Combining CRP and CA19-9 in a novel prognostic score in pancreatic ductal adenocarcinoma.

Inflammation promotes tumor progression, induces invasion and metastatic spread. This retrospective study explored CRP, CA19-9, and routine laboratory values as preoperative prognostic factors in pancreatic cancer patients. Between 2000 and 2016, there were 212 surgically treated pancreatic cancer patients at Helsinki University Hospital, Finland. Out of these, 76 borderline resectable patients were treated with neoadjuvant therapy (NAT); 136 upfront resected patients were matched for age and sex at a 1:2 ratio. We analyzed preoperative CRP, CA19-9, CEA, leukocytes, albumin, bilirubin and platelets. CRP and CA19-9 were combined into a prognostic score: both CRP and CA19-9 below the cut-off values (3 mg/l and 37 kU/l, respectively), either CRP or CA19-9 above the cut-off value, and finally, both CRP and CA19-9 above the cut-off values. Among all patients, median disease-specific survival times were 54, 27 and 16 months, respectively (p < 0.001). At 5 years, among patients with CRP and CA19-9 levels below the cut-off values, 49% were alive and 45% were disease-free. Among NAT patients the corresponding survival rates were 52% and 45% and among those undergoing upfront surgery 45% and 40%, respectively. This novel prognostic score combining CRP and CA19-9 serves as a useful preoperative tool estimating survival.

Toll-like receptor 2 and Toll-like receptor 4 predict favorable prognosis in local pancreatic cancer.

Toll-like receptors play an essential role in our innate immune system and are a focus of interest in contemporary cancer research. Thus far, Toll-like receptors have shown promising prognostic value in carcinomas of the oral cavity, colon, and ovaries, but the prognostic role of Toll-like receptors in pancreatic ductal adenocarcinoma has not been established. We set out to investigate whether Toll-like receptor expression could serve in prognostic evaluation in pancreatic ductal adenocarcinoma, as well. Our study comprised 154 consecutive stage I-III pancreatic ductal adenocarcinoma patients surgically treated at Helsinki University Hospital between 2002 and 2011. Patients who received neoadjuvant therapy were excluded. Tissue microarrays and immunohistochemistry allowed assessment of the expression of Toll-like receptor 2 and Toll-like receptor 4 in pancreatic ductal adenocarcinoma tissue, and we matched staining results against clinicopathological parameters using Fisher's test. For survival analysis, we used the Kaplan-Meier method and the log-rank test, and the Cox regression proportional hazard model for univariate and multivariate analyses. The hazard ratios were calculated for disease-specific overall survival. Strong Toll-like receptor 2 expression was observable in 51 (34%) patients and strong Toll-like receptor 4 in 50 (33%) patients. Overall, neither marker showed any direct coeffect on survival. However, strong Toll-like receptor 2 expression predicted better survival when tumor size was less than 30 mm (hazard ratio = 0.30; 95% confidence interval = 0.13-0.69; p = 0.005), and strong Toll-like receptor 4 expression predicted better survival in patients with lymph-node-negative disease (hazard ratio = 0.21; 95% confidence interval = 0.07-0.65; p = 0.006). In conclusion, we found strong Toll-like receptor 2 and Toll-like receptor 4 expressions to be independent factors of better prognosis in pancreatic ductal adenocarcinoma patients with stage I-II disease.

Increasing the Inflammatory Competence of Macrophages with IL-6 or with Combination of IL-4 and LPS Restrains the Invasiveness of Pancreatic Cancer Cells.

Recent studies suggest that pro-inflammatory type M1 macrophages inhibit tumor progression and that anti-inflammatory M2 macrophages enhance it. The aim of this study was to examine the interaction of type M1 and M2 macrophages with pancreatic cancer cells. We studied the migration rate of fluorescein stained pancreatic cancer cells on Matrigel cultured alone or with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) differentiated macrophages or with Macrophage Colony Stimulating Factor (M-CSF) differentiated macrophages, skewing the phenotype towards pro- and anti-inflammatory direction, respectively. Macrophage differentiation was assessed with flow cytometry and the cytokine secretion in cell cultures with cytokine array. Both GM-CSF and M-CSF differentiated macrophages increased the migration rate of primary pancreatic adenocarcinoma cell line (MiaPaCa-2) and metastatic cell line (HPAF-II). Stimulation with IL6 or IL4+LPS reversed the macrophages' increasing effect on the migration rate of MiaPaCa-2 completely and partly of HPAF-II. Co-culture with MiaPaCa-2 reduced the inflammatory cytokine secretion of GM-CSF differentiated macrophages. Co-culture of macrophages with pancreatic cancer cells seem to change the inflammatory cytokine profile of GM-CSF differentiated macrophages and this might explain why also GM-CSF differentiated macrophages promoted the invasion. Adding IL6 or IL4+LPS to the cell culture with MiaPaCa-2 and GM-CSF or M-CSF differentiated macrophages increased the secretion of inflammatory cytokines and this could contribute to the reversion of the macrophage induced increase of cancer cell migration rate.