M Björkholm

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (430)2116.78 Total impact

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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; · 5.94 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; · 2.20 Impact Factor
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    ABSTRACT: Many malignancies, including multiple myeloma and its precursor monoclonal gammopathy of unknown significant (MGUS), are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenström macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL).
    Journal of Thrombosis and Haemostasis 09/2014; · 6.08 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 & lymphoma. 08/2014;
  • Tiziano Barbui, Magnus Björkholm, Alois Gratwohl
    Haematologica 08/2014; 99(8):1273-6. · 5.94 Impact Factor
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    ABSTRACT: Solid tumors are associated with an increased risk of suicide, however, there is limited detailed information on the risk of suicide in patients with hematological malignancies. Therefore, we conducted a population-based study including 47,220 patients with hematological malignancies (diagnosed 1992–2006) and their 235,868 matched controls to define the incidence and risk factors for suicide and suicide attempt. Information on suicides, suicide attempts, and preexisting psychiatric disorders was obtained from Swedish registers and individual medical records. There was a twofold increased (hazard ratio [HR] = 1.9, 95% confidence interval 1.5–2.3, P < 0.0001) risk of suicide/suicide attempt during the first 3 years after diagnosis in patients with hematological malignancies compared to matched controls. Of all hematological malignancies, multiple myeloma was associated with the highest risk (HR = 3.4; 2.3–5.0, P < 0.0001). Patients with a preexisting psychiatric disorder were at a very high risk of suicide and suicide attempt (HR = 23.3; 16.6–32.6, P < 0.0001), regardless of type of hematological malignancy. Among patients who committed suicide, 19% were in a palliative phase and 44% were in remission with no active treatment. In conclusion, the risk of suicide and suicide attempt is elevated in patients with hematological malignancies. Certain high-risk patients may benefit from early detection and preventive measures.
    Cancer Medicine 08/2014;
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    ABSTRACT: Quantifying cancer patient survival from the perspective of cure is clinically relevant. However, most cure models estimate cure assuming no competing causes of death. We use a relative survival framework to demonstrate how flexible parametric cure models can be used in combination with competing-risks theory to incorporate noncancer deaths. Under a model that incorporates statistical cure, we present the probabilities that cancer patients (1) have died from their cancer, (2) have died from other causes, (3) will eventually die from their cancer, or (4) will eventually die from other causes, all as a function of time since diagnosis. We further demonstrate how conditional probabilities can be used to update the prognosis among survivors (eg, at 1 or 5 years after diagnosis) by summarizing the proportion of patients who will not die from their cancer. The proposed method is applied to Swedish population-based data for persons diagnosed with melanoma, colon cancer, or acute myeloid leukemia between 1973 and 2007.
    Epidemiology (Cambridge, Mass.) 07/2014; · 5.51 Impact Factor
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    British Journal of Haematology 07/2014; · 4.94 Impact Factor
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    ABSTRACT: Polycythemia vera, essential thrombocythemia, and primary myleofibrosis are chronic myeloproliferative neoplasms (MPNs) associated with an increased morbidity and mortality. MPNs are also associated with progression to acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS). The “true” rate of transformation is not known mainly due to selection bias in clinical trials and underreporting in population-based studies. The outcome after transformation is dismal. The underlying mechanisms of transformation are incompletely understood and in part remain an area of controversy. There is an intrinsic propensity in MPNs to progress to AML/MDS, the magnitude of which is not fully known, supporting a role for nontreatment-related factors. High doses of alkylating agents, P32 and combined cytoreductive treatments undoubtedly increase the risk of transformation. The potential leukemogenic role of hydroxyurea has been a matter of debate due to difficulties in performing large prospective randomized trials addressing this issue. The main focus of this review is to elucidate therapy-related leukemic transformation in MPNs with a special focus on the role of hydroxyurea.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 06/2014; · 2.81 Impact Factor
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    ABSTRACT: In patients undergoing induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), posaconazole has been proven more effective in the prevention of invasive fungal infection (IFI) than fluconazole or itraconazole (standard azoles) The current analysis seeks to estimate the cost effectiveness of prophylactic posaconazole compared with standard azoles in AML or MDS patients with severe chemotherapy-induced neutropenia in Sweden. A decision-analytic model was used to estimate life expectancy, costs, and quality-adjusted life-years (QALYs). Efficacy data were derived from a phase III clinical trial. Life expectancy and quality of life data were collected from the literature. A modified Delphi method was used to gather expert opinion on resource use for an IFI. Unit costs were captured from hospital and pharmacy pricelists. A probabilistic sensitivity analysis (PSA) was used to investigate the impact of uncertainty in the model parameters on the cost-effectiveness results. The estimated mean direct cost per patient with posaconazole prophylaxis was 46,893 Swedish kronor (SEK) ( 5,387) and SEK50,017 ( 5,746) with standard azoles. Prophylaxis with posaconazole resulted in 0.075 QALYs gained compared with standard azoles. At a cost-effectiveness threshold of SEK500,000/QALY the PSA demonstrated a more than 95 % probability that posaconazole is cost effective versus standard azoles for the prevention of IFI in high-risk neutropenic patients in Sweden. Given the assumptions, methods, and data used, posaconazole is expected to be cost effective compared with standard azoles when used as antifungal prophylaxis in AML or MDS patients with chemotherapy-induced prolonged neutropenia in Sweden.
    Clinical Drug Investigation 05/2014; · 1.70 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) survival rates in younger patients have improved considerably since the 1970s. In order to evaluate the impact of AML and its treatment on fertility and family situation in adult long-term survivors, we used the Swedish population-based registries to identify 161 adult patients diagnosed with AML within the Leukemia Group of Middle Sweden (LGMS) 1973-2003, who survived for more than 5 years and were alive in 2010. Ninety-eight patients (61 %) completed a questionnaire including items on reproductive concerns, family situation, and infertility-related distress. After excluding women >45 years and/or postmenopausal women and men >55 years, 22 women and 38 men were included in the final analysis. Nine of the women (41 %) tried to conceive after treatment, but only three succeeded. Five (83 %) of the unwillingly childless women reported "a moderate" or "a lot" of distress caused by this. Among men in the same age group, all six who wanted children after treatment succeeded. None of the men 46-55 years old cryopreserved their sperm or tried to father a child. Among patients who wanted children after AML treatment, 46 % of the women and 40 % of the younger men reported that they were not, or not fully, informed about fertility-related issues. In contrast, among men 46-55 years, none reported they would have wanted more information. Infertility among young female AML survivors thus remains an important clinical issue, and there is a need for improved clinical counseling and education in this area.
    Annals of Hematology 04/2014; · 2.87 Impact Factor
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  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2014; · 10.16 Impact Factor
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    ABSTRACT: TERT promoter mutations are identified in many malignancies including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC). In contrast, no mutations were found in renal cell carcinoma (RCC) as reported in a recent study. Because the mutant TERT promoter in urine DNA was recently tested as a marker for BC, it is important to ascertain whether these mutations are truly absent in RCCs. Here we determined TERT promoter mutations in 109 patients with RCC and 14 patients with UTUC. The mutations were found in 9/96 (9.3%) clear cell RCC (ccRCC) tumors and 1/8 (13%) chromophobe RCC tumors. Among ccRCC patients, the mutation was correlated with the advanced stages and metastasis, and higher TERT expression. Among UTUCs, the mutation was detected in tumors from 3/5 (60%) patients with renal pelvic cancer and 1/9 (11%) patients with ureter cancer. The mutation was also detected in 1 of 4 urine samples from patients with mutation+ UTUC. Collectively, TERT promoter mutations do occur in RCCs and are associated with aggressive disease. The mutation is more frequent in renal pelvic cancer. Thus, the mutant TERT promoter found in urine may come from not only BC, but also RCC or UTUC.
    Oncotarget 03/2014; · 6.64 Impact Factor
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    ABSTRACT: •TERT promoter mutations activating telomerase occur in certain types of cancer.•The mutations were not detected in cancer tissue from 200 gastric cancer patients.•TERT promoter mutation is not a mechanism for telomerase activation in gastric cancer.
    Gene 02/2014; · 2.20 Impact Factor
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    ABSTRACT: Arachidonate 15-lipoxygenase-1 (ALOX15) oxygenates polyunsaturated fatty acids and bio-membranes, generating multiple lipid signalling mediators involved in inflammation. Several lines of evidence indicate that ALOX15 activation in the respiratory tract contributes to asthma progression. Recent experimental data reveals that histone modification at the promoter plays a critical role in ALOX15 gene transcription. In the present study, we examined the status of histone H3 trimethyl-lysine 27 (H3K27me3) at the ALOX15 promoter by chromatin immunoprecipitation assay in human lung epithelial carcinoma A549 cells incubated with or without interleukin (IL)-4. We identified demethylation of H3K27me3 at the ALOX15 promoter after IL-4 treatment. Furthermore, we found that the H3K27me2/3-specific demethylase, ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), mediates the H3K27me3 demethylation during ALOX15 transcriptional activation. When UTX expression was knocked down using siRNA, IL-4-mediated H3K27me3 demethylation and ALOX15 induction were significantly attenuated. The critical role of UTX in ALOX15 expression was confirmed in human monocytes and the Hodgkin lymphoma (HL) cell line L1236, but was in these cells not related to H3K27me3-demethylase activity. These results demonstrate that UTX is implicated in IL-4 mediated transcriptional activation of the ALOX15 gene.
    PLoS ONE 01/2014; 9(1):e85085. · 3.53 Impact Factor
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    ABSTRACT: The serotonin transporter gene (5-HTT)-linked polymorphic region (5-HTTLPR) plays an important role in modulating mood and behavior by regulating 5-HTT expression and thereby controlling the concentration of serotonin (5-HT) in brain synapses: The homozygous shorter allele (S/S) in 5-HTTLPR results in lower 5-HTT expression coupled with stronger psycho-pathological reactions to stressful experiences compared to the homozygous long (L/L) and heterozygous (S/L) alleles. Psychological insults and mood disorders have been shown to cause accelerated telomere shortening, a marker of biological aging, however, it is currently unclear whether the allelic variants of 5-HTTLPR affect telomere length (TL) in the healthy population without mood disorders. In the present study, we determined the relationship between TL and the 5-HTTLPR variants in healthy Han Chinese. The 5-HTTLPR genotyping and leukocyte TL analysis of 280 young female Han Chinese freshmen showed a significantly shorter TL in 149 of them carrying the 5-HTTLPR S/S version compared to those (131) with the L/S or L/S plus L/L genotypes (mean ± SD, 0.533±0.241 for S/S vs 0.607±0.312 for L/S, P = 0.034; or vs 0.604±0.313 for L/S plus L/L, P = 0.038). Similar results were achieved in the other cohort including 220 adult healthy individuals of different age, gender and profession (0.691±0.168 for S/S vs 0.729±0.211 for L/S, P = 0.046, or vs 0.725±0.213 for L/S plus L/L, P = 0.039). Taken together, shorter leukocyte TL is significantly associated with the 5-HTTLPR S/S allelic variant, which may be implicated in psychological stress-related health problems.
    PLoS ONE 01/2014; 9(4):e94442. · 3.53 Impact Factor
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    ABSTRACT: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL. We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients. We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis. COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL. ClinicalTrials.gov NCT01502982.
    PLoS ONE 01/2014; 9(3):e91031. · 3.53 Impact Factor
  • Blood 07/2013; 122(3):460-1. · 9.78 Impact Factor
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Publication Stats

7k Citations
2,116.78 Total Impact Points

Institutions

  • 1977–2014
    • Karolinska Institutet
      • • Institutionen för medicin, Huddinge
      • • Institutionen för laboratoriemedicin
      • • Department of Hematology
      Solna, Stockholm, Sweden
  • 1976–2014
    • Karolinska University Hospital
      • • Department of Hematology
      • • Department of Clinical Pharmacology
      • • Department of Oncology
      Tukholma, Stockholm, Sweden
  • 2013
    • University of Leicester
      Leiscester, England, United Kingdom
  • 2012
    • Linköping University
      • Department of Clinical and Experimental Medicine (IKE)
      Linköping, OEstergoetland, Sweden
    • University of Iceland
      Reikiavik, Capital Region, Iceland
  • 2008–2012
    • National Institutes of Health
      • • Branch of Infections and Immunoepidemiology
      • • Branch of Genetic Epidemiology
      • • Center for Cancer Research
      • • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
  • 2007–2012
    • Shandong University
      • • School of Nursing
      • • School of Medicine
      Chi-nan-shih, Shandong Sheng, China
  • 2002–2012
    • Uppsala University Hospital
      • Department of Hospital School
      Uppsala, Uppsala, Sweden
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
  • 2009
    • National Cancer Institute (USA)
      • Genetic Epidemiology
      Maryland, United States
  • 2000–2007
    • Lund University
      • Department of Clinical Genetics
      Lund, Skåne, Sweden
  • 2006
    • Uppsala University
      • Department of Public Health and Caring Sciences
      Uppsala, Uppsala, Sweden
  • 2004
    • University Hospital Linköping
      • Department of Hematology
      Linköping, Östergötland, Sweden
    • Stockholm University
      Tukholma, Stockholm, Sweden
  • 1975
    • Södersjukhuset
      Tukholma, Stockholm, Sweden