Natural killer (NK) cells are considered crucial for the elimination of emerging tumor cells. Effector NK-cell functions are controlled by interactions of inhibitory and activating killer-cell immunoglobulin-like receptors (KIRs) on NK cells with human leukocyte antigen (HLA) class I ligands on target cells. KIR and HLA are highly polymorphic genetic systems segregating independently, creating a great diversity in KIR/HLA gene profiles in different individuals. There is an increasing evidence supporting the relevance of KIR and HLA ligand gene background for the occurrence and outcome of certain cancers. However, the data are still controversial and the mechanisms of receptor-ligand mediated NK-cell action remain unclear. Here, the main characteristics and functions of KIRs and their HLA class I ligands are reviewed. In addition, we review the HLA and KIR correlations with different hematological malignancies and discuss our current understanding of the biological significance and mechanisms underlying these associations.
Objective:Natural killers (NK) cell function is mainly controlled by the expression of killer immunoglobulin-like receptors (KIRs) and their ligation with the corresponding ligands. The objective of this study was to investigate the putative association of KIRs, HLA class I ligands, and KIR/ligand combinations with rates of development of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML).Materials and Methods:The KIR/HLA I genotypes of 82 patients with leukemia (ALL, n=52; AML, n=17; and CML, n=13) were determined by PCR-SSP method and compared with genotypes of healthy controls (n=126).Results:KIR genotype frequency differed significantly between myelogenous leukemia patients and healthy controls for KIR2DL5A (17.6% vs. 47.7%, p=0.02), KIR3DS1 (17.6% vs. 47.6%, p=0.02), and KIR2DS4*001 (36.6% vs. 20.2%, p=0.017). The incidence of homozygous HLA-BBw4 (31.0% vs. 12.5%, p=0.042) and HLA-Bw4Thr80 Thr80 (13.0% vs. 1.2%, p=0.01) was significantly elevated in myeloid leukemia patients compared to healthy controls. KIR/HLA class I ligand profile KIR3DS1(+)/L (-) was decreased and KIR3DL2(+)/HLA-A3/11(-) was increased among myeloid leukemia cases compared to controls.Conclusion:These data suggest that the activity of NK cells as determined by inherited KIR/HLA class I ligand polymorphisms influences the susceptibility to myelogenous leukemia, but not to lymphoblastic leukemia. Additionally, the KIR genotype characterized by the absence of the inhibitory KIR2DL2 and the activating KIR2DS2 and KIR2DS3 (ID2) was found at a lower frequency in patients compared to controls, which confirmed the need for complex analysis based on all possible KIR/HLA class I ligand polymorphism combinations.
Introduction: Hypomethylating agents have become a standard therapy for certain myeloid malignancies.Aim: The aim of this preliminary study was to assess efficacy and safety of azacitidine in patients with myelodysplas tic syndromes (MDS), chronic myelomonocytic leukemia with 10-29% blasts (CMML-2) and acute myeloid leukemia (AML) treated in a single center.Material and Methods: Twenty-six (69% male and 31% female, median age 67.8 years) patients (MDS, = 15; CMML-2, n = 2; AML, n = 9) treated with azacytidine in the period April 2017 to October 2018 year were included in the study. Disease assessment was performed after the 3rd cycle, 6th cycle, and at progression.Results: The median number of administered cycles was 6 (1-16). Erythroid response was achieved in 46.7% after 3rd cycle and 66.7% after 6th cycle. Platelet response was reached in 72.7% after 3rd cycle and 40% after 6th cycle and neutrophil hematological improvement in 27.3% and 50%, respectively. Only one patient (8.3%) progressed after the 6th cycle, stable disease or better marrow response was achieved in the others. The median progression free survival (PFS) and overall survival (OS) were 7.9 and 10.7 months in the MDS group and 9.7 and 11.5 months in the AML group, respectively. None of the patients with CMML-2 progressed at the end of the study. The only found factor to correlate with shortened PFS and OS was IPSS high risk MDS. The most frequent grade ≥ 3 adverse events was neutropenia 38.5%, followed by anemia 15.4% and thrombocytopenia 11.5%.Conclusion: The therapy with azacitidine is an option for elderly patients with high-risk MDS, AML and CMML-2 that provides PFS and OS for approximately one year irrespective of age or nosological subgroup. These are preliminary data and larger patient cohort and longer follow-up period are needed for clinical conclusions.
Background. Hepatitis B virus (HBV) infection is one of the most common infections worldwide, having negative impact on world health due to the tendency for chronification with late complications such as liver cirrhosis and hepatocellular carcinoma. Natural killer (NK) cells as part of innate antiviral defense influence the clinical course of HBV infection: elimination of the virus or chronic disease. Aim. Therefore, we investigated the polymorphisms of the main gene systems, regulating NK-cell function: killer cell immunoglobulin-like receptors (KIRs) and their appropriate HLA class I ligands in 144 HBV infected patients (124 chronic carriers and 20 spontaneously recoved) and 126 ethnically matched healthy controls from the Bulgarian population in a case-control study. Methods. KIRs and HLA ligands were determined by PCR-SSP or PCR high-resolution typing methods. Results. KIR2DL5B allele variant was significantly less frequent in spontaneously recovered (SR) patients compared to healthy controls (10.0% vs. 45.5%, P corr =0.006). The presence of KIR3DL1*004 allele was higher in chronic HBV carriers (CH) than in controls (33.1% vs. 17.6%, P corr =0.036). Additionally, SR patients differed from healthy individuals by the lower frequency of HLA-Bw4 Ile80 group ligands (30.0% vs 63.7%, P=0.015). Three KIR genotypes were found more frequent in healthy in comparison with HBV infected individuals: ID2 (13.5% vs 5.6%, P=0.025), KIR genotype containing 6 activating KIRs (18.0% vs 7.6%, P=0.017), and KIR genotype composed of 4 activating and 5 inhibitory KIRs (23.8% vs 5.6%, P=0.001). Conclusion. These data suggest that inherited KIR and HLA class I ligand polymorphisms may influence the clinical course of HBV infection.
To assess the cost-effectiveness of pembrolizumab versus paclitaxel or docetaxel monotherapy in patients with locally advanced or metastatic urothelial cancer, who have previously received treatment with platinum-containing chemotherapy in England. METHODS: A three-state partition survival model was developed, projecting costs and outcomes over a 35-year time horizon with a one-week cycle. As per the NICE reference case, costs and outcomes were discounted with a 3.5% annual discount rate. Clinical efficacy, adverse events and quality of life data were derived from KEYNOTE-045; a phase III randomised trial of pembrolizumab versus investigator's choice of chemotherapy. Due to the use of subsequent immunotherapy regimens in the chemotherapy arm, the observed overall survival (OS) was confounded, and as such adjusted using the two-stage adjustment method. Within the model, OS was extrapolated using a piece-wise approach, utilising Kaplan-Meier data (data cut-off date 18th January 2017) until week 40, and the log-normal distribution for the remainder of the time horizon. Alternative extrapolation cutoff and parametric functions were tested in scenario analyses. Qualityadjusted life years (QALYs) were estimated using time-to-death utilities derived from EQ-5D data collected in the KEYNOTE-045 trial. Costs were applied from the NHS perspective. To assess model uncertainty, probabilistic and deterministic sensitivity analyses were performed. RESULTS: The use of pembrolizumab as modelled above demonstrates an increase in life expectancy by 1.18 years for patients, corresponding to a gain of 0.90 QALYs versus chemotherapy. The base case incremental cost-effectiveness ratio (ICER) is £41,004 (confidential discount included). The results are sensitive to assumptions around extrapolation of OS and methodology of utility estimates. CONCLUSIONS: Using a willingness to pay threshold of £50,000 per QALY gained, as per the NICE end-of-life criteria, pembrolizumab represents a costeffective treatment option for NHS England when compared to docetaxel or paclitaxel monotherapy.
Background: Some human tumors exhibit a high requirement for Glutamine (Gln) for metabolic processes, a condition defined "Gln-addiction'' leading to the investigation of Gln-dependence as therapeutic tar-
NK cell function is controlled by the cell expression of killer immunoglobulin-like receptors (KIRs) and their ligation with the corresponding HLA ligands. Various malignancies have been associated with certain KIRs surface cell expression and various KIR/HLA ligand combinations. Prior research using case/control study design demonstrates the role of KIR and KIR HLA ligands as genetic factor involved in tumor susceptibility. The objective of this study was to investigate the family-based association of KIRs, HLA class I ligands and KIR/ligand combinations with leukemia diagnosis in families having a leukemia diagnosed child. Sixty-seven families that met the index leukemia case criteria (acute lymphoblastic leukemia, ALL, n = 45; acute myeloid leukemia, AML, n = 13; chronic myeloid leukemia, CML, n = 9; first degree healthy relatives n = 159) were examined. Our study consisted of two phases. In Phase1 case-control study, we primarily compared patients to their healthy siblings to asses if a marker or genotype may be associated with leukemia, excluding the impact of the environment. Phase 2 consisted of a secondary family-based association study. KIR genotyping was performed by PCR-SSP method. KIR HLA ligands were defined by direct method using PCR-SSP method and/or indirect base on high resolution typing of HLA-A, -B, -C alleles. Results of phase 1 showed an increase in the frequency of KIR genotype (with a ratio = 0.57; higher frequency for inhibitory KIRs vs. activating KIRs) among leukemia patients compared to healthy siblings. Results of the phase 2 familial study observed an association between HLA-C1+/BBw4+/ABw4+ haplotype (a mediator of inhibitory signals) and leukemia. Also, we concluded that the absence of HLA-ABw4 alleles was related to leukemia development.
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