Magnus Björkholm

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (452)2380.56 Total impact

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    ABSTRACT: Background and purpose: Patients with myotonic dystrophy (DM) are at high risk of brain cancer. This study describes the spectrum of brain neoplasms in DM patients. Methods: Data from 1119 DM patients identified from the National Swedish Patient Register between 1987 and 2007 were linked to the National Cancer and the Cause of Death Registers. Standardized incidence ratios (SIRs) and cumulative incidence to quantify the relative and absolute risks of brain neoplasms were calculated and the Kaplan-Meier estimator was used for survival analysis. Patient follow-up started at birth or the age at the start of Swedish cancer registration (1 January 1958) and ended at the age of brain neoplasm diagnosis, death or on 31 December 2007. Results: Twenty patients developed brain neoplasm during follow-up {median age 53, range 2-76 years, accounting for a five-fold excess risk of brain tumors during the patient lifetime [SIR = 5.4, 95% confidence interval (CI) 3.4-8.1, P = 1 × 10(-5) ]}. Astrocytoma was the most common histological subtype (n = 16, 80%), and almost all cases (n = 19) developed after age 20. No statistically significant differences in gender-specific risks (SIR in men 6.3 and in women 3.8, P-heterogeneity 0.46) were observed. After accounting for competing mortality related to DM, the cumulative incidence of brain neoplasms reached 2.9% (95% CI 1.8%-4.7%) by age 70. Five-year survival after brain tumor diagnosis was 52% (95%CI 29%-75%) overall (number at risk 8) and 34% (95% CI 26%-47%) for malignant neoplasms (number at risk 5). Conclusion: Despite the high relative risk of DM-related brain tumors, the absolute risk is modest. Nonetheless, careful evaluation of DM patients with new central nervous system symptoms is warranted.
    European Journal of Neurology 10/2015; DOI:10.1111/ene.12886 · 4.06 Impact Factor
  • Xinyu Ci · Bingnan Li · Xueping Ma · Feng Kong · Chengyun Zheng · Magnus Björkholm · Jihui Jia · Dawei Xu ·
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    ABSTRACT: Bortezomib inhibits the ubiquitin/proteasome pathway to achieve its anti-cancer effect and its well characterized activity is the NF-κB inhibition through which the anti-apoptotic bcl-2 expression is down-regulated and apoptosis is subsequently induced. However, the downstream molecular targets of bortezomib are still incompletely defined. Because telomere stabilization via activation of telomerase, induction of telomerase reverse transcriptase (hTERT) and appropriate expression of shelterin proteins is essential to cancer development and progression, we investigated the effect of bortezomib on telomere homeostasis/function in malignant cells. The bortezomib treatment of leukemic (HEL) and gastric cancer cells (BGC-823) led to significant inhibition of hTERT and telomerase expression, widespread dysregulation of shelterin protein expression, and telomere shortening, thereby triggering telomere dysfunction and DNA damage. hTERT over-expression attenuated bortezomib-induced telomere shortening, abnormal shelterin expression and telomere dysfunction. Importantly, bortezomib-mediated apoptosis of malignant cells was partially prevented by hTERT over-expression. Mechanistically, hTERT first robustly enhances bcl2 expression and maintains significantly high residual levels of bcl2 even in bortezomib-treated HEL cells. Second, hTERT protects against bortezomib-induced DNA damage. Our findings collectively reveal a profound impact of bortezomib on telomere homeostasis/function. Down-regulation of hTERT expression and telomere dysfunction induced by bortezomib both contribute to its cancer cell killing actions. It is evident from the present study that hTERT can confer resistance of malignant cells to bortezomib-based target cancer therapy, which may have important clinical implications.
    Oncotarget 10/2015; DOI:10.18632/oncotarget.5752 · 6.36 Impact Factor
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    ABSTRACT: Trends in Hodgkin lymphoma (HL) survival among patients treated outside of clinical trials provide real-world benchmark estimates of prognosis and help identify patient subgroups for targeted trials. In a Swedish population-based cohort of 1947 HL patients diagnosed 1992-2009 at ages 18-59 years, we estimated relative survival (RS), cure proportions (CP) and median survival times using flexible parametric cure models. Overall, the CP was 89% (95%CI:0.87-0.91) and median survival of the uncured was 4.6 years (95%CI:3.0-6.3). For patients aged 18-50 years diagnosed after the year 2000, CP was high and stable, whereas for patients 50-59 years cure was not reached. The survival of relapse-free patients was similar to that of the general population (RS5-year:0.99; 95%CI:0.98-0.99, RS15-year:0.95; 95%CI:0.92-0.97). The excess mortality of relapsing patients was 19 times (95%CI:12-31) that of relapse-free patients. Despite modern treatments, patients with adverse prognostic factors (e.g., advanced stage) still had markedly worse outcomes [CPstage:IIIB 0.82 (95%CI:0.73-0.89); CPstage:IVB 0.72, (95%CI:0.60-0.81)] and patients with international prognostic score (IPS) ≥3 had 2.7 times higher excess mortality (95%CI:1.0-7.0, p=0.04) than patients with IPS <3. High-risk patients selected for 6-8 courses of BEACOPP (bleomycin, etoposide, doxorubicin, cyclofosphamide, vincristine, procarbazine, prednisone)-chemotherapy had a 15-year relative survival of 87%, (95%CI:0.80-0.92), whereas the corresponding estimate for patients selected for 6-8 courses of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was 93% (95%CI:0.88-0.97). These population-based results indicate limited fatal side-effects in the 15-year perspective with contemporary treatments, while the unmet need of effective relapse treatment remains of concern. BEACOPP-chemotherapy was still not sufficient in high-risk HL patients. This article is protected by copyright. All rights reserved.
    American Journal of Hematology 09/2015; DOI:10.1002/ajh.24184 · 3.80 Impact Factor
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    Haematologica 07/2015; 100(10). DOI:10.3324/haematol.2015.125765 · 5.81 Impact Factor
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    ABSTRACT: The key enzyme in leukotriene (LT) biosynthesis is 5-lipoxygenase (5-LO), which is expressed in myeloid cells and in B lymphocytes. There are three phosphorylation sites on 5-LO (Ser271, Ser523 and Ser663). Protein kinase A (PKA) phosphorylates 5-LO on Ser523. In this report, we demonstrate by immunoblotting that native 5-LO in mantle B cell lymphoma (MCL) cells (Granta519, JEKO1, and Rec1) and in primary chronic B lymphocytic leukemia cells (B-CLL) is phosphorylated on Ser523. In contrast, we could not detect phosphorylation of 5-LO on Ser523 in human granulocytes or monocytes. Phosphorylated 5-LO was purified from Rec1 cells, using an ATP-agarose column, and the partially purified enzyme could be dephosphorylated with alkaline phosphatase. Incubation of Rec1 cells with 8-Br-cAMP or prostaglandin E2 stimulated phosphorylation at Ser523. Furthermore, FLAG-5LO was expressed in Rec1 cells, and the cells were cultivated in the presence of 8-Br-cAMP. The 5-LO protein from these cells was immunoprecipitated, first with anti-FLAG, followed by anti-pSer523-5-LO. The presence of 5-LO protein in the final precipitate further supported the finding that the protein recognized by the pSer523 antibody was 5-LO. Taken together, this study shows that 5-LO in B cells is phosphorylated on Ser523 and demonstrates for the first time a chemical difference between 5-LO in myeloid cells and B cells. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Prostaglandins Leukotrienes and Essential Fatty Acids 06/2015; 100. DOI:10.1016/j.plefa.2015.06.003 · 2.35 Impact Factor
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    ABSTRACT: Classical Hodgkin lymphoma (cHL) has a unique pathological feature characterized by a minority of malignant Hodgkin Reed-Sternberg (H-RS) cells surrounded by numerous inflammatory cells. Cysteinyl-leukotrienes (CysLTs) are produced by eosinophils, macrophages and mast cells in the HL tumor microenvironment. In the present study we have explored the signal transduction pathways leading to leukotriene (LT) D4 induced expression of cytokines in the Hodgkin lymphoma cell line L1236 and KM-H2. Stimulation of L1236 and KM-H2 cells with LTD4 led to a concentration- and time-dependent increase at the transcriptional level of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, Chemokine (C-C motif) ligand 3 (CCL3) and CCL4. The expression of several transcription factors was induced upon stimulation of Hodgkin cell lines with LTD4. Among these, EGR-1 was required for cytokine production. Inhibition of EGR-1 expression using shEGR-1 transduced by lentivirus led to suppression of the expression of TNF-α and IL-6. The effect of LTD4 on the expression of transcription factors and cytokines were also blocked by the specific CysLT1 receptor antagonist zafirlukast. These results demonstrate that EGR-1 plays a critical role in LTD4-induced cytokine transcription in Hodgkin cell lines. Copyright © 2015. Published by Elsevier Inc.
    Prostaglandins & other lipid mediators 06/2015; DOI:10.1016/j.prostaglandins.2015.06.004 · 2.38 Impact Factor

  • Blood 06/2015; 125(23):3665-6. DOI:10.1182/blood-2015-04-639039 · 10.45 Impact Factor
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    ABSTRACT: Myeloproliferative neoplasms (MPNs) are associated with a shortened life expectancy. We assessed causes of death in patients with MPN and matched controls using both relative risks and absolute probabilities in the presence of competing risks. From Swedish registries, we identified 9,285 patients with MPN and 35,769 matched controls. A flexible parametric model was used to estimate cause-specific hazard ratios (HRs) of death and cumulative incidence functions, each with 95% CIs. In patients with MPN, the HRs of death from hematologic malignancies and infections were 92.8 (95% CI, 70.0 to 123.1) and 2.7 (95% CI, 2.4 to 3.1), respectively. In patients age 70 to 79 years at diagnosis (the largest patient group), the HRs of death from cardiovascular and cerebrovascular disease were 1.5 (95% CI, 1.4 to 1.7) and 1.5 (95% CI, 1.3 to 1.8), respectively; all were statistically significantly elevated compared with those of controls. In the same age group, no difference was observed in the 10-year probability of death resulting from cardiovascular disease in patients with MPN versus controls (16.8% v 15.2%) or cerebrovascular disease (5.6% v 5.2%). In patients age 50 to 59 years at diagnosis, the 10-year probability of death resulting from cardiovascular and cerebrovascular disease was elevated, 4.2% versus 2.1% and 1.9% versus 0.4%, respectively. Survival in patients with MPN increased over time, mainly because of decreased probabilities of dying as a result of hematologic malignancies, infections, and, in young patients, cardiovascular disease. Patients with MPN had an overall higher mortality rate than that of matched controls, primarily because of hematologic malignancy, infections, and vascular events in younger patients. Evidently, there is still a need for effective disease-modifying agents to improve patient outcomes. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 06/2015; 33(20). DOI:10.1200/JCO.2014.57.6652 · 18.43 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is consistently preceded by the precursor state, monoclonal gammopathy of undetermined significance (MGUS). The average annual risk of progression from MGUS to multiple myeloma is 0.5% to 1.0%. Current guidelines suggest life-long clinical follow-up of individuals diagnosed as having MGUS depending on risk stratification. The impact of diagnosing and conducting clinical follow-up of MGUS on MM survival is unclear. To estimate the impact of prior knowledge of MGUS diagnosis and comorbidities on MM survival. We conducted a population-based study including all patients with MM (MM patients) diagnosed in Sweden (n = 14 798) from 1976 to 2005 (with follow-up until 2007); 394 (2.7%) had previously been diagnosed as having MGUS. Information on comorbidities was gathered for all patients. We calculated survival rates from the time of MM diagnosis, comparing patients with vs those without prior knowledge of MGUS. Using Cox proportional hazards models, we calculated hazard ratios (HRs) and 95% CIs for risk factors for death. χ2 Tests were used to evaluate differences in comorbidities. Prior knowledge of MGUS among MM patients. In a subanalysis, monoclonal (M)-protein concentration and type were used as exposure. Risk of death and comorbidities. Patients with MM with prior knowledge of MGUS had significantly (HR, 0.86; 95% CI, 0.77-0.96; P < .01) better overall survival (median survival, 2.8 years) than MM patients without prior knowledge of MGUS (median survival, 2.1 years), although MM patients with (vs without) prior knowledge of MGUS had more comorbidities (P < .001). Among MM patients with prior knowledge of MGUS, low M-protein concentration (<0.5 g/dL) at MGUS diagnosis was associated with poorer MM survival (HR, 1.86; 95% CI, 1.13-3.04; P = .01). Patients with MM with prior knowledge of MGUS had better MM survival, suggesting that earlier treatment of MM leads to better survival. The observation that a low M-protein concentration at MGUS diagnosis was associated with poorer MM survival may reflect less frequent clinical follow-up. Our observations stress the importance of clinical follow-up in patients with MGUS, regardless of risk stratification.
    05/2015; 1(2). DOI:10.1001/jamaoncol.2015.23
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    ABSTRACT: Posaconazole prophylaxis during induction chemotherapy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has been shown to significantly decrease the incidence of invasive fungal disease (IFD) and increase overall survival in a trial setting, but only small real-life studies have been published. This was a retrospective cohort study including consecutive AML/MDS patients treated with intensive induction chemotherapy; 176 patients received fluconazole prophylaxis 2008-2011 and 107 patients received posaconazole prophylaxis 2011-2013. Only proven and probable IFD according to the revised EORTC/MSG criteria were included in the analysis. The two cohorts were well matched without significant differences in patient characteristics. At day 100, patients receiving posaconazole had a significantly lower incidence of total IFD (0.9% vs. 10.8%, p < 0.01), invasive aspergillosis (0% vs. 5.7%, p = 0.02), and invasive candidiasis (0% vs. 4.0%, p < 0.05). There was no significant difference in overall survival, neither at day 100 (87% in the posaconazole group vs. 85% in the fluconazole group) nor at end of follow-up (78% vs. 7%). Posaconazole prophylaxis decreased the incidence of IFD but did not improve short-term overall survival. Improved treatment efficacy of manifest IFD is likely to explain the lack of survival benefit. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 04/2015; DOI:10.1111/ejh.12565 · 2.07 Impact Factor

  • Blood 03/2015; 125(13):2174-2175. DOI:10.1182/blood-2015-01-622068 · 10.45 Impact Factor
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    ABSTRACT: Patients with Hodgkin lymphoma (HL) have a well-characterized immune deficiency of T cell function, originally identified by increased susceptibility to certain infections. Epidemiological evidence has long pointed to infectious etiologies in younger HL patients. With the aim of expanding our knowledge on the potential role of pre-existing immune deficiency in HL and an infectious/inflammatory etiology, we conducted a comprehensive population-based case-control study in HL patients diagnosed in Sweden in the period 1965-2004, and their matched controls. In a large population-based study including 7,414 HL patients and 29,240 matched controls, we evaluated the subsequent risk of HL in relation to a broad range of infectious and inflammatory conditions, using unconditional logistic regression. A previous history of any reported infection was associated with an 11 % increased risk of HL (P < 0.05). More specifically, we found sinusitis (odds ratio = 1.81; 95 % confidence interval = 1.06-3.07), tuberculosis (1.76; 1.01-3.07), encephalitis (7.88; 1.97-31.5), and herpes zoster (2.20; 1.11-4.35) to be associated with excess HL risk. A personal prior history of chronic inflammatory condition was not associated with an increased risk of HL (0.94; 0.71-1.14). Our results suggest that underlying immune deficiency is a primary phenomenon in HL. Alternatively, certain infectious agents may be potential HL triggers.
    International Journal of Hematology 03/2015; 101(6). DOI:10.1007/s12185-015-1772-6 · 1.92 Impact Factor
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    ABSTRACT: Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 3·7 (range 0-9·9) years, 65 (7·5%) patients developed 75 second malignancies (non-haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 1·52 (95% CI 1·13-1·99). The SIR before and after the second year following diagnosis of CML was 1·58 and 1·47, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population-based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 03/2015; 169(5). DOI:10.1111/bjh.13346 · 4.71 Impact Factor
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    Xiaolu Zhang · Bingnan Li · Nick de Jonge · Magnus Björkholm · Dawei Xu ·
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    ABSTRACT: DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for treatment of acute myeloid leukemia (AML) and other malignancies. Although inhibiting global/gene-specific DNA methylation is widely accepted as a key mechanism behind DNMTI anti-tumor activity, other mechanisms are likely involved in DNMTI's action. Because telomerase reverse transcriptase (TERT) plays key roles in cancer through telomere elongation and telomere lengthening-independent activities, and TERT has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Down-regulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZA-mediated DNA damage, telomere dysfunction and apoptosis of AML cells. Collectively, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction, which consequently exerts an anti-tumor activity.
    Oncotarget 01/2015; 75(15 Supplement). DOI:10.1158/1538-7445.AM2015-3816 · 6.36 Impact Factor
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    ABSTRACT: Larvae of the Northern pine processionary moth (Thaumetopoea pinivora, TP) carry microscopic needles (setae), which by penetrating skin and mucous membranes, may cause inflammatory/immune derived symptoms in man. In the present study the stimulatory effects of setae on human blood lymphocytes in vitro was investigated. Blood mononuclear cells were separated from venous blood or buffy coat of ten healthy individuals, six previously exposed to setae and four with no known exposure. Lymphoproliferation was measured as uptake of 3H-thymidine. Setae were prepared from TP larvae. Setae and saline setae extracts stimulated proliferation of T-lymphocytes in the presence of monocytic cells. Stimulation was pronounced in cells from persons who had been exposed to setae, and weak in cells from non-exposed donors. Chitin also induced lymphocyte proliferation in most donors, but to a lesser extent and independently of donor's previous exposure to setae. In conclusion, setae contain molecules that in the presence of monocytes activate human T-lymphocytes to proliferation. The antigenic nature of stimulatory molecules was supported by the significantly stronger lymphocyte response in persons previously exposed to setae than in non-exposed donors. The nature of such molecules remains to be defined.
    PLoS ONE 12/2014; 9(12):e113977. DOI:10.1371/journal.pone.0113977 · 3.23 Impact Factor
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    ABSTRACT: TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.
    Oncotarget 11/2014; 5(23). DOI:10.18632/oncotarget.2660 · 6.36 Impact Factor
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    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=9 253) 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.
    Haematologica 10/2014; 100(1). DOI:10.3324/haematol.2014.107714 · 5.81 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) develop in the bone marrow from haematopoietic progenitor cells. Two subsets, plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) have been identified. Little is known regarding DC levels in bone marrow of acute myeloid leukaemia (AML) patients before and after chemotherapy. We investigated relative pDC and mDC levels in bone marrow from 37 hospital controls and 60 AML patients (at diagnosis, complete remission [CR], and follow-up) using four-colour flow cytometry. The pDC immunophenotype was characterized as lin-⁄HLA-DR+ ⁄CD123+ and mDC as lin- ⁄HLA-DR+ ⁄ CD11c+. In 69% of AML patients, no DCs were detected at diagnosis. At CR, mDC levels were the same in AML patients and hospital controls while pDC levels were slightly lower. There was no association between minimal residual disease or survival rates and DC levels. Patients with low mDC levels at CR were more likely to suffer from complicated infections, though the difference was not statistically significant.Altogether, there was a profound decrease in DC levels in AML patients at diagnosis. DC levels increased at CR and were higher than in hospital controls after post-remission therapy, suggesting that DCs recover after repeated chemotherapy. There may be an association between mDC levels and infectious complications.This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 10/2014; 80(6). DOI:10.1111/sji.12223 · 1.74 Impact Factor
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    ABSTRACT: Background Many malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenstrom macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). Objectives To assess the risk of venous and arterial thrombosis in WM/LPL patients in a large population-based cohort study in Sweden. Patients/methodsA total of 2190 patients with WM/LPL and 8086 matched controls were identified through Swedish registers between 1987 and 2005. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL was obtained through the centralized Swedish Patient Register, with follow-up to 2006. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsPatients with WM/LPL had a significantly increased risk of venous thrombosis and the highest risk was observed during the first year following diagnosis (HR=4.0, 95% CI 2.5-6.4). The risk was significantly elevated 5 (HR=2.3, 95% CI 1.7-3.0) and 10years after diagnosis (HR=2.0, 95% CI 1.6-2.5). There was no increased risk of arterial thrombosis during any period of follow-up time (10-year HR=1.0, 95% CI 0.9-1.1). Conclusions Venous thrombosis is a significant cause of morbidity in patients with WM/LPL. The potential role of thromboprophylaxis in WM/LPL, especially during the first year after diagnosis and in patients treated with thrombogenic agents, needs to be assessed to further improve outcome in WM/LPL patients.
    Journal of Thrombosis and Haemostasis 09/2014; 12(11). DOI:10.1111/jth.12724 · 5.72 Impact Factor
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    ABSTRACT: Abstract Imatinib has revolutionized the treatment of chronic myeloid leukaemia (CML). We evaluated clinical outcome and cost-effectiveness, using Swedish registry data based on CML-patients diagnosed 1973-2008. Outcome from three time periods (I: 1973-1979; II: 1991-1997; III: 2002-2008) associated with symptomatic treatment, interferon-alpha/stem cell transplantation and implementation of imatinib, respectively, were compared and a lifetime cost-effectiveness model developed. Survival data from population registries, estimated resource use from clinical practice and QoL estimates were employed. Substantial health gains were noted over time, paralleled by increased treatment costs. Median survival was 1.9, 4.0 and 13 years during the respective time periods. The incremental cost-effectiveness ratios (ICER) between periods III and II was €52,700 per QALY gained. An estimated 80% price reduction of imatinib, related to patent expiry, would reduce this ICER to €22,300. Our data from four decades reveal dramatically improved survival in CML, paralleled by ICER levels generally accepted by health authorities.
    Leukemia and Lymphoma 08/2014; 56(5):1-16. DOI:10.3109/10428194.2014.953141 · 2.89 Impact Factor

Publication Stats

10k Citations
2,380.56 Total Impact Points


  • 1977-2015
    • Karolinska Institutet
      • • Department of Hematology
      • • Department of Medicine, Huddinge
      • • Omvårdnad
      • • Department of Medical Biochemistry and Biophysics
      • • Department of Microbiology, Tumor and Cell Biology (MTC)
      Solna, Stockholm, Sweden
  • 1976-2015
    • Karolinska University Hospital
      • • Department of Hematology
      • • Center for Molecular Medicine (CMM)
      • • Department of Clinical Pharmacology
      • • Department of Hematology, Immunology, and HIV
      • • Department of Oncology
      Tukholma, Stockholm, Sweden
  • 2010
    • National Institutes of Health
      • Center for Cancer Research
      Bethesda, MD, United States
  • 1994-2009
    • Uppsala University Hospital
      • • Department of Hematology
      • • Department of Internal Medicine
      Uppsala, Uppsala, Sweden
    • Laboratory for Molecular Infection Medicine Sweden
      Umeå, Västerbotten, Sweden
  • 2003
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2001
    • Kochi Medical School
      Kôti, Kōchi, Japan
  • 2000
    • Lund University
      • Department of Clinical Genetics
      Lund, Skane, Sweden
  • 1997
    • Herlev Hospital
      Herlev, Capital Region, Denmark
  • 1988
    • Örebro University Hospital
      Örebro, Örebro, Sweden
  • 1981-1982
    • Danderyds Sjukhus AB
      Tukholma, Stockholm, Sweden
  • 1975
    • Södersjukhuset
      Tukholma, Stockholm, Sweden