EFFECTS OF DIFFERENT TREATMENT OPTIONS ON THE LEVEL OF SERUM CYTOKINES IN PATIENTS WITH LIVER CANCER.

Liver cancer is a highly lethal cancer, in which local tumor microenvironment and systemic immune suppression allow tumor to escape immune surveillance. Intervening in tumor microenvironment by locoregional treatment options can be beneficial for patients. We aimed to study changes in serum cytokines levels due to local disturbance of tumor microenvironment after radiofrequency thermal ablation procedure compare to liver resection in patients with primary and metastatic liver cancer. A total of 17 patients with primary (HCC and Cholangiocarcinoma) and secondary (metastatic) liver cancer were enrolled in this prospective study. Out of 17 patients, 7 were referred to RFA procedure and another 10 underwent surgical liver resection using non-RF based devices. Blood samples were collected from each patient before and after 1 and 3 months of treatment. The following serum cytokines: IL-10, IL-17, INF-γ, TGF-ß were assayed by ELISA (ebiosciences, USA). RFA procedure unlike liver resection decreased serum level of IL-10 in patients with liver cancer. No significant changes in the level of the studied cytokines were revealed.

COMPLETE BLOOD COUNT DERIVED INFLAMMATORY BIOMARKERS IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES.

Inflammation sometimes can be associated with the development of number of diseases, among them cancer. Few studies show prognostic value of different inflammatory markers, such as lymphocyte and monocyte count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and others in some types of blood cancers. There is further need to investigate easy measurable diagnostic and prognostic novel biomarkers in hematologic malignancies. Our aim was to investigate the role of inflammatory markers: NLR, PLR, platelet-monocyte ratio (PMR), hemoglobin-platelet ratio (HPR), hemoglobin-lymphocyte ratio (HLR), lymphocyte-monocyte ratio (LMR), systemic immune-inflammation index (SII) and derived neutrophil-lymphocyte ratio (dNLR), which were used alone or in combination, in early diagnoses of hematologic malignancies. The counts for total white blood cells, neutrophils, lymphocytes, platelets, monocyte and hemoglobin as well as systemic inflammatory factors, such as NLR, PLR, PMR, HPR, HLR, LMR, SII and dNLRwere analysed from patients with hematologic malignancies and their age-matched controls. The area under the curve (AUC), sensitivity, specificity and cut-off values, as well as correlations between these inflammatory markers were analyzed. The patients with hematologic malignancies have significantly increased level of inflammatory markers: NLR, PLR, PMR, HLR, SII and dNLR in comparison with age-matched controls. NLR and PLR positively correlate with each other and SII and negatively correlate with HGB. Additionally, PLR has positive correlation with HLR. dNLR has the highest AUC score. For diagnosing hematologic malignancies the AUC of the ROC curve for dNLR was 0.810 with a 95% CI of 0.646-0.975. However, combining these six markers - NLR, PLR, PMR, HLR, SII and dNLR reached the best AUC score - 0.923 with a 95% of CI of 0.778-1.000. Results indicate that NLR, PLR, PMR, HLR, SII and dNLR, which are easily detectable laboratory parameters and reflect systemic inflammatory response can be predictive factors for hematologic malignancies.

PERIPHERIAL BLOOD BIOMARKERS IN PATIENTS WITH REFRACTORY IMMUNE THROMBOCYTOPENIA.

Immune thrombocytopenia is an acquired thrombocytopenia caused by autoantibodies against platelet antigens, the pathogenesis of ITP is incompletely understood. Evidence regarding association between inflammatory factors in patients with ITP who are refractory to first line treatment is limited.The purpose of our study was to investigate the diagnostic value of NLR, PLR, and PMR, dNLR, and SII in ITP patients who were refractory for the first line treatment and had splenectomy as a second-line therapy. Statistical analyses of inflammatory biomarkers were performed using SPSS v.26 and Graph Pad Prism. Correlations between the variables were determined by Spearman's correlation coefficient. The area under the curve (AUC), sensitivity, specificity, and cut-off values were compared using the receiver operating characteristic (ROC) curve. Our data revealed that NLR and dNLR were increased (p<0.0001), while SII level was decreased (p=0.0003), PMR and PLR were also significantly low (p<0.0001) in ITP patients compared with the age matched conrl group. In addition PLT level was negatively correlated with NLR and dNLR (r=-0.605, P<0.01), while there was positive correlation with SII, PLR, PMR (SII r=0.799; PLR r=0.863; PMR r=0.40, P<0.01). ROC curve analysis revealed ACU of PLR and PMR were 1.000 (P=0.05 and P<0.001), followed by SII 0.899 (P=0.002), NLR 0.875 (P=0.04) and dNLR 0.869 (P=0.05). We observed that inflammatory factors in ITP patients significantly differ from the age matched controls, however larger scale research is needed to confirm the validity of such biomarkers.

Fcγ receptor expression on splenic macrophages in adult immune thrombocytopenia.

Splenic macrophages play a key role in immune thrombocytopenia (ITP) pathogenesis by clearing opsonized platelets. Fcγ receptors (FcγR) participate in this phenomenon, but their expression on splenic macrophages and their modulation by treatment have scarcely been studied in human ITP. We aimed to compare the phenotype and function of splenic macrophages between six controls and 24 ITP patients and between ITP patients according to the treatments they received prior to splenectomy. CD86, human leucocyte antigen D-related (HLA-DR) and FcγR expression were measured by flow cytometry on splenic macrophages. The major FcγR polymorphisms were determined and splenic macrophage function was assessed by a phagocytosis assay. The expression of the activation markers CD86 and HLA-DR was higher on splenic macrophages during ITP compared to controls. While the expression of FcγR was not different between ITP and controls, the phagocytic function of splenic macrophages was reduced in ITP patients treated with intravenous immunoglobulin (IVIg) within the 2 weeks prior to splenectomy. The FCGR3A (158V/F) polymorphism, known to increase the affinity of FcγRIII to IgG, was over-represented in ITP patients. Thus, these are the first results arguing for the fact that the therapeutic use of IVIg during human chronic ITP does not modulate FcγR expression on splenic macrophages but decreases their phagocytic capabilities.

HEPATOCELLULAR CARCINOMA: CURRENT AND PROSPECTIVE IMMUNOTHERAPEUTIC STRATEGIES.

Hepatocellular carcinoma (HCC) is a highly lethal and the most common primary liver cancer with increasing worldwide incidence. Pathogenesis of HCC is immune mediated, however, not completely understood. Chronic low-grade inflammation alters both innate and adaptive immune responses. As a result tolerogenic environment is established in damaged organ. Up to date, incomplete understanding of HCC pathogenesis and the extend of biomarker variability among patients represent the major obstacle for early diagnosis and for the choice of effective treatment. Among current treatment options for HCC, thermal ablation strategy, which in addition to cancer eradication provides adjuvant/"danger"signal to the patient's immune cells, has demonstrated its active immunotherapeutic effect. In ongoing phase I/II clinical trials, tumor antigen loaded dendritic cell (DC)-based vaccines as well as tumor-specific cytotoxic T cells are being tested. Genetically redirected T cell therapy and more refined autologous vaccines are still awaiting approaches in HCC. The topic of this review focuses on current and bench-to-bedside immunotherapeutic strategies for HCC and discusses their advantages and limitations in clinic. We also weight up several prospective immunotherapeutic approaches which in theory have the potential for further implication in HCC. Combination of the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression ought to be a key objective in these future developments.

Pathogenesis of giant cell arteritis: new insight into the implication of CD161+ T cells.

Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that usually affects the aorta and/or its major branches, especially the branches of the carotid arteries. Histo-pathological lesions are observed in all layers of the artery leading to segmental and focal panarteritis with a polymorphic cell infiltrate that includes T cells, macrophages and multinucleated giant cells, a fragmented internal elastic lamina and intimal hyperplasia. The pathophysiology of GCA is complex and not fully understood. In this review, we discuss the immunological aspects of GCA pathogenesis with a particular emphasis on T cell responses. Upon dendritic cell activation in the adventitia, CD4 T cells co-expressing CD161 are recruited in the arterial wall and polarised into Th1 and Th17 cells that produce IFN-γ and IL-17, respectively. These cytokines activate macrophages, giant cells and vascular smooth muscle cells, thus inducing vascular remodelling which leads to the ischaemic manifestations of GCA. Macrophages infiltrating the adventitia produce IL-1ß and IL-6, which are responsible for the general symptoms encountered in GCA.

Haemolytic-uraemic syndrome during severe lupus nephritis: efficacy of plasma exchange.

Systemic lupus erythematosus (SLE) has been described as a cause of thrombotic microangiopathy, especially thrombotic thrombocytopenic purpura (TTP). Haemolytic-uraemic syndrome (HUS) is less frequent in SLE. We report a case of such an association during an episode of severe lupus nephritis in a young woman, who was successfully treated with steroids, cyclophosphamide and especially plasma exchange with plasma replacement. This report highlights the importance of recognising atypical HUS in SLE patients by looking for schistocytes in case of haemolytic anemia with a negative antiglobulin test, in order to begin plasma exchange.

Modulation of neutrophil motility by curcumin: implications for inflammatory bowel disease.

BACKGROUND: Neutrophils (PMN) are the first cells recruited at the site of inflammation. They play a key role in the innate immune response by recognizing, ingesting, and eliminating pathogens and participate in the orientation of the adaptive immune responses. However, in inflammatory bowel disease (IBD) transepithelial neutrophil migration leads to an impaired epithelial barrier function, perpetuation of inflammation, and tissue destruction via oxidative and proteolytic damage. Curcumin (diferulolylmethane) displays a protective role in mouse models of IBD and in human ulcerative colitis, a phenomenon consistently accompanied by a reduced mucosal neutrophil infiltration. METHODS: We investigated the effect of curcumin on mouse and human neutrophil polarization and motility in vitro and in vivo. RESULTS: Curcumin attenuated lipopolysaccharide (LPS)-stimulated expression and secretion of macrophage inflammatory protein (MIP)-2, interleukin (IL)-1ß, keratinocyte chemoattractant (KC), and MIP-1α in colonic epithelial cells (CECs) and in macrophages. Curcumin significantly inhibited PMN chemotaxis against MIP-2, KC, or against conditioned media from LPS-treated macrophages or CEC, a well as the IL-8-mediated chemotaxis of human neutrophils. At nontoxic concentrations, curcumin inhibited random neutrophil migration, suggesting a direct effect on neutrophil chemokinesis. Curcumin-mediated inhibition of PMN motility could be attributed to a downregulation of PI3K activity, AKT phosphorylation, and F-actin polymerization at the leading edge. The inhibitory effect of curcumin on neutrophil motility was further demonstrated in vivo in a model of aseptic peritonitis. CONCLUSIONS: Our results indicate that curcumin interferes with colonic inflammation partly through inhibition of the chemokine expression and through direct inhibition of neutrophil chemotaxis and chemokinesis.