| 21. |
- Jönsson, Sofia, et al.
(författare)
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Imatinib inhibits proliferation of human mesenchymal stem cells and promotes early but not late osteoblast differentiation in vitro.
- 2012
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Ingår i: Journal of bone and mineral metabolism. - 1435-5604. ; 30:1, s. 119-23
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Tidskriftsartikel (refereegranskat)abstract
- Altered bone metabolism has been reported in patients with chronic myeloid leukemia treated with the tyrosine kinase inhibitor imatinib. Several studies have shown that imatinib inhibits the differentiation and activity of osteoclasts in vitro, whereas the effects of imatinib on osteoblast differentiation are less clear. In this study osteoblast differentiation was induced in human mesenchymal stem cells (hMSCs) by treatment with bone morphogenetic protein 2 in vitro. Imatinib inhibited proliferation of hMSCs in a dose-dependent manner. Even though imatinib promoted early osteoblast differentiation assessed by alkaline phosphate activity, mineralization measured by Alizarin Red staining (ARS) was reduced by imatinib. Moreover, the inhibitory effect of imatinib on mineralization was most prominent at low concentrations of imatinib. When we measured the relative mRNA expression levels of Runx2, we found that Runx2 expression was higher in imatinib-treated (5 μM) cultures at early time points during differentiation. On the other hand, the expression of Osterix late during differentiation was lower in imatinib-treated (5 μM) cultures, corresponding to the ARS results. Thus, the effect of imatinib on osteoblast differentiation is not only dependent on the drug concentration, but indeed also on the maturation stage of the cells. This finding might partly explain why previous studies on the effects of imatinib osteoblast differentiation have shown different results.
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| 22. |
- Koskenvesa, Perttu, et al.
(författare)
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Imatinib and pegylated IFN-alpha 2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response
- 2014
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 92:5, s. 413-420
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Previous studies indicate that 40-50% of patients with chronic myeloid leukemia in prolonged complete molecular remission may discontinue imatinib therapy without imminent relapse. The combination of pegylated interferon-alpha (Peg-IFN-alpha 2b) and imatinib may increase the rate of successful discontinuation. Methods In this pilot study, we prospectively stopped imatinib from patients (n=12) who had achieved major molecular response (MMR) after >= 12months of treatment with either imatinib or imatinib+Peg-IFN-alpha 2b. Molecular monitoring was carried out monthly for BCR-ABL1. In addition, analyses of lymphocyte immunophenotype, function, and plasma cytokines were performed. Results In the monotherapy group, 5/6 patients lost MMR within 4months. One patient remains to date in MR4.0 61months after discontinuation. In the combination therapy group, 2/6 patients relapsed within 4months while still receiving Peg-IFN-alpha 2b. Four of six patients were able to discontinue both treatments, but three of these patients relapsed after 3months. One patient is still in sustained MR4.0 at 58months off all treatment. All relapsed patients re-responded to imatinib. The two successfully discontinued patients had either an increased number of NK-cells or functionally active T-cells. Conclusions A higher frequency of relapsed patients in our study in comparison with other studies may be due to the shorter duration of imatinib treatment prior to discontinuation. However, in selected patients with an active immune system, even a short duration of TKI therapy (<2yr) may allow for therapy discontinuation but this needs to be confirmed in larger prospective studies.
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| 23. |
- Kreutzman, Anna, et al.
(författare)
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Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line
- 2019
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Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naive and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.
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| 24. |
- Kreutzman, Anna, et al.
(författare)
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Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia
- 2012
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 40:11, s. 906-913
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Tidskriftsartikel (refereegranskat)abstract
- Tyrosine kinase inhibitors have greatly improved the prognosis of chronic myeloid leukemia (CML). In addition to direct kinase inhibition, their effects can also be mediated through immune modulation, such as expansion of cytotoxic T and natural-killer cells observed during dasatinib therapy. As natural-killer cell and partially CD8(+) T-cell function are regulated by killer immunoglobulin-like receptors (KIRs), we studied whether the KIR gene profile is associated with clinical therapy response in dasatinib-treated CML patients (n = 191). In first-line patients, the absence of the inhibitory KIR2DL5A (p = 0.0489), 2DL5B (p = 0.030), and 2DL5all (p = 0.0272) genes were associated with improved molecular response at the 12-month time point. In addition, the same trend was seen with two activating KIR genes, 2DS1 (p = 0.061) and 2DS2 (p = 0.071). Furthermore, when patients were clustered into two groups by their KIR gene profile, the BCR-ABL1 transcript levels differed significantly between the groups (p = 0.047), showing that patients who lacked several KIR genes had better response. The comparison of first-line and second-line patients did not show any significant differences in either KIR or human leukocyte antigen genotypes. Our results show that immunogenetic factors, such as the KIR gene profile, can play a role in tyrosine kinase inhibitor therapy response. Additional studies are warranted to elucidate the functional significance of KIR genes associated with treatment outcomes. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
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| 30. |
- Pedersen, Camilla, et al.
(författare)
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Somatic disease in survivors of childhood malignant bone tumors in the nordic countries
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:18
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Tidskriftsartikel (refereegranskat)abstract
- Survivors of malignant bone tumors in childhood are at risk of long-term adverse health effects. We comprehensively reviewed cases of somatic diseases that required a hospital contact in survivors of osteosarcoma and Ewing sarcoma. In a population-based cohort study, 620 five-year survivors of osteosarcoma (n = 440) or Ewing sarcoma (n = 180), diagnosed before the age of 20 years in Denmark, Finland, Iceland, and Sweden during 1943–2008, were followed in the national hospital registers. Overall rates of hospital contacts for any somatic disease and for 12 main diagnostic groups and 120 specific disease categories were compared with those in a matched comparison cohort (n = 3049) randomly selected from the national population registers. The rate of hospital contact for any somatic disease was 80% higher in survivors of malignant bone tumors than in comparisons and remained elevated up to 30 years after diagnosis. The rate of hospital contacts was higher after Ewing sarcoma (rate ratio (RR) 2.24; 95% confidence interval (CI) 1.76–2.85) than after osteosarcoma (RR 1.67; 95% CI 1.41–1.98). Elevated rates were observed for 11 main diagnostic groups, including infections, second malignant neoplasms, and diseases of the skin, bones, and circulatory, digestive, endocrine, and urinary systems. Survivors of malignant bone tumors in childhood are at increased risk of somatic diseases many years after diagnosis. This comprehensive study contributes new insight into the risk of late effects in survivors of osteosarcoma and Ewing sarcoma, which is an essential basis for optimal patient counseling and follow-up care.
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