

Pyruvate kinase M2 (PKM2) is the key enzyme in the Warburg effect and plays a central role in cancer cell metabolic reprogramming. Recently, quite a few studies have investigated the correlation between PKM2 expression and prognosis in multiple cancer patients, but results were inconsistent. We therefore performed a meta-analysis to explore the prognostic value of PKM2 expression in patients with solid cancer. Here twenty-seven individual studies from 25 publications with a total of 4796 cases were included to explore the association between PKM2 and overall survival (OS) or disease-free survival (DFS)/ progression-free survival (PFS)/ recurrent-free survival (RFS) in subjects with solid cancer. Pooled analysis showed that high levels of PKM2 was significantly associated with a poorer overall survival (HR = 1.73; 95%CI = 1.48-2.03) and DFS/ PFS/ RFS (HR = 1.90; 95%CI = 1.39-2.59) irrespective of cancer types. Different analysis models (univariate or multivariate models), sample-sizes (≤100 or >100), and methods for data collection (direct extraction or indirect extraction) had no impact on the negative prognostic effect of PKM2 over-expression. Nevertheless, stratified by cancer type, high-expression of PKM2 was associated with an unfavorable OS in breast cancer, esophageal squamous carcinoma, hepatocellular carcinoma and gallbladder cancer; whereas was not correlated with a worse OS in pancreatic cancer and gastric cancer. In conclusion, over-expression of PKM2 is associated with poor prognosis in most solid cancers and it might be a potentially useful biomarker for predicting cancer prognosis in future clinical applications.

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study.

BackgroundPancreatic adenocarcinoma (PDAC) incidence is increasing worldwide. Several studies have shown that lymphopenia was correlated with a poor prognosis but the potential interest to measure lymphopenia in the pre and post-operative setting as well as its added value among conventional prognostic factors was never investigated.MethodsData from two independent cohorts in whom patients underwent resection for pancreatic carcinoma were retrospectively recorded. We examined the association between perioperative findings, pre and post-operative lymphocyte counts and overall survival (OS) in univariate and multivariate analyses. Performance assessment and internal validation of the final model were evaluated with Harrell’s C-index, calibration plot and bootstrap sample procedures.ResultsThree hundred ninety patients were included in the analysis between 2000 and 2011. Pre and post-operative lymphocyte counts were independent prognostic factors associated with OS in multivariate analysis (p = 0.0128 and p = 0.0764, respectively). The addition of lymphocyte count variable to the conventional parameters identified in multivariate analysis (metastatic lymph node ratio, veinous emboli and adjuvant chemotherapy) significantly improved the model discrimination capacity (bootstrap mean difference = 0.04; 95 % CI, 0.01–0.06). The use of a threshold and combining the categorical (≥1000; <1000) information in pre and post lymphocyte counts permitted the identification of 4 subgroups of patients with different prognosis (p < 0.0001). Finally, the description of patients in long-term remission showed that only 3 of 65 (4.6 %) patients with post-operative lymphocyte count under 1000/mm3 were alive 4 years after surgery contrary to 54 of 236 (22.8 %) patients with a post-operative lymphocyte count above 1000/mm3.ConclusionPre and post-operative lymphopenia are independent prognostic factors for OS and they have an additive value regarding conventional prognostic factors for death-risk stratification and to predict long-term survival. Lymphopenia should be included as stratification factors in future clinical trial assessing overall survival in pancreatic cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2860-6) contains supplementary material, which is available to authorized users.

Neutrophil and lymphocyte counts at diagnosis are associated with overall survival of pancreatic cancer: A retrospective cohort study.

Neutrophil to lymphocyte ratio (NLR) has been found to be significantly associated with pancreatic cancer (PC) survival. However, no existing studies discussed the association between neutrophil count, lymphocyte count, and PC survival jointly. In this study, we aimed to analyze the influence of neutrophil and lymphocyte counts measured at disease diagnosis on the overall survival (OS) of PC. A total of 288 PC patients diagnosed between January 1, 2012, and December 31, 2013, were retrospectively selected from a population-based electronic inpatients database. Multivariate Cox model and restricted cubic spline (RCS) were used to estimate the associations between neutrophil count, lymphocyte count, and OS of PC. We found that a decreased lymphocyte count at diagnosis was significantly associated with OS of PC: for PC patients whose lymphocyte counts were less than 1.5 × 109/L, the hazard ratio (HR) was 1.82 (95% confidence interval: 1.37–2.40). Although abnormally increased baseline neutrophil count in general was not associated with OS of PC, RCS found a prominently deteriorated survival for PC patients whose baseline neutrophil counts were close to the cutoff point (7.0 × 109/L). Our study results indicate that neutrophil and lymphocyte counts at diagnosis may have prognostic relevance in PC survival, especially lymphocyte count. The clinical significance of neutrophil inhibition and lymphocyte promotion treatments in PC patients should be further discussed.

The C-reactive protein/albumin ratio predicts overall survival of patients with advanced pancreatic cancer.

Recent studies have demonstrated the prognostic value of the C-reactive protein/albumin (CRP/Alb) ratio in cancer. However, the role of the CRP/Alb ratio in advanced pancreatic cancer (PC) has not been examined. A retrospective study of 233 patients with advanced PC was conducted. We investigated the relationship between the CRP/Alb ratio, clinicopathological variables, and overall survival (OS). The optimal cutoff point of the CRP/Alb ratio was 0.54. A higher CRP/Alb ratio was significantly associated with an elevated neutrophil-lymphocyte ratio (NLR) (P < 0.001) and higher modified Glasgow prognostic score (mGPS) (P < 0.001). Using univariate analyses, we found that the age (P = 0.009), disease stage (P < 0.001), NLR (P < 0.001), mGPS (P < 0.001), and CRP/Alb ratio (P < 0.001) were significant predictors of OS. Patients with a higher CRP/Alb ratio had a worse OS than patients with a lower CRP/Alb ratio (hazard ratio (HR) 3.619; 95 % CI 2.681–4.886; P < 0.001). However, the CRP/Alb ratio was identified as the only inflammation-based parameter with an independent prognostic ability in the multivariate analyses (P < 0.001). The pretreatment CRP/Alb ratio is a superior prognostic and therapeutic predictor of OS in advanced PC.

G-protein-coupled receptor kinase 2 in pancreatic cancer: clinicopathologic and prognostic significance

G-protein-coupled receptor kinase 2 (GRK2) was found to regulate biological behaviors in some cancers, including pancreatic cancer (PC). However, its clinicopathologic and prognostic implications in cancer remain unclear. This study was designed to address the issues in PC. Expression of GRK2 was measured by Western blotting and tissue microarray-based immunohistochemical staining in 3 and 171 patients with PC, respectively. The H-score was used to evaluate the staining results. In addition, GRK2 expression was correlated with clinicopathologic variables and overall survival. Finally, the prognostic value of GRK2 was validated in a publically available PC dataset, GSE21501. It was suggested that GRK2 expression was highly up-regulated in 2 out of 3 tumor samples, in contrast to corresponding non-tumor ones. Furthermore, H-score of GRK2 staining was significantly higher in tumor than in non-tumor tissues. Tumoral expression of GRK2 was significantly associated with T stage. Univariate analysis showed that high GRK2 expression in tumor tissues was predictive for poor overall survival of PC. However, GRK2 expression was not identified as an independent prognostic marker in multivariate Cox regression test, although close to the statistical significance. In dataset GSE21501, GRK2 was also revealed to be prognostic. Our data establish that GRK2 is overexpressed in PC, and might serve as a potential indicator of unfavorable prognosis.

Immunoglobulin G4 (IgG4)-positive plasma cell infiltration is associated with the clinicopathologic traits and prognosis of pancreatic cancer after curative resection.

Interactions between pancreatic cancer cells and inflammatory cells play crucial roles in the biological behavior of pancreatic cancer. Abundant infiltration of immunoglobulin G4 (IgG4)-positive plasma cells in the pancreas is the most significant feature of autoimmune pancreatitis; however, the clinical significance of IgG4-positive plasma cell infiltration in pancreatic cancer has not previously been reported. Herein, we analyzed intratumoral and peritumoral infiltrations of IgG4-positive plasma cells in 95 pancreatic cancer cases after curative resection. The correlations between IgG4-positive plasma cell infiltration and the clinicopathologic traits and overall survival of pancreatic cancer were investigated. IgG4-positive plasma cells were found in 86% of tumor tissue samples compared with 69% of peritumoral tissue samples (P=0.0063). The high-level infiltration of intratumoral IgG4-positive plasma cells was positively correlated with poor histological grade (P=0.017). The high-level infiltration of intratumoral IgG4-positive plasma cells was significantly correlated with worse prognosis (P=0.01) in multivariate analysis. We further found that intratumoral M2-polarized tumor-associated macrophages (TAMs) were positively, linearly correlated with IgG4-positive plasma cells. In conclusion, IgG4-positive plasma cell infiltration is correlated with the clinicopathologic traits and overall survival of pancreatic cancer. High-level intratumoral infiltration of IgG4-positive plasma cells is an independent predictor for poor overall survival in pancreatic cancer patients after curative resection. Intratumoral M2-polarized TAMs probably induce IgG4-positive plasma cells.