Project description:Pancreatic cancer is the fourth leading cancer-related death in United States. The clinical relevance of genomic imbalances in pancreatic cancer is uncertain. We performed array-comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens from a Korean cohort. We observed recurrent copy number gains were observed in chromosome 1q, 11q, 18q11.1-11.2, and 20q13.13; and losses in chromosome 2p, 9p, 10q, 14q, 15q, 18q12.2-23, 19q, 20q11.1, 21p, and 22q. High copy number gains, with log2 ratio >2.0, were observed in 4 cytobands, encoding genes such as G protein-coupled receptor 48, c-myc and gamma-catenin. By comparing the aCGH results of long survivors and short survivors, determined according to the median survival, we observed that loss of cytoband 18q22.3, encoding 5 genes, was the only alteration with significantly different frequencies. The copy number of the CPGL (Carboxypeptidase of glutamate-like) gene in cytoband 18q22.3 was found to be significantly associated with overall survival in univariate analyses (p=0.019 by log-rank test). This was subsequently assessed in the Italian cohort: 41 out of the 61 specimens carried deletion of the CPGL gene. Patients with deletion of the CPGL gene also had shorter overall survival (p=0.003 by log-rank test). Multivariate analysis of the two cohorts combined showed that loss of 18q22.3 / deletion of the CPGL gene was an independent poor prognostic factor for overall survival after adjusting for other factors which were found to impact the outcome (hazard ratio 2.72, p=0.0007). overexpression of the CPGL or its alternating splicing isoform CPGL-B in a pancreatic cancer cell lines resulted in slower proliferation of cells, G1 cell cycle arrest, and reduced migration activity. In conclusion, through aCGH analysis, we identified loss of 18q22.3 / deletion of the CPGL gene as potentially being an independent poor prognostic factor in resected pancreatic cancer. We further identified the CPGL gene as a potential tumor suppressor for pancreatic cancer cell lines. Array-comparative genomic hybridization was performed in 44 resected pancreatic cancer specimen from a Korean cohort. Genomic alteration relating to prognosis of the Korean cohort was further validated in a Italian cohort containing 61 resected pancreatic cancer specimens.

Project description: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.

Project description:Pancreatic cancer is the fourth leading cancer-related death in United States. The clinical relevance of genomic imbalances in pancreatic cancer is uncertain. We performed array-comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens from a Korean cohort. We observed recurrent copy number gains were observed in chromosome 1q, 11q, 18q11.1-11.2, and 20q13.13; and losses in chromosome 2p, 9p, 10q, 14q, 15q, 18q12.2-23, 19q, 20q11.1, 21p, and 22q. High copy number gains, with log2 ratio >2.0, were observed in 4 cytobands, encoding genes such as G protein-coupled receptor 48, c-myc and gamma-catenin. By comparing the aCGH results of long survivors and short survivors, determined according to the median survival, we observed that loss of cytoband 18q22.3, encoding 5 genes, was the only alteration with significantly different frequencies. The copy number of the CPGL (Carboxypeptidase of glutamate-like) gene in cytoband 18q22.3 was found to be significantly associated with overall survival in univariate analyses (p=0.019 by log-rank test). This was subsequently assessed in the Italian cohort: 41 out of the 61 specimens carried deletion of the CPGL gene. Patients with deletion of the CPGL gene also had shorter overall survival (p=0.003 by log-rank test). Multivariate analysis of the two cohorts combined showed that loss of 18q22.3 / deletion of the CPGL gene was an independent poor prognostic factor for overall survival after adjusting for other factors which were found to impact the outcome (hazard ratio 2.72, p=0.0007). overexpression of the CPGL or its alternating splicing isoform CPGL-B in a pancreatic cancer cell lines resulted in slower proliferation of cells, G1 cell cycle arrest, and reduced migration activity. In conclusion, through aCGH analysis, we identified loss of 18q22.3 / deletion of the CPGL gene as potentially being an independent poor prognostic factor in resected pancreatic cancer. We further identified the CPGL gene as a potential tumor suppressor for pancreatic cancer cell lines.

Project description:BackgroundPancreatic cancer is a highly malignant tumor with a poor prognosis. Chemotherapy such as gemcitabine is still an important treatment. Gemcitabine (Gem) may prolong survival time and delay the development of recurrent disease after complete resection of pancreatic cancer. Currently, some control studies have been performed between certain drugs and gemcitabine monotherapy after pancreatic cancer surgery, but the outcomes were uncertain. Here, we implemented meta-analysis to compare the efficacy between adjuvant treatments and gemcitabine monotherapy in patients with resected pancreatic cancer.MethodsPubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library searches were undertaken to identify randomized controlled trials (RCTs). Date of search ranged from January 1997 to December 2017. The meta-analysis included six RCTs. The major endpoints involved overall survival (OS), disease-free survival/progress free survival/relapse-free survival (DFS/PFS/RFS) and grade 3-4 toxicity.ResultsPooled meta-analytic estimates were derived using random-effects model. Subgroup analysis used fixed-effects model. The outcome showed that there was no difference in OS (hazard ratio (HR), 0.87; 95% CI, 0.70-1.07; P = 0.19) and DFS (HR, 0.85; 95% CI, 0.71-1.02; P = 0.08) between the adjuvant treatments group (fluorouracil+folinic acid, S-1, gemcitabine+capecitabine, gemcitabine+erlotinib and gemcitabine+uracil/tegafur) and Gem monotherapy group. However, the subgroup analysis showed that only S-1 chemotherapy, which is an oral fluoropyrimidine agent containing tegafur, gimeracil and oteracil, was significant in OS (HR, 0.59; 95% CI, 0.46-0.74; P < 0.0001) and DFS (HR, 0.63; 95% CI, 0.52-0.75; P < 0.00001) compared with Gem alone. Toxicity analysis showed there was an increased incidence of grade 3/4 diarrhea (risk ratio (RR), 5.11; 95%CI, 3.24-8.05; P < 0.00001) and decreased incidence of grade 3/4 leucopenia (RR, 0.55; 95%CI, 0.31-0.98; P = 0.04), thrombocytopenia (RR, 0.61; 95%CI, 0.39-0.97; P = 0.04) in adjuvant treatments group. Neutropenia (RR, 0.69; 95%CI, 0.36-1.29; P = 0.24) and fatigue (RR, 1.29; 95%CI, 0.95-1.77; P = 0.11) for patients between the two groups were not significantly different.ConclusionsIn our meta-analysis, a significant survival benefit is only observed in the S-1 regimen, but the results are yet to be determined. Optimal cytotoxicity or targeted drug regimens need further validation in clinical trials in the future.

Project description:BackgroundProgrammed cell death protein 1 (PD-1) is a key immune checkpoint that regulates peripheral tolerance and protects against autoimmunity. Programmed death ligand-2 (PD-L2) is a less studied ligand to PD-1 and has yet to be fully explored, especially in pancreatic ductal adenocarcinoma (PDAC).MethodsIn this study, we performed immunohistochemistry to detect the PD-L2, CD3, CD8, transforming growth factor-β2 (TGF-β2) and FOXP3 levels in paraffin sections from 305 patients with resected PDAC as a training set. Expression levels of intratumoral and stromal immune markers were compared in relation to survival using Kaplan-Meier curves, random survival forest model and survival tree analysis. A multivariable Cox proportional-hazards model of associated markers was used to calculate the risk scores.ResultsPD-L2 was expressed in 71.5% of PDAC samples and showed strong correlations with CD3+, CD8+ T cells and FOXP3+ regulatory T cell densities. High levels of intratumoral PD-L2 and FOXP3 were related to poor survival; only stromal FOXP3 overexpression was associated with worse prognosis. Four patterns generated from survival tree analysis demonstrated that PD-L2lowstromalFOXP3low patients had the longest survival, while PD-L2highintratumoralCD3low patients had the shortest survival (P < 0.001). The area under the curve was 0.631(95% confidence interval (CI): 0.447-0.826) for the immune marker-based signature and 0.549 (95% CI: 0.323-0.829; P < 0.001) for the clinical parameter-based signature, which was consistent with the results in the validation set including 150 patients (P < 0.001). A higher risk score indicated shorter survival and could serve as an independent prognostic factor. PD-L2 was also showed associated with TGF-β2 and other immune molecules based on bioinformatics analysis.ConclusionsOur work highlighted PD-L2 as a promising immunotherapeutic target with prognostic value combined with complex tumor infiltrating cells in PDAC.

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DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer.

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DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer.

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