| 1. |
- Betten, Åsa, 1967, et al.
(författare)
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Oxygen radical-induced natural killer cell dysfunction: role of myeloperoxidase and regulation by serotonin
- 2004
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Ingår i: J Leukoc Biol. ; 75:6, s. 1111-5
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells are functionally suppressed and induced to apoptosis by reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs). These inhibitory events are reversed by the biogenic amine serotonin. MPs generate hydrogen peroxide (H(2)O(2)), which is processed further by myeloperoxidase (MPO) to even more toxic compounds. Earlier studies suggest that serotonin scavenges MP-derived oxygen radicals generated by the MPO-H(2)O(2) system. These findings led us to explore the capability of MPO-deficient MPs to induce NK cell dysfunction. We show that MPs recovered from subjects with MPO deficiency trigger inhibition of NK cells. In addition, MPs recovered from healthy subjects conveyed suppression of NK cells in the presence of the MPO inhibitor ceruloplasmin. We conclude that ROS-dependent inhibition of NK cell function is unrestricted by the availability of MPO-derived oxygen radicals and that the protecting properties of serotonin may operate in the absence of functional MPO. Our data suggest a complex mechanism of MP-induced NK cell inhibition, which comprises the generation of interchangeable oxygen radicals.
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| 2. |
- Blimark, Cecilie, et al.
(författare)
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Melphalan 100mg/m(2) with stem cell support as first relapse treatment is safe and effective for myeloma patients with long remission after autologous stem cell transplantation.
- 2011
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Ingår i: European journal of haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 87:2, s. 117-22
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Today, a number of therapeutic options are available as the patient with myeloma relapses from initial treatment with high-dose melphalan and autologous stem cell transplantation (ASCT). For patients who experience a durable response to primary ASCT, retreatment with high-dose melphalan is recommended by many current guidelines. Yet, toxicity is an important aspect in the choice of relapse treatment, and a second ASCT in this setting could be associated with enhanced toxicity. As the goal for the treatment for relapsed myeloma should be disease control while maintaining quality of life, lower doses of melphalan might be preferable. Methods and Objectives: In this retrospective study, we account for the outcome of 66 patients with myeloma in first systemic relapse after ASCT, who were treated with intermediate-dose melphalan, 100mg/m(2) , and stem cell support (MEL 100). The aim was to evaluate this treatment in relation to prior response duration after initial ASCT and with respect to response rate, toxicity and survival. Results: The overall response rate was 62%. There was limited, mostly haematological, toxicity, and no treatment-related mortality was observed. The median progression-free survival (PFS) was 8.5months, and the median overall survival was 24months. Patients with time to progression of 34months or more (n=17; ≥75th percentile) after initial ASCT had a median PFS of 12.5months after MEL 100. Conclusion: For patients with a long-lasting response after ASCT, MEL 100 could be a therapeutic option with low toxicity and with efficacy comparable to newer immunomodulatory drugs.
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| 3. |
- Blimark, Cecilie, et al.
(författare)
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Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients.
- 2015
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 100:1, s. 107-13
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Tidskriftsartikel (refereegranskat)abstract
- Infections are a major cause of morbidity and mortality in patients with multiple myeloma. To estimate the risk of bacterial and viral infections in multiple myeloma patients, we used population-based data from Sweden to identify all multiple myeloma patients (n=9253) diagnosed from 1988 to 2004 with follow up to 2007 and 34,931 matched controls. Cox proportional hazard models were used to estimate the risk of infections. Overall, multiple myeloma patients had a 7-fold (hazard ratio =7.1; 95% confidence interval = 6.8-7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8-7.4), and for viral infections 10-fold (10.0; 8.9-11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to controls (P<0.001). At one year of follow up, infection was the underlying cause in 22% of deaths in multiple myeloma patients. Mortality due to infections remained constant during the study period. Our findings confirm that infections represent a major threat to multiple myeloma patients. The effect on infectious complications due to novel drugs introduced in the treatment of multiple myeloma needs to be established and trials on prophylactic measures are needed.
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| 4. |
- Blimark, Cecilie, et al.
(författare)
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Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry
- 2018
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 103:3, s. 506-513
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent 'real-world' patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients' characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabi-ants per year. Among initially symptomatic patients (n= 3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (P<0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95% CI: 0.77-0.92; P<0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95% CI: 0.87-0.99; P<0.05). We report here on a near complete 'real-world' population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period.
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| 5. |
- Bylund, Johan, 1975, et al.
(författare)
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Cytochalasin B triggers a novel pertussis toxin sensitive pathway in TNF-alpha primed neutrophils
- 2004
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Ingår i: BMC cell biology. - 1471-2121. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cytochalasin B does not directly activate the oxygen-radical-producing NADPH oxidase activity of neutrophils but transfers desensitized G-protein coupled receptors (GPCR) into an active signaling state by uncoupling GCPR from the cytoskeleton. The receptor uncoupling results in respiratory burst activity when signals generated by reactivated formyl peptide receptors trigger the NADPH-oxidase to produce superoxide anions. RESULTS: Tumor necrosis factor alpha (TNF-alpha) primes neutrophils for subsequent activation by cytochalasin B. Pretreatment with TNF-alpha induced mobilization of receptor-storing neutrophil organelles, suggesting that receptor up-regulation significantly contributes to the response, but the receptor mobilization was not sufficient for induction of the cytochalasin B sensitive state. The TNF-alpha primed state resembled that of the desensitized non-signaling state of agonist-occupied neutrophil formyl peptide receptors. The fact that the TNF-alpha primed, cytochalasin B-triggered activation process was pertussis toxin sensitive suggests that the activation process involves a GPCR. Based on desensitization experiments the unidentified receptor was found to be distinct from the C5a receptor as well as the formyl peptide receptor family members FPR and FPRL1. Based on the fact the occupied and desensitized receptors for interleukin-8 and platelet activating factor could not be reactivated by cytochalasin B, also these could be excluded as receptor candidates involved in the TNF-alpha primed state. CONCLUSIONS: The TNF-alpha-induced priming signals could possibly trigger a release of an endogenous GPCR-agonist, amplifying the response to the receptor-uncoupling effect of cytochalasin B. However, no such substance could be found, suggesting that TNF-alpha can transfer G-protein coupled receptors to a signaling state independently of agonist binding.
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| 6. |
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| 7. |
- Hansson, Markus, 1974, et al.
(författare)
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Histamine protects T cells and natural killer cells against oxidative stress.
- 1999
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Ingår i: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. - 1079-9907. ; 19:10, s. 1135-44
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress inflicted by monocytes/macrophages (MO) is recognized as an important immunosuppressive mechanism in human neoplastic disease. We report that two types of lymphocytes of relevance for protection against malignant cells, T cells and natural killer (NK) cells, became anergic to the T cell and NK cell activator interleukin-2 (IL-2) after exposure to MO-derived reactive oxygen metabolites and subsequently acquired features characteristic of apoptosis. The MO-induced anergy and apoptosis in T cells and NK cells were reversed by histamine, an inhibitor of reactive oxygen metabolite synthesis in MO. We propose that strategies to circumvent oxidative inhibition of lymphocytes may be of benefit in immunotherapy of neoplastic disease.
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| 8. |
- Hellstrand, Kristoffer, 1956, et al.
(författare)
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Alleviating oxidative stress in cancer immunotherapy: a role for histamine?
- 2000
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Ingår i: Medical oncology (Northwood, London, England). - 1357-0560. ; 17:4, s. 258-69
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-2 is a remarkable activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells, but tumor regression only rarely occurs in interleukin-2-treated cancer patients. In this review, we focus on interactions between monocytes/macrophages and T-cells/natural killer-cells, and in particular the role of such interactions for the outcome of cancer immunotherapy with interleukin-2. We propose that interleukin-2 therapy should be supplemented with compounds that alleviate toxicity inflicted by monocyte/macrophage-derived reactive oxygen metabolites within and around tumors. The hypothesis is founded on data demonstrating that (i) functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen metabolites, generated by neighboring monocytes/macrophages, (ii) interleukin-2 only weakly activates T-cells or natural killer cells in an environment of oxidative stress, and (iii) inhibitors of the formation of reactive oxygen metabolites or scavengers of reactive oxygen metabolites synergize with interleukin-2 to activate these lymphocyte subsets. We also review the preclinical background to the use of histamine dihydrochloride, an inhibitor of reactive oxygen metabolite formation in monocytes/macrophages, as a supplement to cancer immunotherapy with interleukin-2.
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| 9. |
- Hellstrand, Kristoffer, 1956, et al.
(författare)
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Histamine: a novel approach to cancer immunotherapy
- 2000
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Ingår i: Cancer investigation. - : Informa UK Limited. - 0735-7907 .- 1532-4192. ; 18:4, s. 347-55
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Tidskriftsartikel (refereegranskat)abstract
- The functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen species (ROS), generated by adjacent monocytes/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) only weakly activate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scavengers of ROS synergize with IL-2 and IFN-alpha to activate T cells and NK cells. In this review, we focus on the immunoenhancing properties of histamine, a biogenic amine. Histamine inhibits ROS formation in MO via H2-receptors; thereby, histamine protects NK cells from MO-mediated inhibition and synergizes with IL-2 and IFN-alpha to induce killing of NK cell-sensitive human tumor cells in vitro. Histamine also optimizes cytokine-induced activation of several subsets of T cells by affording protection against MO-inflicted oxidative inhibition. The putative clinical benefit of histamine as an adjunct to immunotherapy with IL-2 and/or IFN-alpha is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.
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| 10. |
- Hellstrand, Kristoffer, 1956, et al.
(författare)
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Histamine and cytokine therapy.
- 1998
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Ingår i: Acta oncologica (Stockholm, Sweden). - 0284-186X. ; 37:4, s. 347-53
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are potent activators of natural killer (NK) cells and other anti-tumor effector cells, but the results obtained in clinical trials with these cytokines have proved disappointing in many forms of cancer. It may be that IL-2 and IFN-alpha are often not sufficiently effective because intratumoral monocytes/macrophages (MO) inhibit the cytokine-induced activation of cytotoxic effector lymphocytes such as NK-cells at the site of tumor growth. An essential part of this inhibitory signal is conveyed by MO-derived reactive oxygen species (ROS), which potently inhibit NK-cell-related functions, including the constitutive and cytokine-induced cytotoxicity against tumor cells. Histamine, a biogenic amine, inhibits ROS formation in MO; thereby, histamine synergizes with IL-2 and with IFN-alpha to induce killing of NK-cell-sensitive human tumor cells in vitro. Furthermore, treatment of tumor-bearing mice with histamine potentiates cytokine-induced killing of NK-cell-sensitive murine tumor cells in vivo. In ongoing clinical trials, histamine has been added to IL-2 or IFN-alpha in immunotherapy of human neoplastic disease. The results of two pilot trials in metastatic melanoma suggest that the addition of histamine to IL-2/IFN-alpha prolongs survival time and induces regression of tumors, such as liver melanoma, which are considered refractory to immunotherapy with IL-2 or IFN-alpha. In acute myelogenous leukemia (AML), histamine and IL-2 have been given in order to protect patients in remission against relapse of leukemic disease. The potential benefit of histamine therapy in melanoma and AML will be evaluated in randomized trials.
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| 11. |
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| 12. |
- Hou, M, et al.
(författare)
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Impact of endogenous thrombopoietin levels on the differential diagnosis of essential thrombocythaemia and reactive thrombocytosis.
- 1998
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Ingår i: European journal of haematology. - 0902-4441. ; 61:2, s. 119-22
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Tidskriftsartikel (refereegranskat)abstract
- By using the newly commercialized Quantikine human TPO immunoassay, plasma thrombopoietin (TPO) concentrations were measured in 12 patients with essential thrombocythaemia (ET), 13 patients with reactive thrombocytosis (RT) and 11 healthy volunteers. For the healthy volunteers the mean plasma TPO concentration was 21.1+/-11.0 pg/ml. The mean plasma TPO concentration in the group of RT was slightly lower (16.4+/-8.6 pg/ml) but did not differ significantly from the control group. The mean plasma TPO concentration in ET patients (44.1+/-45.2 pg/ml) was significantly (p<0.05) higher than the mean for RT patients, but did not differ statistically from the mean of healthy volunteers. These data suggest a defective clearance of plasma TPO in patients with ET.
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| 13. |
- Hou, M, et al.
(författare)
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Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes.
- 1998
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Ingår i: British journal of haematology. - 0007-1048. ; 101:3, s. 420-4
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the diagnostic value of thrombopoietin (TPO, c-mpl ligand) measurements, and clarify the regulatory mechanisms of TPO in normal and in thrombocytopenic conditions, the plasma TPO concentration was determined in normal individuals (n = 20), umbilical cord blood (n = 40), chronic idiopathic thrombocytopenic purpura (ITP; n = 16), in severe aplastic anaemia (SAA; n = 3), chemotherapy-induced bone marrow hypoplasia (n = 10), myelodysplastic syndrome (MDS; n = 11), and sequentially during peripheral blood progenitor cell transplantation (n = 7). A commercially available ELISA and EDTA-plasma samples were used for the analysis. The plasma TPO concentration in the normals and umbilical cord blood were 52 +/- 12 pg/ml and 66 +/- 12 pg/ml, respectively. The corresponding values in patients with SAA and chemotherapy-induced bone marrow hypoplasia were 1514 +/- 336 pg/ml and 1950 +/- 1684 pg/ml, respectively, and the TPO concentration, measured sequentially after myeloablative chemotherapy and peripheral blood progenitor cell transplantation, was inversely related to the platelet count. In contrast, the plasma TPO recorded in patients with ITP (64 +/- 20 pg/ml) and MDS (68 +/- 23 pg/ml) were only slightly higher than normal levels. In conclusion, TPO levels were significantly elevated in patients in which bone marrow megakaryocytes and platelets in circulation were markedly reduced, whereas TPO levels were normal in ITP patients, and only slightly increased in the MDS patients. These latter patients displayed a preserved number of megakaryocytes in bone marrow biopsies. Our data support the suggestion that megakaryocyte mass affects the plasma TPO concentration. In thrombocytopenic patients a substantially increased plasma TPO implies deficient megakaryocyte numbers. However, TPO measurements do not distinguish between ITP and thrombocytopenia due to dysmegakaryopoiesis, as seen in MDS patients.
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| 14. |
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| 15. |
- Mellqvist, Ulf-Henrik, 1961
(författare)
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New prognostic tools for myeloma
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 125:13, s. 2014-2015
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Tidskriftsartikel (refereegranskat)abstract
- In this issue of Blood, Palumbo et al show, in a study performed with the cooperation of the International Myeloma Working Group (IMWG), that detailed systematic geriatric assessment of elderly myeloma patients might be a useful tool for identifying fit and frail individuals.1 Like most malignancies, multiple myeloma mainly affects elderly patients. Even so, in daily clinical practice, we usually only consider chronological age (ie, is the patient under or above 65 years of age?). However, it is quite obvious that there is a huge difference between a 70-year-old fit patient and a frail patient above the age of 80. © 2015 by The American Society of Hematology.
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| 16. |
- Pellmé, Sara, 1975, et al.
(författare)
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Localization of human neutrophil interleukin-8 (CXCL-8) to organelle(s) distinct from the classical granules and secretory vesicles
- 2006
-
Ingår i: J Leukoc Biol. - : Oxford University Press (OUP). ; 79, s. 564-573
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Tidskriftsartikel (refereegranskat)abstract
- Mature human neutrophils contain small amounts of interleukin-8 [CXC chemokine ligand 8 (CXCL-8)], which upon proinflammatory activation, increases significantly. It has been suggested that the CXCL-8 content of resting human neutrophils is stored in the secretory vesicles. Here, we have used a fractionation technique, which allows isolation of these vesicles, and we find that CXCL-8 neither colocalizes with the secretory vesicles nor with markers of any of the classical neutrophil granules. To increase resolution in the system, we induced CXCL-8 production by lipopolysaccharide. After 8 h of stimulation, CXCL-8 was visualized within the cell using immunoelectron microscopy. The images revealed CXCL-8-containing stuctures resembling neutrophil granules, and these were distinct from all known neutrophil organelles, as shown by double immunostaining. Further, the CXCL-8 organelle was present in nonstimulated neutrophil cytoplasts, entities lacking all other known granules and secretory vesicles. Upon fractionation of the cytoplasts, CXCL-8 was found to partly cofractionate with calnexin, a marker for endoplasmic reticulum (ER). Thus, part of CXCL-8 may be localized to the ER or ER-like structures in the neutrophil.
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| 17. |
- Ridell, Börje, et al.
(författare)
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Incidence of chronic myeloproliferative disorders in the city of Göteborg, Sweden 1983-1992.
- 2000
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Ingår i: European journal of haematology. - 0902-4441. ; 65:4, s. 267-71
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Tidskriftsartikel (refereegranskat)abstract
- An estimation of the incidence of polycythaemia vera (PV), essential thrombocythaemia (ET) and chronic idiopathic myelofibrosis (CIM) in the city of Göteborg, Sweden during the period 1983-1992 was made from a retrospective case analysis of patients registered as chronic myeloproliferative disorders (CMPD) at the Departments of Medicine and the Department of Pathology of the two major hospitals in the city. A total of 125 cases of PV, 56 males and 69 females were identified. The number of cases as well as the age-specific incidence increased with age. The over all annual gender-specific incidence was 2.69 cases per 10(5) male inhabitants and 3.12 cases per 10(5) female inhabitants. The incidence of PV in relation to the European Standard Population was 2.02 cases per 10(5) inhabitants and year. There were 72 cases, 20 males and 52 females, with ET. The age-specific incidence was in all ages higher for females than for males and increased with age. The annual gender-specific incidence was 0.96 per 10(5) male inhabitants and 2.35 per 10(5) female inhabitants. The incidence of ET in relation to the European Standard Population was 1.28 per 10(5) persons and year. There were 20 cases of CIM, 11 males and 9 females. The annual gender-specific incidence of CIM was 0.53/10(5) male inhabitants and 0.41/10(5) female inhabitants. The incidence of CIM in relation to the European Standard Population was 0.31 per 10(5) persons and year. Seven persons, 2 males and 5 females, had a CMPD that could not be included in any of the above-mentioned groups, but were registered as CMPD, unclassified.
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| 18. |
- Rodriguez-Catarino, M., et al.
(författare)
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Percutaneous vertebroplasty at C2: case report of a patient with multiple myeloma and a literature review
- 2006
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Ingår i: Eur Spine J. - 0940-6719.
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Tidskriftsartikel (refereegranskat)abstract
- Percutaneous vertebroplasty (PVP) of the axis is a challenging procedure which may be performed by a percutaneous or a transoral approach. There are few reports of PVP at the C2 level. We report a case of unstable C2 fracture treated with the percutaneous approach. The fracture was the first manifestation of multiple myeloma in a previously healthy 47-year-old woman. After local radiotherapy and chemotherapy, the fracture was still unstable and the patient had been continuously wearing a stiff cervical collar for 9 months. Complication-free PVP resulted in pain relief and stabilization and use of the cervical collar could be discontinued. At 18 months follow-up the patient remained free from pain, the fracture was stable and she had returned to work. The purpose of this article is to present the technical facts and to highlight the benefits and potential complications of the procedure. The technical characteristics of the procedure, the indication and results of the present case are discussed together with previously reported cases of PVP treatment at C2.
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| 19. |
- Veskovski, Ljupco, et al.
(författare)
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Serum metabolomic profiling correlated with ISS and clinical outcome for multiple myeloma patients treated with high-dose melphalan and autologous stem cell transplantation.
- 2021
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Ingår i: Experimental hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 97
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Tidskriftsartikel (refereegranskat)abstract
- The metabolome, which is the final down-stream global product of metabolic processes in organisms, is not sufficiently described in multiple myeloma (MM) patients. The aim of this study was, therefore, to study the serum metabolomic profile using proton nuclear magnetic resonance (1H-NMR) spectroscopy, and its relationship to clinical characteristics and patient outcome. Serum samples, which were taken at diagnosis, from 201 MM patients who underwent high-dose melphalan followed by autologous stem cell transplantation as the first-line therapy, were analyzed. We found that the metabolomic profile differed between patients with different MM International Staging System (ISS) stages. The profile revealed increased levels of cholesterol, phospholipids, high-density lipoprotein, low-density lipoprotein, apolipoproteins A1 and A2, valine, and leucine in ISS I patients compared with ISS III patients. The metabolomic profile also differed between patients with IgA and IgG paraproteins, predominantly because of higher levels of high- and low-density lipoprotein subfractions in IgA patients. The exact pathway of metabolism leading to accumulation of these metabolites is still elusive, but this study indicates an area of interest for further investigation in the search for new therapy targets and prognostic markers for this disease.
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