Browsing by Author "Mustonen, Harri"

Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-related death globally, and, despite improvements in diagnostics and treatment, survival remains poor. Matrix metalloproteinases (MMPs) are enzymes involved in stroma remodelling in inflammation and cancer. MMP-8 plays a varied prognostic role in cancers of the gastrointestinal tract. We examined the prognostic value of MMP-8 immunoexpression in tumour tissue and the amount of MMP-8-positive polymorphonuclear cells (PMNs) in PDAC and their association with immune responses using C-reactive protein (CRP) as a marker of systemic inflammation. Tumour samples from 141 PDAC patients undergoing surgery in 2002–2011 at the Department of Surgery, Helsinki University Hospital were stained immunohistochemically, for which we evaluated MMP-8 expression in cancer cells and the amount of MMP-8-positive PMNs. We assessed survival using the Kaplan–Meier analysis while uni- and multivariable analyses relied on the Cox proportional hazards model. A negative MMP-8 stain and elevated CRP level predicted a poor prognosis (hazard ratio [HR] = 6.95; 95% confidence interval (CI) 2.69–17.93; p < 0.001) compared to a positive stain and low CRP level (<10 mg/L). The absence of PMNs together with an elevated CRP level also predicted an unfavourable outcome (HR = 3.17; 95% CI 1.60–6.30; p = 0.001). MMP-8 expression in the tumour served as an independent positive prognostic factor (HR = 0.33; 95% CI 0.16–0.68; p = 0.003). Tumour MMP-8 expression and a low CRP level may predict a favourable outcome in PDAC with similar results for MMP-8- positive PMNs and low CRP levels. Tumoural MMP-8 expression represents an independent positive prognostic factor in PDAC.

BACKGROUND: Toll-like receptors (TLRs) play an essential role in our innate immune system and are a focus of interest in contemporary cancer research. Thus far, TLRs have shown promising prognostic value in carcinomas of the oral cavity, colon, and ovaries, but the role of TLRs in pancreatic ductal adenocarcinoma (PDAC) awaits exploration. We set out to investigate whether TLR expression could serve in prognostic evaluation in PDAC, as well. METHODS: Our study comprised 154 stage I – III PDAC patients surgically treated at Helsinki University Hospital between 2000 and 2011. Patients who received neoadjuvant therapy were excluded. Tissue microarrays and immunohistochemistry allowed assessment of the expression of TLR2 and TLR4 in PDAC tissue, and we matched staining results against clinicopathological parameters using Fischer'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. RESULTS: Strong TLR2 expression was observable in 51 (34%) and strong TLR4 in 50 (33%) patients. Overall, neither marker showed any direct coeffect on survival. However, strong TLR2 expression predicted better survival when tumor size was less than 30 mm (HR=0.32; 95% CI 0.13 – 0.75; p=0.009), and strong TLR4 expression predicted better survival in patients with lymph-node-negative disease (HR=0.21; 95% CI 0.07 – 0.65; p=0.006). CONCLUSION: We found strong TLR2 and TLR4 expression to be independent factors of better prognosis in PDAC patients with stage I-II disease.