Abstract
Liver cancer is a rapidly lethal cancer and is on the rise worldwide. Surgery is a gold standard treatment for primary liver cancer and liver metastases, however, non-surgical locoregional treatment options are of increasing clinical interest when tumor size, number and sites permit. Previous studies underline immunomodulatory effects of radiofrequency ablation (RFA) in patients with liver cancer. RFA seems to promote effector immune cell frequencies and diminishing immunosuppressive leukocytes. Nevertheless its impact on extracellular tumor matrix is practically uncovered. Herein we report on the differential effects of RFA and surgical liver resection on serum level of anti-inflammatory marker IL-10 in patients with hepatic cancer.
Introduction
Liver cancer is a highly lethal tumor and the third most common cancer of digestive system according to SEER data.
Introduction
Surgery has always been regarded as a gold standard treatment for liver cancer. In recent years, however, patients with liver cancer are often managed by non-surgical locoregional treatments including ablative therapy (radiofrequency ablation, microwave ablation, cryoablation and so on). Among them radiofrequency thermal ablation (RFA) represents a minimal invasive treatment option and demonstrates good survival rate over the surgical resection when the tumor size is <3 cm [1] [2] [3] . RFA results in higher rate of tumor necrosis, nevertheless tumor size, number and sites are of central importance when performing RFA. In addition to its clinical benefits, experimental studies report that RFA provides adjuvant/"danger" signals to the immune cells, as a consequence it stimulates CD4+ T helpers and causes a drastically increase of antigen-specific CD8+ T cells within the tumor microenvironment and tumor-draining lymph node [4] [5] [6] . In light of its immunomodulatory effects, we have recently demonstrated than RFA application correlates with the diminished NLR and PLR and reduced frequencies of CD4+CD39+ lymphocytes in patients with liver cancer [7] . We and others have additionally shown that the decrease of certain immunoregulatory markers corresponds to a better survival of patients with hepatic cancer [7, 8] .
Introduction
Therefore, RFA, by influencing tumor microenvironment, potentially imposes the immune surveillance of cancer calls. Importantly, however, cellular composition of tumor microenvironment and immune cell recruitment at tumor beds are largely guided by extracellular matrix proteins such as cytokines and chemokines which are negligibly explored in regards to RFA treatment [9, 10] .
Introduction
Among several regulatory cytokines, numerous studies have uncovered the cardinal role of IL-10 not only in deviating anti-inflammatory immune responses in patients with liver cancer, but also in influencing the malignant transformation of hepatocytes [11, 12] . IL-10 triggers the upregulation of Bcl-2 and the downregulation of apoptosis [12] . Interestingly, HCV patients with high serum level of IL-10 are more susceptible to develop HCC than ones with low IL-10 [13] . Though, liver fibrosis and necrosis support lowering IL-10 in such patients [13] [14] [15] . Studies also support to the knowledge that IL-10 assists the detachment of tumor cells from their primary sites and promotes the development of metastases [13] . Thus, IL-10 represents an important target of intervention and treatment of hepatic cancer.
Introduction
Herein we report on the differential effects of RFA and LR on serum IL-10 levels in patients with hepatic cancer.
Introduction
Such findings should facilitate the patients selections for effective treatment options and could broaden the armamentarium of successful application of RFA.
Material and Methods

Patients
A total of 17 patients with primary (HCC and Cholangiocarcinoma) and secondary (metastatic) liver cancer were enrolled in our study. 
Treatment techniques
An image-guided RFA procedure was performed as described in [2] . Briefly, the tumor was localized and RF antenna introduced into the target tissue under ultrasound guidance. RF processing increases temperature into the target tissue up to 102 0 C leading to the irreversible damage by coagulative necrosis. Abdominal contrast computed tomography (CT) was performed to document completeness of the procedure. Liver resection (LR), both anatomic segmental hepatectomy and non-anatomical liver resection, were carried out under the general anaesthesia using an upper middle incision, using non-RF based liver resection devices.
Cytokine measurement
Blood samples were collected from each patient at the diagnosis and after 1 and 3 months of treatment (RFA or LR).
Cytokine measurement
The following serum cytokines: IL-10, IL-17, INF-γ, TGF-β were assayed by ELISA (ebiosciences, USA). Data were analyzed using Graph Pad Prizm software and the Student's t-test was applied to compare data between RFA and LR groups. Furthermore, both study groups were compared with healthy control subjects. P values less than 0.05 were considered as statistically significant.
Results and Discussion
We and others have previously reported that the destruction of tumor microenvironment by RFA results in accumulation of necrotic cancer cells, release of a wide spectrum of tumor antigens and adjuvants therefore favoring effector immune responses [4] [5] [6] . We have also demonstrated that besides the elevation of pro-inflammatory immune cells, RFA triggers the diminution of immunosuppressive cells in blood of patients with hepatic cancer [7] .
Results and Discussion
However, changes in immune cell characteristics largely reflect the altered extracellular matrix composition. Data on pro-vs. anti-inflammatory cytokines and chemokines are still limited in patients receiving RFA.
Results and Discussion
A total of 17 patients with liver cancer was included in the study. Patients' demographic characteristics have been listed and compared between treatment groups in Table 1 . The mean age of patients in RFA and LR group was 55.1 ± 11.2 years and 58.6 ± 8.1 years respectively (p>0.05). There were 3 women (43%) and 4 men (57%) in the RFA cohort whilst, 5 women (50%) and 5 (50%) men in the LR group. No significant differences were observed between groups regarding the number of tumors, tumor size, tumor stage, HBsAg, Anti-HCV positivity.
Results and Discussion
Serum levels of IL-10 were elevated in patients referred to RFA compare to healthy age-matched volunteers (6.97 ± in the extracellular matrix [17] . In tumor microenvironment, it exerts immunosuppressive effect on antigen presentation and recruitment of effector lymphocytes therefore supporting escape of tumor cells from immune recognition. IL-10, together with TNF-a, stimulates the expression of negative costimulatory molecule B7-H1(PDL-1) on macrophages in an autocrine manner, thereby impairs CD8 + T cell activity and supports tumor progression [17] .
Results and Discussion
Previous reports demonstrate that IL-10 modulates liver fibrogenesis and promotes carcinogenesis [13] [14] [15] .
Results and Discussion
Interestingly, Aroucha et al reported that the severe necro-inflammatory state is associated with low IL-10 production in HCC patients [18] . In this line, our results revealed that, RFA, which establishes severe necroinflammatory state, significantly lowers serum levels of IL-10, in contrast to LR. This data indicate that tumor removal itself does not impact IL-10 and this process is more complex involving microenvironmental remodeling.
Results and Discussion
Noteworthy to highlight that opposite to RFA, patients in LR group showed elevated IL-10 levels that kept In conclusion, RFA and LR have a distinct impact on tumor microenvironment and its further exploration should, in a long term, improve the guidance of treatment in clinical cases.
Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this manuscript.

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